rtl)(.

Genetics Pa [|uman
spina bifida or cleft lip/palate. These trairs may clusrer rn families but usually do not segregate in accordance w'ith mendelian domrnant or recessive inheritance. The responsrble genes are unknown, and genetic counseling is based on empirical data. The conceot of mulcifactorial rnheritance extends to common disor ders, iuch as asthma and diabetes mellitus. With the completion of the human genome sequenceand the haplotype map, investrgacive and diagnostic tools are available to determine the qenetic contributions to both uncommon and common disordirs. Information about the genetic aspects of all pedi ric diseaseshas grown rremendously and is readily avail able n muftiple websitesand in other locations (Table 78-1). DISOBOEBS CHI[0H000. Although lN 0F THE BURDET{ GENETIC RCIAIiVCI,V THE CHANGINGPARADIGMOF GENETICS IIiIEDICINE, IN few genecic disorders were amenable to treatment in the pasr; management was focused largely on prevention and management of chronic illnesses. lnborn errors of metabolism &'ere the first genetic disorders to be recognrzed; many are amenable to treacment by dietary manipulation (seeChapter 84), These condirrons result from genetically determined deficrency of specific enzymes, leading ro the burldr.rp of coxic substrates and/or defciency of crirical end products. The expansion of newborn genetic and metabolic screening includes a much larger array of screened disorders, made possrble by the use of tandem mass spectrometry, permirting detection of a wide vanety of metabolites in a single, inexpensive assay. Expanded newborn screening will dramatically increase the number of metabolic disorders in children that are amenable to rrearmeflt (see Chapcers 84 and 94i. programs,more therapiesare ln addition co availablescreening in development for the treatment of many lysosomal storage disorders that were lerhal or associated wrth intracrable chromc illness. The basis for rreatment in this caseis enzyme replacement, usrng specially modified enzymes that are administered by intravenous infusion and are then taken up by cells and incor purared rnto ly'osome:. Conditions such a, Gau.her drsea.eand Fabry diseaseare rouonely treated; rreatments for others such as are Pompe diseaseand mucopolysaccharidosis in developmerc. This places an added responsibiliry on the pediatrician to establish an early diagnosis, which is a challenge given rhe rarity of these disorders and relatively nonspecific naturc of early svmDtoms. Tlrerapeutic advances are extending to other nonmetabolic genetic drsorders as we)1. Improvemenrs in surgical treament of congenitalanomaliessuch as hearr defectsare excendingrhe survival of children with birth defects or conditions such as Dorvn syndrome. The life expecrancy of those rvirh cystic fibrosis has steadily increased,largely owrng to improvements in antibioric therapy as well as the managementof boch chronic pulmonary drsease and malabsorpcion. A malor consequence of these advances is that affecced individuals survive inco adulthood, crearing a need to transirion care from pediatric to adult provrders. Gene replacement therapies have long been anticipared, though there have been major challenges rn developmenr of safe and effective approaches for the insertion of genes inro diseased rrssuesand achievement of physrologically meamngful levels of gene expression. The advent of therapeutics based on use of stem cells also offers the possibilrtv of rrearmenc for previously rntractabledisorders. Longsrandrng and highly successfulcarrier screening prograns have existed for disorders such as Tay Sachs disease and many orher rare, single-genedisorders rhat are prevalent in specifrcpopulations. Couples are commonly offered screening for a variety of conditions, in parr based on ancestry (Tay-Sachs disease, hemoglobinopathies, cysdc 6brosrs).Couples found to be at rrsk can be offered prepregnancy or prenatal testing, rvhich is based on gentic tests aimed at detecrion of specific mutarions. Pre-

mr-rltifacrorial genetic condition was a major contributor to pediatric hospital admissions (in 1978) in approximately 257o of patients. The majority of chronic diseasesin children has an obvious genetic component or is influenced by genetic susceptibility. Thirty-four percent of deaths of hospitalized childten are associated with an underlying genetic disorder. Major categories of genetic disorders rn chrldren include single gene, chrornosomal, and multifactorial conditions. lndividualll', single-genedisorders are rare, but collectively they They representatr rmportanc contribution to childhood disease. include disorderssuch as sicklecell anemia and cystic 6brosis,as rvell as a myriad of extremely rare conditrons thar have been seen rn only a few families. Srngle-genedisorders tend to occur when mutations have a pro{ound effect on function of the gene product. Such effects include product (structural protein, enzyme, rnetabolite) denciency as well as loss or gain of fLrnction, The phenotypes associared with single-gene disorders can be variable and modi6ed by the action of other genesor the envrronment.The hall-

cases this is due to rhe founder effect, in which a mutalion population derived from achreves relarively high frequency in a small number of Foundersthat rem ns closed to rnterbreeding lvith those outside the populatron- Thrs is the case for Tay-Sachs disease in Ashkenazi Jews and French Canadians. Other muta-

to resistance malaria, Chromosomal disorders such as Down syndrome are assocl_ ated with rhe presenceof an extra copy (trisomy) of chromosome 21. Only a few trisomies are compatible with live birth (chromosomes 13. 18. and 21, as well rhe X and Y chromosomes)j most lead to early miscarriage as a result of severegenetic imbal ance. Subtle changes of individual chromosome srructure (rnicrodeletions) hate also been rdentified. Many of these are associated with disrinctive phenotypes thar can be recognized clinically; some produce nondescrrpt phenotypes of developmen ral impairment wirh variable effects on intellect as well as growth and physrcalappearance. Multifactorial inheritance occurs when multiple genesor geneenvironmental effecrs cause a disorder Multifactorial inheritance in pediatrics is seen with certain congerriral anomalies, such as

486 x PART F Human lX Genetics rolc ifl all aspects of pediatric pracfice. Genctic variations in enzyrnes involved iLr drr.rg mctabolisrn underhe differcnccs in thcrapeunc effecr and roxiciry, arrd should bc taken ilto accounl SAIE WEBADDSTS5 DAIA il rhe determinationof clrug dosage.Basecl their gerlotrle, on difh!ta:// nln rlfrQat 6eneiaiRhretue by l,lalicnai of Library maintained "wi.ndi ferent individuirls rvill respond diifcrcnrly to specificdrugs. TarMedne r Loring trearment ro individual variations in clrug rnetabolism, http//twi.rabt ninntltqat-/Anin Mendel,rn 0nne nhertaiceln kNlrcmely Nlin u5eful responsiveness, susceptibility coxiciq rvill leaclto person and to fof ncans orerl0,000entresofqenetlciraits c qene indered namp,tmplonrs,and 50 by fcrthJ aiizatronof rnedrcaltrcatment. Genetictestsrvill c()nret() nndel ni dere|lce(ffenteifortslo the n :// ,hti.n(bi.nitn q,r/Ee\ncp Genera t0 map \lrnan lic a high proporcion of all medical decisions and rvill be qen0nle scamlessllincorporatcd rDto rourine medical care. (ieneric tests qcv t ttp:/ /vi. i.nin nth /lLb/eenbank tearchab rcry iDNA erepos lrfa 5equence data /,\t,t n(b r-ilL also be used in predicnve festinglbr predispositionro chsease I tti :/ /,r'ttii.n(bi.n nilt qtl tl.rgat (lletondl(ai(er p in Gncer Geforu Analomy PrcF:t ro the exteri! lhirt such tesrine can lcad to strafe.qiesto llre\,eDt l|rsttute) disease improve outcome (secChapter 8j). or Ilat Humrn rute onal Ge.Dme Reiarch \!ebS nsl te (usefu infomdtor !lLrman and about genelit5 e ic,r 5 ej tl. I i5u 5 6EMrlCS AND PEOIAIRIC PRACTICE Genetics profcssiooals lThble (5earchabh oi hilp,//w,t/rwcn.ntuiJuw(n/ng/hgnd0.htni HunarGpn?Mutation Ddtdba5e hdex 78 2) includc ph,vsicians n'ho complcrercsidencies generics in and genes a deso muQtonghLrman wth n ben arc cerrified by rhc American tsoard of l\.'ledical (icrLcrics, recog and entet Plrenot!ff5 rele nized bv rhc American Board of N'lcdjcal Special,ies. Generic hilP:/t\twNge t6t : aq a Drect0ri ns and forielr 0fgenetir of( ab ng / coLrnselofs rccelvea l1raste]-'s dcgrccin genericcou[s,:ling ard are d50r6et5 ccrtifiedhy rhe -\merican Board of (ienetic Couuselitrg. Thcrc atc (ounselaqdaE Te [gand :1lsonursc-gcneticists who rccoiveadr.arced trairin.g in gcnctics hilpf/ww q?nekteKattr Heiltlr,(lnlcal,lega,50(ssuei a,ard c eth lblLou,ilg complerrono{ nursing educarron. Arcican soderyHuman 6eftt6 ife hitp:r'ttwwotlq.a.g ,f For rare singlc-genedisorders, rhe pcdratriciarr u'ill rvork o o / i5lkn I [cmn on ltee Genelic Amef Aaadem/ ofrhe cn of hryJ/ vtt/tw 0p. tg V T te 1 htn poundium closell rvith specialisrs many disciplines(Tablc 711-3). Pediata6[d!cat aened15 onal [om site in N.fanquldelines |Jed5upesiscn th fcr ommcn aeneti( agerneurn'ill focus on achieving a correct diargnosiri, counseling c s0rle6 the family regardingnatural hisrory and managernelrof the dis order as wclL as recurrenccrisk, anrl implemenradcn oi a m:rna q r t n c r r t. r r r . ir l e a t r n c n rp l r n . A . t h e s . o f ' c , ' i t e r r r t r i t e ' t r n g increases. rhe pediacrician rvill be ncreasingly chelk:ngcdro recognizerelativcl,v rare clisorders rhat arc amcnablefo trearnrentor to identifv chiLdren\,!'hoare ar risk on rhe basisoi f:rrnil)'hisrorv rvho ma,vrof !et dispLay symptornsof disease. Tcsrinj panelslrral' naral tesrirg ls aLso offered for chromosorral clisordcrssuch be developedfor conmoLr, conplex problems. sucl as develop as Do$'n syn(lrome. wich !rn increasing numl)cr of affecred mental delav. Some disorders for lvhich eallv rreafrnenris criripregnanclcs berngrecognizcdby nonirlvasive sclccnllls tesfssuch cal nray bc added to novborn or earl,v childhood scrccnitg aDd fcra] ulrrasound. Prena as matcfl)ai serllnl markcr screening patels; ochcrsr,r.rll the subjccf oi clinical practice guidclincs. be ral diagnosiscal be conlirmcd by anuiocenccsis l6-18 rveeks ar Fanrily historl n'rll be an incrcastnglv r.aluablc rool to recognizc er chorionic villus sampling at l0-12 weeks. Prcimplantation chilclrenar risk. rvho can be tesredend thcn oFieredpersonalizcd gcnetic diagnosis (PCD) of earll' cmbfTos Lr,v analvsis of srngle approaches ro preventx)r of managemenr. Cicnetic resrs rvill can selcctonlv ullaffectcdcmbrvos ior implantarron. blastorneres (lar fo ddv treatmcnl dccisionsfor comrron Lrcreasingly LLndcrlie Approaches ro notrlvasile prcnaral cliagnosislry samplng of disordcrsnor rraditiorrall,v vicrvcd as genefrc. letal cclls or fefal I)\A in maternal blood are also being devcllaLroratorics. oped irr spccialized (;enefic tcstinS is increasingl,v available fbr:r u'ide variety of ETHICAIISSUES Gcnctic tescing,diagnosis,:rrrdtrearmcnt nLtsr be performcd rvirh a hr._eh borh rerc and rclati!'clJ cornmon gcnctjc Jlsorders Testing can degree of confidcntialitl. rvojdirg :rrl resolve LrnccrtalnryregardiI1gdiagnosis, pror.rde r basis for srig,mafor fhe paficnr. (lenetic clscriminafion shorrld bc illcgal gcnctic counseljrrg, serveils r prcludc for becausesubdc or nor so subtle elfects of havine,a persorlalor alnd,in some ilrsrirnces, plav an incre:rsinl:Ly frmil,v gcncrrcdiagnosismay occasionall_1 specificfrenrrncnt. C;ereticresting$'i1L ccrtral affect employrnentor thc ebilir), ro obtarn healrh or life insuralce. Norhing is so pcrsoual as one'r geneticlnatcrial. The decision to Lln(ler[lo gcncli. tcsllng is complicarcd. Ihe tlecisronabout whethcr !() pcfiofrn a

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qeIetrr LlSe De59n nrerprctte(5i ard (cmp a2!e5; te5b guide io mald(e ex perforn fieamgn] farnjly 5cLs5 aoJlntng;0 gefet FFredtnerap,

. Chapler r TheHuman 79 Genomo 4f,

the seletic test on a child is even more drfficult, because child about the testtng.The -annot al*ays participatein discussions uftimatedecisionhingeson how the resultsoi the test will help or harm the child. The interestof rhe chrld is always foremost; thus, open discussionof rhe pros and cons of testing should Molecular diagnosticcests alwayscenreron the chrld'sinterests. are often used to diagnosemalformation syndromes,mental retardation,or orher disabilirieswherein there is a clear benefit the to the child. In other cases, decisronwhether to test a child is more difficult. Policiesregardinggenerictestingof children have beenissued jointly by the American Societyof Human Genetics and Ameri(Amer I Htm Genet 1995;57:. can Collegeof Medical Genetrcs (Pediatr 1,233-1,241,) by the AmericanAcademyof Pediatrics and include the The 2001,;107:1,451-1455). AAP recommendations following:

Knorvledge the structureand funcrion of DNA usheredin the of rich undersrandera of molecularbiologn with arr increasingly ing of the processes DNA replication, transcription,translaof tion, and protein processing. Many genetic disorders are diagnostic understood the molecularlevel,resultingin specifrc at testsand appropriacetreatments. The Human GenomeProject, madert posculminatingin chesequencing the humangenomej of sible to study virtually any human geneand to explore the roles of senesin both rare and common disorders. has also become It apparentthat the genomeincludesfar more than a coded store of informatronto produceproteins. The human genomehas approximately25,000 genes,which pmit Keenin{ tetttthould teviewedandevaluatedPedodi(allyto the individual units of heredityof all traits. Reproductive be l. Btablirhed newborn or are (omponntt.inlroduction of The ofineffective of oralimination nodifGtion theprogram germlinecells contain one copy (N) of this genericcomplement (onduded rctcarh thrc0gh carcfully monitoted ter$ b ne* newbom 9(eening should and are haploid, whereassomatic (non-germline) cells contain ptoto(olr, rwo completecopies(2N) and are diploid, The genesare orgaapn(est oI endeavo6fordildren,requite diagnostkor barapenk 2. Ceneti( like tertt most nrzedinto long segments DNA, which, during cell division,are of (onrent theolder prograns parental Ne{,bom t(ening are dild3astent. infomed and compactedinto inrricarestructureswith proteins to form chropaPntt obtained. proto(ok whkh is lhe infomed ontent from to in enouragedevalu.te mosomes. Each somatrccell has 45 chromosomes {22 oairs of to tfieeffdenq and should monitored. be negeard improve firquenq infomed of refugah aurosomes, non-sexchromosomes. I pair of sei chroor and t(recning warnnted, it conrent natbon for effectivenelt infoflned of mosomes[XY in a male, XX in a female]).Germ cells (eggs, or or in tfie ui4 3. The doer lupport broad of(adettetting 5(eeningdildrefl adoles- sperm)contain 22 autosomes AAP not and 1 sex chromosome, a !o!al for (ondwted (ar d iteening dildrcn adoles' (entr. i[ and on rreadl needt be to Additional of 23. At fertilization,the full diploid cbromosome complement (entr, population should be in of lhe rk andbenefitt (adet tmening the pediatti( of 46 is again realizedin the embryo. it on in monitored dini(alt alsbt0re ir offered a hoad(ale (arier evallated (arfully Mosc of the geneticmaterial is containedin rhe cell'snucleus. may ontidnggrcgnanq be adoles(entr toneadolesrenE otfot irceninq pregnalt for The mitochondria(thecell'senergy-producing organelles) contain appropriate. their own unique genome,The mitochondrialchromosome con(onditiofi generally bedeferted aduhhood until or thould L Geneti( teating adult-onset for sistsof a double-stranded circular pieceof DNA, which contains cap.dtiet. nuturc intererted interting developed dedtion'maling hat untilan adolescent pairs(bp)of DNA and is completely 16,568base The sequenced. toptedict late-ontet ditor' adoleg(entt The believes geneti(testingofdildtenand AAP th.t proteinsthat comprisethe mitochondriamay eicherbe produced geneti( rcduce motbidity infomation notben has shown to ate th der ir inappop when in the mitochondria (from information containedin the mitointerventionr initialed ft ildhood. in and mortalitythrrough chondrial genome)or produced from information containedin pediatftiant t0 need geneti( may r(rceling teslinq notbewellunde6tood, and 5, Becaure the nucleargenomeand transporred rnto the organelle. miroAll parentg neaessary lnowl' prcvide informition @unreling thlimittofgenetk and about the chondria are maternallyderived (becar.rse sperm do not usually potenthl thatmiybedone gailng(ertnin by capabilitiei, the harm dge treatment and carry mitochondria into fertilized eggs);different mitochondria geneti( fot hanh, and induding portibilitiet Pty(hological ttigmatitation, the intonnatioD within a singlecell with a variety of genomes reflect the mater(onditiong ditability potential and trcatmeiB seryi(e! and medi(al and dircrimination,and nal linesfrom which rheydescended. (nn (onditiontPediatftiant bea5sittedninaging in nany th 0f fordildrciwithgeneti( (oun_ (omplex involvedgenetk gamtk with i!ru6 in ttting (ollaboBtion genetkittg, b, prcvideE. reloE, prenatalcare and genatic medi(il fot opportunitiet inhuman the o[ 5. The supporb elp.nsion educational AAP progtamt piytidant theexpantioi training for ind of rtudents, residentr, pradi(ing and gneti( prcfegtionab.

snd deveLBorighr AP, Kere J, SchererSw: The genericsof childhood disease opment, A serresof review ardcles. ?eddtr Res 2003;53:4-9. Braude P: Preimplanration diasnosrslbr senetic susceptibjliry.N Ersl / Med 2006;355:541-541. Burton PR, Tobin MD, Hopper JL: Key concepts in generic epidemjology. Lancet 2005;366:941-9 50. creety HT: Bannrns seneticdiscrimjnarion- N Ezgl l Med 2005;353:865-867. Gu$macher AE, Collins FS: Genomic medicine--A ptilller N Ensl ! Med 2002;347.1572-1520. Hall lC, PowersEK, Mcllvaine Rl et al: The frequencl.and financial br.rrden of seneric diseasein a pedialric hospital. Az / Med Geftet 1978;11417. McCandless SE, Brunser Jw' Cassidy SB: The burden of genetic diseaseon inpatienr care in a children's hosplral.Au.,f H!l,n Cenet 2004;7+121 127 StevensonDA, Care-v JC: Contribudon of malformations and senecicdisorders to mortatity in a children's hospital. Az l Med Cerct A 2004r126:393-337

FUNDAMENTATS M0LECUIAB 0F GENETICS- cenrral tenet of The moleculargenerics that rnformationencoded DNA predomis in inantly locacedin the cell nucleusis transcrjbedinto messenger RNA (mRNA), which is then rransported the cytoplasm, to $,'here ir is rranslated into proteil. A geneis a unir that rncludes rega ulatory region and a coding region that storesinformation correspondingto the sequence amino acidsin a specrfic prorein. of DNA consistsof a pair of chainsof a sugar-phosphate backbone linked by pynmidine and purine basesto form a double helix (Fig. 79-1). The sugarin DNA is deoxyribose. The pynmidinesare cvtosine(C) and thymine (T); the purinesare guanine (G) and adenine (A). The bases linked by hvdrogen are bonds such that A always pairs with T and G with C. Each strand of the double helix has polariry, wirh a free phosphateat one end (5') andan unbonded hydroxylon the sugar the orherend (3'). at The cwo srrandsare oriented in oppositepolaritv in the double neltx. The replicarion of DNA follows the paring of basesin the parenr DNA strand.The original two strandsunwind by breaking rhehydrogenbondsbetween pairs.Freenucleotides, base consisting of a base attached ro a sugar-phosphate, form new hydrogen bonds with their complemenrary baseson rhe parenr suand; ne&' phosphodiester bonds are created by the enzyme DNA polymerase. Replicarionof chromosomes beginssimulta

488 r PABIlX I Human Genetics sequence.Specific proteins bind to the reglon to either repress or derepress transcription by opening up the chromatin, which is a complex of DNA and histone proteins. It is the production of these regulatory proteins (transcription factors) that determioes when a gene is turned on or off. Some genes on specific chromosomes rn defined areas are turned off more or lessoermanentlv by epigeneticmerhylarion ol cyrosine baser rhat are adjacent to guanines (CpG bases).Gene regulation is flexible and responsive, with genes being turned.on or.off during development or in responselo envlronmenralsllmulr, Transcriprion proceeds rhrough the full length of the gene, synthesizing mRNA in a 5'to 3'direccion. RNA, hke DNA, rs a sugar-phosphate chain with pyrimidines and purines. The sugar in this case is ribose; uracil replaces thymrne rn RNA. The RNA reads off one strand of DNA to copy a complementary RNA sequence. A "cap" consisrrng of 7-methylguanosine is added to the 5' end of the RNA rn a 5'-5' bood and. for most lranscriots several hundred adenine bases are enzymatically added to che 3' end after transcriprion, mRNA processing occurs in rhe nucleus and consists of excrsron of the inrrons and splicing togerher of lhe exons. Soeci6c seouencesat the start and end of introns mark rhe sires where the splicing machinery will act on the transcripr. In some cases,there mav be tissue-specificpatterns to splicing, so that the same primary transcript can produce multiple distinct protelns. The processed transcript is next exported to the cyroplasm, where it binds to ribosomes, which are protein-RNA complexes. The genetic code is then read in triplets of bases,each tnplet corresponding wrth a speciGcamrno acrd or provrdng a signal that terminates translation. The triplet codons are recognized by transfer RNAs (tRNAs) rhat include complemencary "anticodons" and bind the corresponding amino acid, delivering it to the growing pepride. A new amino acid is enzymatically attached to the peptide; each time an amino acid is added, the ribosome moves one rflplet codon "step" along che nRNA. Eventually a stop codon is reached, at which point translation ends and the peptide is released, In some proceins, there may be posttranslational modifications such as attachment of sugars (glycosylatron); the protein is then delivered to its destination within or outside the cell by trafficking mechanisms that recognize portions of the peptide.

"'1-

E :

I I
I
I

'fl=,

Adenine Thymine Guanine Cytosine

Fisure 79 1. DNA double helix, nrrh sugarphosphatebackbone and nitroge nous bases.(From lorde LB. Carey JC, Bamshad lv!, et al leditorsl: Medical Cenetics,)nd ed. St. Louis, lv{osby,1999, p 8.)

neously ar multiple sites, forming replication bubbles that expand brdirectionally unril the entire DNA molecule (chromosome)is repllcated. Errors in DNA replication, or mutations induced by environmenral mutagens such as irradiation or chemicals, are detected and potentially corrected by DNA repair systems, A procotl'pical gene consrsts of a regulatory region, segments called exons thar encode the amino acid sequence of a protein, and intervemng segmentscalled introns (Fig. 79-2). Transcription srarts at the promorer region and contmues through the enrire length of the gene to form mRNA. The introns are then removed and the exons spliced together to form a marure message,which is then exported to the cyroplasm. There the mRNA is bound to ribosomesand ffanslatedlnlo protein. Transcnptron is iniriared by attachment of RNA polymerase to rhe promoter site upstream of the beginning of the coding

GENETIC VARIATI0N.The process of production of protein from a gene is subjectto disruption at multiple Jevels owing ro alterations in rhe coding sequence(.Ftg.79-3). Changes in rhe promoter region can lead to altered gene regulatron, including increased or decreasedrares of rfanscrlptron, failure of gene actro v a t r o n , r a c r i v a t i o n f r h eg e n ea r i n a p p r o p r i a r r i m e so r i n i n a p o e propriate cells. Changes in the coding sequence can lead to substitution of one amino acid for anorher (missense mutation) or creation of a stop codon in the place of an amrno acrd codon. Some srngle-basechangesdo not affect the amino acid, since there may be several codons thar correspond with a single amino acid (silentmutarion). Amino acid subscitutions may have a profound effecr on protein function if the chemical properries of the sub slituted amino acid are markedly differenc from the usual one; substitutions may have a subtle or no effect on protein function if the substituted amino acid rs chemically similar to the original one. Genetic changes may also include insertions or deletions. Inser rions or deletions of a non-integral multiple of three bases into leads to a frameshift, altering che grouping rhe coding sequence of bases into triplets- This leads to translation of an rncortect amino acid sequenceand usually the eventual production of a srop codon. Ioserrion or deletronof an inregral muhiple of three bases into the coding sequence will insert or delele a corre sponding number of amino acids from the protein. Larger scale insertions or deletions can disrupc a coding sequenceor result in compleLe delerion of an entire Henc()r group ol genes.

. Cha[ter79 r The Homan Genome /Ug

7 F i l i t s r c 9 . : . S u m m a r vo f t h c s t e p sl e a d i n gf r o n D N A b p r o o a teins Rephcaoon nd transcription .cur in thc cell nucleus The nRN-A is rhen transported k) thc crroplasm, rvhete rransa s l a r i o n o l ' t h e m R N A r n t o a m i n o r c i d s e q u e n c ec o m p o s r n g protein oc.urs. (l.rom Jorde l.B. alarey i(i, Bamsh.td\'U. er al led;tots): Medrcdl Ce etirs,2nd ed Sr louis, Mosbl. 1999, p 121

as Mutations usually can be classified causinggain of function or loss of fulrcnon. A gain-of-functionmuration can resulr in an increasein the abilicv of a proteiD molecule to perform one or more normal functions! or, more comm()nl)',ir can result iu ovetoi expressionor inappropriareexpression a geneproduct. Gainofliuncti{)n mutations most frequentl,v produce aurosomal dominant disorders (see Chapcer 80). Charcot-Marie-Tooth disease, type lA, or peroneal muscular atroph)'. the most of common form of chronrc peripheral neuropath-y childhood, resulcsfrom dup[cation of rhe gene for penpheral m,velin protein of 22, rcsultingin ovetexpression rhe geneproduct. The gain-ofiunccion murarion in achondroplasia,the rnost comrnon of rhe exernplifies the enhancedfuncshorc linTbedskeletaldysplasias, from a mutarion of a normal ororein. Achondroplasia resuLts rion in fibroblast growth recepror 3 (FCFR3). w'hich leads to of acti\.arionof the recepror, evenin the absence 6bnrblasrgrou rh iacror (FGF). Loss-of-function mutations are frequendv observed in autosomal recessive disorders in rvhich loss of 507" enzyme continues fo allow fbr normal func activity in the heterozygote tion. Alternativell.,loss of funccion mutations can result in condirions in which 50% of the gere product is insufficiencfor Loss of-function rnutations normal function (haploinsufficiencv). rhe can have a dominant negariveeffect r,r,hen abnormal protein product actively rnterferesrvirh rhe function of rhe normal protein produo.

Anochercategorvof mLltations ma]''confer a novel property on ',vichouraltering the proteins normal fhe protein sy'nrhesized, fernctions.ln sickle cell disease,an amino acrd is subscituted into the hemoglobin rnoLecule tbat has no effect on the abiliry of che protein to transport oxvgen. Howeve! unlike normal heruogLobin. under condicionsof deoxygenation, sickle hemoglo Lrin chains aggregare! formrng fibers that deform the red cells. A 6nal caregorl'o( mutations resultsin abnormaLexpressjon of a gene over space and time. Many cancercausing genes (oncogenes) are normal regularors of cellular proliferation during devel<:pment;when expressed in adulc life, and in cells in rvhich they usually are not erpressed, thev may resulr in lreoplasla. l)elerions can varl in rheir extent and, even .rvhennot visible at the cytogeneticler.el,can involve severalgenes;fheseare often tenned microdeletions. 81. a variety of rearrangemencs, condirions reterredto as contiguousgenesyndromesmay be generated. The clinician ma1,be alerted to this possibilitv bv an unusually diversearray of chnical fearuresin any indrvidual or thc presence of addirional featuresro a known conditiol. For example,ou.ing ro the closeph,vsical proximicl' of a seriesof genes, different dele rions involving the shorr arm of cheX chromosomecan produce inclividualswith various combinations of the followine Features: s , r i h t h r , , . r . ,K a l l r n a n n l r r d r o m e o i u l a r a l b r n i r m ,m c n ( ; l r e l a r J a rion, chondrodysplasia punc!ata, and short srature.The rndrvrd-

490 ! PAnT I HunanGeneticg X

Promoter

Filwe 79-3- Various types of inrragenic mucations. Promoter mutarions alrer rate of transcription or disrupt gene reguLarion.Base changswithin e{ons in can have various effects!as shown. Mutations within Lntronscan lead ro inclusion of some rnrronic sequence the final processedmRN-A" or can lead to exon skipping.

ofthesegenes rn on ual features eachcasedepend the involvement in and the lossof DNA sequences the underlyilg reaffangement. Many other chromosome deletion syndromes have been described in humans, including Smith-Magenis,RubinsteinTaybi, DiGeorge,!0illiam, and Prader-Willisyndromes. Rearrangemenls such as translocations also take place in that somaticcells. The best understoodare the rearrangements are occur in lymphoid cells. Somerearrangements required for the formation of funcrional immunoglobulin in B cells and of receptorson the T cell, Large segments antigen-recognizing DNA, which code for the variable and the constantregionsof either immunoglobulin or the T-cell receptor, are physically joined at a specilicstagein the development an immunocomof petert lymphocyte.The rearrangemenrs placeduring develtake opment of the lymphoid cell lineagein humansand result in the extensive diversiryof immunoglobulinand T-cell receptormoleDNA rearrangement cules.It is as a result of rhis post-germline rhat no t'vl'oindividuals,not evenidenticaltwins, are really idenmaturelymphocltesfrom eachwill have undergone tical, because at random DNA rearrangemenls theseloci. reveal thar any two Studiesof che humin genomesequence individualsdiffer in about one basein a thousand.Someof these that explain Phenoare differences silent;someresult in changes (hair or eye coloq physicalappearance); some typic differences causingsinglegenedisorderssuch as have medicaL significance, to sicklecell anemiaor explainingsusceptibility common disorderssuchas asthma.Geneticvariantswithin the samegeneoccur

commonly in the population and are referred to as polymorphisms.Thesemay be silenr or subtleor have signilicantphenotypic effects. CORREI.ATIONS GENETIC IN DISEASE. GEI{OTYPE-PHENOTYPE Genotypeis the geneticconstirutionof an individual and refers to which particular alternative version(allele)of a geneis present PhenotJpe the is at a specfic location (locus)on a chromosome. structural,biochemical, and physiologiccharacteristics observed of an individual, determinedby the genotype,and refersto the obseped structuraland functional effectsof a mutant alleleat a phenotypes, specificlocus.Many mutationsresult in predictable Therefore,identificationof a specilicmutation in an individual ofren can be used to predict clinical outcomesand plan appropriate treatmentstfategles. exemplifies disorderwith predictable a The long QT syndrome genotype-phenotype corelations (seeChapter 435.5). Long QT syndrome (phenotype)can be causedby mutadons in several geaes (genotypes), whicb are designatedLQT1, LQT2, and LQT3, all encodingcardiac ion channels,The risk for cardiac abortedcardiacarrest,or suddendeath)is higher events(syncope, with mutations ^t the LQTL locus (53%) or the lQT2 locus (46y.) thar among subjectswith mutations at the l8T3 locus with LQfl mutarions experience most In those { l8o/o). addition, and rarely during rest or slep; of their episodes during exercise thosewith LQT2 ar.dlQT3 mutationsare more likely to have episodes during sleepor rest, and rarely during exercise.

r ChaDter a The Human Genome 491 79 $'ith Marfan synl\'lutationsrn the 6bnllin-1 gene associaled diome reptesent another example of predictable genorypephenotype correlations (see Chaprer 700). Marfan syndrome rs charactenzedbv the combination of skeletal,ocular, and aorric outcome being aortic manifestarions, rvith the mosc devastacing root djssectronand sudden death. Sixcy-fiveexons make uP the fibrillin 1 gene, and mutations have been found in almost all of rhese exons. The locatron of the mutarion within the gene (geno-

lung diseasecaused by mutations in the CF transmembrane con duccance regulator (C}-TR) gene. More than 1,000 different mutations harrebeen identified; the most common is the AI508 mutation, which accounts for 707" of all mutalions and is assorvirh mrld disease. Severalmulations associated ciated with severe diseasehave been idenrified, including 3272-25A+G, 3849+10 kb C-+T, IVSS-5T, and 2789+5GrA. Patienrsu'rrh at least one 3272-26A-+G allele and a second mutaced allele (compound heterozygote) associated rvirh severe disease are more likely to be diagnosedlater and have berter lung function, a lower incidence of Pseudomonas aeruginosa colon:tzatton,and normal pancreatic funcrion. Homozl,gotesfor rhis mutarion are no! obseruedand may nor have clinical disease. Conversel)', lhose with 2183AA-+G mutations, eicher homozygous or heterozygous ',rvrth severe another CF muration, are more likely to have early-onset, disease. Those wich this mutation tended to have severepancrearic involvement, failure to thflve, varrable lung Involvemenc, and relativelyearly death. With any given mutation! modifrer genes for a different gene producl may altenuate the murared gene's phenotvpe. W'hen srckle cell anemia is co-inherired rl'irh the gene for hereditary per srstence fetal hemoglobin, the sicklecell phenotypicexpression of is less severe. Modifrer genes in CF may rnfluence the development of congenitalmeconiu ileus,or colonizationwith P aerlgfuosa. -Nlodifer genes ma also affect rhe manifesrations of

Genemapping is performed by genetic PB0JEGT. HUMANGEN0ME at linkage analysis,*hich is based on the principle that Leles t\r'o genetic loci thac are located near one another rvill gregate together i a family unless they are separated bv genetic recombination, he fre<luercyof recombinarion between the loci is a measureof physical distance.A set of polvmorphic generic loci spacedalong tbe entire human genome is identifiedand is closely' t a n d e o u l d b e u s e dr o m a p a n r g c t t e t t er a i t . isolation of segmenrs Phy mapping of the genomeinvoLves of rhe an genome with lengths from hundreds or thousands to a ferl million base pairs and placing them in micloorganisms svstem\ pcrmit su!h a\ hacrerir or )ea\I. AuronratedseqLren(ing the base sequence of these segments to be decermined The segments could chen be pieced togerher by examining !he sequence of overlap regions and by relacing rhe sequenced segments to

sequencingtbe fragments,and rhen using a compllter to order the fragmentsbasedon overlapping segments. Analysis of the human genome has produced some surprising resulcsas well. The number of genesis strll not known preciselY but appears to be around 25,000. This is fewer rhan had been

of alternarive promoter regions in some genes, alternatite splicing, and post cranslational modrfications. Ic is also apparent that mosc of rhe genome does not encode prorein (lesschan 5% is rranscribedand translared). Many transcribed sequences are not translated but represent genes that encodeRNAs that servea regulatory role. A high proporcion of the genome consistsof repeatedsequences thac are interspersed among chegenes. Someof theseare transposable genericelements rhat have the ability ro move from place co place in lhe genome. Others are stacicelementsthat Eere exoanded arrd disoersedin \ r h e p a r t d u r r n g h u m a n e v o l u r i o n O r h e i r e p e a r e de q u e n ( e \I n a ' . play a struccural tole. There are also regions of duplication cr{ genomic regions. Such duplJcationsare substratelbr evolution, allowing genetic mocifs to be copied and modified to servenew roles in the cell. Duplicarions mav also form rhe basis for chromosomal rearrangement,permitring nonhomologous chromosome segmentsto pair during merosrsand exchange materialThis is another sourceof evolutionarv chanse.and also serves as a p ' t r n r i a l \ o u r c eo l c h r o m u \ o r n ar n s t a b i l i i y e a d i n g o c o n g e n l l r ital anomaliesor cancer Availability of the genome sequencepermits the stud,v of large groups of genes, looking for patterns of gene expression or genome alteration. N,licroarra]shave beendevelopedthat permit tens or hundredsof thousandsof gencsro be anaLyzed a small on glass chrp. Patterns of gene expression prQvide sigcatures for par ticLllar diseasestates,such as cancer,or rn responseco therapy (Frg.79-4j.

492r PAnT I Humrn GGnotics f

ChristensenK, Murray JC: whar genome-wideassocia.ionstudiescan do for medicine. N Engl J Med 2007;356:1094-1097. Cordefl HI, Clayton DG: Genetic association sfidies, Ldn et 2005i366:1121-1130, Hatrersley AT, Mccarthy Ml Wlrat makes a good genetic associarionsrudyl Lancet 2005i366 :13 15 -L323. profiling: Time lorclinical apphcation? JarvisJN, Centota M: cene-expression Lancet 200 5 i36 5 1199100. Lander ES, Linton LM, Birren B, er al, Initial sequencingand analysisoI rh human genome. Naturc 2001;4091.6822):860-921. Mcchee SA, Mccabe ERB: Genome-wide tesrhg: genomic medicine. PedrTtt Res 200660243-244 . TeareMD, BarreftJH: Genetic tinkage studies.I-rncet 2005i36611036-r044. Venrer JC, Adams MD, Myers EW, et al: The sequence the human genome. o{ Science7001 2911S 5O7 tl 3O4. l

tttare Femate Sexunspecified

Marriag union or Divorced Consanguinity twins Monozygotic Dizygotic twins

ra |,1$'.:1,',::i#"" ff
lO,qfiecteo
will carder, E O Obligala disea$s notmanifest

r. il:lH::[3$ffi'"XT;

Twins ot unknown zygosity

T
j/.

Proband

individual F Deceased sti bidh No otfspring lvlultiple unions

trl Adoptedintofamily
Adopted ol family od FAmltY HISTORY AIUDPEDIGREE ll0TAnOfl. The farnily history remains the most important screeningtool for pediatriciansin identifying a patient'srisk for developinga wide range of disincludingmultifactorialconditions,like diabetes eases, and attention defrcitdisorder, single-gene to disorderssuchas osteogenesis imperfectaand cystic fibrosis,Through a detailedfamily history the physiciancan ascertain modeof genetictransmission the and not all familial clustering the risks to family members.Because of disease due ro geretic factors,a family history can alsoidenis tify common environmental and behavioralfactorsthat influence the occurlence disease. The main goal of the family history is of to identify genetic susceptibility, the cornerstone the family and of pedigree. hisroryis a systematic srandardized and A pedigree providesa gaphic depictionof a famrly'sstructure and medical hisrory. The person providing the information is termed the proband, and is typically designatedby an artow- h is important when raking a pedigreeto be systematicand use standardsymbolsand configurations(Fig. 80-1) so that anyone can read and understandthe information. A three-eeneration pedigree as shouldbe obrained an inirial screen iue.y ne* for patienr to identify possiblegeneticdisorderssgregating within the familn the inheritancepattern, and rhe risk to the patient. The closerthe relationshipof rhe proband to the personin the family with the geneticdisorder,the greateris the sharedgenetic complement. First-degree relatives, such as a parent, full sibling, 1st or child, shareY,their geneticinformation on average; cousins shareY5. in Sometimes disease a more distantrelativemay create a may be a greaterrisk; for thar reason,a more extendedpedigree A needed identify risk for certaindisorders. hisrory of a distant to maternallyrelaredcousinwith mental retardationdue to lragile for X syndromemay have litde significance the male infant you risk are examining,or it may mean thar this child is ar elevated for fragile X syndrome.

Figur 8O-1. Peati4reenotation. Symbols commody used ir pediSree charts. Alrhough there is no uniform systmof pedi8reenotation, the symbols sho['n here are according to recent recommendationsmade by professionalsin the 6eld of geneticcourselhg, (From Bennett RL, SteinhausKA, Llhrrch SB, et al: Recommendationsfor standardizedpedigree nomenclatve. I Genet Couxsel 1995 A:267 -279.1

MEITI DEtIAl{INHEBITAI{CE
There are three classicforms of geneticinheritance:autosomal dominant. autosomalrecessive. XJinked. Theseare referred and to asmendelian inheritance forms,after GregorMendel,the 19th century monk whoseexperiments to the laws of segregation led These of characteristics, dominance, and independent assortment. inheritance. remainthe foundationof single-gene !0ith mendelian inheritance,a single gene'seflect rs necessatyand sufficiefltto causea particular phenotype.This is in conttast to othr forms

of geneticallydeterminedtraits, such as impriotirg conditions, triplet repeatdisorders,and multifactorial traits, in which other factors influence whether the disease will be presentin someone who carriesthe geneticchange. Autosomal Dominant Inhoritance. Autosomal dominant inheritanceis determined the presence one abnormalgeneon one by of (chromosomes of the autosomes 1-22), The genes thesechroon mosomesexist in pairs, with each patent contnbufing one copy. !7ith an autosomaldominant trait, one of the paired geneshas the an effecton the phenotypethat dominates effectof rhe other refersnot only to physicalmanifestations of the pair. Phenotype but also to behavioralcharacteristics to differences or detectable only through laboratorytests,suchas biochemical abnormalities. The pedigreefor an autosomaldominant disorder (Fig, 80-2) (1) certain characteristics, The disorder is transdemonstrates mitted in a vertical (parentto child) pattern, appearingin multiple generations. This is rllustratedby individual I.1 (see 80-2) Fig passing the changed geneto IL2 and II.5. (2) An affectedindion vidual has a 50% (1 in 2) chanceof passingon the deleterious genes eachpregnancn for and thereforeof havinga child affected risk for the by the disorder.This is referredto as the recurrnc who do not disorder.(3) Unaffectedindividuals(family members manilestthe !:.aitl do not passthe disorderto their children. (4) Males and femalesare equally affected.Although nor a characteristic per se,(5) the finding of male-to-male transmission essentially confirms autosomal dominant inheritance. Vertical transmission alsobe seen can with X-linked traits. However,since a father passeson his Y chromosometo a son, male-to-male transmissioncannot be seenwith an X-linked trair. Therefore. male-to-maleuansmissioneliminatsXlinked inheritanceas a exolanation.While male-to-male tlansmission can occur oossible with YJinkid genes well, there are very few Y-linkeddisorders as dominant inhercomparedwith thousands havingthe autosomal rtanceDattem, Although parent to child transmissionis a characteristic of with an autoautosomal dominantinheritance, many patreflts for

r ChaFor I P|ttor[! ol Gonotic m Trsnsmislion 4gl somaldominart disorderthereis no history of an affectedfamily possible first, the patienrmay reasons, Thereare several member. represen!a new mutation; second,many autosomaldominant rneaning that not incompletepenetrance, conditionsdemonsrrate all individualswho carry the mutation have phenotypicmanifesin this may appa!as a ekippedgeneration, tations.In a pedigree which an unaffectedindividual links two affectedpersons(Fig. 80-3). There are many potential reasonsthat a disorder may including the effect of modifier exhibit incompletepenetrance, factors,gendeqand age,Third, individuals environmental Benes, with the same aurosomaldominant mutation will manifestthe This is termedvariableexpression disorderto different degrees. of and is a characteristic many autosomaldominant disorders. geneticmutationsoccur not in the egg Founh, somespontaneous or spermthat forms a child but rather in a cell in the developing embryo. Such eventsare referredto as somatic mutations.The causedby a somaricmutation can be varied, resultingphenotype but it is usually milder than if all cells contain the mutation. In germlinemosaicism,the mutation occurs in cells that populate the gernline that produceeggsor sperm.A germlinemosaicwill of haveno manifestations the disorderbut will producemultiple eggsor spermthat carry the mutation. Autosomal recessive inheriInheritance. Autosonal Recessive tance involvesmutations in both copiesof a gene.Examplesof are autosomal recessive diseases cysdc fibrosis and sickle cell rraits (Fig. 80-4) of disease. Characteristics autosomalrecessive the include (1) horizontal transmission, observationof multiple affectedmembersof a kindred in the same generation,but no (2) risk in affectedfamily members other generations; recurrence of 257o for parentswith a previousaffectedchild; (3) malesand femalesbeingequally affected,though sometraits exhibit different exprssionin males and females(ovarian cancer,hypospaparticularly for frequencyof consaDguinity, dias); (4) increased tate tratrs. The chancethat any two parentscarry an identical mutant Consanguinity if alleleis increased the coupleis consanguineous. from a common ancestor. Consanguinis relationshiobv descent geneticdis;rder ity betweenparinrs of a child with a suspected inheritance. implies (but does not prove) aurosomal recessive unions are uncommon in Western Although consanguineous society,in other parts of the world (southernIndia, Japan, the

Fture 80-3. Incomplete penetrance.This family segregates familial cancer a syndrome, familial adenomatous pollposis, Individual II.3 is an obligace carrleq but there are no findings to suggestthe disorder. She is rermed nonpenerranr.

Middle East)they are cornmon.The risk of a geneticdisorderfor the offspring of a first-cousinmarriage(6-8%o)is about double population (3-4"/.), Thereare somegenetic the risk in the general rsolates(small populations separatedby geography,religion, culture, or language) which rare recessive in disordersare more common than in the generalpopulation. Even though consanguinity may not be increasedin thesepopulations, because of limited mate choice, the chanceof a couple from an isolated geneticregion having a child wirh an autosomalrecessive condition may be as high as that observedin first-cousinmarriages. programshave beendeveloped such groups to deScreening in

Figure 80-2. Autosomal dominant pedigree.Pedigreeshowing ryprcal inheritance of a form of sensorineuraldeafnessfDFNAS/ inhedted as an aurosomal dominant trait, Blue. affecred Datints.

494 r PART ! Human lX Gonrtics

pedigreex.ith parental consanguinitr. Purple, carriers; Red, afl'ected Fisurc ti(}4. ,qurosomatrecessive

tect heterozygotes rrsk for having affectedchildren,A variety at of autosomal recessive conditions are more common among populacion. Natronalpractice Ashkenazi Jewsthan in the general asymptomaticAshkenazr guidelinesrecommendscreening Jews for rhe neurodegenerative drsorder Tay-Sachsdisease, and carrier screening other disorders(Fanconi for Canavandisease cystic fibrosrs,familial dysautonomia, anemia,Gaucherdisease, for rs nesidioblastosis) under consideration this population. genes The prevaLence carriersof certainaulosomalrecessive of hetis in sornelarger popr-:lations unusuallyhigh. In such cases, of erozygoteadvantagers postulared.The carner frequencies in sicklecell disease cheAfrican popularionand of cysticfrbrosrs populationare much higherthan would in the northern ELrropean that heterozygous from new mutations.It is possible be expected in carriershave had an advanrage terms of survival and repro the ducrion over noncarriers.In sickle cell disease, carrier stale to may confer some resrstance malaria; in cystic fibrosis, rhe to carrier state has beenpostulatedco confer resistance cholera Population-based coh rnfections, Escherichia or enteropathogenic for for carrier screening cysticfibrosisis recommended individuals of northern European and AshkenaziJewish background; is for population-based screening srcklecell disease recommended for individualsof African background. disease known, is If the irequencyof an autosomalrecessive or chefrequencyof lhe heterozygote carrier statecan be calcuformula: lated from cheHardy-Weinberg = p: +2pq+q' 1 where p is the frequencyof one of a pair of allelesand 4 rs che frequencyof the other. For examp , if the frequencyof cystic librosis among white Americansis in 2,500 (p2),then the fre-

(2pq an be calculated: pr = Yr,'en, if quencyof cheheterozygote approximately 2pq= x Ysoxa%o,or thenp=|ro and q = a'7t,, t/2. 3.921"). lor Every human probably has severalrare, harrnful, recessive genes. Because thesemutant genes frequendynot identifiable are adult usually learnsabour by laborarorytests,the heterozygous genesafter the birth of a homozygous theseharmful recessive (and therefore affected)child. Related parents are much more genes for likely to be heterozygous the same harmful recessive they have a common ancestor because refers Inheritance, Pseudodominant ioheritarrce Psudodominant to rhe observationof apparentdominaflt (parentto child) crans recessive disorder(Fig.80-5).Tbis missionof a known autosomal affectedindividual hasa parrnerwho occurst 'hen a homozygous is a heterozygous carrierrand it is most likely to occur for relatively common trarts, such as sickle cell anemia or congenital genemutation, deaFness to connexin26 due of Xiinked lnheritance.Characteristics X-linked inheritance (Fig. 80-5) include the following: (1) Males are more commonly (2) and more severely affectedthan females. Femalecarriersare generallyunaffected, if affected, or they are affectedmore mildly than males.(3) Affecredmaleswill have onLvcarrier daughters. They have no chanceof havrng an affectedson (male-to-male with aurosomal dom excludes X-linkageand is seen transmjssion (4) inant and Y-linked inheritance). Carrier women have a 25ok risk for havrngan affecredson, a 257. risk for a carrier daughter, and a 507o chance for a child rhat does not inherrt the mutated X-linked sene. A femalemay oicasionally exhibit signsof an X-hnked trair similarly to a male. This may occur owing to nonrandom Xof for inacrivarion,homozygosiry an X linked trait, or presence abnormality (45,X or 46,XY female). a sex chromosome

r GhoDter r Pon.ms otceletic Tr6nsnission 4ll5 8{l

Fisurc 80'5. Pseudodominanr inherirance. Red, alfected (deaf).

and X chromosomeinactivation occursearly in development involvesrandom and irreversibleinactivation of most geneson a cases, preoneX chromosome eachcell(Fig.80-7).In some by ponderanceof cells may inactivate the same X chromosome, of resultingrn phenotypicexpression an Xlinked mutation if it resideson the active chromosome.This may occur owng to a againstcellsthat haveinactivated nolmal chance to selection or X if the other X carriesa structuralrearrangemen!. calledX-linked dominant, Thereare someX-linked drsorders, in which femaleca ierstypically manifesrabnormalfindings An affectedman rvill ave only affecteddaughtersand unaffeced sons, and half of rhe offspring of an affectedwoman will be affecred 1Fig. 80-8). Some X-linked dominant conditions are lethal in males. An example is incontinentia pigmentl (see and an females, showsonly affecred Chapter651). The pedigree number overall ratio of 2 : 1 femalesco maleswich an increased (Fig. of miscarriages 80-9). There are few Y-linked craits, These Y-I|NKEDINHEBITANCE. and ozly male-tomale traDsmission, only malesare demonstrate are affected(Fig. 80 10). tr{ost YJinked genes relatedto male sex with rnferand reproduction,and are associated decermination of tility. Therefore,ic is rare to see familial transmrssion a Yreproductivetechnologres linked disorder Advancesin assisred of may make possiblefamilial lrarismission male infertiliry

Of specialnote is rhe pseudoautosomal regiorton the Y chromosome,the smallregionof bomologychatis sharedby both Xp and Yp- Very few genesresidein this region. One of the few is SHOX. Hererozygous SHOX mutadofls cause Leri-Weil dyschondrosteosis,rare skeletaldysplasia a rhat involvesbilateral bou.ineof the forearmswith dislocarions the ulna at the wrist of and generalized short stature.Homozygousmutationscausethe Langer mesomelic much more severe dwar6sm. Digenic inheritanceexplains the occur0lGENlC INHERITANCE. (RP)in childrenof parents who each renceof retinitis pigmentosa gene.Both parentshave normal carry a different RP-associated vision, as would be expected, the offspring who were double buc hererozygotes developed RP Digenic pedigees (Fig. 80-11) exhibit characceristics both autosomal dominant (vertical of and autosomalrecessive transmission) inheritance(1 in 4 recur rencerisk). A couple in whrch the two partnersare carriersfor rwo different genes may have affected children. Anv child, however,might transmit both mutations to an offspring, as in dommant lnherltance, PSEUD0GENE IC INHERITANCE FAMltlA[CIUSTERING. There AND are nongenetic reasols for the occurrence a disease multiin of ple family members; thesecan mrmic geneticffansmissron. Possible explanations include environmental factors, teratogen exposure,and as yet undetermined and undefinedfactors. Multiple srblings !o may haveasthmadueto exposure cigaretre smoke from rheir parents.A woman may have multiple children with small size,developmental delay,and unusualfacial appearance owing to her useof alcohol during pregnancl'. Ahernatively,the disease may be very common in the generalpopulatiol- Breast cancerwill allect 1|Yo of all womenr it is oossiblethat several womenIn a familywill develop brealrcancer because yerundeo|; termined faccors.It rs usually possibleto differentiatefamilies with generrcally determined high-risk cancersyndromes, such 6s that associated with a BRCAI mutation, by their earlier age of onsetof breastcancerin multiple family members.

T I
Figure 80-6. Pedigreedemonsnating Xlinked recessivejnheritance- (From Nussbaum RL, N'lclnnesRR, Vitlard HF, ThorllPson & Tboh'Pson Gehetics in Medidne,5th ed. Philadelphia,\rB Saurders, 2001.)

NONTRAOITIONAT INHERITAIiIGE
Sone eenetic disorders are inherired in a manner that does not follou.classical mendelian oatrerns. This nontraditional inheritance partern includes mitochondrial disorders, triplec repeat expansion diseases,and rmpnnting defecrs.

lX 496 r PAET r Human Gerctics

B ffig H
x,xe x-x" X.Xo X.Xo / / ' \ \

X X,

X-XU

X.X.

X.X,

x.xo

x,xo

x.x

x.x,

X.Xo

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x.x"

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Figure 80-7. X inactivation.

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x_x"

Mitochondrial lnhelitance.An individual's mitochondrial genomeis entirely derived from the mother (Fig, 80-12). Sperm contarn few mitochondria, most of which are shed upon fertila ization. Mirochondrial disordersexhibit maternalinheritance; woman with a mitochondrial genetic disotder will have only affectedoffspringof eithersex,while an affectedfather will have no affectedoffspring (Fig. 80-13). Although such an inheritance patterncan be explained autosomal dominantor X-linked by inheritance,it suggescs mitochondrial basis(Table80-1). a of The mitochondriaare the cell! suppliers energy, that the so of organsthat are most affectedby the presence abnormal mito-

Figure 80-8. Pedigreepatrern demonsrratingx-linked dominanr inheritancelFrorn Nussbaum RL, Mclnnes RR, Wrllard Hr: Thompson It Thonptu11 Geneti.s in Medicine,6rh ed. PhiLadelphia, WB Saunders,2001.)

chondria are rhose that have the greatest energy requirements, such as the brain, muscle, heart, and liver (see Chapters 87.4, include developmental 358, and 598). Common manrfestations delal seizures,cardiac dysfunctron, decreasedstrength and cone, as well as hearing and vision problems. Examples include MELAS (myopatby, encephalopathy, lactic acidosis, and strokelike episodes), MERRF (zryoclonic epilepsy associated with ragged red flbers), and Kearns-Sayre syndrome (ophthalmoplegia, pigmentary retinopathy, and cardiomyopathy) [see Chapter 5981, Mitochondrial drseasescan be hrghly variable in clinical manifestatrons. Cells may contain a mixture oI mutant and normal mitochondria, referred to as heteroplasmy. Unequal segregation of mutant and normal mirochondria (rephcative advantage) can result in signilicant drfferences in expression of a mirochondrial trarr ,n the ovum and different cells of an individual or different offspnng of a carrier mother. Becauseof rhis, the mother niay be asl'mptomatic. In affected offspring, disease manifestations tend ro occur when 50-507o of mrtochondria carry a single large delenon or when 80-c0o/ohave a poinl murarion. TriFlet RepeatExpansionDisordeis. Triplet repeat expansron disorders are distinguished bv the special dynamic nature of rhe diseasecausrng mutation. Triplet repeat expansion disorders include fragrle X syndrome, myotonrc dystroph)', Huntir8ton disease, spinocerebellar disorders, and several others (Table 8021. These disorders are causd by expansion in the number of three-base-pair repeats. The fragile X gene, FMRI, normally has between .5 and 50 CGG rriplets. An error in replication can result ln expansion of thar numbeq referred to as premutation. For fragile X, premutation comprises 50-200 repears. Individuals

ChdFe.m . Prltems ol G6r6ticTlrlsnissiol r il97

Figur 80-9. Pedigreeof an X-linkd dominant disordr with male lethaliry, such as incontinenla pismenn-

with a premutationare at risk for havingthe geneexpandfurther meiosis,crossinginto the range of full mutation. in subsequent In fragile X, that boundary is above 200 repears.Wirh rhis hypermethylated, number of repeats,the FMR1 gene becomes and protein production is lost. Somemale carriersof the premuby tation develop a syndrome as adults characterized ataxia, tremoq and cognitivedecline, In The effectof the expansionis differentin other genes. Huntington disease, expansioncauses geneproduct to have a the the new, toxic effect on the neuronsof rhe basalganglia,For most

tripler repeatdisorders,there is a clinical corelation to the size wirh a greater of rhe expansion, expansion causing more severe and/or earlier age of onset for rhe disease. The observationof increasing severity disease early ageof onsetin subsequenr of and generalions termedgeneticanticipationand is a delining charis acteristicof triplet repeatexpansiondisorders(Fig. 80-14). Geletic lmp ntittg.The two copiesof most genes functionare ally equivalenr. a small number,only one of the pair is tranIn scribed.The active gene will be that inherited from a specific parent, and the other copy is silencedassociated with methyla-

Figure 80-10. Ylinked inheritance.Blue, aflecred padenr.

498 r PART r HunanGenelics lX

F'igurc80-ll.

Digenic pedigre.

tion of DNA (epigenetic modification of a gene not due to a DNA mutation). In imprinting, gene expression is dependent on the parent of origin of the chromosome (see Chapter 81). Imprinting disorders result from an imbalance of accive copies of a given gene, which can occur for several reasons- Prader-Willi and Argelman syndromes, whrch are two distinct disorders associated with developmental impairmenr, are illustrartve. Borh are associated rvith microdeletions of ch(omosome 15q11-12. The microdelerionin Prader-Wrllisyndrome is always on the paternally derived chromosome 15, u'hereas in Angelman syndrome ic is on the maternal copy. UBE3 is rhe specific gene for Angelman syndrome, and as expected, rhe paternal copy of UBE3 is transcriotionallv silenced in the brain. Uniparental disomy (UPD), the rare occurrence of a child inheriting boch copies of a chromosome from the same parent, is another senetic mechanism thar can cause Prader Willi and Angelman syndromes. Inheriting both chromosomes 15 from the mother is fuflctionally the same as deletion of the paternal 15q12 and will result in Prader-rJ7illisyndrome. About 30% of casesof Prader-Villi syndrome is caused by paternal UPD15, whereas macernal UPD15 accounts for only 3lu of Angelman syndrome (seeChapter 81). A mutation in an imprinted gene is another cause. Mutations m [IBE3 account for almost 307. of patients with Angelman syndrome and also result in familial transmission. The most uncommon cause is a mucation in the imprinting center, which results rn an inability to set the imprint. In a woman, the inability to reset the father's chromosome 15 imprint will result in passing oo ro active copies of UBE3, and the child will have Angelman syndrome, Besides 15q12, other imprinted regions of clinrcal interest include rhe short arm of chromosome 11 (where the genes for Beckwith-Wiedemann syndrome and nesidioblastosrs map) and che long arm of chronosome 7 (maternal uniparental disomy of 7q has been associatedwith some casesof idiopathic shorr stature and Russell-Silver syndrome). Imprinting of a gene may occur during gametogenesisor earlv embryonic development (reprogramming). Genes may become rnaclive or active by various mechanisms inc|.rding DNA methylation or demethylation (or histone deacytylation) with different patterns of (de)methylacion noted on paternal or maternal imprintable chromosome regions. Some genes demonstrate tissue specific rmprinting. There is an increased incidence of imprinting

with in vitro fertilizatronor intracvtoolasmic disorders associated sperm injecrion (Beckwith-Viedemann and Angelman syndrome). Retinoblastomahas also been reported in association with assisred reproducrive rechnologies. Multifactorial inheriMULTIFACT0RIAUPOIYGENIC INHERITANCE. tancerefersto traits thar are causedby a combinationof inherited, environmental, and stochastic factors (Fig. 80-15). Multifactorial traits differ from polygenic inheritance, which refers ro traits thar result from rhe additive effectsof multiple genes. Multifacrorial traits segregate within families buc do not exhibit a consistent recognizable or inheritancepattern. Characteristicsinclude the following: 3-5%) all relaliver l. Ihere arimilar oft(uen(e ii late {typitally among lst-degree (parentr,
dild).ltir un|llualto asubrtaltial einrkl for fnd infie riblingg,off5pdng afferted oIthe 2nd to ca5e. rclativeg Dore aelated dittnntlythan deg.ee theinder ir t0 ofthe dise e. 2. lhedrkofn(ufien(e related theinddefte 3. Some dirodeE a sx have Fedilection, arindiaatedanunequal : female by male in(idence, (ommonmales, i0 wherear congenital dislo(ation hiprirmorc ofthe Pyloft *eno9k more k (ommon fenaler. for in Where ir analtepdrlx la1i0, drki9higher lherelativer there lhe of anindex(deinthele$connonlyaffectedtex.Ihedskto af{eded the 5onofan female widl pylod( i318%ompand lfie5% fortheson with fuk ofanaffe(ed nale. infdntile slenoeis genetk su(eptibilityhpr lhefemale pasred agreater har on t0 offrpng. identiol twins beaffected thesame will with malfomation ir lers 4. lhelikelihood both that tfian (hance botfi that rnembeBofa nonidenli(al pair twin than 100% nu(hgreater the but trequen(y of(on(odan(e identi(.ltwinr for Engetfiom 2l%to6l%. willbe affeftd.lhe (ontras$ that mendelian tan(e,inwhi(hideaticiltwintalwayr with 0f inhe Thit dittdbution gene. a mutant thare dkorder a duato ringle whenmultiple familyrnembers af{ected; are 5. Ihe rhl of rc(u[en(e increared ir the for rnuhifacto from al there ingtanea often mortproblenatk dirtinquirhing ale for deft mendelian etiology. A simple exanpl thattherigk rc(ufience unilateral lip ir of palate 496 a(ouple one $,ith affcted andinsea'trto 996 trvoaffe(ed drild with and is for d\ildren. when disoder more the L revere, infant has The who 5, The ofreorren(e begnater riik may direase a dan(e ofhaving affe.ted an ribling than long-tagment llirsdlrprung has greater HiuchsFung dieease. theinfant lutshort-regmQnt wfio There are two cypesof multifactorial traits. One exhibits contiriuous variation, with normal defined by a statistical range, and outliers of that range, usually two standard deviations, are considered "abnormal" {intelligence, blood pressure, heigbr, head circumference). Offspring represent a modified average of their

r Transmiision 49!l Ch|[to.8o . P.ttornsol Genolic

Aminoglycoside-induced ness deaf 12SrRNA snsorineural deatness (A1555G) 12SrRNA \ \ (A7445G) \

v.l" 12s

P CPEO I\,1ELAS, IRNA'E' \ (A3243G) \ L NDl t M ND2 Q L S H 165

ND5

col

Nna " CO 11 G

NADHdehydrogenase Subunrt 4 (Arg340 His)

co
D

A8 A6
'NARP and Leighdisease ATPase subunit 6 tRNALY" (Leu156Arg, (A8344G, Leu 156Pro) T8356G) K I I/lERRF

Figure 80-12. The hurnan mirochondrial DNA rnolecule,showing rhe tocation of genesencoding22 rRNAs, rwo rRNAs, and 13 proreins of the oxidacivephossubstitutions and deletions in the mtDNA genone are also illustrated. OH and phorytarion (OXPHOA) complex. Some of the most common disease-causjnB OL are the origins of rep)icarion of the two DNA strands, respecrively;12S, l2S ribosomal RNA; 165, 15S ribosomal RNA. The tRNAs are indicated by the single letrer code for rheir correspondingamino acids (e.9., L for leucine,K for lysjne).The 13 OXIHOS polypepridesencodedby mrDNA include components of complex I: NADH dehydrogenas lND1, ND2, ND3, ND4, ND4L, NDs, and ND5); cornplex I[: cytochrome 6 (Cyt ,)i cornplex IV cytochrome c oxidase (Adapted from Shoffner JM, \gallace DC: diseases. I, or Cyr c (COI, COII, COn); and complex V ATPase6 (ATP-6, ATP'8). SeeTabl 80 I for representadve In Oxidative phosphorl.larion drsease. Scriver CR, BeaudetAL, Sly wS, er al [editors]: Tbe Metabolic and.Molealar Basisof lnheti4d Disease,Tth ed. New York. Mccraw-Hrll, 199-9;and Johns DR: Mirochondnal DNA and dise se. N Ensl I M?i 1995;333:638-544. Frorn Nussbaum RL, Mclnnes RR, Willard HF: Thomfrson 0 Thoh'bson Ceneti.s in Medici'e,6th ed, Philadelphia, WB Saunders,2001 )

Fisu.e 80-11. Pedigree of a mitochondrial disorder exhibi.ing marernal inheritance. Btu, affecredPatient.

5m > PART 4' Human lX Genetics

DlStASt

PI{EN0IYPE icLrt te

M05ItntQUEllT MUTATlotlMTDNA lll [,!ott(Utt eectmr iranslortctiinjot'ret er aonrp n 55en5e 0rr5 nru.a Po mJtalions ni inAlh5e bir 16 qene 5. n Poifi Jtaiion tq:iA" m in

Holtl0PLASMYvS HtftnoPrAsMYll]HfRITAN(t

Leba! he'ed t;rI.rtir neu[rFih.v

NANq d 5ea5e Leqh METAS

MERBf Deafnei!

(hmni( ,/e pror_tresl e{sna (aPl0) cphthalmopeqra PBa6cn 5ynCmme ( K e a rln y r l i n c o m eK ! 5 i rs

l,tumpath! a retr t i , qmenl]!i, ,tax cEveloprtil en d e a ) ; , i e n t . a a i 0 1 i c t i id a i l . . m i ? al ,1.1 al oahoncrpni.phalom/oli r ,( d0! irnd tii;ldrt r, nrokelikerodei;nav hn cny ardirbetes ep mar 1I'J5 rne rl] ,f ,{1!oc ephFy'r,rqqed ,lbers mu5rle, a, l)nrr atax !ensor dedlxe! reural rroq|e!!'ve rcural fn.'55,often [y 5en5or dea ncLted amxoglrc5ide bolcs ant ( 5en50r ileaFnesj llonsyndrom neura ?:ogrl]s!:vehraines5 armu(ej cle)lta0(u

|]eterop ( asr |].terop r asft

l,4atena Matemal

Poifi Jtaticn tR\A' m in A15556inut]ton rlT5rRNA

|]etfi0p r ash |]0roplasmii |]olropl;smi. |]eter,lpa5mr

Matema L4atena L4atel|a I L4atenJpc1t trLili0n5 5 p o , a r o m a tm L , t i t o r Id r q rLri:i.rf !pordc5onati. 5

r Ai445G Tutdton ll! rRNA pclr The(ormon \IELAS firJta1i0n inIRNA arqp : 0 c l P r o i r s i . no( 5 5 l iar Panxeaii( in5ufticiet\ipan(ylopenardolj a,r(( Larqe elron5 de p k.r al T . P i l ] o f e i r l o n s e r L l r l h h e , t r t b 0 (g m e ltn ai c n h 5 k 5r r _ c ee t0 n de

ielercpla5Tii

|,.imN-'bz[IRL'!t|i|$iR!'lLidt|i'et|o|\)|h|N\0,ln|11h'npJrn|:|4llr.J]i,1cf6,5rh?dPhadehh,r\'l8rd|[]0],p;46

parents!withltUtritionalandcn\.lr(Dme]1taliactorsp[ayilrgantriLltrriorl|lilbi|ity popuianorr. Lrdivjdurls who cxceed a thrcshold liabiliry ert: inportanr role. l(ith other muLrifactorial rrlirs, thc discinctionl)er$-cen nonnel affectcJ bi the treir. 'l'hc anclabnormal is clearer(pyloric srcnosis, ncurirltuL)e clefect5, c(Jnh.rl-rLr.. hrnr.rr' grrr.rre nnd Lvir()nlnentalfactors is gcnital heart dele*s, al<l cleft lip, clefi palacc). rrartsfollorv clenronstratecl neural rube defects.Clenericfacrors are implr bl SLrch a fhreshold nodel (t-ig. 80 l6). Thcrc is postularecl be a clrsto cated bv fhc increascdlccrrrrcncerisk for partrrts of ln affecred

DIsEAST

0$(ntPTt0N

REPEAT (E 5tQUE

NORMAI 6I, NA AENOR[4AT NAfiGE 6l4,lri 100.'rroil | 14,406l 6l9;4'S1 r! 29,15 9 5 1 i l 6 ; 6 8i t 4 15)", )r7-l5tl8 /ila 2 9 4 l ; 4 75 5 i' 25;4988

PAREII] WHOM IN EXPAIISION USUAtTY OCCURS |!broien frolqh iher lb e1rjten throrqh faihel i c.t|rn lhroLrgh father [hr rflen throuqh lithef

LOCAlION IXPAN5ION Of

Category l (01rc1,derenta,aff$llyf iluxInqlDn 0 51:aja Lo55 ofr0otor c 5orcer iAG l p n i i r i b u l b i ,r ! ( u l i r : t r u p h y Ad',ri r on5etrlolor'r.'rrol /r:h 5eaieas5o(aRd iAG a n r l m lI e n e B l , l t i ln5 ProEetsive dlsa"hr d)'5Teir Jra.\ii, 5pnorerebe dritrxatiF l a, a iA6 aritJra tlpr 2 Poqrer5ive iyldthril araxia, IAG 5pnorerebe ar D ) A na , i5 L r l m r 5 ir ; t r o p h ) l a . a r e a 0 Sp noterebeirirxn tlE.l au i,ert n tA6 lo5eph d sa5e) oprln2mopeqra iMd.hddc Pogre!srrl] dysanhr J::r;, 5pno,:erebe drdtax,r 6 tlp J,ny51iqfl u5 tA6 Progrelsiw aiarE,dlsanhra,rctna 5pro(erebelir ttpe itaxa 7 d?ceneratr0n r-Ac ll PmqrpssNf demenr alrri;, tp noterebeitaxatype dr a,bBdyk fe5L,dismet(a 0c pa [erbclar rtophIaiaria, 0ni( ep!)1 Defi;t.Lrbral corrirdrl mtc( ep aircpfy/|]ir jl"ndrfle F,rar chorenatletosi5, a demenl Gtegory2 P 5 e d o a (d ' r p i 5 a / n I e 'n f tr e r P r y ! e ;Y , l ] i i r c 0(uloiha'ynqea ir JlrrcphI fl J5(Lr I erdotlardilpaj a a j0 n, 5ho[5Lilne,Joint dEenerilive di5e,re rxrt!, Pro{ lirnb rqa $e;lne5t aqia, dy5pf rr0!i5 S h 0 f r 5 t d t J r , o p e r t 5 ke 5 v r - h b u l q l n g ! n ur ! callara (udrhyp0pa5., drv 5h0r1ned ln!eI'dertadnomalies rj'nda.ryl Pcyda(tyl/anc l/,15t 1055.ad arfi!'1hr fmntil e !a a,catira6 1l balC p ly'rsr losi,G'd;a idr!'1hl'1 a,catrratt5, ftonial baliing Prcqresli\r aiaria,dysanhr lmb d,hype(ophrl c,rrc0mFpalh,{pycmda n eqs we;kne55 lvienta retdrdal0n, digee,rfi anc,ar]j, f'ric'corahidr\m ei n ma lvld nefia r.crditof AdJ cn5et d,Ct5,lrthr r atar i, ny5taqmus Aiaxia leIurc5 aff ACXE,eya nofirnentc !clcr5,7a-;l] al e aq? cn5et l I r e l i r e r \ . " 1 t 0 1 0 t 5 , m 0 Dri t d e F ei n 0 sv n yn

Exrn [r]n Exirn [xcn Excn ExoI

i,1cre th,ouqh ofleI faihcf ibr olten h|ot|!h falhel

Exon [xcn

GA' 6ar: [t6,[r:l6iA 6al.,C(lGarl o6 afla

i:6 I 6,i',1 li 2l (expi|.i cb5ered on n 01? yl ?lr1 15i22 5 2 5 17;100 5e'.irt to </5t75 ll,l0r'r Auto5ona f her.r1e,llj rc.ei5ve d seorealle rnher ci rri trd fior1r parli5 00.n 6 5 2 ; 1 0 1 . 0 0 0 ! ' m o , e 1r !5veIlhro[ofrlothPr 0 )j ),100 9il0 no-e r 6 15;>100 l 6 l 7 ; 1 0 7l / l l r ' 6 ; 8 0 0a 5 0 0 ,r l8;66 lS Ill]rcoftenlhiouqh crhl]r l c|e ohen thrulh|rotheIlcrirften th,cLrqh filhef paren!bJt i]1to irther erpan5 a01len l0mr ra tlr0uqf n0thcr

Ircn Excn

9ynpol)da(I'! tategorY3 ( dlslropfl l L'ryotcn iDl,1 ftr,rmc5rme l9) Liy1rhn. dItrcthl iDl"1]: ll drr,rml)itnrc Fredn atarD ih

Fxon l ' u n t r ; r s J t r e !o r ed l ' u n t r J n 5 arte q 1 eo l

Fr;rqrle di.re irFAXAl ):!!f lrdqilerP 5 illAXf) !t norarcbi]itirJ rypc Jr 8 qpc ,rr !t)noairebeiraxa lll aratra rype l2 5r nl]rerbe Prcgrej51,erf c epl:p5l' r)',rc tIlre

[66

5 ' u n t ; r 5 i tre l l {o 5 ' u n [ ; f 5 a r r c q] r cl i l ' L r n t r : f 5 ar e q n t d o lnfrox J ' u n t r a I J t ee !o n |d

[(
06 AJI' (A6

fUI0t0na rc! ft(eiire nler?'rie,50 5'IntEr\aleil i]r pa|eltr lranrm.ted b,vb0.h

i. riidr ,B,l,rr! Ermrh;d h R ,r.1dm lL, lirl,r\,i Jerrfr.,ld ir rLr L1]lU1llll5,p el 6? r

. Cho olm . Prnemsof Genelic Tlansmission 501

41 yl

Figure 80-14. A, Myotonrc dysrophy pedigreeillustrating anricipation ln rhis case,the age of onser for family is members affectedwrth an autosomal dominant disease lower in rnore recent gnerations.Blue, affecredparients. B, An autoradiogram frorn a Sourhern btot analysis of rhe myoronic dystrophy gene in three individuals. Individ ual A is homozygous for a 4- ro s-repeat rllele of 175 repeats;rhis indrvidual has myoronic dystrophp lndividual causingallele of approximately C is also affecredwith myotonic dysnophy and has one normal allele and a disease Center.From Jorde 900 repea6. (4, Counesy of Drs. Kenneth and Elaine Lyon, University of Utah Health Sciences LB, Carey JC, Bamshad MJ, et aL Medical Genetitr, 3rd d. sr. Louis, Mosby, 2006, p 81.)

child comparedto the generalpopulation. This risk is 3%, less if than what would be expected the trait was causedby a single gene.Further emphasizing role of nongenetic environmental the risk can be lowered by vp ro TOyo factors is that the recurrence

if the mother-to-betakes lolic acid at 4 m9lday starting 3 mo prior to conception-Another exampleis that a sequence variation in the interferonregulatoryfactor 5 geners associated wrth afl increased risk for cleft lip and palate.

Genelics 502 r PAnT r Human X

Nalure nurture vs

Many adult-onsetdiseases behaveas if causedby multifactorial inheritance.Diabetes,coronary artery disease, and schizophreniaare examples.

Environmental effect
FiBure 80-15. The progressivedecrease the genecicload contributing ro che in createsa smooth transitron rn the djsribution of illdevelopmenrof a disease nesses an etiologic diagjam. In theory, no diseases completely {ree from on are the influence of both genetrcand environmental facrcrs. (From Bomprezzi R, Kovanen PE, Marrin R: New approaches ro Inveshgating heterogeneiryin complx rraits. / Med Genet 2003t4U553-559. Reproducedwith permissron from the BMJ Pubtishing Group.)

Allegrucci C, Dnning C, Priddle H, et aJ: Srem-ceJl of consequences embryo epiLgeneticdeferts. Lancct 2004;364 206-208. Bomprezzi R, Kovanen PE, Marnn R: New approachesto rnvestrgatingheterogeneityin complex tfttts. I Med Genet 2003;40:553-559. Clayton-Snirh J: Genornic imprinting as a cause of disease. BM/ 2O03;327t1121-1122. Gosden RG, FiDbersAP: Cnetics and epjsenetics-naore's pen-and-pencll ser N Engl l Med 2007;3561731-733. Jacob S, Moley KHr Gamles and embryo epigenencreprogramming affect developmenraloutcome: Implication for assisred reproductive technotogies. Pediatl Res 2005,5 *437 446. Jacquemonr S, Hagerman RJ, Leehey MA, et al: Penetranceof rhe fragile X-associated tremor/ataxia syndrome in a permutatron carrier populatLon. JAMA 2004:291:460468. Maher ER, Brueron L\, Bowdin SC, et al: Beckwith-Viedemann syndrome and assistedreproducrjon technology (ART). .l Med Geftet 2003i4U62-64. Teebi AS, El'Shanti H: Consanguinity:Implications for practice, researchand oolicy. IaRcet 20061367'9 70-97 1.

Low -

Clinicalcytogenetics the studyof chromosomesi is rheir structure, inheritance, and abnormalities. Chromosome abnormalities 1% occurin approximately of live birthsand are responsible for a large proportion of early fetal losses, multiple congenitalmalformations,and cases mental retardation.They have a signifof icant role in the development neoplasias. of Chromosomeanalysisis indicated in dre child with multiple congenitalanomaliesand/or dysmorphicIeatures, is indicated It for the pregnantwoman with advanced marernalage(>35 yr). Ir is also warranted in patientswith (1) two major malformations and/or three minor malformations;(2) problemsin early growth and developmenr, includingambiguous genitaliaor mentalretar()3), stilldatioo; (3) fertiliry problemsor recunent miscarriage birth, and neonataldeath;(4) a first-degree relativewith a known or suspected structuralchromosome abnormaliry. METH0DS CHR0MOS0ME 0F ANALYSIS. Cytogeneticstudies are usually performed on peripheral blood lymphocytes;cultured fibroblastsmay also be used. Prenalalchromosomestudisare performedwith cellsobtainedfrom the amniotic fluid, chorionic villus tissue,and fetal blood, or in preimplantationdiagnosis, by analysisof a blastomere.Cytogeneticstudies of bone marrow have an important role in tumor surveillance, particularlyamong with leukemia. Datients Chromosome anomalies include abnormalities number and of structureand are the resuh of errols in cell division. There are two typesoI cell division:mitosis,which occursin most somatic cells, and meiosis,which is limiced to rhe production of germ cells, In mitosis,two genetically identicaldaughtercellsare produced from a singleparent cell. DNA duplicationhas alreadyoccurred during interphase,so at the beginni[g of mitosis the chromosomesconsistoI two DNA strands ioined together at the centromere. Mitosishasfour srages: prophase, rne;phase, anapha5e. Prophase characterized condensation the and telophase. is by of DNA. Also during prophase,the nucleai membrane and the nucleolusdisappear and the mitotic spindleforms. In metaphase, the chromosomesare maximally compacted and are clearly

High
Liability Figur 80-16. Typical hnear erythemr and blisceringin a female infanr with incontinentia pigmenrj. As the child grows older, the skin lesionswill become flattened, pigmenred streaks. (Photograph courtesy of Mrginia Sybert, University oI\0ashingron, Seatrle. FromNussbeum RL, Mclnnes RR, Wrllard HFr Thompson d Tbompson Genetics ib Med.icine, 6th ed. Philadelphia, WB Saunders.2001.)

r Sl Chapter . Cytogonolics 503

ls
I
Figurc 8l-1. A, Centromere position determining the rhree types of chromosome seen in rhe normal human karyorype-metacentric, submetacentric,and acrocentric. B, MorphoLogic landnarks use{ul in chromosome rdnrification.

Metacentric

fi=ifux>r
tt
ISatellites secondary constriction --i Secondary constrictions

fltt
I
lA

Submetacentric

-\

Acrocentric

i
B

i.. l1 I

/''
16

ahgnacthe center The chromosomes vrsibleasdistinctstructures. of of the cell an spindle fibers connectto the centromere each chromosome nd extend to centnolesat the two poles of the

of two chromatids,In meiosis,a diploid cell (2n = 46 chromosomes)divides to form haploid cells (n = 23 chromosomes). Meiosisconsists two major rounds of cell drvision.In meiosis of pair preciselyso thar I, each of the homologouschromosomes geneticrecombination,involving exchangeberweentwo DNA in over),may occur,This restrlts a reshufflingof itrands (crossing Eacbdaughtercell then chromosomes. alleleson rhe recombined In receivesone of each of the 23 homologous chromosomes.

Many other banding techniques and special stains including (Q-banding),reverse(R-banding),and cencromere qurnacrrne {Cbandrngl are available for use in certain circumstances. Metaphase chromosome spreads are 6rst evaluated microscopically, then their images are capcured by a video camera and stored on a computer Homologous chromosomes from a metaphase spread can be paired and arranged sysrematically into a karvorype. The chromosomes are arranged by size in pairs, the largest autosome being designated chrornosome l and the smallest chromosome 22. The sex chromosomes (X and Y) make up the 23rd pair A description of the karyorype includes two or three parts: (1) the number of chromosomes,(2) the sex chromosome constitution, and (3) any abnormalities noted. A normal karyotype is 45,XX for females and 45,XY for males (Fig. 81-3). If present, abnormalities are noted after the sex chromosome complement. While the internationally accepred system for human chromosome classificatron relies largely on the length and banding

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secondpolar bodn eachwith a haploid (z = 23 chromosomes) the meiosisfulfills rwo crucial roles:It redrlces set.Consequenrly, chromosomenumber from diploid (45) to haploid (23) so that upon fertilization a diploid number is restored,and it allows for genetrc recombination. or Two errors of cell division commonly occur during meiosrs mitosis,and both can resulcin an abnormal nunber of chromosomes.The lirst is nondisjunction,in which cwo chromosomes fail to separateand thus migrate rogetherinto one of the new and cells,producingone cell wrth two copiesof the chromosome lag, in which a another with no copy, The secondis anaphase it is chromatidor chromosome lost because fails to move quickly to enoughduring anaphase becomeincorporatedtnro one of the

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trypsin-Giem which producesG- or GTG-bandrng,a unique (G-negatrve) bands and Lighc combinarion dark (G-posirive)

figurc 61'2. Formation of mosaicism. The X and Y chromosomesare used ro illusrracerwo common errors leading to chromosomalty abnormal cell populations. In normal mitosis /topl, duplicared chrornosomes separate and become incorporated lnro daughrer cells. If one replicated chromosome fails normal septo separate, mirotic nondrsjuncdonoccurs /zrtldlel. Occasionall-v, aration occurs, bur one member fails to misrate. This is knorvn as anaphase l^E (bottom) (Used, wirh perm;sion, Iron wxnrewski LP, Hirschhorn K: A Glide to Huffian Chromosome Defec*,2nd ed. Whjre Plains, NY, Nlarch of vol 16, Dimes Birth DefectsFourdation, Birth Defects:Orieinal Articl Series, 'ec 6. 1980.)

lX Genetics 504 r PART r Human of the 24 differcncchtomosome paints is labcled$.irh a clitferenr coflbinarion of the -i fluorcscentdyes (u'hich cmir ar diifcrcnr n'avelengrhs). Elch oi the 2.2 dutosomes.nd the X and Y chro rnosornes have fheir otvn Lrnique spectraof \\'avelengths flLro of resceDce. Speciallilfers. clnteras, and image processing sofrwarc arc requirecl iclcnrif.v to cach chromosonrc.SKY and M-Fl5H arc especiaily useful for rdenrifl'rng tire complex chr{}lDosoDre rearran[jemcnts loLlnQlll manv tumors. Comparative genonric h,vbridization (CGH) is a FISH basecl method fhar call be usedas a Henome-&'ide screent() rneasure cLlf ierences copy uLrrnbcr a particular l)NA sequence chro in of or mosomirl segmcnl beru.cen ru'o diffcrcnt DNA samples. The tcchnique involvcs.lilferenriallylabelin!i patrerltDNA u'irh a flLrorescentdle (green and normal reference f)NA rvirh another flu ) orescentdye (red). F-qualrmounts of the tr,volabel DNA sa|nples are mixed and fhen lsed es a painting probe for FISH rvirh nornal met.lphase chromosolllcs. The ratio of grcen to red fluo fescence measuredalong cach chromosome.Regionsof ampli is fication of patient DNA u,ouJd ciisplay a exccss oi green rvhilc regrors of loss of paticnt D\A rvould shou. liuorescencc, excessred fluorescence. parient and control D^_A are eqllal]y lf reprcscrltcd, thc green-to-redrario would bc 1 : I rnd thc chro mosornes \\1)r.rldappear yellow High rcsolrrrion (-(iH-bascd microarr:rys (alrlv (l(lH) h,rvc the probe preparatioDthrt is dre same es rra(litionel CGH, but rether thrrr hybridizing the probe to rnelaphasechrornosolne sprcads,large'inscrtclones (such as bacrerial artificidl chromo' somcs;llACls)spotted on nicroarrays serveas rhc targcr. Ihc rcsoluoon of array (lGll is Limitedonl_v thc sizeoi thc inscrt and by thc distancc bcrrveenclones, rvhcreirschromosomc CCH has a resolutioD of only -5-ltJMb. Targered array baseclllGH is an

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t(arvotvpc norrnal of rnale with chronrxonres hte prophxre. in Ijgu.c .31-3. funrb.f oi b^nds Lhcchromosomes onger, i greirer nre tr|rd ift.s.en drtrn ar wherchronxxomes phorogrephcrlnrcraphrsc are

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pattern of each chrol'lrosome. posifion oi thc ccntromererel the atir.cto fhc cnds of rhe chromosome also is e usetul distinguish ing Fcature (scc fig. ll1-1). l'he centrrnere divides rhe chromosorncin trvo, rvirh the short arnr designared fhe I arm as and rhe long arnr designatedas rhe q ann. A plus or minus sign beforc the nrLrnbcrof a chromosome ln(licafesthaf rhere is an e\tra or nlissing chronrosome, rcspcctii,cLy. TaLrlclll-1 shows used for the descnption oi chromo somc of thc abL)re\'ranons somesand rheir abnormalities.A rnccaphasc chromosomc sprcdd will usuallv shorv.150-500 balds. Prophaseind pronefaphase chf(rnos(xnes are k)nge! are less condensed.and ofren shorv 500 850 bands. High resolution analysis is uscfLrlfor dercct irg subtle chromosomc abnormalirics ther mrghr ofherwisc ljo unrecognlzcd. in The fluorescence situ hybridization (FISH) rechnrque uscd is ro ideLrrifyfhe presence,absence,or rearrangemcnrof specific DNA segmenrs.FISH involves using a unique f)NA sequence labelcd rvith a fluorescent d1e, rvhich is exposed ro single srrandedDNA on a microscopeslide- The probc pairs rvirh its complementarl D\A scqucnceand call be visualizedbv lluorescencermcroscopy (Fig. I | 4). In interphaseccLls. rhc number of copies of a parricu)ar f)NA segment can be dcrcrmined. In nletirphascchromosome spreads,the number of copies of the DNA sequence \\'ell as the exact chromosornaL as location of cach prohc copv .an be documenfed. FISH is particularlr uselul for derectingverl. smxll deletions that might escnpenolicc wirh C;\{rirh high-rcsolution chromosome anal,vsis is band anirl-"sis. it i'ery diflicult to rccognrzedelenons less rhal 5-10 miLlion hase plirs {5 10 \1b) in sizc; FISH can reLiablt derecr delerions as small a 1 Nlb. This has allorvcd checlinrcal characrerizarion a of number of njcrodelcrion svndromcs. ln addrtion to laenc-or locus specificprobes. complex mixturcs of DNA from irne part of a chromosome arm, an eltire chromosome arL-n, an entire or chromos()me are availablefor fluorescence srainingof largechro The prohe mixturcs arc mosome seclionsor entire chromosomesrcfcrrcd to as chromosome paints (lig. 81--5). Spcctralkaryotyping (SKY) and multicolor FISH (N4 FISH) are techliques that use.].4 difterent similar molecular c-vtoljenctic chrom()somepainting probes and -5 fluolochromcs to simuiranc ousJl' r,Jsualizc cvelv chrdnosome in a metaphasespread. I-ach

c0NDm0tl XX IY liil ten del der dJ! nJ nv Female [,lale ({ 1 N u r n b etro t ( e 5 [ef0ome0 Deetion Dervaiive Dup,ld1ron Inse{on Inyercn lla'mal e hr',1]i,ne lema 1 Nordlrale a'yotype N J m bo frr e 5 e d (( 1 ] n e e 11 h

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r Chapter8l r Cnogenetics 505 DNA on sltde Chromosomal on Denatural

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2]-spccifcprobeIhc3redsrgnalsnrarkrheprcscnceoi.]chrlnoymes]1t.}IsHena1vsrsofarrreraphasechromrlvllcspreadironlrcnica||lnolmal pa rndlvrdual using a rvhoLc-chromosome

lX 5m r PAnT I Human Gorelics

Normal Ghromosome 22

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array CGH plocs {rom a norrnal control and frorn an indMdual with the 22q11,2 deletior seenin Diceorge syndrohe. Each clone Figure 81-5, Representative is arranged along the *-a-'ris according to i* LocatioR on the clEomosome *'ith th mo6t distalhelomeric p-arrn clones on the left and the most disraVtelomeric q-arm clones on the right. The blue line plots represent the ratios from the fust slide (control Cys/patient Cy3), and the pink plots represent the ratios obtained from the second dide in which the dyes have been reversed (patint Cy5/control Cy3). The mp panel is a norrnal plot for chromosome 22. Th lower plot Ls fron an individual with DiGeorge syndrome ir whom clones in the critical deltion region a-re deleted (dt/ou). (Plots cou{tesy o[ BA Beiiani and LG Shaffer, SrgnatureGenomic Laborarories,LLC.)

effective and efficient technique for detecting cryptic chromosomal aberrations, which rnaybe an important adlunctto FISH and conventionalchromosome analysis(Fig. 81-6), ABNORMATMES CHROMOSDIIIE OF I{UIDER Ansuploidy snd Polyploidy. Human cells contain a multiple of (z 23 chromosomes = 23). A haploid cell (n) has23 chromosomes (ova or sperm).If a cell'schromosomes an exact multiple of are 23 (46, 69,92 inhumars), the cell is referredto as euploid.Polyploid or heteroploidcells are euploid cells with more than the normal diploid numberof 46 (2n) chromosomes, While polyploid conceptionsare usually not viable, the presence mosaicism of with a karyotypicallynormal line may allow for survival.Abnormal cellsthat do not contain a multiole of 23 chromosomes are termedaneuploidcells.Aneuploidyisihe mosrcommonand cUn-

ically significant type of humanchromosome abnormality,occwpregnancies, ring in at lea6t3-4% of all clinically recognized (3n), are Tiiploid cells,thoswith three setsof chromosomes viable in a mosaicform. Trioloid inlants can be liveborn but do not survivelong. Triploidy ii frequendythe result of fenilization by fwo sperm(dispermy). Failureof one of the meiotic divisions, resultingin a diploid egg o! sperm,can also result in triploidy. The phenoqpe of a triploid conceptiondepends the origin of on the extra chromoso$eset.If the exua setis of patemal origin, it will result in a hydatidiform mole. Thosethat have an extra set of marernalchromosomes soontaneously are aborted. Aneuploidies usuallyconsistoi monosomyand trisomy.Monosomy,which may be completeor partial, occurswhen only one insteadof the normal two chromosomes presentin an otheris wise diploid cell, In humans,a1lcomplete autosomal monosomies

r Chapler . Cytogenetics 507 81 s a p p e a r( ) b e L e r h ae a r h i n d e u e l o p m e n r ;u r v i v a lr s p o s s i L r l . ' i n l mosaic forms, An enccption is monosomy for fhe X chronlosonte

sY[DRo E
farlure of chronosorres to disjoin normally durtlg mcit>sts isee can Fig. 81-2). Non disjr.LnctLon occur durilg mclosis I or ll orrhc resultinggrnlctc dur ing nirosis. Aitcr meiotic nondrsjunction, lacks a chrornosomeor has 2 copies,resultinglu e nrttncr eirLrer \ r' m l L' , 1 l ' i n ' r n l r / \ B ' , r e . ' c ' l \ l ' l l \ ( l ! , Trisom,r., characrcrizccL the prcsclce of 3 instead ol thc br
ll,PataLl Tr50my 5yndrome

[{cDt}tG

(trilt(AL $ANtFtsTAIt0lrS

individuals t'tth tr istrrnr cellsor ir may bc in mosarciorrn. N'{osr orr exhibit a consisrcnt and spccilic phenolypc depen<1irrg thc chromosonrc involved. FISH rs c()mrtonly r.rlcdir rhc l)rendreL and rn tLrerapid diagnosisof neu' detectionof fetal aneuploid,v ro borns suspectcd have a crtsotny, are -l rtLrtosoThc major nu c'ncal (lisordcrsof chromosonres r n l l t r i s o r n r e( t r i l o m y l l , u i s o n t y l l l , t r i s o m y l 3 ) , a n d 4 f l p e s s 'Iirrner s,vndrone iusuallv aneuploidics: of scx chrcrnTosornal 45,X); Klinetelter s\'ndrorne l47.XXY); 47,XXXr and'17,XYY B,v far the ilost conmon type oi rrisun-v in livehorr infants is frisonly 21 lkaryotypc 47.XX,+21 or 47,X\+21) or Dou'[ s-vn cornnlou drome.'lrisom-v 1li irncl rrisorny li are also rclativeLY ser $'ith a characcerisric of congcnital ir[onr and are associared alics ald nental rctardarion (Tablc It1-2). l)own syndrome is rssociatedlvith cognirivc impairncnr end characteristic facial and orher dtsnorphic fearures(Figs ill-7 ft) 81-9). Affecred individLralsare nore prone to congcniral heart (atrior.entricul;rr seprdlciefects. vcnrrtcuLat defeccs septai cletecrs, PDA. rerralogyoi fallor). isolaredsecunclum atrial scpraldefecrs,

fnge6 1/10,0{00fth5(left lfren dlin,otflexed wih p0/da,:1y,J4 lo m ctuar noJe; hypoteor 5m,bulbour ow tetmalfomlpd ar9;ima 1 abn0Ima skur;(ercbrdlfralfomat0n,e5pe(ial! h o l o | ) r o 5 e n ( e o h a yanlrd , cp h d r a ( m a f o r m a t i 0 n s ; ; f ro dr icalp dei?cB;hyp0plrsr rbs,vi5(era r orab5en dnd genilalafomale5 ] hnger I[ 5omy8,[dmri]s l/6,000 b(hs Low rthwl:igh[,c05ed ndex 0\rapprnq b hsti wlrr the ng iyndrcme ld c al and 5th cvrddpo lhe4th, the d9{ narcw hlpr \rft |m pilabdLjctrcn,5ho $ernum,r0rker-bofom feel 1r(mrepl; prom cdput,m ieni ooqnathodbc and a, )', rna maiomaton5,dndmerta rctrdat0n;95%0i(as! areetha thehl yr in palpebia iatlace.upl/lard dnted axd 5 Ir5oni 2r,Down t/5cc 800 Hypolonia, lss!e5 anc ( folds,speakled (Erushield irue5 5yndlonr Dtnnl epicinth nq $0n5);$ry qm!Vth deEeesrnentaland aiardirof;dysp cf (he oi a!i malfomatirnr,and (redse;sho^, 5inan broad Flv 5,l:adDr phaanI 5th handl,hyl)opofnrddle agia oi ring4du0dena paale:596 aftesa,a"d ar(hed hqh 0fpatient5 Dcwn \!rth are resull0fa tft!solntcn (l4q2lq), tndrome lhe (l5q2lq),and phen0t}Te r{llq2lq)- i wi chthe isth s,rme lruomy?1 r/ndmme as Down forehead,\{,ide n0jerhi(k Ir 5omy mo5asm l/20,000 8, c bifrh! Long h ghprorheql fa(e, uprurnei everted p,mlooretruqnalhia, l0llrPl ow settars, hgh l:lell pa arched,50metme5ate;0iteDdrtcu afanorndlig (0mm0n,mooetale Elanlit menla 0n

500r PART r Human lX Genetics

&

Figure 81-9. Prehensilefoor in a l-mo-old child. (Frorn Wiedemann HR, Kunze J, Dibbern H: Atlas of Clinical Syndrones: A visual Cuide to Diag, ' o s r r , 3 r d e d . S r . L o u i s ,M o s b l ; 1 9 8 9 . )

panerns the palmof a childwirh Down Figure 81-8. Characterisric derrnal of (sirnian syndrome, singleflexioncrease a crease), axial tlnadills (anol!) in dislalposirion, patrern a areaon rhepalrnbetween third andfourthdigirs, the andulnar loopson all 10 disjts.(FromNussbaurn MclnnsRR, Willard RL, Hl Thoftpsob6 TbonpsonGenetics Medkire, 6rh ed.Philadelphia, h YrB Saunders, 2004,p 160.)

gastrointestrnal anomalies, leukemia, Alzheimer disease,immune dysfunctroo, hypothyroidism, diabetes mellitus, ard problems wrth hearingand vision {Table 81-3), Most maleswith Down syndrome are sterile; some females have been able to reproduce. Individuals with Down syndrome often bene6r from programs aimed at stimulation, development, and education. They also benefit from anticipatory guidance, which establishes the protocol for screening, evaluation, and care for patients with generic syndromes and chronic disorders. The lile expectancy for children with Down syndrome is approximately 50 yr, Down svndrome is the most common chromosome disorder and the single most common genetic cause of moderate mental retardalion. The incidence of Down syndrome in live birrhs rs approxrmatel;r 1 rn 750; the incidence at conception is more than rwice that rate, The occurrenc of trisomy 21 as well as other autosomal trisomies increaseswith advanced maternal aee risk, women at thir age should 6e 12J5 yrl. Due to this rncreased offered genetic counseling and prenatal diagnostic tools (serum screening, ultrasonograph)', ammocentesis, and chorionic villus sampling) [see Chapter 96]. Even though younger women have a lower risk, they represent half of all mothers with babies with Down syndrome because of their higher overall birth rate. All wornen should be offered screening for Down syndrome in rheir second ffimester by means of 3 maternal serum tests (free p-hCG, unconjugated estriol, and c.-fetoprotein), Even more efficient, with a detection rate of 95ol", is a method of screening using maternal age and fetal nuchal translucency (NT) chrcknessalong with maternal serum p-hCG, PA?P-A (pregnancy-associatedplasma prorein-A), unconjugated esrriol. and o.-fetoDroteln. Increased levels of maternal serum cr-

fetoprotein(MSAFP)are alsolinked to orher abnormalfetal conditions,includingopenneuraltube defects and defects the gasof trointesrinalsystemand genirourlnarysystem, In approximately95lo of the cases Down syndromethere of are 3 copiesof chromosome The parentalorigin of the super21. numerarychromosome is marernaln 977o of the cases a 21 as result of errors in meiosis. The maionw occurs rn maternal merosisI (78%). Approximately 1% of individualsare mosaics with some cells having 45 chromosomes, while anorher 47, of individuals have a translocationthat involveschromosome21. The majority of translocations Down syndromeare fusionsar in the centromere between chromosomes 14, 15, or 21, knou'n 13, as Robensonian traoslocations. The cranslocations can be de novo or rnherited.Very rarely is Down syndromediagnosed a in parienrwith only a part of the long arm of chromosome in 21 triplicate (partial trisomy). Down syndromepatientswithout a visiblechromosome abnormaliryare lhe leastcommon.

r ChapterSli Cylogenetics 509

ptesen(e afld dntarfu,ovA die 0fdeep m05a 6 lt (naEcteI5l:c noeirs (l,licaifcatutsrrilrde 1/,XXIX'1,+9 Ihen40r{y di lrtrrti ar6 \lanlg (an0fad3 (hiqh a,lowrel foreheadmi(mphthdlm n dl[orme,l maltornal onl ea6, bulb0,rs noieland skelela conraturea) lj0ifi (6096) dnd heJrt defecls rspontaneous Irsomy 47,XX/XI+16 Them05tftequenty0b5erven,ruto50nilaneLrploldy 16 !e abonrons leturene I nElig rlsk The (ro n lr 5 af Tetrarrmy 47,XX/XX+(12p)w n d 5 P a l iK len r t n d r o m e 5 p a x e l n ire rpfh a r r , (hubby pominent ioPhead, (heek5, onq eldrcw5, eye and aihe5, (onfiqurdror ph1 w rhthDupper dnd d bow .p .rp trurn Polydacry nreaks hyper/hvcop!rnenlation y and have bef of reFrreo

MAfi KARYO]YPT (Ltr{tcAr lttsTATroxs DISORDEN ihe are of and dell(ienry varrable mallrrty paten15 l$omy I 4],XX/XX+8 Grorrh mental ,Ihe paknar p

s It is not possiblero disringuishfhe phcnotypesot inLli\'r(lua Pxtlcntswbo u'ith full trisom,v2l ald rhose\\'ifh a lransl()cetiorr. are nosaic tcnd ro havc r mikler phcnotvpe. (lhrorrosome arallsis is rnclicatcdin indivrduals srLspected oi lf havitg Dou'Lrs,vndronre. a rranslocarionis idcnrilied, plrenral rvherhcr chromosome srucljesmrLst be periorrned to deccrnrrne is:t translocatiol cirrrier,lvhich carrrese hrgh one ol the parcLrts lisk ior havilg another rifccted child. Thar parerrt recLrrrence lnirt dlso have orhcr farnrly nlenlhcrs af risk. Trarslocetiorr l-11;21)cafriers havc r l{)0'ra reclr'rcn.c risk lbr a chromoso Gcnomic dosage irnbalanceconcribures nrallv abnorrral chiL,:1. parhwa.vs rhc l)or'n syodrornephc <r through direcr anJ indJrecr notype and its phenotlprc variatior. TebLes 81 4 arrrl lll-5 providc urorc trrfotnrariol on othct (l aneuploicLies parraL autosomal ancrrploidies igs li I lt) rrr and l.t I il. 1ST OT A B N O B M A T I T I E SC H F O M O S O M E s U C I U R E Translocltions, r,vhLch Lrvolr'c the tralsfer oi Translocaiions. occur wrfh r trc rnltcri:l frrur one chrorrosonre to aLrofhcr, quenc' of 1 in 500 livcl.or:nhunran jnfalrs. Thq mav l.e inhcr

' l l r i , F a c r r la p p c a r a n c c i . 1 . h t l d w r f h r r l s o m y 1 3 ( F r o m W r c d L I , o n r r n n I l l { . K n D r c J , D i b h e n r H . , 1 / l d . o , /O l t r t L L a ly n d r o m e sA Y s u a l ( ; u d c , S : n , l ) r r ! ! o s r s . l r c t . d S t l - o u L sM o s b ! . 1 9 8 9 ) ,

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Tfl150['tY l8

(e ,rppearanie and defe.r5q,(uti apldl a) Smai prem,rture Head fira Sc;p and llghtpapebra i55Lrnl mia, abnoma tr5 Mflophlhd (ornea n05e hypoplar t na5dl aae [kfr I pafu !d alen 6096-80% ofci5e5 Na.mw i]nd Miiro(ep ly pul Proff nentocc llcrochtharia h 1,4 ooliafi a 5otn9 thead l : e l l p o rp a t e a Ho opo5en(ephrly hft nen(ephaiy) Mlc|o(ephaly [ar ]4ry hemanqnmas Deafnel5 (eg d PlA. ril fhesl C c n g e ,h1 3 d i 5 e d 5 e , / i D , P D A , l.orEen hed( 5ea5e9,V5D, r ean k and A!D) and ICJrn % fcae! A 80 o q cr ( 5hl]n rternum,small nrpdP5 T h rp o t t e i r D 5m ! 5 nr i b 5 l fq and {dincdactyy) r |tre di pa b d u . r o f L f Erlftmrte5 0vedaoo0fh0qer5 ice5 (l'rodacryi overapping and firlE15 P|)ydanyly 4 ndex ld, 5ihaver , cfiei h5t o\rr lypopd5t( h,hypPrc,inver nd na, r feet ffoil3f-botom H n o o a sitJ r l r ( pnnaEl ser'ere cpmenta y5.rdprctur: dlve dpvelopmenla]delays and del [enerd seveft prlsinarai retardalcn qrowth grouhrelarcalon and and Fstm(a blth, Refal abnoimalities Premdt,r,? p0yhyd?Tnios iilcrcarpmleit$rsineuvophrls fqJrnilorabdo|I',]lhernia5 0n1y5%rwonqerrhanlwa' f t y t % v eo f g e r l h d nn o 6r pl4i A5D,dLrid nomhb.mdRt,(kqrirn fl!1l?iJcnfJrflrrollftdr,rr Ph 4ftei ?delphi,WB5r!nde62002 !epl;] delerr, paknL irter V5D. PDA" 6u(L!: 05ur wnmolir denr ntla

rfed t'rom a carricr parc t or ilppcar' de novo, n'ith ncr other rfiected fanril\, mcrnbc. Translocationsmal, be elther recjprocel or roircrtsonian(lig. lJ1 1,1). Reciprocal translocationsirrc thc rcsLrltof brc:rks il noriro nrokrgouschrornos<nnes u,lth reciprocalexchangeof the brokcn (larricrs oi e rcciprocal rransk>catiou usually phe \egrrlents. are llorvprcaLl}'nornlxlbur.re lt irn rncreased risk both for miscarriagc duc ro unbalxncedrccipr<>cirl translocatior and for bearing chronrosoarallyabnornral olfsprng. Unbalanced trans]ocafions .| e rhe r esLrlt xbnoromlitiesir rhe secregatiortcrossover rhc of of treLrslocirflon in carrler chtonlosornes rhc gcrrn ccLls, RobertsonianlransJocations invoh'c trvo acrocentricchrorro 5orncslchro[losorDes l.], 14, 1.1.21, ancl 22) that fuse neirr the ccnfrorneric region wirh e subsequcntloss 01 the shorr erms. lJecause shorr arrnsol rll -5pairs of acroccntricchrornosomes the have multipLe copres oi gcLres for ril,osomal RNA. loss of the !h(rrt :rrrr of 2 rcr()cenrncchronosonteshas no deletcriotLs efiect. The resulringkarvotvpe hrs on1y,1-ichromosomcs,including the rrnnslocntcd chromosomerhar is macleup of rhe loig lrm of fhe ()rricrs of Roberrsonidnfranslocations rn'o tusedchronrosorne!. irrc [sua]lv phenof,vpicalll norLrel.]lotvever,the,varc at increased rrsL firr niscarriage lnd u bdlinccd aLrnormaloffspring. Inversiolts ]\lt xlversion re(lurres thJt a single cbromosome break et tu<r poinrs; the broken piece is rhcn inverted and joined llrt(J the s;lnrc chronr(Jsorne, lnversioLrs occur ln 1in 100 lir.e Thcre are t\\1) types of rnversions: l>rrrlrs. pe.icentric and para ccntric. Ilr pericentricinversions,the hreaks arc in the trv<> oprpo srtc arnls of lhe chromosonrerrnd irrcluderhc ccntr()mere. The) .1re LrsualLy discoverecl bccauscrhc_v chrnge rhe posirion of the ccnrromcre. I he bre:rks in palacentric jnvcrsions occur i[ only

lX Genetics 510 . PART r HumEn

Figure 81-11. Trisomy l8; overlapping fingers and hypoplasric nails- (From Wiedemann HR, Kunze J, Dibben ft Atlds of Clinrcal Syk*omes: A visual Cuide to Diagnosis,3rd ed. St. Louis, Mosby, 1989.)

one arm. Carriers oI inversions are usually phenotypically rormal, but they are at increased risk for miscarriages and chromosomally a bnormal offspring. Deletioffi ald Duplications. Deletions may be simple, wich a piece of the chromosome missing, or rhey mav occur along with a duphcation of another chromosome segment, resulting in an unbalanced reciprocal chromosomal translocation. The latter is r-:suallydue to abnormal crossover or segregation in a tra[slocat10n ot lnvetslon carrlet Deletions may be located at the end of the chromosome or in interstitial segments,A carrier of a deletion is monosomic for the generic informatior of the missing segment. Deletions are usuall,v associatedwith mental retardation and malformations- The most comrnonly observed deletions in routine chromosome preparations ioclude 1p-,4p-, 5p-, 9p-, 11p-, 13q-, 18p-, 18q-, and 21q

(Table 5 andFig.81-15). Deletions 81 may beobserved routine in chromosome preparations,wich deletions and translocations larger than 5-10 Mb usuallyvisiblemicroscopicalll'. High-resolutionbanding techniques, FISH, and DNA studies that are too small to be seenin ordinary or can revealdeletions routine chromosome spreads. Microdeletionsare small chromosome delerions,rhe largesr of rvhich are dececrable only with prophasechromosomestudiesand./orDNA probes.For submicroscoprc deletions,the mrssingpiececan only be detected using FISH or DNA-imolecular studies. The presence extra Senetic materialfrom the samechromoof some is referredto as duplication, Duplicationsor partial (segmental) trlsomles are less frequent than rvhole trisomres. Duplicationsmay be sporadicor result frorn abnormal segtegaor Lionin translocation inversion carriers.

Fisure 81-12. Trisomy 18: rocker-bottom feet lprotruding calcanei).{Frorn V/iedemann HR, Kunze J, Drbbern H: Atlas of Clinical $,ntuomes: A Visual Guide t ^ D M E h ^ < t <l.r d e d . S t . L o u s . M o \ b t . l c 8 '

l5ll Chapter . Cytogeneficr 81

Figure81-13.Male inJentwirh trisomy 78 ar age 4 days.Nore prominni occiput, mlcrognathia,low-sl earsrsholt stemum,narrow pelvjs' prominent of abnormalities the fingers. calcaneus, fler.ion and

E A

I I
1 3 ds(13;t.l) t a B
Figur 81-14. A, khematic djj?.F/zm(left) and panial G-banded karyotpe (ri8ht) ot a rcciprocal Eanslocarion between chromosome 2 (blue)and chromosome 8 (pink). The breakpornmare on the long (q) arm of both chromosomesat bands 2q33 and 8q24.1 with the reciprocal exchangeof material betweenrhe deriv. ative (der) chromosomes2 and 8. This translocation is balancd,with no net gain or loss of malerial. The nomenclaturefor this aychangeis t(2;8)(q33:q24.1), B, khenetic d|agr^m (W) and paftial c-banded ka.yorype (ight) of a Robensonian translocalion between chromosomes 13 (blue) and 14 (pink). The breakpoints are at rhe cnrromere (band q10) of both ckomosomes with tusion of the long arms into a single derivative chromosome and lo6s of the shon (p) arm macrial.The nomenclature for rhis exchangeis der(13;f4)(q10;q10).

512 r PART r Human lX Genetics

c
FisureSl-l5.A,Childwithvelocardiofacialsyndromc{deletion22qll.2).B,Childwithlr:rdeGVitlis,vndrome(deletionl5qll-13) C, Child wnh Angelrnan s y n d r o n e i d e l e d o nl i q l 1 - 1 3 ) . D , C h i l d u i t h \ i l l i a m ss v n d r o m el d e l e r i o n7 q l 1 . 2 3 ) . l F r o n l L l n R L . C h e r r y A L I , B a n g sC D . e t a l ; F l s r l i n s f o r a n s r v e r sT h e : use of moJecularc-vrogeneric rechniquesin adolescentmedicnc practice. In I{yme HE, creydanus D [edirorsl: Ceneti. Disoders in Adolrsrent' Srafeof rhe AJt H p R e ' i e \ r ' s A d o l e s c e nM e d i c i n e .P h j l a d e l p h i a , a n l e y a n d B e l f u s , 2 0 0 2 , t 3 0 5 - 3 1 i . ) . r

N'Iicrodelerions ard microduplications usDally involve regions rhat include several genes, so that the affected indivrduals have a disrrnctive phenotype. When such a deletion involves more than a single gene, the condirion is referred to as a contiguous gene svndrome (Table 8l-7). Subtelomeric regiofls are ofien involved in chromosomal reauangements that cannot be visualized using routine c_litogenetics.Telomeres, u'hich are the distal ends of the chromosomes, are gene-richregrcns, Small subtelomericdeletions/duplicacions (translocations, or rearrangements inversions)may be relatively common in nonspecific mental retardation wirh mjnor anomalies. Subrelorneric rearraneements hale been found in 3-7?. of children r.r'ichmoderare to mild mental rerardation and 0..5% of chrl

dren rvirh mild menral retardarion. Clinical iearures i>309i,) include short stacure, nasal aod ear microcephah;hypertek>rism, abnormaliries,and cryptorchidism m males. Thrs group is also characterizedby''a iamiLy hiscory of mental retardarion and an increased Likelihood of retarded gro\4'th beginning in the prenatal period. Both rhe suhtelomeric rearrangements and rhe microdelecion/microduplicationsyndromes are diagnosed br FISH or other molecular means. Insettions. Insertions occur rl.hen a piece of a chromosome broken ar trvo poincs is incorporared inro a break rn another part of a chromosome.A total of three breakpointsare then required, and thev mav occur bet\\,'een tllo or vvithin one chromosome. A form of lonreciorocal translocation. insertions are rare. Insertion

r Chapter r Cytogenetics 513 81 carriers are ar risk of having offspring wirh delerionsor duplications oi rhe rnsettedsellrnent. consist of two copresof rht Isochromosomcs lsochromosomes. same chrornosomearnl loined through a single cenrrolnerealtd lbrning rnirror images of one another. The most frequcntlr' reported aurosomal rsochronlosones tcnd b involvc chronro solneswi!h sma]l arms. Sone of chc mote colnnr()nchromosome arms invohed in thjs formation Lncludetp,8p, 9p, l2p, ltip, rnd

sornic for the genespresentin thc isochronosorne. Marker chrornosonres arc AND BING CHR0MOSOMES. MARKER rare and are usual[ychromosomefragmelrs tbar arc f(x) sn]all rc chcy usually occur rn addi be idenrified bv bonded c,vtogenericsl tl(r1 ro the normal .16 chrontosomes.\'lost arc sporadic (709i,); is Lnosaicism often (.50%) nolcd becatse of the mirocic irtscabi[ity of rhe marker chromosonle.The incidencein neu horn infants is 1 in.l,l00. and rhe incidenccrrr rndividualsrvith nrelrtirlrerardation is 1 in l(10. Their phenotvpe rarlges hom normal lo a srverelv bnormal.

APPNOIIMAIT II.I(IDEII(E MRYOTYPT 47,XXY 1/5/5-lil,000l,la er l/80,000lvid 48,XXXY li 50,000 e biIh\ 49,IXXYt 0lher l48,XXYY, m0$1rt IYYilndrcme l/80C l,0lllNbe5 47,XYY Other XorYchmmc4omeabnolnal I / I ,500 es l,rld tle5 XXmaes 46,XX l/20,011[4alrJ l/2,50J1/5,C00;ema,e5 Tumeriyndofire 45,X Variail5 nrolai(s dnd l/1,000 TrisomyX 47,UX Females 48,UXX 49,XXXXXRarc and 0lher (hmmosome X dbnomta riel l/1,000 kmales fenae5 l/20,000 XY 46,XY tulralet Ki nehller sFdrcfire

DIJORDTR

are of a chrornosorne delcrcdand the ends are then ioincd to firrrrr rnarerial thar a ring. Depcnding on rhe atnount of chromcrsomc is lacking or in erccss (ii rhe ring is in cddition ro the nornral chromosomes),a patient wirh a ring chrotnosolrtecan afl)ear and normai or nearl-ynormal or may have mental retarc]arron s. multipie congcnital anorll.rlie Y. C E S E X H R 0 M 0 S 0 M A N E U P L O I 0A b o u t 1 i n , 1 0 0n t a l c sa n d 1 r n 6-50 fcmales hare some lorrn of sex chrotrosome abnlrrntalitr" (-onsiderecl rhe uosf sex chromosonrcabnormaljtres,rrc rogerher, connron chromosonre abnornrlities seen in lireirorn rnlents, cln b.'erther childrer, and adults.Sexchromosorle abnorrnaliftes

stmcturaL or numerical and can be prcsent in all cells or in a mav har.e rrosaic form. Those aficctcd rvirh theseabrrormaliries 'l r L u ' r r r r r , l h r , s r r , r r J c r c . ' p m e n r . p lr o h l e r nls . r h l ex l - t r . r l TurnerSyndrome. Turncr slndrome, a coldition charactcrized Lrr rhr complere or partial aLrsence rhe sccond sex chrouro of some. is defined b-va conrhination of phenotypic featurcs(Table 81 9t. Hrlf oi rhc patienrs rvirh Turnel syndrome have a 45,X chronrosorne complelrrenf. The other h:llf cxhibits rnosaicrsnr and rane.l stmcfural abnorrrirlirics oi the X or Y chromosonre, I)arentalage is not a factor in the 45,X abnornahty; its variancs occur rn approxintately I in .5,000ternalelrve hirrhs. In 7-l% of prrLenrs, rs rhe lost chr()mos()me of parcrrralorigrn, 4-5.X is one of rhc chromosorrc a[.normalities rrrost frcquentl,vassociated rrirh spontancoLrs aborrion. lt has been esrimaredthac 9-5-9991' ol ,15.X conceprions.rre rniscarriecl Thc phenotype irr rhe ncrvborn can includc shott stature, prr)rnrner! eirrs,ucbhing of rhe neck. and edema of thc hands

Dtttltoil lpl6 5ql5 6p25 7q1'1.))

Spll 8p2ll 8 q 2l4q l 4 l l 9q22

JY DNOMI lpdeldion (50%) -bto5 Axenfed-Riegel

FtSlAIl0N5 cL r(AtMAl,

8D1l

Growthretardaran,dysmorphr(fearurc5wlhflatndiabdqe,,rbrcrmaear,deep-iereyetherrn9105r,5e handi fpl and dislinrtiw fearures, disabilric5 la(idl fieftal macrocphaly, laqe 0yergrohlh, il5morphi!$ heannq hearldefe.ttdent?e5,develo!menhldeay5,fada an0ma Arenfud malfornrdton, ors,r0ngenrla Rieqer RaUndfacWithfL]LChel5ancipl'5teldtepafefn|r'$labhmL]5,5|]po\'J|V!ar.]0I|it5tenc5i5ando mmtalrtardatendpeBonalty on,l y Kallmansyndrcme2,5phem(ylosr5,mLrtrpeongenrla,rnomaie5,mefiaretard,itron pulmonrr onqenib ocl y, deld]5, ASD.VSD 5teno5i5, behdv abnorma iter [,1i(rcepha dewlopnrental

rype

tt4 l0pl2'pll
llpll2-pl4 llpll 11q24lllqlel 15q11'q1l har) (maU l5qllq1l 15q21 l6plll 1/Q111 1/pll i 20p12 22qll 2 de 22q1l.l et,or Xp21 3 2'p2t xp .) )l Il/t1

9ql4 eeton d D6eoqe I Poro([-5haffer

ldoDsen Pradef-Wii Ar4eman l5q2ldel..tlon Fubin5rein-Taybi sfiith Magerf t{llerDeker Aliqile5yndrome -D syndmme Ve o(ardEfa(id George

(Vl5) ltl r0llldlrr 4 l-lhPardet''I\

pirItum. paotrudea6,m nen(a 1d relalrjat on ar,lp 0g (el(arclnomas,odontoqenrr pdlmopantara ( ficaton cerebr pi$, keratol:y(! fak Ilu ple b,]5a DIlln(facW]lh5/nophry5,lnlevaledndIe5'tentedupperiDprot|LldingtongUe,mrdfatehypopa5id,conolrn.h$(de I featLrres l\/lanyof andvelocardi0facal rhpCiGeorqel r:ap nd,(dn Multiph exo5toses, pareldlforam 05yn0sfo5 dysmorDhi5m, haid enlarged me0c ! fucla N}peinephromdlW|mslUnrol),anrda'ma|eqenti|hyoopa5iaoIvaringdegees,gonadob|a{0rna'onglarP'Upwi|dl ioimed es,menla reiada{on set aun( be,rked no3e,low pcorly 0to!r5, and d lhmmboqlopen and rerardat;oi,ordar qitinonrlie5, a Menia growtt (re5pon5ive hormoI1e),s,na and hypogoiladmentalrcladaiicn atbnh,obesrry,5h0rtitatJre toqrowlh hands feet, Jr'r, Seterehyp0t0nra HypoIonla'fai|ha|I'midb(ehypop|a5d,pm9n.]lh5m,5ezUre5'jeiqa1axitm4emefl'unconI@llab|eb0U]5of|al]ghte'sveretr *aked n05e,rh i upper lip,5mailhands ment]l aIdfe4 reladalron Gmu]lh atadaton, ptori5, 005e lowlynq LIrunr, lhLrmb5 arge mental broad and tlrs, retardalr0n l\,1.forephal)1beaked with 0h problem5, mdrar 5m,myop pa menDlretadat0n behavora Brachxephaly, alhrpopla5d,pralndth d,deh atg$o( ralure, l.,1(|orPph,r|y,i59enGphay,padygyra'nar|oWlofheadhyp0p|anicma|eeX|erna|ge01a9,9lot{hre|ard Bkdu(paucqwf{ho|e5i]55;heande|ec|l'pani0|ar|ypLrmoadIydtteIyJteno5i5;o(ulalabncmaiteloig|0ienbro]fh) onq w mid-nole veltebnei n05e th bmad ru(h bunerlly a5 Hyp1jpa5iaofa9ene5i5oilFethymL]5andNrdthyroidq|a0d5'hypopd5iofaui(eandextema|a]drIy pob behavroci erns 5hoat siaturc, gmwth,ptori5,dysp ls,abnormilea[,poinled a((eehled aft torna chin a,dpvel0pmentilde dy,n0rmaior Hypoion n 1ii retrrdat on,gly(erclkna5ede6oenq Du(henne ardystrophy,ltlpigrnento5a,adrenalhypoFla5ia,menb muscu mef o0,cho0dr0dy5D atapun(ati Kai ta dthyosi5,nin 5yndtorne, leudat retadat on lUcro0hthalrna,Lnedrikindereds,p0rkl0dem,r,i:ooqenihlhedrtdefe(1s,sezureS,menta

lX Genetics 514r' PART r Human

:|l0rtrlrture ymphedemi Lonqenitd Paiela5oct cn d i];e ncrea5ed anqle bcw cryinq phy56) illaielLlrg def0rmiy a ds cfdinacdalep irh0ndrcdysp [ o n q e i : i lpd Jc ( a r o n h 5 r oo r 5 'y'/ de5pread e! n pF 5 h e dh e e t r E e d u n d a n t f* i1,( r u i p r o i y $ iE ] 0 r n d ) u [ hl po5terhar ne Lcw or [oardal0n olao{a Ei(u5pid i {a!e ao'i Lard rordLrrton ar Jbnotru lte5 Fyp()plaqi{hea'i lPir irfdrorel :0radaidt\!leire!ilin ril'l)1pindrlamenorrhea) [0nad0bl{lmal'Yihomo5cFremrieridlpreserl) Lean d r blrrll]s nq mcror y 5k l15l lnonverba caceprud and 5105pd1:al I n 70%] ie!eloprnental I n 10%) Cea)" ioca dL!klvddre55 (a.qu,,.d15 ll]-lr6) iypothyrcd5m f Ii0e2ddbete5 rur{riurnret6lal)ej mel 5trJbriLrj [aia,r( qreen Red rclcioIndness n; ejl la5n Reaurien: m'd,l ctrtl serioxn.rn hParnq oss Inflamm?tory d sei5e bowe (,,8(lireasg?

5M[5tat",re Fa' torhrive ure tpcnthafcidr fuo\i5 nypene ff!m Low a5dlbrdqe n pa DoLlnlad 5lanlinqpebri f5iu.5 r,lppa \ynaqtrr$ -0w-5elaLllaes Denla DrilLl5on md Low rosrerio,i r ha

webbed nc(k Snorr rht5t 5hieli o(ov3ium Ganaium or Prius S(olosi5 vaq$ [ubtus valve PLi ironJfy steio!i ordiomyocahy llypertrophk d Atdlsephelerl(A-iDl of lelriloqy tr lot

(ry!rcrch drr

p Smaleis d Bhednqttrde[,r(irdngttromboqtopeni?

and feef,l) t m r) nc$'horns afcfhcno!\.picallv rrormal illg. lJ1'| 61. Oldcr chilclrerrirnd adults have shorr stacure ancl exhibit vari able d,vsnorphrc ieatures. (irngrnital hcart dcfccts (40%) anrl Thc most 5tructrrrirl renai d.omalies (607.) are coLunolr connon heart defects are bicuspid aorric r,ahcs. coarctation ol t h c a o r t a , l o r r i c s r c r r D s i s )a n d m i t r a l v a l v e p r o L a p s e . T h e g o r r r d s are gererall,\'streaks of librous tissuc (gonadal dysgenesjs). Ihere is primarv aurenorrhea and lack of seconclarv scxual characreris t i c s . T h e s e c h i l d r e n s h o L r i d r e c e r v e r e l l u l a r e n d o c r i n r > 1 o g i cr c s t i n g isee Chapter 587). Patienrs tend rcl be of normal inrelligcnce bur a r e a t i n c r e a s e d r i s k f o r b e h a r . i o r a l p r o b l c m s a n c l c l c l i c i e n c i e si n (iuidclincs for hcrlrh supen'ision spatlal an(l mofor fercelron. slrrdrome arc publishcd br'the AAP ior children u'rfh'lirner

Approximarcly l0% of pdtienfs wirh 4-5,X,/46,XYmosaicism have extemal geniralLa thar are crthcr ar.lbiguots or female.Thc rcmxining 90-9i'rvill have nornaL appearin[jcxternal n1.rle genitalia. I his va.raLlfis esrirnared rcprssentapproxinately 6o, ot b prrticnlswith nrosric TurLrer Somc ofthe patienfswith s_vndromc. 'Iurner sl.ndrome phenor,vpe ancl a Y cell line lvill exhibrr mas culinizatiorr. PhcnocyprcflnaLes rvirh 4.5,X/46,XY irosaicisLr have a 15 .10')1, rlsk of clcvclopine gonadoblastoma. Thc risk lor fhe patients \i'ifh a nele ph.notlpe and exfern.ll testes is lroc so high. but funlor sLrrvcillarccis nevertheless recomrnerldcd The A,A.P h:rs recornmer(Le.l usc of FISH anaLrsis L(x)kfor rhc ft) Y-chromosorre mosaicism in lll 4-5.X patients. Ii Y chromo sornc mntcrirl is idcnriiied. laparoscopic gonadectomy is rccommct)oeo, \oonan syndromc is arr aLrtosorlalclominanr clisorcler due in solne patienfs (609i,) ftr a rnulation in PTPN/, n-hich elcodcs a n o n r e c e p t o r v r o s i n ck i n a s e( S L l l ' - 2 )o n c h r o m o s o r r e1 2 q 2 4 . 1 . irtclr.rcle Features conmon to \oonal s,vndrorne shorf starurelorv posrcrior hxirlirrc, shicld chesr, cougenitaLheart discirsc,arrcle s h o r r o r r v e b b e d e c k I l a b l e 8 l - - 1 0 ) .L l c o n f r r s f f o I u r n e r s y n r . l r r r r c .N , ' , ' r . ' . \ r , d n , n r cr i t c c rb . , r h. r r . ' , r ' d \ . r , . r d i i l ,r r r r . ' paftern of coLrgeniral beart diseascKlittelelter Syndrote. F.ighrl-percenr childrerr $'ith l(hnefeloi ter syndrorrc hevc a m,rlc karyotype n'rrh an exfra ahromosotle X-47,XXY1 thc rcrnainlng209i, have a higher grrdc oi scr chlo mosome ilrlcLrploidr(43,XXXI'18,XXYY; , 49,XXXXY), mosaicisrr l46.XY/.17,XXY1, or srrLrcrlrrall_rabnorrnal X chrcr mosomcs.Thc grcalcr rhc dnetlploidy,the more scvcrerhe sexual and rncntal impairnrcnt arrd dvsnlorphisrn. Indivicluals rvich

Nfrgi,l

, V t J 2 0 0 4 i 1 . 5 1 : 1 2 2 - - . - 1 2 i C o p l r i g h r O 2 0 r ) 4 \ . l a s s r c h r L s c tNs { e d r . :Slo c r e i }A l l r i e l i t s r c s c r i c f j 8 r. r

r Chopter8l I Cytogenolics 515 Klinefelter are male; this syndtome is the most common causeot hypogonadismand infertility in males and the most common sex chromosomeaneuploidy in humans (seeChaprer 584). The rncidenceis approximarely 1 in 575 liveborn males.Errors in paternal nondisjunctionin meiosisI (MI) account for half of the cases. from fibroblasts and is seldorn present in lymphocltes. The abnormalities seen in affecred individuals probably reflect the presence abnormal cells dunng early embryogenesis. of Hypomelanosis lto. This entity is characrerized unilateral ot by or bilateral macular hypopigmented whorls, streaks, and patches (see Chapter 652), Abnormalities of the eyes, musculoskeletal sysrem! and central nervous system may also be present. Patients wirh hypomelanosis of lto have rwo genetically distinct cell linesThe mosaic chromosome anomalies that have been observed involve both aulosomes and sex chromosomes and have been in demonsrrated about 507o of patients.The mosaicismmay not be visible in lymphocyte-derived chromosome studies; it is more lkely ro be found r.yhen chromosomes are analyzed lrom skin fibroblasts. The drstinct cell lines may not ahvays be due to observable chromosomal anomalies but to single gene mutations or other mechanisms. CHBOM0SOME INSTABIIITY SYNDBOMES. Ch.omosome nstabrl iry syndromes, formerly knou'n as chromosome breakage s,vnrrsk of malignancyand dromes, are characterized an increased by specific phenot,vpes.They display autosomal recessiveinhentance and have an rncreasedfrequency of chromosome breakage ard,/or rearrangement, r,r,'hetherspontaneous or induced. Thev result from specific defecrs in DNA reparr, cell cycle control, and apop tosis.The resultingchromosomalinstabilicl'leadsco rhe increased risk of developrngneoplasms,The classicchromosome instability syndromes are Fanconi anemla, ataxia celangiectasra, Nijmegen svndrome, ICF (immunodeliciency, centromere instabrlrty., and facJal anomalies) syndrome, Roberts svndrome, \ferner syndrome, and Bloom syndrome. UNIPARENTAI 0lS0MY Uniparenral drsomy (UPD) occurs when both chromosomes of a pair of chromosomes ilr a person with a normal number of chromosomes have been inherired from only one parent. Uniparental isodisomy means lhat che cwo chromosomes are identical, whereas uniparental heterodisomy means rhat the two chromosomes are different members of a pair. both o[ which were inheriredfrom nne parent.l he phenorypicalresult of UPD varies according to the chromosome involved, rhe parenr who contributed the chromosomes, and whether it is isodrsomy or heterodrsorny, Three types of phenotypic eifecls are seen in UPD: (1) those relared to imprinted genes, thal is, the absence of a gene that is expressed only when inherited from a parent of a specific gender, (2)rhose related to autosomal recessivedisorders, and (3) rhose related to a vestigial aneuploid producing mosaicism(seeChaoter 80). In unipareocal isodisomn boch chromosomes (and thLrs tbe genes)in tbe pair are identical. This is particularly important when the parent is a carrier of an autosomal recessivedisorder. If the offspring of a carrier parent has uniparental disomy rvith isodisomv for a chromosome that carries an abnormal gene, the abnormal gene will be present In rlr.o copies and the phenot}'pe disorderi the chrld has an wrll be rhat of the autosomal recessrve autosomal recessivedisorder even though one parent is a carrier of tha! recessivedisorder. It is esrimated rhat all human beines genes. carrl 5 to 8 abnormal autosomal recessrve The autosomal recessivedisorders sprnal musctrlar atrophy, cystic 6brosis, cartilage-hair hypoplasia, cr- and p-thalassemias, and Bloom syndrome have occurred because of uniparental disomy'. The possibility of uniparenral isodrsomy should also be considered rvhen an individual is affected with more than one recessivedrsorder because the abnormal genes for both disorders could be carried on the same isodrsomic chromosome. Uniparental isodisom-vis a rare cause of recessively inherited disorders. Matemal uniparental disomy involving chromosomes 2, 7, 14, and l5 and paternal uniparental disomy involving cbromosomes 6, 11, 15, and 20 are associated with phenotypic abnorrnaliries ofgrou'th and behavior.UPD maternal 7 is associatedwitha phe-

pr()gnosis for testicular function. Although individuals with Klinefelter do not have a reduced intellect. rle)'show deEcits in language and executive funclions. 47,XYYThe incidence of 47,XYY is approximately I in 800 to sincemosl remainingundiagnosed, 1,000 males,with many cases affected individuals have a normal aDDearanceand normal fer-

Iigence but are at nsk for learning disabilitiesand hyperacrive behavror fBAGltE SITES. Fragile sices are regions of chromosomes that show a tendencyfor separation,breakage,or aftenuation under parricular growth conditions. They appear as a gap in the staining- At least 120 chromosomalloci! many of rhem heritable,have bein idencrfied as fragile sites in the human genome (see Table is 80-1). One fragile site that has clinical significance that on the distal long arm of chromosome Xq27.3 associatedwith tbe fragile X syndrome. Fragile X accounts for 37" of the cases of males wich merrtal retardanon. There is another fragile sitc on the X chromosome (FRAXE on Xq28) that has also been impli cared with mild menral retardacion. The FRA11B (11q23.3) breakpoinrs are associated wirh Jacobsen svndrome- Fragile sires may also play a role in tumorigenesis. The main clinical manifestations of fragile X syndrome rn affecred males are mental retardation, autistic behavjor, macroorchidism, large size, and characterisdc facial fearures.The macroorchidismmay not be evident until pubertp The facial fea tures, which include a long face and prominent jau', become more obvious with age. Females affected wich tragrle X shorv varying Diagdegreesof menral retardatron and/or learning disabiliciesand oosisof fragileX is possibleby irs molecular characterizarion wirh an expanded DNA by the observationthat rr is associated segment. The expansion involves an area of the gene thar conrains a variable number of trinucleocide(CGG) repeats. an MOSAICISM, N{osaicismdescribes individual wrth 2 or more different cell lines derived from a single zygote and is usuaLlythe result of miroric nondrsjunction(seeFig 81-2). Scudyof placen tal tissue from chorionic villus samples collected at or before the 10rh wk of gestationhas shown rhat 27o or more of all conceptrons are mosaic for a chromosome abnormalitt-. !(/ith the excep tion of chromosomes 13, 13, and 21, compJete aurosomal of trisomiesare usually nonvrable;the presence a normal cell line

mosaicism may be present in some trssues early embryogenesis, but not in orhers. Germline mosaicism,which refersto lhe Presence of mosaicism rn the Eerm cells of the gonad, is associated with an increased risk for recurrence of an affected child. PallisteFKillianSyndrome,This disorder rs characrerizedby coarse facies, pigmentar,v skin anomahes, localrzed alopecia, diaphragmatic hernias, cardiovascular anomalies, supernumerary nipples, and profound mental retardatjon. The svndrome is due to mosaicism for isochromosome 12p. The presence of the isochromosome 12p in cells gives four copies of 12 in the affected ceils. The isochromosome 12p is preferentially r.rltured

516 r PAnT

t Human Gontics

J--- +-.'Figure 81-17. In pediBrees suggesrive parernal impnnnng, phenorypic effects occur only when the gene is transmitred from the mother but not when transof nnred frorn the facher.Equat numbers oI matesand femalesare affectedand not affected phenotypically in each generation.A non manifesringtransmitrer gives geneticinformation; in other words, in paternal imprinrinB, lhere are "skipped" non manilesting females. a ctue co rhe sex of the parent 11hopasses expressed the

notype similar to Russell-Silversyldrome with intrauterine growch resrriccion. Thesephenotypic effectsmay be related to imprinting (seeImprinting, below). of UPD for chromosome15 is seenin somecases Prader-!7illi syndromeand Angelman syndrome.In Prader-Willi syndrome, have maternal UPD (missingche paternal abow 60o/" of cases 15). In about 5% of individualswith Angelmansynchromosome (missing 15 the drome,paternalUPD of chromosome is observed 15). The phenotypefor both Prader-!(illi maternalchromosome syndromeand Angelmansyndromein cases UPD is thought of to be due to the lack of the functional contribution from a oarticular parentol rheir chromosome Thesefindings 15. suggesr in thereare differences function of certainreeionsofchromosome 15.depending wherher is inherited on rt froir rhemotheror from tbe father, Uniparentaldisomymost likely ariseswhen a pregnancy starts off as a trisomy.Most trisomiesare lethal, and rhe fetus suryives to only if a cell hne losesone of the extra chromosomes become disomic.Onethird of chetime, the disomiccell line is uniparental. Usually the viable cell line outgrowsthe trisorniccell line. When mosaic trisomy ls foufld at prenatal diagnosis,care should be taken to determine whether uniparentaldisomy has resultedand involvedis one of the disomiesknown whether the chromosome to be associatedwith phenotypic abnormalities.There must ahvaysbe concernthat someresidualcellsrhat ar trisomic will leadingto malformatiols or dysfuncbe presenrin sometissues, of tion, The presence aggregares trisomiccellsmay accountfor of the sDectrum abnormalities of seenin individualswith UPD,

IMPBINflNG. Genomic imprinting occurs when the phenotypic on expression depends the parentof origin for certaingenes and Whetherthe genetic chromosome segments. materialis expressed depends the genderof the parent from whom rt was derived. on (Figs. Genomicimprinting is suspected the basisof a pedigree on 8L-1.7and 81-18) with unusualtransmission. Imprinting probably occursin many different parts of the human genomebut is related thought to be particularly important in geneexpression to development, Browth, cance.,and behavior. Imprinting in humansrs noted by phenotypicdifferences seen rn Prader-Williand Angelmansyndromes, which are assocratd with deletionand uniparentaldisomyof the sameregionof chromosome15. Thus, in uniparentalmaternaldisoml chereis also lack of rhe parernal segme[t of chromosome15, resulting in Prader-Willi syndrome as well, In Prader-Vill syndrome,the deletion,when it occurs,is alwaysof the paternallyderivedchromosome15, suggesting that the phenotypeof Prader-\(illi is due to a lack of paternallyderivedgeneticinformationcarriedon that segment chromosome15. In contrast,when there is a deleted of chromosome in Angelmansyndrome, deleted 15 the chromosome is alwaysmaternalrn origin, and the IJPD is alwayspaternal,that is, there is lack of maternal information. There are likely to be many other disorderswith this type of parent of origin effect. ABN0RMAUTIES. ACOUIRED CYTOGENETIC Acquired(clonal)cytogeaeticchanges can be found in most tumor cells.Chromosome analysis an important tool for the classilication many hemais of Most leukemias rologicdisorders. displaynumericalchromosome

--l---.''-.' -+--r--.,
Figurc 81 18. lD pedigreessuggestive maternal imprinting, phenotypic effects occur only uhen the gene is transmrtted from the facher but not when trans' of mitced from rhe morher Equal numbers of males and fernalesare affecred and not affected phenowpically in each gener3tion. A non-manifesting rransmifter grvesa cJueco the sex of the parent *ho passes genetic informacionj in orher words, in mateinal imprindng, rhere a.e "skipped" non rnanifesring the expressed

Chapter12 r Genetics ol Common0isorders: 0iagnosis and Management r 517

(mairrly trans]ocations), abnormalities, structural rearaanSemenrs or borh (see Chaprer 495). Many of rhe chromosomal abnormalities are nonrandom and have been shou'n to be useful in diagnosing rhe leukemia subtype afld predicting treatmenr outcome, This has been especrally true in the case of acute lymphoblastic leukemia (ALL). PREI{ATAL DIAGN0SIS.Prenaral diagnosis is indrcated q'hen there rs a familial, marernal, or fetal condition that represents an rncreased rrsk for malformation, chromosome abnormalitn or genetic disorder. Advanced maternal age (235), whrch is associated with an increased risk for aneuploidies, rs che most common reason for prenatal diagnosis. Chromosome analysis and genetic counseling are also warranted in the event of (1) an abnormal screening result; (2) a chromosome abnormality in a previous offspring, parent, or close relatrve; (3) a previous offspring with multiple congenital anomalies on whom no chromosome study was obrained; i4) the need for fetal sex determjnation in pregnancies ar risk for serious X-linked disorders for which speciflc prenatal diagnostic tests are nor available (see Chapter 83). Prenatal diagnosis usrng cell or rissue samples for chromosomay be performed mal, biochemical, or molecular genetic str.rdies using a number of technrques, incl:ding transabdomin amniompling, centesis, chorionic villus sampling {CVS), fetal blood and preimplantation genetic dia8nosis (PGD). In addirion, fetal cells and free fetal DNA have been detecred in the mother's circularron and can aid rn the prenatal diagnosis of fetal condirions (seeChaprer 96).
Alfirevic Z, Neitson JP: Antenatal screening for Down\ svndrome BM"/ 2004;329:811 812. Anronarakis SE, Lyte R, De.mnzakis ET, et al: Chronosorne 21 and Dorvn syndrome, From genomics to parhophysiolog-v. Ndt Rev Cenet 2004;5:725-738. BandyopadhvayR, Heller A, Knox DuBois C, el at: Parentalorigin and timinB of de novo Robertsonian rranslocarion formation. Am I Hun Ceflel 2002;71:7456 1452. Beiiani BA, Srleki R, Ballit BC, er at: Use of targeredarray-basedCGH lor the ctinical diagnoslsofchromosornal imbatance:k lessmorcl Am I Med Genet 2 A 0 5 : r 3 4 A : 2 5 92 6 7 Bondv CA, Van PL, Bakalov VK, et al: Prolongation of checardiac QTc interval in Tu.ner svndrome. Medicine 2006,8s:7S-81. deteclion of Down's svndrome Caine .c..Lfaftbv AE, Parkin CA, et al: PrenataL by rapid aneuploirly resrins lbf chronosones 13, 18, and 21 by FISH or PCR without a full karyotype: A cyrogenetic .rsk assessmenr La,.ef 20O5;366:'t23-128. Carrel AL, Moerchen V Myers SE, er al: Grolr'rh hormone improves mobiliry and body composirion in infan$ and coddterswirh Praderwilli syn&ome. I Pediat 2004:145:744-149 Cicero S, Bindra R, Rembouskos G, et al: Inregrated ulrrasound and bio' absenr chemical screeningfor trisomy 21 using feral nuchal rranstucency, fetal nasal bone, {ree 0 hCG and PAPP-A at 11 co 14 weeks Pleut Diagn 2003i23:306-310. marker chromosomes CrolJa JA, Youings SA, Ennis S, et aLrSLrpernumerary in man: Parenralorigin, mosaicism and maternal aee rcvtsied. Eur I Hum C enet 2OO ;l 3 :7S4-l 60. 5 CuDnrff Cr American Acadmv of PdialricsCornmitreeon Genetics;Prenaral screeningand diagnosisfor pediarricians.Petlahics 2004\114:889-894 De Vries BBA, LeesM, Knisht SJ,et rl: Clinical studiesof submicroscopicsub telomeric rearrangenents:A checklist./ Med Gezar 2001;j8:145-150 Douglas SD: Down svndrome:Immunologic and pidemiologjcass,xiarionsEnismas renaln../ Ped,.rtt 2005;r47:723-725 . Dyken ME, Lin'Drken DC, Poulron S, et al: Prospectivepolysomnographic analysiso{ obstructivesleepapnearn Down syndrome.Arch Pediztr Adolesc Med 2003 t1. :655-460. 57 Garrison MNl, Jeffr;es H, Christakis DA: Risk of death for children with Down syndrome and sepsis. Pediatr 2005;147:748-752. J Gibson PA, Newron RW, Selby K, et al, L:ngitudinal srudy of rhyroid func rion in Down\ svndrome in rhe first rwo decades. Arch Dis C,h d 2005r90:574-578. cicquel C, RossignolS, Cabrot S, et al: Epimutarion of the telomeric imprinr ing center rgion on chromosome 1lplJ in Silver Russll syndrome. Nat C efl et 2O05 ;J7 :100 3-7oo7

Heffner LJ: Advanced marernal age How old is roo old? N Eflsl -l Med 2004t3 5l:1927 -1929 . JcquemontS, Hagerman RJ, Hrgerman PJ, LeeheyMA: Fragile X syndrorne and fragile X associated rrernor/araxia syndrome: rwo faces oI FNIRI Ldaret Neurol 2007:'6:45^5 5. KLeefsrra Yntema HG, Nillesen \(/M, et al: MECP2 analysis rn menrally T, .etarded patients: Implicarions for routine DNA dta9nos.j'cs. Eur J Hun Genet 2004112124-28 . Lanfranco 4 KamischkeA, Zirzmann M, ec al: Klinefeiter'ssvndrome. ldficst 2004.,364..273-283. lvlalone FD, Canick JA, Ball RH, et al: Firsr trimester or second-rrimester screening, or both, for Down's syndrome. N Ensl J Md 200.5i353: 2001-2010 Massa C, Verlinde \ De Schepper er a| Trends in age at diagnosisoI Turner J, syndrome. Arci D,s CDild 2005;90)67-268. Mazzan.i L, Cicognani A, Baldazzi L, er al: Gonadoblascomain Turner syndrome and Ychromosome derived marerial. Az I Med Genet 2005t135A: 150-1i4 NeiLson JP: OptiDlsrng prenatal diagrosis of Doon's syndrome. BM/ 2005;332:433-434. Rappold GA, ShanskeA, SaengerP: All sbook up by SHOX deficiency..f Pedia* 2005 ;147 :422424. Rio M, Molinari I Heuertz S, et al: AucomaredIluorescentgenotyping decects 10% of crypric snbretomericrearrangemenrs idiopathic s,vndromic in mental relldarion. I Med Cenet 2002:39:166-270. Robin NH, ShprinrzenRJ: Defining the ctinical spec(um of delerjon 22q11.2. J Pediatl 20Q5 t147 :90-9 6. Roizen NJ, PatrersonD, Downt syndrorne Laftcet 2003\36111281-1288 Schubbert S, Zenker M, Rowe SL, er al: Cermline kR,4S mutarions cause Noonan svndromeNar Cert 2006:38:331-336. . Schwartz S, Graf MD: Microdelerion svndroms:Characteristicsand diagnosls. Methods Mol Biol 2002;704127 5-290. S,vberrVP, Mccaulet E: Turner\ syndrorne. N Engl J Med 2004;3511 1227-7238. Tarraglia M, PennacchioLA, Zhao C, r at: Crin-of-tunL-tionSOSI mL,rations causea distinctive aorm oiNoonan syndrorne.Nat Genetics2007,39:75-79. VissersLELM, van RavenswaaiiCMA, Admiraat R, et al, N.lutationsin a new rnember of the chromodomajn een ramily causeCTLA.RGE slDdrome. l{!?r C e n e tZ 0 D 4 : j 6 15 5 - 95 7. 9 Watter S, Sandig K, Hinkel CK, er al: SubtelomereFISH in 50 children 1tirh mental retardarion and minor anomalies,idenrified by a checklist, selecrs 10 rearrangements including a de novo balancedtrandocation ofchromosomes 1 7 p 1 3 . 3a n d 2 0 q 1 3 . 3 3 .A n I M e d G e n e t2 0 0 4 1 1 2 8 4 : 3 6 4 - 3 7 3 . Vhpner R, Thom E, SimpsonJL, er al: Fi.st-trimester screeningfor rrisomies 21 and 18. N Ersl.J Med 20033411405-1412. V'arburron D, Dallaire L, ThangaveLu e! al: Trisomy recurrenc:A recon' M, sideration based on Norrh American d^a. Am t Hhm Cenet 2004:75:376-385. Yagi H, I'urutani ! Hamada H, et al: Role of TBX1 in human de122q11.2 syn&ome. Lan.zt Z[0i;362:l jri6-1 37j Youings S, Etlis K, Ennis S, er a| A srudy oI reciprocal rranslocarionsand invrsionsderectedby lighr microscopy wirh specralreference origin, segro regation! ard rcurrenr abnotmaltties.Am J Med Genet 2O04i126A146-60. Zenker M, Gemor BDheitelG, Rauch R, et al, Genor.vpe-phenotvpe correlations in Noonan sy\dror^e. I Pediatr 2004:14+368-374.

Geneticstudiesare useful in diagnosingand trearingrare pediatric conditions,ofren alleviaringsuffering,e)rTending and in life, the caseof neonatalmetabolicscrening, preventing injury before symptomsdevelop,Ceneticstudiesmay also rdentify the causes of more common diseases An suchasasthmaafid obesiry, understanding of the complex and potentially multiple pathways leading to disease crucial ro rhe development appropriate rs of prevenlion strategies{including screeningof presymptomatic parents),as well as effectrve and specificrherapies.

518. PART r Humon lX Gonotics are Common pediarric diseases often multifacrorial, with the combinationof many genes and eflvironmental factorstriggering of Each indivrdual a complex sequence eventsleadingto disease. has variations in his or her set of genes; the interactionsof the individual'sgenevariantswith eachother and with the environment determinesusceptibilrty disease. ro The complexiry in the combinationoI facrorsincreases challenge iinding generic the of variants that causedisease. Genetictools include the completed public databases genericvariants, human genomesequence, of and the human haplotypemap. The incorporationoI thesetools populatronstudiesis the field of genetic into large well-designed epidemiology. compoflents a[alysis,atld the amountof variability of a rrait that is due to inherited factors is termed the heritabilitv of a trait. wirh genes Chromosomal regions that may conrribuie disease ro susceptibility be locatedwith lintage mapping,which locates can regionso{ DNA that are inherited in families with the specific disease. Genedcassociation studies seekto determine relativerisk of disease individr:alswith specific in geneticvariants.Derection of the modesteffect of each variaff and inreractions with environmentalfactors reouireswell-ooweredstudies. Both linkagemapping and association studies requiremarkers along the DNA rhat can be ascertained, genotyped, or with largescalelaboratory techniques. Markers that are typically used are in the form of microsatellitesand single-nucleotide polymorphisms (SNPs) [Fig. 82'3]. rVhile humans all have the same geneticmaterial, every person'sgenomels shghtly different. A comparisonof any two copiesof the sameregion of genome will reveal that about one in every 1,200 baseswill be different, usually in the form of a SNP Most SNPsidentifiedby comparirtg two chromosomes common and are essentially equivare the alencof geneticdialect,or random differences coding with no in significance functional consequence, few of thesepolvmoror A phismswill alter the biologicfunction of a gene,either by affecting the structure of the protein or by altering rhe location, amoun!.or time at which the oroteinis made.Someof these functional alterationsmay affect iusceptibllty !o disease. Outcomesin geneticstudies clinical phenoqpesand can be are a clinical diagnosis a disease a discrete of or measurement traiL or relatedto disease. phenotypecan be measured the presence A by or absence a disease a quahtativetrait, or by usinga marker as of of disease, such as pulmonary function testsin asrhmaor body mass index in obesiry as a quantitativetrait. A homogeneous phenorype ideal to avoid conflictingresultsfrom rhe scudyof is a trait that has tt'o or more etiologies.Genetic heterogeneity refersto a trait resultingIrom more than one genetic mechanism. The develooment a trait or disease of from a differenc mechamsm resultsin iphenocopy, the occurrence which would dininish of gene,A pafticular genevariant the detectibilityof the responsible may not causethe sameoutcome,and rhis pleiotropic effect of eachvariant depends other geoeticeffectsand environmental on exposures.

82.1 . MAJOR GEI{ETIG APPROACHES SIUDY TOTHE OF COMMON PEDIATRIG DISORDERS

A model for the genetic conuibution to health is shown in Figure 82-1. Genetic liability is present from conceprion in all persons. Sometimes this liability rs predominant and results in a srnglegene disorder such as cystic librosis or sickle cell anemia, In most the liability is latent at binh but over time contributes to the emergenceof specific medical conditions, particularly upon exposure to envrronmental factors. The goal in medical genecicsis to identify the generic factors in che hope of preventing the occurrence of disease,erther by avoiding inciting environmental factors or by instrturing trearmenrs that reduce risk. For individuals who cross the threshold of disease,the goal is to better understand the parhogenesis in rhe hope that this will suggest better approaches to rrearmenr. A srarting pornt in the genetic analysis of a complex trait is to obtain evidence in support of a generic contriburion and co estimare the relacive strengrh of genetic and environmental factors (Fig. 82-2), This rs done by determining u'hether a trait clusters in famrlies and is seen amons related individuals more often chan in the general population. Possible inheritance models are delineated by such segregation analyses, The relative strength of genetic and nongenetic risk factors can be estimated by variance

t.iguIe82-l.Modelfortheinfluenceofgenetrcsonhealth.Everyoneinherirssomegeneticliability{ordiseasrisk,buriornuttrfactorialdisordersthistslnsfficienr ro produce diseaseon its own. Over time, exposure !o environmencalfacrors leads from a presymptomatic co a diseasestate. Identificatron of rhe genes responsiblefor risk can lead to orevenrionstrateeres treatments. or

r Chalter82 r Genetics Common of Disorders 519 GeneticEnvironmental [4easurement variance variance variance v P : v A + v D + v E + v t + c o v c E+ v M genetic ance va VA=Additive VD Devialion to domindnce epistasis due and VE=Environmental variance V :lnteraction variance CoVcE:Covarianceot genelicsand environmeni Relationship i,lonozygotic twins Sib-sibor Dizygotictwins One parenFOne offspring l\,'! parenF Otfspring id Firsl cousins Uncle-Nephew h2:2r h2:2r h2= 10 5=to.7o71 h2=8r h2:41 Hedtability

l i i g u , c S 2 L H e r i t i b i l i r y c r ) n c e p tl h e n o q v p i c a r i a n c e a n b e p a r t r v c ttuned into gererrc uararce, ervrronmentalvariance, rhe covanance benveel rhe tlvo. and measurementvariance. Generic variarce can Lre Iurrher partitnrncd inro addirrveatfectsand gene gere interactrons ( e p j s t a s i s ein v i r o n m e n t av a n a n c ec a n l i k e r v t s e e p a n t r i o n e di n r o t b l addnive atrd inreracriveeffecrs.HerLtabilitv is defined as the propor tion of phcnotlplc veri:rn.e dc.ounred ior by genenc variance. One caD esrimate hentabilirv in the ndrfow senselron corrclation of .t quanrirarive r.ait betrveenrelatives,as sho*'n in the table

There are many factors that may colnplicate scgrellarion and that are found to crack in famheritability srudres. Many disedses ilies rna,vappear to skip a generation; a person could inherit an allele (inherired unir, DNA segorent,or chromosome) and not show any sign of the disease, phenomenon called incomplere a penetraflce. manifesr signs only larer in life, u'hile Some dLseases orhers become lessobvious as rhe child grows olderi study par as ticipanrs could be misclassi6ed unaffectedvgho actuallv have gc \ t h e d i s e . r s e - l r ' r d u c r n g n e . M a r r v L " m n r u r rd r s e a s e m d t r l t e \ t il with varying severit,v families,and this variable expressivityis of another factor that could causemisclassification People. associaTb maximjze rhe ability ro derecra gene wirh disease tron, environmelral exposures need ro be measured and and accoulted for in a populatlon. The interactionberweengenes

the environment is called cpjstasis.Epistaciceflects could affect the expressivityof a rrait as well as rhe penetrance. erample An of this is G6PD deficiency. An individual could carry the alrered gene aod be deficient in lhe enzyme. 1er would never have a hemolyriccrisis unless exposedto an oxidative stress. Peoplelvith inherited propensity for malignant melanoma lr.ho live in darker geographicregionsor limir their sun exposuremay neeer cxpress people may the phenoc,vpe cance. Asthma in some susceptible of develop only afler exposureto cerlaln antigensor pollucants. LinkageMapping. Linkage studies rvere used in the pasr to isolaregenes that causerare geneticsvndromes; modrfiedmerhods have been used to identi$ chromosomal regions linked to more common diseases. Lrnkage srudiesinvolve taggrngsegments a o{ person's genome with markers thar allow identilication of seg-

Whal is an SNP? Differentpeoplecan have a ditferenlnucleotideor base al a given locationon a chromosome What is an SNP map?
Figu.c 81.-:i. Ditfercrt combinarions oa single nucleoljde polymorphisrns {SNPs) are found in different indn'iduals. The locations oi rheseSNlrs crn be pinpointed on Drps oI h u m a ng c n e sS u b s e q u e r r t l ) ,e vc a n b e u s e dr o c r e e t tp r o . th files that are assocjrred rvrrh difference Lrrresponsckr i drug, such as eificacv and nonei6cac-v.lAdapted rt{,m RosesA l'hafmacogenericsand the prd.hce ot rnedrcrneNdt'/zd 2000;40J 857-865 Copvrishr 2000 Rcprinred b1 permission for Llacmillan Publ,shersLrd )

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profjle oction SNPgqnoype of

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Predictive no etficacy of

T|_ImTIlm-

520 I PART r Hurnan lX Genelics menls that bave been inherited through the famrly along wrth disease, The markers are typically microsatellites or SNPs that define u'hich tvpe of an allele any person carries. The type of an allele is referred ro as a genotype. Linkage anal,vses common of diseaseshave shorvn inconsistent results. Facrors sucl as heterogenerty, plerotropy, variable expressivitl'. and reduced penetrance in additron ro varrabiliry in envrronmencal exposures \l,eaken the porver of linkage studies in complex craits. Genetic Association. For multifactorial common diseases, asso ciation analyses mav be better suited to detect small effects than linkase studies. Genetic assocratron srudies are simrlar ro rraditronal disease association studies,with a person'sgenoc,vpe being used as a predictor of a disease or trait. The goal is to identifv the actual alleles at a locus that confer the risk for a disease.Three basic designsare used: (1) a case-coltro] design,with a compar ison of che frequency of an allele in affected people compared with unaffecced people, (2) a population based studl', in u'hich a n i n c r e a \ e n J q u a n l r l a l r v er a r t o r c o n t i n u o u s e a \ u r e m e nit\ i l m correlated with genotype, and (3) a family-based test, in which cransmissionof alleles to affecred and unaffected offspring is cested. Thjs lasc rype of anah'sis,known as a transmissiondisequilibrium rest (TDT), looks for an allele that is cransmicted to an affected person more often than rhe other allele. lf there is nc> assocrarron between an allele and disease,che transmrssionof each allele should be equaL, with each having a 50/50 ratio. If an allele confers risk of disease, the rransmission rario rvill be drsrorted, u.irh one allele showing higher transmissron ro affeced analvsrs chrldren,The success all 3 types of associatxrn of depends on the desiEnof a well-poweredstudn wrrh enough sub;ects, and atr accurately measured trait ro avord misclassificatron due to variable expressivit,v reducedpenetranceand ro minimize the or effect of genecic heterogeneitv and pJeiotropl.. In large population-based studies, confounding bv erhniciry or population strarificarion could distort results. Some senenc varlanrs are more lrequentlr round rn people lrom a p.rrricularethnic group. rvhich could cause an apparent associationof a r.arianrwrth a disease, when the disease rate happens ro bc higher in that group. This association would not be a true associalion betrveen ao allele and a djsease, as the association *'ould be confounded bv ethnicitl', rl,'hich is oftel re(erred to as population strarification. The famil,vbased cestsusing the TDT are immune co population stratifica tiofl because the associationis rot wich a soecificallele.but rvith o a d i s r o r r i o n l r r a n \ m i \ \ i o n i n a t f e . t e dp e o p l eu i r h i n a t . r m i l 1 . Assocrarion srudies should be a powerful rool to find genecic variation that confers risk ro an rndividualt rhe effecrof any one genetic varianr rvill be a verv small conrrlburion ro the complex diseasepathrvay. Genetic variants have been found that implicate inro a novel genein a process,modvating more in-depth research svstems that &'ill affecr diseaseoutcome. Associations such as the ApoE4 variant with an increased risk of Alzheimer drseaseare nored by many srudies.Many published associationresults are not reproducible; insuflicient pow'er and stratl6cation may account for rhe inconsistencies. Genetic discovery is also possible by focusrng on specrfic candidate alleles. There are 5 10 million SNPs across the genome, far more chan can be cested any single associarion in study'. Candidare SNPs are identrfledfrom genesthat are suspected conto tribute to risk, perhaps because of a known phvsiologic or biochemical role in che disorder A major limitarion is that unexpected genetic contributions will be missed, leading to failure to take advancage of the potencial power of rhe generic associalion approach to uncover ner!'disease mechanisms.Sequencingof each rndividual's genome u.ould detect all variants but is rmpractical and expensive. However, by using known patterns in the genome, lhe rnajoflty of vaflants can be assessedfor each indi vidual rapidly. SNPs are arranged in the genome on blocks of 10,000 base pairs or more that have nor been interrupted by recombinatron through generations; the SNPs in a block iorm an inherited unit called a haplotvpe. The HapMap proiect has delined these blocks in four populations around the world, providing measurements of the relationship betrveen SNPs in the blocks. This allows for rhe selectionof SNPs that are proxies or "tags" for a haplotype block. Genotyprng chis smaller subset of SNPs captures most of the common variarion in a regon with far fe*er genotypes. Current estimares show that 500,000 SNPs are sufficient to represent about 907n of variation in the human senome. The H a p M a p i s a r a r l a b l e : a p u b l i t J a r a b a ' e .a . ; l u a b l e r e s . r u r c e a for the design of association sudies that can be tailored to spe crnc Popularrons.

. UrrrorRsrnnorruc 82.2 CURRENT oFGENErrcs 0F

IN COMMON DIsoROrRsCHITDREN
The impacr of generic scudies of common pediarric disease is being reahzed. Prevention and incervention may soon be possible using valid genecic association resultsto identif,vchildren at risk. Three examplesof diseases under intensescrutiny for geneticrisk factors are tvpe I dlabetes mellitus, asthma, and obesit,v.

TYPE DIABETES 1 MELTITUS

Type I diaberesmellirus (T1DM) is the best characterized the of (sceChapter 590). It poJygenic, multifactorial pediatric illnesses is a common diseasewith a well-defined phenotype and evidence of environmental and genetic components. Linkage studies in families rvith an affectedchild yield many loci thac appear to be risk for Tl DN{. A |:ewgenevari consistentlylinked to rncreased ants have been found rhat confer risk for disease,and some envi ronnental factors have been idencilied includrne vrral infections rriggering rhe autoimmune process. While rheie are rare 'vn dromic forms, such as Wolfram syndrome, resulting liom knorm monogenicmutations,most children diagnosed rvith T IDN{ bave a currently unidentrfied etiology. Heritability estimates for T1Dtr'l are cstimated bet\r'een 66910 and 72o/., u.irh trvin concordance of 307. to 50%. Although these studies ma,v be confounded by shared environmenr, it is evident that, at least in part, there is an inhericed component tcr T1D1!{ risk. The relative risk to a child in che general populatir;n is 0.47", whereas{or the sibling of a child with drabetes rs 15 ir trmes higher ar 67". The Type 1 Diabetes Consortrurn (wtuw.tldgc.org) has undertaken a meta-anal,vsrsof all of the linkage dara. They have also devised a uniform nomenclature s1'stern,such that promising linkage regions have been assigned numbers, designatedIDDN{ 1-18. lt'{any early scudiesdetecced linkage at the MHC locus on chromosome 6p21 u.ithin the HLA gene region. A meta-analvsis these linkage studies shoned a of very srrong [nkage signal wirh a LOD score of 65 at this locus! nhich has been designated IDDM1, '$(rhrle rhe HLA-{DDM1 locus has been studied extensiveJn it presents many chalJengesin dececting causal genetic alteratrons. Many of the genes in the region have sjmilar functions and acr in coflcett in tbe Th2 immune system, The region also has high linkage disequilibrium (LD); many of the proposed risk alleles are inherited together, making it difficult ro isolate a srgnal from anv one as being drrectl,v responsible for the rncreased risk. Thircv percent of children diagnosed with TlDNI have rhe combrnacion of ailelesac rhis locus that code for HLA-DQ2/DQ8 (genocype). Cornbinatrons of alleles (haplorypes) at two loci in the HLA region are risk alleles;none of these has pinpointed discincrive causal varlants. The IDDM2 locus encompasses insulin 11NS/gene.Asso the ciation studies idennfied varianrs rn this sene thar conferred rrsk for TID\|. A rrpeat regionrknotrn a' r VNTR. or variable number tandem repeat) near the INS gene has been associated

Di$o.deF . 521 Chapter r Genelics Comnon 82 of with diabetes risk, with a longer repeat correlated with increased risk for T1DM. The mechanism of gene dysfunccion due to the repeat is unknown, an it rs very likell, that rt is in LD with arother \.ariant thar do alter funcoon or inreraccion to predispose an individual to diabetes. A varianr of the CTLA4 gete is found in the coding region of this gene, suggestingthat a firnctional change in the protein could cause suscepribility. Additional studies found a variant in rhe 3' untransLated region in LD with the coding SNP ro be an even better predictor of risk. Thrs SNP was in che promoter region of a the gene,whjch could also suggest functional role in ttanscrip tion regulation. The mechanism by which alterations in this gene increases susceptibiliry ro TIDM reguires a thorough search for regulatory genes that may interact with rhe promoter region. inflammation. It mav resuft from dysregulation of the Th2 inflammacory cells with hrgher serum levels of IgE. Children with two parents affected with asthma have a 507o increased risk of atopy. The odds of asthma dragnosisin children aged 3 to 6 yr increase by 2-fold in children u'ith two rather than one affecred parent. Twin studies rn S$,eden and Finland bave found asthma heri tability esrimates of 80%, ',r.ith much hrgher concordance in monozygocic twins than in drzygotic rwins. Children of asthmaric mothers have a higher risk than those wirh aschmatic fathers, suggesting the possibilit_vof in ureto mechanisms nfluencing risk of deveJoping disease. In utero exposure to tobacco and maternal aslhma are associared with jncreased IgE leveLs in infants and a higher rate of asthma. Early pulmonary infectrons wrth respiratory synrytial virr.:s (RSV), rhinovrus, and Chlamydia pneumonia have also been implicated in rhe developmenr of asthma. Associations have been demonstrated wrth enviionmental exoosures such as endot o r i n , . o c k r o a c ha n d d u s r m r t ea n r r g e n s .n d d i e t e lp a r r i c l e s I. h e a lack of exposure to a differenr set of pathogens has been shown to inctease immune deregularion and asthma, as proposed in rhe hygiene hypothesis. Exposure to parasites in early childhood has beeo correlated with prorection against asthma and atop,v. Asthma has quantifiable markers such as pulmonary function cests,Linkaee studies of asthma and its markers have demonsrrated somi overlap of DNA regronson chromosomes5q, 6p, 12q, and 13q. Linkage ro 20p13 has motivated association studiesin the geneADAM3.3 la member of the a disintegrin and metalloprotease domain farnily); this finding has not been reprolsE ducible. lncerleukins4 and 13 are associated with rncreased levels.r,rhrlelL-4 and l0 are assocrared with airway rersranie as measured bv FEV,. Increased TNFo levels in bronchral secretions led ro a str-rdyof polymorphisms in that gene wrth levels and asthma severitv. ln childhood asthma rhere is great variability in response to medications.Large cohorc srudiesin children (such as the Childhood Asrhma Managemenr Program and che Tucson Children's RespiraroryStudy) have provided evidenceof subgroupsof chrl dren with asthma that drffer in the natural historv of the disease as w.ell as in drurg response. Cbildren vary greatlv in response to leukotriene inhrbrtors and corticosteroids, another hetero!!eneous aspect of rhe asrhma phenotype. Varratron in the []j-receptor has been shou'n to influence response ro $ agonist therapy with one particular genotype in rhe receptor causing reslstance to the stabi[zrng and dilating effecc of the drug. SUMMABY It is clear that there is much yet to be discorcred about the common drseases affectingmosr children. Successful therapies and prevention strategies will depend on the dissection of complex pathways in whrch many small changesand environmenlal interaction\ can acl rn urder for a per*on fo enc(,untera threshold for drsease development. Gene therapy techniques could be applied as treatmen! focused on modif,ving rhe actual genetjc risk facro! bur will reqr.rireidentilication of specilic targets in diseasepathwal's. Efforrs rn the past to supply a gene to take the place of a mulated gene had some success, but were limrred bv hrrst re;ection of the vectors. New discoveries promise more precrse modulation of gene products using techniques such as RNAi (RNA interference) with synrhetic RNA molecules targerted for specific genes. The new tools availableto researchers have allowed detection of a number of novel genes and pathways for common diseases, and the adveot of whole genome association studies promises an acceleration theseresults.Interactionsbetw.een veri6able risk of allelesand environmentalfactors as uell as epistaricinteracrions wiii be increasingly possible. Whole genome association studres will provide vast amounts of data, requiring new anal,vtrc cools to dissect the true effects and inreractrons, Whole senome assoc i a r i o nr e \ f i n gp r o m i s e s o h i g h l i g h tm a n y g e n e l i c a r i a n r \ l h a t , t i in relation to each other and environmental factors wrll elucidate

OBESITY
Childhood obesity in rhe UntcedStatesis increasingat an alarmwith ing rate (seeChapter 44). Obesity is a multifactorial disease, man-v of che conrributing factors still unknolr'n. Ic is likelv a het many dif erogeneous phenorl.pe resulting from dysfunction a modern ferent parhways. Concributing factors ma,v inclu environment of plentiful calories and low phvsical activitn whrch combined rvirh inherited risk genes results in obesiry Prevrousll., childhood obesity was rare enough that a severel)' obese child warranted consideration of rare syndromes such as POMC (proopiomelanocortin) deficiency, Prader-rJ0illis,vndrome, rhat and Bardet-Biedl syndrome. A few studies have suggested trait childhood obesrtyis due to rare geles lhat act as a recessive and can explain a larger fraction of tAe variation in body mass. Melanocortin 4 receptor (MC4R) rs an example of a gene wrth murations that are found in 3% of children with severe recessive early-onset obesity. Polymorphisms in MC4R have not been found to be associatedwith more common polvgentc obesity observedin the generalpopularion. Common forms of obesiqv show a complex pattern of family segregation. Family srudtes and twin studies yreld estimaces of heritabrlrty ranging from 3Oo/"to 70y", $.ith the t,vpical estimate at 5070, meanjng that about half of the variation in body mass within a pooularion is due to inherited factorsBody mais index (BMl) is a phenotype obtained in many cohort collecnons. Whole genome linkage studies have shown evidenceoi linkage regionson every chromosomeibur a number of regronshave beendeteced in severalstudiesthat hold promise for genes associated with common obesiry. Linkage studies in children have resulted in the discovery of rare mutatrons in genes such as leprin and melanncorrin thaf account for some of rhe severe early-onsetobesity;thesegeneshave not beenconsrstenrlv found ro conrribute to comrlon obesrt).. Studies have also focused on candidare genes thougbr to be pathways, such as tnsulin signaling, involved in obesity-related fatty acrd oxidation, and appetire regulation, N{ore than 100 genetrc assocrationswith obesitv have been reported in posirional and funcnonaLcandrdace genes,;ier verv few of these findings are reproducible; none have led to a novel prevention or therapv for common obesity. Haplotypes in rhe ghrelin recePtot, ENPPI, leprin. and insulin signaling protein 2 are reported to he rssoei ated with. common obesrty',yet only rhe /NSIG2 finding has been repllcareo.

ASTHMA
Asthma is a common childhood condition; rr is increasrngat an epidemic rate (see Chapter 143). In rhe United Srares,asthma is more orevalent in Hispanic and African American chiLdren. Atopy and aschma are heritable. Asthma is a heterogeneous drag nosrs and is delined as reversrble airway narrowing with obstruction associated wirh small airlt'av bronchospasm and

522 r PART . Human lX Genotics the pathlvavs leading to common disease, leading to rreatment and ultimately preventiol of disease. responsible gene js mapped bur not yer identified, or if it is impraccical ro frnd specific murations, usually becauseof chelarge siTe and Iarger number of differenr murarion' in some genes. Drrect mutation analysis rs Dreferred and is facilitated as the human genome sequence is ftrrther elucidated a[d cechnologies for mutation analysis improve. Linkage testing involves tracking a genetic trait rhrough a family using cJosely linked polymorphic markers as a surrogate for the trait (Fig, 83-1). It requirestescingan exrendedfamily and is vulnerable rc' 5sveral pitfalls, such as genelic recombination, genelic hererogeneirr,, and incorrect diagnosis in che proband, Genetic recombination occurs betrveen any pair of loci, the frequency being proportional to the distance between them. This problem can be amehorated b,v che use of very closelv linked markers, and, rf possible, using markers that flank the specific gene, Genetic heterogeneity can be problemaric for a linkagebased test rf there are multiple distrnct loci that can cause che same phenotype, resulting in risk that the locus tested rs not the one responsible for diseasern the family. Incorrect proband diagnosis also leads to tracking the wrong gene. Linkage cesting remains useful for several genetic conditions. I! is critically important that genelic counsehng be provided to the familv to explain rhe complexities of interpretatron of test results. Direct mutation testing avoids che pitfalls of linkage restirg by detection of the specilic gere muration. The specilic approach used is customized ro the biology of fhe gene beingtested. In some disorders one or a few distincc mutatrons occur in all affected individuals. This is the case in srckle cell anemia, in which the same single base substitution occurs in everyone with the disorder In orher conditiols, there may be many possible mutations that accoun! for the disorder in different individuals. C_vstic fibrosis is an exampler over a lhousand distinct mutatrons have been found rn the CFTR gene. Mutalon analysis will be challengrng because no single cechnique will decect all possible mutations. Direct muratlon tescsare interpreted in llght of 3 factors: analytical validrry clinical validiry, and clinical utilitl-. Analytical validity is test accuracy-does the lest correctly derect the pres ence or absenceof mutation? Most genetic tests have a very high analvtical vahdity, assuming that human error such as sample mix-up has not occurred. Such errors are possible, and unlike

Al6huler D, er al: A haplorype map of rhe human genome. N'atere 2005;437:r299-1320 Balicki D, Beuder E: Gene therapy oi human disease. Medirme 2002181:69-196. Bracken NlB, Belanger K, Cookson ViO, et al: Genetic and perinatal risk facrorstbr asthmaonsetand severiry:A review and rheoreticalanalysjs.Ipi demiaI Rer 2002,24,L75-1 89. Carroll W, ,{sthma generics: Pit{alls and triumphs. Paediatr Resph ReN 2 0 0 5 ; 5 : 6 87 4 . Cavazzana'Calvo \1, FrscherA: Efficacy of gene therapt for SCID is bejng conf'tmed. Ltln.et 2004\364:275 5J1 56. Escolar DM, ScacherjCC: Pharmacologicand genedc lherap). for childhood muscular dvstrophies.Cwt Ne rol Newosci Rp 2001,,11158-174. Ferry N. Heard J\.{: Liver direcred gene rransfer veaors. Hum Gene Ther 1998..9:1.975-1981 FrschrAr Gene therapy oI tympboid prinary rmmunodeficiencies. Crr Opi' Pediatr 2000,12:s 57-5 52. Crimm D, Kay MA: TherapcutLcsho.t hanpin RNA expression,n the liver: viraL targets and lectots. Ce11e Thenpy 2006j13(rt):563 575. High KA: Gene transter as an approach ro rreating hemophilia. Cil. Rrs 2001i88:137-144 Hirschhorn JN: Genetic epidemiolosv of qpe 1 diabete!. Pediatr Diabetes 2003;4:87-100. Kaiser J: Seekins the cause of induced leukernrasin X SCID trial- Sciezce 2003j299:495 Kozarsky KF: Gene therap_v cardiovasculardisease Atrr Opin Pbarmacol fbr 2001;1:'t97-202. Krvon Hl,, BelangerK, Bracken MB: tffect of pregnancy and stage oi pregnanc,v on asrhma severity: A systematic revie$,. Al, / Obstet Gynecol 2004;190:1201-1210 Lyon HN, Hirschhorn JN: Genetics of comnon forms ol obesiry: A brief o v e i e \ i 1A l z / C r , N r t / 2 0 0 5 ; 8 2 : 2 1 5 5 - 2 1 7 5 . Liu I Huang L: Development of non viral vcctors for systemicgene deLivery. 2C02;18:259-256. J Control Release McCormick F: Carcer gene derapv: Iiinge of curting edge) Ndt ReL Cd'1cer 2001;1:130-14r. Onengut Gurnuscr:S, Concannon P: The genecics rype 1 diaberes:Lessons oI learned and furure challenges. Atutoi'11nun2005;25:S34-S39. J Richardson PD, Kren B! SteerCJ: Cen .epair in the nerv ageolgene therapy. Hpdtolosl 2002,15:512-.t18. Schmidt Y/otf CD, Schmidr-Y/olf IG: Immunomodularory gene therapy for haematologicalmalignancies Br J Haenato! 2002111/-:23 32. Thornas CE, Ehrhardt A, Kav MA: Progressand problems wrth the use ofviral vectors for gene rhetapv. Nature Reltiew Ceretr.s 2003i4(5):146-358. \X:eis S! Rabv BA: Asrhna genetics 2001. Hrm Mol Gezel 2004;11(Spec No 1):R83-R89 Yoon lw, Jun HS: Recentadvances insulin gene therapy for rype I diabetes. in Ttends Mal lvled 2002;8-.62-68.

c
Disease gene

TESTING. Genetic testing involves analysis of genetic GENETIC material to obtain information related to an individualt health status using either chromosomal analysis (see Chapter 81) or DNA-based re5ring. 0IAGN0STICTESTING.Diagnostic generic resting helps explain a set of signs and/or symptoms of a disease. The list of disorders for which speciEc genetrc tesrs is avajlabLe is extensrve. The ,NebsrtetLrtu)ta-gefietests.org provides a database of available tests. Single-genedisorders can be tested by two approaches: hlkage analysis aod direcr mutation analysis. The former rs used if the

2 2
2 2 2 4 Figurc tll-t. Use of linkage analysis in prenaral diagnosis oI an aurosomaL recessive disorde.. Both parents are carriers, and rhey have one alfecred son The numbers betow the symbols indicate allelesar 3 polvnorphic Loci:A, B, and C. Locus B resjdeswithin rhe disease sene The aflecred son inherned the 1-2-2 chrornosone from his facher and the 2-1-2 chromosome frorn his mother. The fetus has inherited rhe samechrornosomefrom the father, but rhe 3-2-4 chromosome fron chemother, and rheretoreis mosr likely to bc i carrier

PraclicoI 523 Chapter r Integration Gerelicsinto Podiatric 83 of most medrcal tests, a genetic cestis unlikely ro be repeated, since ir rs assumed that rhe resuft will not change over time Therefore, human ettors may go undetecced for long periods. Clinical validity is the degree ro which the test correctly preent genes that contribuce to risk of any speciflc condrtlon (see Chapter 82). Mosr of rhe genetic vananrs that have been found to correlate wrth risk of a common diseaseadd small increments of relatrve risk, probably in most cases too little to guide management. lc is possible, however, that further discovery of genes lhar conLribute !o common disorders will reveal examples of variants thar convey more significant levels of risk. It is also possrble that testrng several genes rogether will provide more information about risk chan any indrvidual gene variant would confer. The rationale for predispositional cestingis tbat the results would lead ro srrategies airned ar risk reducrion. Thrs mighr include avoid ance of environmental exposures that would increase risk of disease,medical surveillance, or, in some cases,pharmacological lreatment. The vah.reof predispositional tescing lr'ill need to be cfltically appraised through outcomes studies as these tesrs are deveLoped, PHABMAC0GENETIC Polymorphisms in drug metabolism TESTING. genes may result in distinctive pacrerns of drug absorption, mecabolism, excretion, or effectiveness(see Chapters 56 and 82). Knowledge of individual genotypes will guide pharmacological therapy, allowing customuation of choice of drug and dosage to avoid roxiciry and prurrde a rherapeulicresponse.

not prove rhat rt is the cause of the individual's disorder Various lines of evrdence are used to establish pathogeniciry These include: finding rhe variant only in ffected individuals; inferring that the variant alters rhe funcrio of the gene product; decermining whether che amino acid alcered y the mutatron is conrvhether tbe rnuca served in evolution; and determinin

incidental. False-negative results reflect n inability to detecr a mutation in an affected indrvidual, Thi occurs principally in disorders

gene, since mutarions can be varied both in locatron *'ithin the will miss genedelegeneand rype of mutatron, Direct sequencing and mutations may be found wrrhrn tions or rearrangements, such as introns or the promoter; a negalive noncoding sequences DNA tesc does not necessanly exclude a diagnosis. Clinical utility is the degree ro which che results of a test guide clinical management. For generic testing, clinical utilitv includes establishinga diagnosrs that obviales che need for additional workup or guiding surveillanceor treatment. Test results may also be usedas a basisfor geneticcounseling There are some disorders for which genetic rescing rs possible but in whrch the test If resultsdo not add ro the clinical assessment. lhe diagnosisand genetic implications are already clear, it ma,v not be necessary ro pursue geneltc tesnng. TESTING.Predictive genetic testirg involves perforPREDICTIVE mance of a tesr rn an individual who is at risk of developing a all,v on the basis oi family genetic drsorder (presympromatic), sl/mptoms. This is usually hisrory; yet does not manrfest signs done for disorders thar display age-dependent penetrance; the likehhood of manifestingsignsand symptoms increases "ith age,

83.1. GENETIC GOUNSELII{G

Genetic counseling is a cornmunicarron process in rlhich the genetic contribudon to health is explarned, along with specific risks of transmissionof a trart, and options !o manage the condition and its inheritance(Table 83-1). Tbe counseloris expected to oresenr nlormation in a neutral. non-direcrive nanner and co pro,ride support to che individual/family to cope with decisions t|lat are made. Genetic counseline has evolved from a model of care that was devek;ped in the contexr of prenatal diagnosis and pediacrics (see Table 83-1). For prenatal diagnosis,the task is to assess risk to a couple of havrng a child with a genetic condrtion and advise the couple about options to manage that risk, including reproductive options such as artiEcial insemrnarion and prenalal or preimplanration genetic diagnosis. In pediatrics, the task is to establish a diagnosis in a child, provrde longicudinal care for che chrld. and advisethe Darenrsabouc risk of recurrenceas r.ell as options to deal with that risk, The generic counseling role has expanded, particularly !'itb advances in understanding the geneticsof adult-onset or common disorders. Genetic counselng has a major role in risk assessment for cancer, especially breasr and ovarian cancer or colon calcer, for which rvell defined genenc tests are available to assessrisk to an irdividual. TAIKING T0 FAMltlES. The type of information provided to a family depends on the urgency of the situation, che need to make decisions, and the need ro collect additional information. There are 3 srtuations in which genetrc counseling is parhcularly rmPortant. The lirst is the prenatal diagnosis of a congenital anomaly or genetic disease. The need for information is urgent because a famill musr ofcen decide wherher to continue or to terminate a pregnancy. Risks to the mother must also be considered. The second rvoe of situarion occurs when a child is born with a lifethrearemng congenital anomaly or genetic disease. Decisions must be made immediacely with regard to holv much supporr should be provided for the child and whether certain types of therapy should be artempred. The rhird situation arises latr rn life rvhen (11a diagnosiswrth a genelic implication is rnade; (2) a couple rs planning a family and there is a family history of a

concern that a positive DNA rest may reslrlt in stigmarizationof an rndividual and may not as yec provide ioformation that rvill guide medical managemenr. Stigmatization might include psl' chologJcalstress,buc could also include discrimination, includ ing denral of heafth, life, or disabilitv rnsuranceor employmenr (seeChaprer 78). lt is generally agreed thar predictive genetic tests should be performed for children if the resulcs of the rest will beneft the medical management of the child. Otheru'rse, che test should be deferred until the child has grot'n up to the point of underscanding rhe risks and benefirs of resting arrd can provide rnformed consenc.Indivrdual states offer varyrng degrees of prorection from discrimination on che basis ofgeneric resting; federa) legrslationhas noc yet passedrhrough the U.S. Congress. TESTING. is expectedthac genetictestsmay It PREDISP0SITI0NAt Common disbecomeavarlablethat will predict nsk of disease. orders are multifactorial in etiology; there may be many differ

524 r PABT r HumarGenetics lX knou-ledgc and rhrr additional researchrvill probabll, lead to betcerinformation in the future. Knowledge the Diagnosis the Pa.ticularCondition. of ol Alrhough it js not aiu.ayspossible!o lllake an exact diagnosis,having as accuralea diagnosisas possibleis important. Esnmateso|: recurrcnce risk ir|r.ariorLs family mernbers depend on an accutate diagnosis.l0hen a specilicdiagnosiscannot lle made (as in nan1, casesof multipie .ongenitaI anomalies),the vari<>us diiferenrial diagnosesshould be discrLssed u'irh the iamilv and empirical i n [ u r m a r i o r 5 ' r r r d e d . I f ' p c Li f ic d r a g n , ' s o c , " , t r . r r e o "tr'l"l'1", thcv should be discussed. NaturalHistoryof the Condilion. rs very important to discuss ft the natural history of the specificgeletic disorder in the familv. A f l e rr e d i n d i l i d u r l . l n d t h e r rl a m i l i e s i l l h av . . t u c , r i n n .r e s a r . l u t n g t h e p r o A n ( , \ l a l | d p o f e n t i J l h r r J p \ r h . l ti . l n b r r , \ c r c d o r r l \ s with knorvledge of fhe ritlrral hiscor,v. rhele are other possible lf drffercntialdiagnoses, their natural history ma,vdlso be discussed. lf rhe disorder is associared lvith a spectrumof clinical ourcomes or complications,rhe worst and best scenarros, \,r'ellas trearas men! and referral to thc appropriate specialist, shouJd be addressed. Genetic Aspects o{ the Csndition and BecurlencB Eisk. This information is ilrrporfant for the family because all farnily mernbersnecd ro bc mate of their reproductive choices.The generics rhe drsordercan bc explarnedrvirh visual aids ifigures of of chromosornes). is inrportant co provide accurareoccurreice Ic and recutrencerlsks for various members of rhe farnill', rnc)udiLrgunaflectcdindividuals.lf a de6nitediagnosiscannot Lrc made, ir is recessary to use empirical recurrence risks. Counse[ng shouLdgivc the individuais the necessary infonnarion to rrnder scancl the varrous oprioos and let the patients nake their orvn infonned dccisions regarding pregnancl,, adoptr<>n,arri6cial inseminarion,prenrral diagnosis, screening, carrier derection,nnd lennlnatiol of preenancv. It ma,v be necessar,v hirve more fhan to one counselingsessi()n. PrenatalDiaqnosisand Preventi0n. Ir.'lan,v differcnc merhods of prenatal cliagnosis available,dependingon drc specilicgenenc are disordcr (seeChaprer95). The useof ultrasonographyallovr.s prc natal dia8nosis of auatornic abnormalities such as congenital heart defccts. Amniocentesrs ald chorionic vrllus samplinq are u s . ' dt u o h t . r i n i e r , r lr r ' . u c t . r . r n a l l s i i r ' f c h | o n r o . o n r i la b n , ' r maliries, biochemicirl disorders, and DNA studies. Maternal blood or serumsampling is usedfor some t,vpcs screenrng. of Feral cells can be rerrieved from the urnbilical cord or from maternal bltxrd for tcsting.although nothers may harbor cellsfrom all pre vrous preSndncreS, Thetapiesand Beferral.A number of generic disordersrequirc lhe care of a specialisr. Individualswirh Turner s,vndron,te usuall,v need R) be evaluatedby an endocrrnologist, Preventionof knolvn conlpLcations is a priorir,t. The psychologic adjusrmenr of the family may require speci6cintetveDtron. Suppon Groups.A large number of communitv Iay supporc groups have been iormed ro provide informarion and to fund research specific genericand nongenetic on colditions. An impor tanr par! o|. geneticcounselil1g to glve informarion rl)oLrtrhese is groups ro individualsand to suggest contact personfor the fama ilies. Many groups have establishedwebsitesu'ifh ver,v hclpful rntormatron. Follow-up.Families shorl]d be encouragedto continoe to ask questionsand keep up u'irh new information about thc specilic disorder. Nerv developnents oitcn influence the diagnosis and therapv oi specilicgeneric disorders.Lay supporr !(roups are a good source of nerv infornation. (ienetic counselingis usually nondi Nondirective Counseling. recrive;choicesabout reproducrionare left to the familv to decide what is tight for thern. Ttre role oi rhe coulselor (physician, gencuc counsel()r, nurse, medical geneticistlls ro provide information in undersrandable and outline the ranse of oDtions cerurs avaiiable

(onranguinity (o(upational, Terat0gen exposure abure) pregnancy orinfe ility Repeated lors Pregnancy 5(reening abnolmality MitenJl5e:ufrletcpr,r o ?n M a t e m a liI! ( r ? ec rr , J l ] f l h J i . , i t c n ltlal ullaronoErfiy fetdlaryotipe Heterozygote rcrening based thnktitl on Sd,.aliremd IJr.5;clt aJrrir!ar, 6JL(h.{jaiia! d Ihai5gem a5 genetk F0llow-up abnormal to ne0natal testing

genctic pfoblem. includrng rvhethcr one member oi a couple carriesa translocationor is a carrier of an abllorlna] gene for an autosomaLrccessive X-Llked disordcrl i3) ao adolescentor or young adulr has a family historv ot an adult-onsergcnelic disorder iHuoringtoo disease, breastcancer);(4) unrlslralfeaturesare presentand a (llagnosisis wanting or not possibletrrfld (5)there is suspecred cxposureto a loxrc subsrance tcratogen.lf is often or necessirrv have severalmcetingsrvich a famiJl.in this third cat!o egorl'. l-lrgcnc,v ooc as much of an issucas being sure that the,v is have as much iniormation and as many options as are available. GENETIC C0UNSEtING Provrdrngaccuratcinformacionto families requires (1) raking a careful famrly historl. and constructing il pedigree rhat lists rhe patrenr! relatives (including abortions, srillbirrhs,deceased individuals) n ith tlreir sex, age, and state of healrh, up ro and ircluding rhird-degreerclativcs; (2) garhering informatjon from hospital records aboLlt the affecredirdividual (irr sorne cases,ahout orher famiLy members); (3) d()curnenring preretal, pregnancl; :rnd delverl.histories; (4) rcvierving che larestavailablcmcdical. laborarory., and geneticin[ornratiou concerning the disordcr; i5) careful phvsical cxamilarion of rhe alfected individual (photographs,lneasuremenrs) and of appar entl)runaffecrcdindividualsin rhe family; (6) establishing conor firming the <iiagnosis the diagnosrrctesrsavailable;17) grving bv rhc family informatron abolrt sLrpport groups; (8) providing neu' information to the family as it becomesavailable (a mechanism ii'r updrtingneeJ'l.' hr <.Lablirhed). Counselingsessrons mus! include the folkrt'ing information: The Specific Conditionor Conditions. a specilic diagnosis is If rnadc and confirmed, that should be drscussed u'ith che family nnd inlbrmation provided in wrrtrn!, However. ofcen the disorder firs ittto a spectrum (1 of manv types of arthrogryposis)or rhe diagnosisis clinrcalrather rhan laboratory based.ln those sir uarions, the famil,v needs to undersfand fhe limits oi preseDt

Practice| 525 into Chaptor | htegralioftol Genetics Podiatric &}

OF At{D 83,2. MAI{AGEMENT TREATMENT DISOBDERS GENETIC

Pancreatrcenzymes are easily administered orallJ, since rhey must be delivered to che gastrointestinal tracr. Enzyme replacement strategies are effective for some lYsosomal storage disorders. Enzymes are targeted for the lysosome by modification wrth few are amenable mannose-5-phosphate, which binds to a specific receptor This Geneticconditionsare often chronic disorders; Ihere Nevertheless. are many management receptor is also present on the cell surface, so lysosomal enzymes therapies. ro curative should be provided wirh exposed mannose-6-phosphate residues can be tnfused into All individuals/families oprronsavailable. the blood and are taken into cells and EansDotted to lvsosomes' anticrpatory counseling, rnformation about the disorder,genetrc

olism, and hematologic or rmmunologic disorders A successful rransplant is essentially curative, though there may be signifi.cant risks and side effects (see Chaprer 134). Replacement of a defective gene (gene therapy) may offer a less invasive means of achieving a cure of a genetic disorder (see Chaoter 82).

Alliance of Genaic Support Gtovps Directory of Ndtio,Bl Genetic Voluntary Orsonizatiots, 35 Wisconsin Circle, Suite 440, Che\'! Chase, MD

for of such as avoidaace phenylalanine indrvidumanrpulations, for suPplementarion lome coenzyme als with phenylkeronurra; 1o ial o{ parients ylmalonicacidem provision substrates wirh merh ixcrete ammonia for those with urea cycle disorders;bisphosro imperfecca phonaterrearmentfor rhose wirh o\teogenesis smokingfor of and avoidance cigaretre ieducebone fracrures;

20815-70r5.
BarrelsDM, LeRoy BS, Mccarrhy 4 et at: Nondirecdvenessin genelic counseling: A survey of practilione..s.Am J Med Genet 1997;72:172-179 Bowles'Biesecker Marteau TM, The fuure of geneticcounseljng:An interB, national perspctive,Nat Cenet 1999;22:133-137. Burke w: Genetic tesrins. N Engl I Med 2002i347:1867-1876 Farrell MH, Certain LK, Farrell PM, Generic cor:nsetingand risk conmunication servicesof newborn screeningprograms. Arcb Pediatr Adolesc Med 2001r155:120-125. and Acriviry, outcome, effctiveness qualrty Frver AEr Clinicat geneticservicesr Summary of a report of rhe Clinical Genetics Commifte of the Royal Coljege of Physicrans- Roy Coll Physidans Lond 1997\3r:624-621. / ceneclinrcs:geneclinics@geneclinics.org. Hayflick SJ, Eiff, M?, Carpenter L, et al: Primart care Physicians'ut,lization and perceprionsof geneticsservices.Genet Mea 1998\1:13-21 Holornan NA, Watson MS: Prornoring safeand effectivegenerictesting in the United Srates:Final report of the rask force oD geDetjcresting, Bethesda, MD, Human Genome Resea.chInsrilute, 1997. Hubbard R, Lewontin RC: Prrfalls of genetic testins N t,gl / Med 199ti:3i4:1192-1194Preimptantation genetic diagnosis-For or a8ainst humamty? Ldn.et 2O04t 364:1729-1730. of PressN, Brownr CH: Characterrsrics wornen who refuse an offer of prenatal diagnosis:Dara from the California marernal serurnalpha fetoprotein blood tesr experience.Am I Med Geftet 1998;781433445. Sermon K, Van SteineghemA, Liebaers I: Prermplantariongenetjc diagnostsLaicet 2004,363:16 3 3-l 640. HLA tesdng ve.linsky Y, Rechitsky S, Sharapova T, et al: PreirnpLantation . I AMA 2O04;291:2O79-2085 Ve.linskv ! Rechrtsky S, Verlinsky O, er al: Preimplantat,on diagnosjs for sonic hedgehogmutation causing familial ho{oprosencephalytr" EzglJ Med 2001r348:1449-1454.

Many physiologic therapies use THERAPIES. PHAffMACOLOGIC

v
it is highly effective in rreatment of CML and several other malignancies. THERAPIES'Replacement rherapies include REPTACEMENT of reDlacement a missingmetabolite,an enzyme' an organ, ol is gene.Enzymereplacement a comPonentof the evena specific of rreatmenc cy'itic 6brosis to manageinteslinal malabsorPlion.

IiseasBs )(. PartlVletabulic

calcium and response to intravenous injection of glucose or calcrum usually establishthese diagnoses. Becausemost inborn errors of merabolism are inherited as autosomal recessive rraits, a history of consanguinitv and/or death in che neonaral period should increase suspicion of rhis diagnosis. Some of these disorders have a high incidence rn specific population groups. Tyrosinemia t1'pe 1rs nore common among French-Canadians of Quebec than in the general population. Therefore, knowledge of the echnic background of the patient may be helpful in diagoosis. Physical examination usually reveals nonspecifc 6ndings, with most signs related to rhe central nervous s,vstem. Hepatomegaly is a common finding rn a variety of inborn errors of merabolism. Occasionally, a pecuhar odor may off-er an rnvalu able aid to the dragnosis (seeTable 84-3). A physician caring for a sick infant should smell the patient and his or her excretrons; for example, patients with maple syrup urine disease have the unmisrakable odor of maple syrup in their rrrine and on their
DOOleS.

errors of metabolism. and represent Most mutations are clinically inconseguenlral

rn clinicaldisease e lifenmeof the individual. may nevercause Potencial psychosocialimplicatio of such findings can be der.astatingand deservesserious consideratrons.Intrauterine and conditions not' feasible hasbeen rs of diasnosis mosrgenetrc in to usei routinel-v Jetecraffectedferuses the population ar risk (see 96). Chaprer with may present Childrin with inborn errorsof metabolism Thesemay of and symptoms. one or more of a largevarier-v srgns persistenc fatlureto rhrive, vomiting, acidosis, include metabolic

diagnosis. causingclinical PER|0D. Inborn errors of mecabolism NEONATAffindings are usuallv nonspecificand simiLar to lhose seen in should conbe An u..ith sepsis. inbornerrorof metabolism infants ill of sideredjn the differennaldiagnosis a severely neonatal if shouldbe undertaken the index of srudies infant, and special is susprcion high (Fig.84 1). normal at birrh; disorders usualLy are Infantswich mecabolic

Diagnosis usually' requires a variety of specrfrc laboratory st dies. Measurements of serum concenlrations of ammonia, bicarbonate, and pH are often very helpful initialLy in differenti acing major causesof metabolic disorders(seeFig. 84-1). Elevation of blood ammonia is usually causedby defecrsof urea cycle enzymes.lnfanrs with elevatedblood ammonia le"els from urea cvcle defecrs commonly have normal serum pH and bicarbonate values; rvirhouc measurement of blood ammonra, they mav Elevation of remain undrasnosedand succumb ro their disease, is also observed rn some infants with cercain ,...,. u-.oii" organic acrdemras.These infants are severely acidocic because of accumulation of organic acids in body Ouids. When blood ammonia, pH, and bicarbonatevaluesare normal, other aminoacidopathies (such as h,vperglycinemia) or galac infants may also tosemia should be considered; galaccosemic manilest cataracrs, hepatomegalr', ascites, and jaundice. Most inborn errors of merabolism presentingrn the neonaral penod are lethal il specific tredtffient is not iniriated rmmediately. Specilic diagnosrs, even in an infant in rvhom death seems inevitable, is of great importance for genetic counseling of the familv (seeCbapter 83;. Every effort should be made co determine the diagnosrs while the infant is aiive; postmortem examinarion is noc ah,r'avs helpful, A specr6c diagnosis may be esrablishedb-v measuremenrof abnormal metabolicesin bodv flurds, bv assay of the specific enzyme activit-vr or by identilicarion of chemutant gene. CHILDBEN AFIER THE NEONATAI PER|0D. Most inborn errors of metabolism rhat cause symproms in the 1sr ferv days of life exhibit milder varianc lbrms chat have a more insidious onset. These forms may escape detecrion during tbe neonatal period, and the diagnosis may be delayed for months or even years. Early clinical manifestations in children wrrh rheseforms are commonly nonspeci6c and may be attributed to perinatal nsulcs. Clinical manifestations, such as mental retardation, motor delicits, developmental regressron,convulsions, m,vopathr',recurrent emesis, and cardromyoparhy are the common findings in older children. There may be an eprsodic or intermiftent paftern, with episodes of acure clinical manrfesrations separated bv periods of seemingly disease-freestates. The episodes are usually

An inborn error of metabolism should be considered in anv chrld

r X Di$rs6 5Ag PARI r Mebbolic

Initial findingB include oneor moreot the following: a) Poorfeeding b) Vomiting cl !'BthargY . NorrsDonsive to o) uonvuElon intrave;ous t olucose calcium or e) uoma

Obtain
Figure 8+1. Clinical approach co a newborn infant wirh a suspected metabolic disorder This schemais a guide ro rhe elucidadon of some of rhe metabolic disorders in oewborn infants, Although rome exceprjonqro rhis schemaexisr, ir is appropdate for most cases,

High

Nomal

I
Obtain bloodpH and COz Obtain bloodpH andCO2

Normal

r-rr--l

Normal aniongap

AcidsI 529 85 in ol Ch6pler r Delgsti Metabolisn ArDiro studiedby magletic resor]ance specroscopy(MRS) and imaging (MRI) techniques. Severe CtASSICPHEt{YLKETONURIA(PKUl. hyperphenylalaninemia (plasmaphenylalanine levels>20 mg/dl-),if unrreated'invariably resultsrn the development signsand symptomsofclassicPKU, of occasions exceotin rare unDredictable The ClinicalManitestations. affectedinfant is rormal at birth. Mental rerardation may develop gradually and may not be evrdentfor the 1st few months. It is usually severe,and most patients require institutional care if the condidon remains severeenough co be misdiagunreated. Vomiting, somerimes nosed as pyloric stenosis,may be an early symptom. Older movewith purposeless unreared children becomehyperactive, ments. rhyrhmicrocking, and arhetosis, infantsare lighrerin their comOn physicalexamination,these r-rnexplained with one or more of rhe following mani{estations: or plexion than unaffected siblings.Somemay have a seborrheic or delay ot regression, motor mental retardation,developmenral as rash,which is usuallymild and disappears the child eczematoid unusualodor, particularlyduring an acute deficit or convulsions; odor of phenygrows older.Thesechildren have an unpleasant of illness;intermittent episodes unexplainedvomiting, acidosis, lacetrc There as acid, which has beendescribed musty or mousev. renal stones;or menral deterioration,or coma; hepatomegaly; are no consistent Endings on neurologic examination. Most or muscleweakness cardiomyopathy. infanrs are hypertonic wirh hyperactivedeep rendon reflexes. and more than 507" have Abour 25% of childrenhave seizures, prominent Microcephaly, abnormalities. electroencephalographic jnherired metabolic disease and growth Grosse SD, Dezateux C: Newborn screenirg for rnaxiJla with widely spaced teeth,enamelhypoplasia, Lancet 2007;369:5-6. rerardationare other commonfindingsin unueatedchildren The Marsden D, Larson C, Levv HL: Neit'born Screenihsfo. rnetabolic disorders' PKU are rarelyseenin those clinicalmaniFesrations classic of -5 J Pediatu 2006;148 51 7 84 programsfor the detection countriesin which neonatalscreening McBryde KD, Kershaw DB, Bunchman TE, er 1, Renal replacemenrtherapv of PKU are in effect. i born errors of rnetabollsm./ rreatment of confirmed or suspected
in rhe Pediatr 2006;L 48:7 7 0-7 7 8. Warsbren SE: Neuborn Screening for )006;29 6:993-994 . merabolid dtsorders -/AMA

. lrai Bezvani 85.1 PHENvIALAI{INE.

viduals was found to be close to that of normal subiectswhen

HYPERII{EMIA" IION-PKU MITDER FOBMS HYPEBPHENYI.ATA O' In PHENYIAIANII{EMIAS. any screeningprogram for PKU, a gror-:pof infants are identilied in whom initial plasma concentrations of phenylalanine are above normal (2 mg/dl, 120 pmoleil) but <20 mgidl (1,200pmole/L). Theseinfants do not excretephenylketones. Clinicalln rhesein{ants may remain but asympromatic) progressive brain damagemay occul gradu_ of ally with age,Thesepatientshave milder deficiencies phenylalanine hydroxylaseor its cofaclor retrahydrobiopterin(BHa) than rhosewith classicPKU. AftemDtshave beenmade to claspatienrsin differentsubgro s depending the degree on sif,vthese but of hyperphenylalaninemia, such practicehas little clinical PKU, defciencyof BFI+ As or therapeuticadvantage. with classic rn should be investigated all infants with milder forms of hyper(see phenylalaninemia later). of Because gradualdevelopment clinical manifesof Diagnosis. early diagnosiscan only be tarions of hyperphenvlalaninemia, achieved massscreening all newborn infants (seelater). In by of for infantswith positiveresultsfrom the screen hyperphenylalanrnemia, diagnosrs should be confirmed by quanticative measurement of plasma phenylalanine. Idenctfication and of in measurement phenylketones the urine has no place in any program.In countriesand places where suchprograms screening in are not in effect,however,identificationof phenylkecones the of urine by ferricchloridemay ofler a simpletest for diagnosis Once infants with developmental and neurologicabnormalities. deficiency is of the dragnosis hyperphenylalaninemia established, of cofacror(BHa)should be ruled out rn all affectedinfants with rer). proper studies( Effectiveand relfor Hyperphenylslaninonia. Neonatsl Scre atively inexpensivemethods for mass screeningof newborn and infantshave beendeveloped and are usedin the UnitedStates of several other countnes.The bacterialinhibition assav Guthrie, which was the 1st method for the purpose,has beenreplacedby and quanritative merhods(fluorometricand candem more precise mals specrrometry). thesemerhodrrequirea fe* drops of All blood, which are placedon a filter paper and mailed to a central in laboratoryfor assay. Blood phenylalanine affectedtnfantswith levelsas early as 4 hr after birth even PKU may lse to diagnostic

r 530r PARTX Metabolic Diseasos Protein synthesis

synthesis Protein

Succinylacetoacelate

Fumarylacetoacetate

Succinylacetone

Fumarate

Acetoacetate

I I

co2 + H2o
Fjgur 85- 1. Parhways of phenylalanine and ryrosin metabolism. Inborn effors are depided as bars crossing the reaction ato1r,(s). Path*'ays for synrhesisof cofactor BH, are shown in rrlpl?. PKU. refen to defectsof BFli metaboLsm that affect rhe phenvlalanine,tyrosine, and tryprophan hvdroxylases(seeFigs. 852 and 85-5). Enzlmes: (1) phenylalanine hydroxylase, (2) carbinolamjne dehvdratase,(l) d,hydrobioprerin reducrase,(4) 6,pvruvoylrerrahydroprerin synrhase, (J) guanosine trjphosphate (GTP) c-vclohydrolase, tyrosine aminotransferase,(7a) intranolecular reaffangernent,(7+7a) 4-hydro4?henylpvruvare dioxyge(6) nase, (8) homogentisicacid dioxygenase,(9) rnaleylactoacerare isomerase,(10)fumaryLacetoacecate hydrorylase.

in the absence protein feeding.It is recommended, of however, that the blood for screemns obtained in the 1st 24-48 hr of be life after feedingprotein rJreduce the possibility of false negative results,especially rhe milder forms of the condition. in Treatment, goal of therapyis to reducephenylalanine the The in body; formulas low in or free of this amino acid are available commercially. The diet should be startedas soon as diagnosis is established. is generallyacceptedrhat infants wirh persistent It plasma levelsof phenylalanine mg/dl (360 pmole/L) should >6 be treatedwith a phenylalanine-rescricted similar to that for diet classic PKU. No dietary restrictionrs currentlyrecommended for

infants whose phenvlalanine levels are between 2 and 6 mgldL. Plasma concentradons of phen;rlalanine in treated patients should be maintained as close to normal as possible. Becausephenylalanine is not synthesized by the body, overtreatment rnay lead to phenvlalanine deficiency manifested by lethargy, failu(e !o thrive, anorexia, anemia, rashes, diarrhea, and deathi moreoveq tyrosine becomes an essential amino acid in this disorder and its adequate rntake must be ensured. Controversies exist regarding the "allowable" degree of residual hyperphenylalaninemia rn treated patients. It is generally believed that plasma phenylalanine levels should be maintained between 2 and 6 mgldl- (120-350 prnole/L)

in ol Chaprer r Delects Metabolism AminoAcid$ . 5il1 85 thich cat5). BHr is also a cofactor for nitric oxide s-lnthase, al,vzes generationof nirric oxide from arginine. Patientswrlh the in allparienrs ver,vearl-v life because BH1 delicienc,v diagnosed are u'ith PKU and hvperphenylalanirremja are rested for the possibilir,v of this cofactor deliciency. diet for life. alanine-restricted BH. is svnthesized from guanosine triphosphare through Oral adminisrration of the cofactor tetrahydrobiopterin (BH.) reactions (sce Fig. 85 1). Four enzvme defiseveral enz-vmatic BHq fbrlnacion have been described. cienciesleading to defectrve .\{ore than half oi the reported patienrshave had a deflciencyof synthasc(PTPS). 6 pvrur.o,vhetrahydropterin Clinical Manifestations. Inianrs with cofactor deficiency are programstor PKU because evidence of idencified during screening PLasma phenylalaninelevels may be of hvperphenvlalaninemia. as high as rhose in classic t'KU or in rhe range of nilder forms of hvperphenylalaninemia. NeurologJc manifestations, such as .lossof }ead controlr truncal hl,potonia (floppy baby), drooling, su.allowing diflicufties, and myoclonic seizures, develop atter therapv. 3 mo of age despiteadequarediecary0iagnosis. BHa deficiencv and the responsible enzyme defect through a regional treatment centet (Maternal PKU). mav be dragnosed by rhe following tests: measurement of in Pregnancy Womenwith Hyperphenylalaninemia neoprerin (oxidarive product of dihydroneoprerin triphosphate) and biopterin (oxidative producr of dihydrobiopterin and unne (seeFig. 85 retrahydrobiopterin)in body fluids, espectallv 1). ln patientswirh guanosinerriphosphate{GTT) cvclohvdrolase defciency, urinary excretion of both neopterin and biopterin is very lorv. In patients wirh 6 pyruvo,vhetrahydropterin synthase rhere rs a marked elevation of neopterin excretion and deficienc,r', rn a concomiraot decrease biopterin excrelion. In patienrs rvich diet before and during nraiata-iledon a phenylalaninc-restricted dihydroptcridine reducrasedeficiency,neoptern is normal, but in bioprerin rs verv high. Excretion of biopterin rncreases chis enzylrre deficiency because rhe quinonoid dih,vdrobiopterin cannot be rec,vcledinto BHa. Patients u.ith carbinolamine deh,v dracase deficiency excrete 7-bioprerin (an unusual isomer of che jusc describedcongeniralanomahesin therr offspring bioDrerin)in their urinc. llt{r l.OADlN-c I-Il5 l. Ar oral dose of BH4 (20 mg/kg) norOT FROM HVPERPHENYLATANINEMIA DEFICIENCY THE COFACTOR malizes piasma phenylalanine in parients *'ith BHa deficiency the BHa. 1 2% of infants tith hyperphenylalaninemia, defecr In rr.ithin 4 to 8 hr The blood phenylalaninesbould be elevated fot residesin one o{ rhe enzymesnecessatY producoon or recv (>400 gmole/L) to enable interpretarionof che results.This may be achievcd by discontintJng diet rherapy for 2 da1's before the tesr or by administering a loading dose of phenylalanine 1100mg/kg) 3 hr before tlre tesr. t\lYN'lll ASSAY,The accirity of dihydropreridine reductasc can be measuredin che dr,v blood spocson the filter paper used transmitrersdopamine (seeFig. 85-2) and serotonin (seeFig. Il5-

Melanosome------

Tyrosinase Tyrosine DOPA

Tyrosinase
3,4,dihydroxy(DOPA) phenylalanine

HO

cH2-cH cooH
NHz

DOPAQuinone

16t
Dopamine

Tyrosine

l o
Norepinephrine
l

| (41 Epinephine

I
Thyroxine
L

Pheomelanin (yellow-redpolymer)

t Eumelanin (black polymer)

r a iB e F i e u r e 3 j t . O r h e r F r t h w a " s i n ' o l v i n g t _ v r o s i n m e t a b o l i s m .P K t J ' i r d r c . r r e ! h y p e r p h e u , v l a l a n c Ldru t r o r e t r a h , r d r o b i o p t e r m H ! ) d c l i c i e n c y( s c c F i g n l i 8 j 1 ) [ n z y m e s : i t ] r _ v n r s i nh _ v d r r x i l a s ei, ) a r c m . r i c L - a m i n o a c r < d c c a r b o x r l a s eA A D C ) , ( 3 ) d o p a m r n ch v d r o x l l a s e ,l 4 ) p h e n y L e r h a n o l a m lN em e t h y L e 2 ! r a n s t i r a s eP N N { T ) . i

532 r PARTXr MetaholicDisoases for screening purposes. 6-Pyruvovltetrahydropcerin synthase to all extremities wichin a few years. Torlicollis, dystonia of the activity can be measured in the liver, krdneys, and eryrhrocvtes. arms, and poor coordination may precede dystoma of the lower Carbinolamine dehydratase activity can be measured in the liver and kidneys. GTP cyclohydrolase activify can be measured in the liver and in cvtokine {interferon-y) stimulared mononuclear cells becoming worse by rhe end of the dav and improving with sleep, or fibroblasrs (the enzyme activity is normally very low in unstim Parkinsonian signs may also be present or develop subsequenrly ulated cells). with advancing age. Patients may be misdiagnosed as having cereIreatneol. The goals of therapv ate to correct hyperphenylala bral palsy. Late presentation in adult [fe has also been reported. ninemra and to reslore neurotransmifter deficlencies in che CNS. Laboratory findings shou. no hyperphenylalaninemia, bur l h e c o n r r o lo f h l p e r p h e n y l a l a n i n e miis i m p o r t a n ri n p a t i e n r s a reduced levels of BHr and neoptenn are found rn rhe spinal fluid. n'ith cofactor defciencl., because high levels of phenylalanine D o p a m i n ea n d t r s m e r d b o l i r e t h o m o v a n i l l r c c i d ) m l y a l , o b e \ a interfere with che rransport of neurotransmifter precursors (cyroreduced in the spinal flLrid. lt is believed that the enzyme defi sine, tr,vprophan) inro the brain. Plasma phenylalanine should be ciency in this condition is less severe than that of rhe autosomal mairtained as close to normal as possrble (<6 mg/dl). This can recessiveform of GTP cyclohydrolase deficiency, which rs assobe achieved bv a combinarion of a low phenylalanine diet and (seeearlier]. The existence ciated wirh hyperphenylalaninemia of oral supplementation of BHa, Intbnts with GTP cyclohydrolase asymptomatic carriers indicates that other factors or genes may or PTPS deticiencies respond more readrly to BHa rherapy (5play a role in parhogenesis of the phenorype. The asymptomatic 10 mg/kgiday) than those with dihydropteridine reducase deficarrier mav be rdentified by measuring the rario of plasma phetycrencl', In the latter patients, doses as high as 20 mg/kg/day may lalanine to tyrosine after an oral dose of phen,vlalanine be required. BHa for replacemenc rherapy is commercially avail(100 mgikg); the ratio increases significantlv (=3 times above able, although ir rs expensive. n o f m a l v a l u ea t 2 h r ) i n t h e a s v m p l o m a t t c a r r i e r . Adminisrration of defrcient neurorransmirrers iL-dooa and 5Diagnosis may be confirmed by reduced levels of BH4 and hldroxvtryprophant ir recommendedeven when rrear;ent wirh neopterin in rhe spinal fluid, by measuremenr of the enzyme actrvBHr normalizes ptasma levels of phenylalanrne. BHa does nor irr. and by idenrificarion rhe genedefect Lsee oi earlrer].Clinically, readily enrer the brain to restore neurotransmitter production. the condirron should be differentiated fuom orher causes of dysSupplemenration wirh folinic acid is also recommended in t o n i a sJ n d c h i l d h o o dP a r k i n s o n i s m ,s p e c i a l l f ) r o \ i n e h v d r o x v e v patients \:r,lth dihydropteridine reductase de6ciencl.. lase (seeChapter 85.2) and aromatic amino acid decarboxylase Hyperprolactinemia occurs in patients with BHa deficrency and deficiencies.The sriking diurnal partern of dystonra is an impor may be due to dopamine deficiency lwhich is the major prolacrin r a n t c l i n r c a l6 n d i n g i n t a v o r o i C T P c y c l o h y d r o l a sd e f i c i e n a t . e inhibiting factor) rn rhe hypothalamic region. Measurement of Treaiment wirh L-dopa in conjunction with a peripheral dopa serum prolactin levels may be a convenient method for monitordecarboxylase inhibitor usually produces dramaric improvement. ing. adequac,v of rreurotransmitter replacement in affected panents, Some drugs such as trimetoprin sulfamethoxazole, methofiexatet and other antileukemic agents are known to inhibit dihydropteridine reductase enzyme activity and should be used with grea! caurion in patients with BHa deficiencv. Genetics and Prevalence. AIL defecrs causing hyperphenylalaninemra are inherited as autosomal recessive trairs. The orevaTyrosine, obtained from ingesced proteins and synthesized l e n i e o i P K U i n r h e U n i r e d S t a r e si s e s r i m a r e d t l / 1 4 , 0 0 0 r u a endogenously from phenylalanine, is used for protein synthesis 1/20,000 live births. The prevalence of non-PKU hyperphenyand is a precursor of dopamine, norepinephrine, epinephrine, lalamnemia is esrimated ar 1/50,000. The condition is more melanin, and thyroxine- Excesstyrosine is metabolized to carbon common in whrtes and Native Americans and less prevalent in dioxide and warer (see Fig. 85 1). Hyperryrosinemia is observed blacks,Hispanics,and Asians. with de6ciencies of r_vrosne aminorransferase, 4 hvdroxvphenThe gene for phenylalanine hydroxylase is located on chromopyruvate diorygenase (4-HPPD), or fumarylacetoacetate h1'drosome 12q24.1 and many disease-causing murations have been lase (FAH). Deficiencies of other enzymes involved in rvrosine idencified in drfferenr families. The majority of parients are comdegradation cause liftle or no increase in blood levels of tyrosioe. pound heterozygotes for rwo different mulaflr alleles. The gene Acquired hypertytosinemia may occur tn severe hepatocellular for PTP synthase, the most common cause of BH4 deficiency, d y s f u n c t i o n l i r e r l a i l u r e t ,s c u r v y r v r t a m i nC i r r h e i o f a c r o r t o r r resides on chromosome 71q22,3-23.3, the gene for dihyche enzyme 4-HPPD), and hyperthyroidism; hyperc,vrosinemiais dropteridine reduclase is locared on chromosome 4p15.3, and a common artifact in blood samples obtained soon after eating, those of carbinolamine dehydratase and GTP cycLohydrolaseare on 10q22 and 14q22.1-22.2, respectively. Many disease-causrng The clinical specrrum of heledltary byPertyro*nemias is not lully mutations of these genes have been rdenrified. Prenaral diagnosis is possible using speci6c geneuc probes in cells obrained from chorionic villi hiopsl'. wBosrNrMrA | TypE {wBosr osts, HEREDTTABY TyB0stNEMtA,

r Grant Mitchell . 85.2 TyRosrNE A. and lrai Bezvani

TETNAHYDROBIOPTEBII{ WITHOUT DEFECTS PCRPHEIIYTALANII{ETJIIA HY IIEREDITAEY PROGBESSIVE DYSTOI{IA, AUTOSOMAT DOMIIIAIIT ooPA-sEsPol{srvE DysToNrA, SEGAWA D|SEASE ArS0 {SEE
GHAPTER 59t.3). Thrs rare form of dystonia, 1st described in Japan, is caused bv GTP cyclohydrolase deficiency. ft is inherired as an autosomal domrnan! ffaic and ts more common tn females than males (4:1) Clinical manilestations usually occur around 5-6 yr of age and are heralded bv dystonia of the lorver Lmbs, which may spread

HPAT0RENAL TYE0S|NEMlAl. this condition, causedby a de6In ciencyof the enzymeFAH, a moderateelevarionof serum rvrosine is assocrated with severeinvolvementof the liver. kidnevs^ and peripheralnerves.These findingr may be due ro accu. mulation of metabolites of tyrosrne degradation, especially succrnylacetone. Clinical Maoifcstations. The affecredinfant rypically presents between and 6 mo of agebut rarely may becomesympromatic 2 as early as 2 wks o{ ageor may remainseemingly healthyfor the 1st vr of life. The earlierthe presentation, poorer rs the progthe nosis. The l yr morcality,which is abour 60y. in infants who develop5y11p1o-.6efore2 mo of age,decreases 47o rn infants to who becomesymptomaticafter 5 mo of age.

in ol Acidsr $13 ChaDter | oelects MetabolismAmino 85

The major organs affected are the liver, peripheral nerves, and kidneys. An acuce hepatic crisis commonly heralds the onset of the disease and is usually precipitated by an intercurrent illness that Droduces a catabolic state. Fevef, irritabiliry, vomirrng, hemoirhage, hepatomegaly, jaundice, elevated levels of serum transaminases, and hypoglycemia are common. An odor resembling boiled cabbage may be present, due ro increased methionine metabolites. Most heparic crises resolve spontaneouslt but may progress ro liver failure and death. Berween the cnses, varying degrees of farlure to thrive, hepatomegaly, and clotttng abnormalties often persist. Cirrhosrs of the liver and, eventually, age;carcrnomai'' carcinoma occur with increasing heparocellular unusual before 2yr oI age. Episodes of acute peripheral neuropathy resembling acute porDhvria occur in =407" ol affected children These ctises, often iriggered by a minor nfection, are characterized by severe pain, wtth hypertonic postunng of the head often in the legs, associaced and trunk, vomiring, patalytic ileus, and, occasronally, selfinduced injuries of the tongue or buccal mucosa' Marked weakwhich may lead occur rn =307o of the episodes, nessand paralysrs to resprratory farlure requiring mechanical ventilation. Crises cypicallv lasr I to 7 daYs. Renal involvement rs manifested as a FanconiJike syndrome with normal anion gap metabolic acidosis, hyperphosphaturia, and vitamin D-resistanLrickets. Nephromehyp.,phosphatemia, are often found by giiy and .ome degree of nephrocalcinosi', ultrasound examination. Hypertrophic cardiomyopathy is occasionally seen in these lnfants. Laboratoty Findings. In untreated patients, liver function tesrs are perturbed in a characterisnc fashion. c feroprorein level is incriased, ofcen markedln and liver-synthesized coagulation factors are decreasedin most parients; serum levels of transaml nases are increased, parlicularly during acute heparic episodes. Serum concentration of bilirubin is increased with hver failure. Increased levels of cr-fetoprotein are present in rhe cord blood of affected infants, indicaring intrauterine liver damage Plasma ryrosine level is dependent on diet; tyrosine level has less diagnosdc value than that of succinylacetone (seelater) Elevations rn serum concentratiorls ofmethionine and other amino acids, characreristic of liver farlure, may also be present. HyperphosPhaturia and hypophospharemia are common. Generalized aminoaciduria mav occur. The urinary level of 5-aminolevulinic acrd is elevated (due to inhJbition of 5-aminolevulinic hydratase by succinylacetone). The presenceof elevated levels of succinylacetone in serum and urine is diagnoscic(seeFig. 85-1). Diagnosis is usually established by dernonstration of elevated levels of succinylacetone in urine or blood. Neonatal screening methods detect h;rpenyrosinemra; only a minority of patjents wirh ryrosinemia type I ate identrlied by these methods. Succinylacetone, whrch is not detected by the current screening methods, rs rhe preferable initial metaboLite tested. Tyrosinemia rype I should be differentiared from other causes of hepatitis and hepatrc failure in infants, including galacrosemia, hereditary fructoie intolerance, neonalal iron storage disease,giant cell hepatl tis, and citrullinemia type II (seeChapter 85 11) Treatmentand outcome. A diet low in phenylalanine and tyro sine can slow down but nor halt rhe progtession of the conditjon. The treatment of choice is nitisinone (NTBC, 2-(nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione), which inhrbits tyrosine degradation at 4-HPPD {see Fig. 85-1), Thls treatment prevents acute hepatic and neurologic crises. Patienrs treated wich nrtisrnone are also prescribed a diet low in phenylalanine and tvrosine, Ahhough nrtisinone stops or greatly slows progression of the disease, much preffeatment liver damage is noc reversible. Therefore, patients must be followed for development of heparocellular carcinoma. On imaging, the presence of a liver nodule usually indicates generalized crrrhosis. Accurace distinction between benign nodules and malignant ones is difficult to obtain

is therapyand through imaging.Liver transplantation an effective alleviatesthe risk of hepatocellularcarcinoma.The impact of nitisinonetrearmenton the needfor liver transplantationis still at under study but dependson the stage of the drsease whrch therapybegins. Genetics ald P]evalence. Tyrosinemiarype I is an aurosomal trait. The genefor FAH has beenmappedto chromorecessive some15q;nunerous mutationshavebeenidendfied.DNA analy in and for rescing sis is useful for molecularprenatal dragnosis groups at risk for specificmutationssuch as French-Canadians Saint-Jean region of Quebec.Tvronrnefrom the Saguenay-Lac lack of FrenchCanadianor Scandinavian mra type I is panethnic; of ancesrrydoes not excludethe diagnosis.The prevalence the live births in the Saguenavcondition is estimated be 111,846 to to Lac Sarnt-Jean is region.The worldwide prevalence estimared diagnosis beenachieved Prenatal has be 1/100,000 1/120,000. to in by measurement succinylacetone amniotic flurd, by the of enzymeassayin amniocyresor chorionic villi biopsv, and by DNA analvsis. OGUTOCUTYROSINEMIA TYPEII {RICHNER.HANHART SYNOBOME, TANE0US WB0SINEMIA). rare aucosomal This recessive disorder enzyme, is caused by deficiencyof ryrosine aminotransferase herpetiform which resultsin palmar and plantar hyperkeratosis, corneal ulcers, and menral retardation (seeFrg. 85 1). Ocular manifestations excessive of tearing, redness,pain, and photophobia ofren occur beforeskrn lesions.Corneal lesrons preare sumedto be due to tyrosine deposirron. contrast to herpetic In ulcers, corneallesionsin tyrosinemiatypeII stainpoorly with fluorescrnand often are brlateral.Skin lesions,which may develop lacerrn life, include painful, nonpruritic hyperkeratoticplaques on rhe soles,palms, and fingertips.Mental retardation, which in is occurs <507oof patients, usually mild to moderate, Abnormal laboratory findings are limited to significanthypertyrosinemia(20-50 mg/dl; 110-2,750pmole/L) and tvroiluria. acid and its merabolites are Surprisingly, 4-hydroxyphenypyruvic also elevatedin urine desprtebeing downstreamfrom the metabolic block (see Fig. 85-1).This is presumed be due ro shunt to of ing of ryrosinevia other transaminases rhe presence hrgh in of The is ryrosineconcencrations, condicron due to the deficiency In che cyrosolic fraction of hepatic tvrosine amrnofiansferase. contrastto tyrosinemiatype l, liver and kidney function, as rvell as serumconcentratlons other amino acids,are normal. of Diagnosisis established assayof plasma lyrosrneconcenby hypertyrosinemia a nonrestncted on diet is also tration. Susrained seen in liver failure; the level of plasma tyrosine is hrgher in are tyrosinemia manifestations absent rypell and oculocu!aneous of may be confirmed in liver fail-rre.Diagnosis rypeII ryrosinemra of by assay ryrosineaminorransferase activity in liver or bv DNA of ana)ysis the mutant EeDe. Treatmen! wjth a diet low io tyrosine and phenylalanine improvesthe biochemicalabnormalitiesand may result in dra matic healing of the skin and eye lesions.Some observations the sr.rpport reasonable claim rharmentalrerardationmay be preventedby earlv dietary restrictionof t,vrosine. The genefor ryrois 16q and several sineaminotransferase mappedto chromosome disease causinemurarions have been identilied. About halt the caseJare Italiandescent. reported of DEFICIENCY rYR0SltlEM|A TYPE {PRIMARY lll 0F {-HPPDl. Only a bv few cases have beenreported;most were detected amino acid performedfor vatrousneurologicfindings.There determinations deficiency causes clinrcal any is doubt as ro whether this enzyme abnormalities. Age of onsethas beenfrom 1 to 17 mo, Developmental delan seizures, inrermittenr ataxia, and self-desrructive behavior are reDorted. No liver or renal abnormaliries are present.Asymplomaticinfants have beenidentilied in neonaral programs, screenlnS

53{ r PARTXr MetaholicDiseases The diagnosis is suspected in chrldren with sustained moderate iflcreasesin plasma levels of tyrosine (350-700 pmole/L) and the presenceof 4-hydroxyphen,vlpvruvic acid and rts metabolites (4-hvdroxvphenyllaccic and 4-hvdroxyphenylacecicacids) in urine. Diagnosis ma,v be confirmed by denonstration of low activir,v of 4 HPPD enz,vmein liver biopsv or presence of mutations rn the 4-HPPD gene. Given rhe possibleassocrarion rrith neurologrcabnormaliries, dietary reduction of plasma tyrosine levels is reasonable. It is also logical co atrempt a trial of vitamrn C, the cofaccorfor 4-HPPD. The condition is inhericedas an aulosomal recessive rrait. The gene for 4-HPPD rs mapped co chromosome 12q24-qter TBANSIENT TYR0SINEMIA THENEWBORN. a small number 0F Irl of newborns, plasma cvrosine may rise co as high as 60 mg/dl (3,300 pmole/L) d uring rhe 1sr 2 u'k of life. Most affectedinfanrs are premature and are receiving high-prorein diets, The condition is presumablydue to dela,red maruratron of 4 HPPD enzyme (see Fig. 85-f). Lethargl',poor feeding,and decreased moror acrivity are noted in some patients; most are asympromatic and come to medical attention becauseof a high blood phenylalaninelevel, rendering rhe screening rest for PKU posirir.e. Laboratory findings rnclude markcd elevation of plasma tvrosine wlth a moderate increasein plasma phenylalanine,The presenceoi marked hyperty rosrlemia ditferenciates this condition from phenylke tonuria. 4-H_y-drox),phenylpyruvic acid and irs metabolires (4hydroxyphenyllactic and 4-hydroxl'phenylaceticacrds) are also present in rhe urine. HypertJ'rosinemia usually resolvesspontaneously jn the 1sr mo of life. The condirion is often cottected prompdv by reducing the amount of protein in the dier (to 2 Elkg/24 htJ and by administering vitamin C (200-400 mg/24 hr). Mild incellectual dellcitshave beenreporredin some full-term infanrs lr.ith this disorder, but rhe causal relationship to hyperc,vrosiiemia is nor conclusivelvescablished, order in children is a blackening of the urine on standing. This rs caused by oxidatron and polymerization of the homogentisic acrd. Urine uirh acrd pH may not darken even affer man,v hours. This sign may never be noted, delaying rhe diagnosis unrrl adult, hood. Ocbrcxosis, seen clinrcaily as dark spots on rhe sclera or ear cartilage, results from rhe accunulation oF the black polymer of homogentisic actd, Arthritis can be disabling and occurs in almost all affecred subjeccs wrth advancing age. It involves rhe large joints (spine, hip, and knee) and is usuallv more severein m a l e r . I i l e r h s u m a t o i da r r h r r t i s r h e a r r h r i c i rh a ' a c u r er \ a ( e r , bations, buc the radiologic {indings are typical of osceoarthritis, with characteristic narrorving of the jornt spacesand calcification L (mitral of the intervertebra discs.High incidences hearr disease of and aortic valvulris, calcificarion rhe heart valves,and m,vocarof diaL infarction) have been noted. The diagnosis is confirmed by finding massive excretion of homogentisrc acid in urine. The enzl,me is expressed onl;' in rhe liver and kidneys. The gene for alcapronuria maps ro chromo some 3q and severaldiseases-causing mutations have been jden ti6ed, Alcaptonuria is most common in the Dominican RepubLic and Slovakia. There is no effecrive treatrnent for this disorder Nitisinone (see treatment of tyrosinemia rype I) inhibrrs homogentisic producrioni its administration to patrents rvitb alcapronuria beiore plgment deposirionma1' be useful in prevention of archntis.

(INFANTITE TYROSINE HYDROXYTASE DEFICIENCY PARKINSONISM. AUTOSOMAT BECESSIVE DOPA-RESPONSIVE OYSTONIA) ISEE CHAPTER Tyrosine hydroxylase calalyzes thc formation of 597.31. L-dopa from tyrosine (seeFig. 85-2). Deficiencr.of this enzyme has been reported in a felv chrldren r.ith dystonia and parkinsonism. The clinical picture resembles the aurosomal dominant dystonia due to GTP cyclohvdrolase deficrencv (see Chaprer 85.1). The spectrum of the condition is nor full,v appreciated. Clinical manifestations such as jerky movemenrs of the limbs HAWKINSINURIA. This rare condition (named after the 1st leading to spasriciry ard muscJe rigrdiry, expre$sionless face, aifecced family) is causedby a mutant 4-HPPD enzymethar carptosis,drooling, oculogyric crises,and parkinsonismmav srart Jn alyzesa partial reactiolr aDd releases intermedrate an compound early rnfanc1.. Psychomotor rerardation has been secn in some used for diagnosis (see Fig, 8-5-1).This rntermediarers either parients. No diurnal variation of the svmproms has been uoted. reduced rcl li:rm 4-hydroxycyclohex,vlacetic acid (4-HCAA) or Laboratory lindings include reducedlevelsof dopamJne and its reacts with glutathlone to form the unusual organic acid merabolicehonovanrllic acid (HVA) and normal concenrrations hawkinsin (2-L-cysreine-S-y1-1-4-dihydroxvcvclohex-5-en-1-yl of retrahydrobiopterinand neopterin in the spinal fluid. Serum acetic acid); secondarv glutachione de6ciency may occuf. prolactrn levelsare usually elevated. Individualsrvichrhis disorder becomesvmptomaticonl,vdunng Diagnosisshould be consideredin any patientsrvich dystonia infancl'. The symproms usualLyappear after u.eaning from breasrand parkinsonism. GTP cyclohydroxylase defrcienc,vshould be Feeding rvith rhe inrroduction of a high-proteindiet. Severe mecaruled out bv proper studies(seeearlier). Diagnosisis established bolic acidosis,kerosrs,failure to firive, mild hepatomegah;and bv chelaboratory findings (seeearlier) and gene study. an unusual odor (of a s&'imming pool) are described. N'lental Treatment with L-dopa resufts in a dramatic improvemenr. developmenrrs usually normal. Patients unresponsrve to L-dopa have recentlv been reporced, Affected children and adults excrete the organic acids 4hora'ever,The cofldition is inhericed as an autosorlal recessive HCAA, 4-hldroxyphenylpyruvic acid and its merabolites traic. The gene for tyrosine hl.droxylase is rnapped to chromo (4-hvdroxvphenyllaccrc and 4-hydroxyphenylaceric acids), s o m e1 1 p . .5-oxoprotine(owing to secondarl glutathione deficiency),and hawkinsil in rheir urine. Plasma t,vrosine level is usually norma[. Treatmcnt consrsts a lor-protein drer (breasrmilk) or a diet of AIBlNlSM. Albinism is due to defecrs in the biosvnthesis and dislorv in phenylalanineand t,vrosine.A trial rvith large doses oi tribution of melanin (Table ll5-1). N{elanrn is synthesizedb_v vLtamin C (up ro 1,000 mg/24hr) rs also recommended. No melanocyresfrom tyrosine in a membrane-bound intracellular therap,v is needed after 1 yr of age. The same mutation, a substrorganelle, the melanosome. Melanoc,vres originate from fhe tution of threonine for the normal alanine codon a! position 33 embr,vonic neuralcrest and migrate ro the skin, eyes(choroid and of the 4-HPPD gene, has been idencified in unrelated patients wirh iris), and hair follicles.The melanin in the eye rs not secreted inro harvkinsinuria. the adjacent tissues, whereas the pigmenr in skin and hair follicles is secreted into the epidermis and the hair shaft. The rate of ALCAPT0NUfiIA. This rare (incidence =1/250,000) aurosomal melanogenesis is ver,v low in the eye and very hJgh in che skin recessive disotder is due to a deliciencl' of homogencisic acid and hair The bios-vnthetic parhnay for melanin synthesis is not oxidase, ra'hrch causes large amounts of homogentisic acid to complerelyelucidared(seeFig. 85-2). The end products are two accumulate in the body and lhen lo be excreted il the urine lsee pigrnetts: pheomelanin, which is a yellov,red pigment; and Fie. 8-5-'ll. euffieldnin, a brown-black pigment. tlinical manifestations of alcapronuria consist of ochronosis Clinical rnanifesratiolls common in generalized albinism are and archritis, rvhich occur in adufthood. The only sign of rhe dis h v p u p i g m e n r a r r o n t h e s k i n a n d h a i r .P a t r e n rn i r h i n v o l rc m e l t of s

. Acids! Eb GhaDtol86 Defccrs llslrtolilm d Amino ir somepigmentwith ageand becomelight blond with developing light blue or hazeleyes.They developpigmentednevi and freckon les and they may tan. Thesepatients,depending the degreeof pigmentation,rtrereonce subdividedinto different groups and were thought to be genetically different.One interestingform is the temperature-sensitive albinism in which the tyrosinase more active in cooler pans of the body such as limbs. becomes Theseindividuals have no pigment in the scalp and uunk but developsomepigment in arms and legs. OCA, (TYROSINASE-POSITM OCA). This is the most common form of generalized albinism.It is particularly common some in African blacks.Clinicallv.theseindividualsdemonstrate pigmentation the skin and eyesat birth and continueto collect of pigment throughout their lives. The hair is yellow at birth and may becomedarker with age. They have pigmentednevi and frecklesbut do not tan. They may be clinically indistinguishable activity. from OCAI B. Theseindividualshave normal ryrosinase The defectis in the p (pink-eyeddilution) gene,which is located on chromosome 15q. This gene produces the P prolein, a melanosome membraneprotein, the function of which is not Patients completely understood, with Prader-Williand Angelman syndromes who have deledonoI chromosome15 lack one copy Chapter of the OCA, geneand havemild pigmentarydilurion (see 80). OCA3 (RUFOUS ALBIMSM). This form has beenidentified and only in AIricans,African-Americans, nativesof New Guinea, Patientshave reddishhair with reddishbrown skin as an adult. The color of the skin is peculiarto this form. In the young, the may be confused with manifestation with that of oCAr. Patients The mutaOCA3 can make pheomelanine but not eumelanine. relatedprotein 1 (TYRP1)gene,the function is in the tyrosinase rion of which is nor understood. HERMANSKY-PUDLAK SYNDROME. This is a group of disHPSI orders,eachcausedby mutation of one of the sevengenes for to HPS7. Thesegenesare necessary normal sfiucture and function of lysosome-derived organelles including melanosomes and platelet densebodies.In most forms, a tyrosinase-positive with platelet dysOCA of highly variable severityis associated function (owing to the absence platelet densebodies)and an of The condition accumulationoI a ceroid-likematerial in tissues, is transmittedas an autosomalrecessive trait and is most prevalent in Puerto Rico (types 1 and 3, frequencyabour 1:2,000). often manifesredas epistaxisand a proBleedingtendencies, longed bleedingtimer are common. The ceroidJike material is similar to that found in neuronalceroid lipofushistochemically cinosis.The accumulationof this material in tissuesresults in resrictive lung disease,inflammatory bowel disease,kidney of failure, and cardiomyopathy the 3rd or 4th decade life. The in majoriry of patientshavemutationsin IIPSl, which is locatedon cn ASHI SYNDROME. Patientswith this rare condition have partial albinism and suscepautosomalrecessive dbility to infectionwith the presence giancperoxidase-positive of lysosomal granules in granulocytes(see Chapter 129), These patienashave a reduced number of melanosomes, which are Patienrs who survive abnormally large (macromelanosomes). early childhood may develop a lympho{ollicular malignancy. Mutadons in CHS1 gene (locatedon the long arm of chromosome l) have beenidentifiedin thesepatients, All 0cularAlbinisn{041,Albinism is limited to the eyes. th eye frndingsof albinism (seeearlier)are present. The Xlinked recesentity. Most sive form (OAr) has beensegregated a separate as of cases autosomalrecessive ocular albinism are Ielt to be mild variantsof OCA2. OCULAR ATBINISM 1 (OA, NET'TLESHIP-FALLS TYPE). while Only the hemizygote male has the completemanifestation some abnormal refinal pigmentation may be preserf in hete-rozygore female carriers. The gene for this condition is located on the short arm of rhe X chromosome.An X-linl<ed ocular

85-1), Attempts to differentiaterypes of albinism basedon the mode of inheritance, tyrosinase activity, or the ettent of classifihave failed to yield a comprehensive hypopigmentarion is .rtion. The followine classification basedon the distribution of albinism in the body and the qpe of rnutatedgene.Not all conditions associatedwith albinism are discussed lnterested sources{seereferreadersare referred to more comprehensive ences), (0CA). (Generslized)Albinism Lack of pigmentis 0culocutaneous disgeneralized, affecringskin. hair, and eyes.Three generically iincr formsexisr:OCAI, OCA2,and OCAj. The lackof pigrnent is usually more severein patientswith OCAI; thesetypes may clinicalln however, becauseoI a great nor be distinguishable gene,which is located in theseparientsresidesin the tyrosinase on chromosome11q. Many mutant alleleshave beenidentifred. for Most affectedindividuals are compound heterozygote two different mutant alleles.The condition can be subdivided to OCAI A and OCAI B basedon enzymeactiviry and, to a lesser clinical manifestations. er.:tent, OCA), A number of mutations OCAI A (Tyrosinase-Negative in the tyrosinasegene render the enzymecompletely inactive' Individuals with this form usually have the most seve!casof skin(milky lack in generaUzed Clinically, of pigmenr che albinism, whire),hair (whitehair).and eyes(redgray irideslis evidentat throughout life. They do not tan binh and remainsunchanged and do not developpigmentednevi or freckles. OCA1 B. These mutations in the tyrosinasegene result in enzymes with some residualactieities.Clinically theseindividuals, although completelydepigmentedat birth, are capableof

536r PART r Metabolic X Disga6ss albimsm with lare-onsetsensorineural deafness has also been reporled. Localized Albinism.This disorder is characterized locahzed by areas hypopigmenration skin and hair,whicb may bepresent of of at brth or developwith time, PIEBALDISM. In this autosomaldominant inherrredcondi tron. cheindividual is usually born with a whrte forelock. The In underlying skin is deprgmented. addition, there are usually white macules the face,trunk, and extremities. on The white hair lock and che depigmented underlying skin are devoid of melanocytes. Mutatlons in the KIT gene have been shown in patients. affecred \\,AARDENBURC SYNDROME. In this syndrome, laceral drsplacement inner canthi, broad nasalbndge,heterochromia of of irides and sensonneural are with a white deafness associated forelock, This condirron is inherited as an autosomaldominant trart. !'our typesof this syndromehave beenidentilied,Patiencs of with rype I have displacemenr inner canthi, The condrtion is causedby mutations in rhe PAXJ gene.Type ll patients have normal inner canchi,and mutationsin the MITI genehavebeen shown in somepatients.Patientswith type Ill have alLthe findiogs seenin individuals with rype I, plus hypoplasiaand contractures of rhe upper limbs. The gene abnormalitv rs in the PAX3, Type IV is assocrared rvrth Hirschsprungdisease, hetis erogeneous, and mutations Lndifferent genes(EDN}, EDNRB, or SOXl0) have beenidentifiedin different pacients.
viduals with homocystinuria manifest skeletal abnotmalities resembling those of Marfan syndrome (see Chaprer 700); they are usuaUy tall and thin, with elongated limbs and arachnodactyly. Scoliosis, pectus excavatum or carinum, genu valgum, pes cavus, high arched palate, and crowding of the teeth are commonly seen. These children usually have fair complexrons, blue eyes, and a peculiar malar flush. Generalized osteoporosis, especially of the spine, is the marn roentgenographic finding, Thromboembolic episodes involving both large and small vessels, especially those of the brain, are common and may occur at any age. Optic acrophS paralysis, cor pulmonale, and severe hypertension (due to renal infarcts) are among the serious consequences of thromboembolism, whrch is caused by changes in the vascular walls and increased plarelet adhesiveness secondary to elevated homocl'stine levels. The risk of thromboembolism rncreases after sr-rrgicalprocedures. Sponraneous pneumothorax and acute pancreatitis are rare comphcadons. Elevations of both merhionine and homocystine (or homocysreine) in body fluids are rhe diagnosric laboratory findings, Freshly voided urine should be cestedfor homocystine, since rhis compound is unstable and may disappear as che urine is stored. Cystrne rs low or absent in plasma. The diagnosis may be esrablished by assay of the enzyme in liver bropsy specimens, cultured fibroblasts, or phytohemagglutinin-strmulated lymphocytes or by DNA analysis. Tieatment with high dosesof vitamin Bs (200-1,000 mg/24 hr) causes dramatic improvement in most patients who are respon srve to this therapy. The degree of response to vrtamin 86 treatment may be different in different families. Some patrents may not respond becauseof folate depletion; a patient should nor be considered unresponsive to vitamin Bo until folc acid (1-5 mg/ 24 hr) has been added to the ffealment regimen. Resrriction of methionine intake in conyunctionwith cysteinesupplementation is recommended for parients who are unlesponsive to vitamin 85. The need for dietary restrictrcn and its extenc remains controversial in patients with vitarmn 86 responsive form. ln some parients wrth this form, addition of betaine may obviate the need for any dietary restncrion. Betaine (trimethylglycioe, 6-9 yJ24 hr for adults or 200-250 mg/kg/dav for children) lowers homocysteine levels in body flurds b1' remethylatrng homocysteine ro methionine (see Fig. 85-3); this may resuk in further elevadon of plasma methronloe levels. This treatment has produced clinical improvement (preventrng vascular events) ln patients who are unresponsive to vitamin 86 therapy. Cerebral edema has occLrrred in a patient with vitamin 86 nonresponsive homocysrinuria and dietary noncomphance dunng betaine rherapy. Administracion of large doses of vitarnin C (1 gi day) has improved rhe endothelial function; lonB-term clinical efficacy is not known. More than 100 pregnancies in women wich the classic form of homocystinuria have been reported with favorable outcomes for boch mothers and infants, The majoricy of infants were full term and normal. Postpartum thromboembolic events occurred in a few morhers. All but one of the 38 affected male patients has had normal offsprrng. The screening of newborn infants for classrc homocystinuria has been performed worldrvrde and a prevalence of:t/200,000 ro 1/350,000 has been estimared, The condition seems more common in Neu.South Wales,Australia {1/60,000) and Ireland. Early trearment of patients idencified by the screening process has produced favorable results. The mean IQ of 16 patients wich vitamrn Bu unresponsive form treated in early infancy lvas 94 t 4. Dislocation of the lens seemed to be prevented in some paflents. Homocvstinuria is inherited as an autosomal recessive trarr. The gene for cystathionine p-synthase is located on chromosome 21q22.3. Prenaral diagnosis is feasible by performing an enzyme assav of cultured amnrotrc cells or chorionic villi or by DNA analysrs. Many disease-causing mucations have been identified in different famihes. The majorrty oF affected paciencs compound are

. Rezvani 85.3 METHIoNINE.lrai and DavidS. Bosenhlaft

The normal pathway for catabolism of methionine, an essential amino acid, produces S-adenosylmethionine, whrch serves as a methyl group donor for methylation of a variety of compounds rn the body', and cysteine, which is formed rhrough a series of (Fig. 85-3). reacnonscalled rrans-sulfurarion H0M0CYSTINURIA Most homocysteine,an {H0M0CYST|ilEMlA). intermediate compound of mechronine degradation, is normally remechy'latedro methronine, This mechionine^sparing reaction is catalyzed by the enzyme methionine synchase,which requires a metabolite of folic acrd (5-rnethyltetrahydrofolare) as a methyl donor and a metabolite of vitamrn Br2 (methylcobalamin)as a (and cofactor (see Fig. 85-3). Only 20-30% of rotal homocvsterne ics dimer homocystine) is in free form in rhe plasma o{ normal individuals. The rest is bound to proterns as mixed disulfides. Three major forms of homocystinemia and homocystrnuria have been rdentiGed. p-Syntha$e (CBS) Homocysliruria Due to Cystalhionine Deliciency (Classic Homocvstinurial. This is the mos! conmon rnborn error of methionine metabolism. About 40% of affected patients respond to hrgh doses of vitamin B{,and usuall,vhar.e milder clini c a l m a n i f e s r a r i o n r a n t h o s ew h o a r e u n r e s p o n s i vte v l t a m i n th o B, rherapy. These patients possesssome residual enzl'me activiryInfants rvith this disorder are normal at birth. Clinical manifestarions during infancy are nonspecifc and may include failure to thrive and developmental delay. The dragnosrsis usually made afrer 3 yr of age, when subluxation of the ocular lens (ectopia lentis) occurs. This causessevere myopia and rridodonesis {quivering of the iris), Ascigmatism, glaucoma, staphyloma, cararacts, retinal derachment, and optic atrophy may develop larer in life, Progressive mental retardation is common. Normal intelligence, however, has been reported. In an international survey of >600 patients, IQ scores ranged from 10 to 135. The higher IQ scores were noted in viramin 86 responsive patients, Psychiatric and behavioral disorders have been observed in >50% of affected pacients. Convulsions occur in =207o of patienrs. Affected indr-

85 ol Chapter r oelectsin Metabolism AminoAcids r 537 NH' I

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for hererozyg,'ter two ditfercnt allele''.Heterozygoutcarriers are u . u a l l . a ' t m p t < r m a r i . ;t h r o m b o c m h o l i ce v e n t s a n d c , ' r o n a r ' he.rrt disease ,r" rno." aoarrrrn rn rhere rndrvrdualsthan in rhe

Methylcobalamin is rhe cofaccor for the enzyme methioninc synthase, which catalyzes remethylation of homocysteine to methionrne. There are at least iive distincr defects in the inlracellular metabolism of cobalamin thar may interfere wirh the formation of methylcobalamin. To better understand the merabolism of cobalamrn, see merhylmalonic acidemia (see Chapler 85.6 and

amjn is impaired (se ChaPter 85.6). Patients *.rrh cblE nd rblG defeccsare unable to form methylcobalamin and develop homocysrinuria rvirhout methl'lmalonic

acidemia {see Fig. 85-4); fewer than 40 patients are known *'ith each of thesediseases. The clinical manifestations are similar in patients wich all of rhese defects. Vomrting, poor feeding, letharg,v, hypotooia, and months of life. One developmental delay may occur in the 1st fer,.. patient \r.ith rhe cblG defect was not symptomatic (except for when mild developmental delay)until shewas 21 yr old, horvever, she developed difficuJty in walking and numbness of the hands. Laboratory findings include megaloblastic anemra, homocystrnuria, and hypomethioninemia. The presenceof megaloblastic anemia differenciates these defects from homocysrinuria due to merlvlenetetrahydrofolate reductase deicjency {see later). The presence of hvpomethioninemia differentiates borh of these conp-synthase dirions from cystachionine deEciencylseeearlier). Diagnosis is established by complementacion studies performed in cuhured fibroblasts.Prenataldiagnosishas beenaccomplished by studies rn amniotic cell cukures. The gene for c6lE (MTRR) is mapped to chromosome 5p15.3-p15.2 and that for cblG (MTR) is mapped lo chromosome 1q43; severaldisease-causing

r 538| PAnTX Motatolic oiseases

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|
'

\-\)i;;"","; '\ r

Il3-Hld,.']+l"9ihvrffii|l
l\
Acetoaclc acid + Acelyl CoA

t-

\'Mehon,ne 'cBestercl Methytcttncacd

fTiil;Gii"d,-l
-+ -,-.1F- Melhyl cbl

I
(;

cbro cbrc Fffi;Hcu-l I I

oHcbr+3

Figur 85-4. Pachways the metabolism ofthe branched-chainamino acids, biorin, and vrramin BD (cobalamin).MMA, methylmalonic acidemE; HCU, in c1'stinuria;CbJ, cobalamin; OHCbl, hvdroxycobalamin; cbl, defect in merabohsm of cobalamin; TC, rranscobalamine.

mutations,includrnga common missense mufation (P1173L)in the MTR gene,have beendescribed. Tlearmentwith vitamin 812in the form of hydroxycobalamin (1-2 m9l24 hrl is used ro coffect the clinical and biochemical lindings.Resultsvary among both diseases sibships. and Homocystinuria to Deficiency Methylsnetotrahydrololate Due ot Beductase This enzyme 5-10 methylenecetrahyreduces {MTHFBI. drofolate to form S-methyltetrahydrofolate, which providesthe methyl group needed for remethylation of homorysteine ro (see merhionine Fig. 85-3). The severir,v the enzymedefectand of the clinical manifes, of tations variesconsiderably different families.Clinical findings in

vary from apnea, seizure, microcephaly, coma, and death ro developmental delan ataxia, and motor abnormalities or even psychiatric manifestations, Premarure vascular diseaseor peripheral neuroparhy has been reporred as che only manitestaironof this enzyme deficiency in some patients. Adults with severe enzyme defrciency may even be completely asymptomatic. Exposure to the anesthetic nitrous oxide (which inhibrts methionine synthase) in patients wirh MTHFR deficiency may result in neurologic deterioration and dearh. Laboratory fndings include moderate homocl'stinemia and homocystinuria. The methionine concentration is low or low normal. This findine differertiates this condition from classic

Ghapter r Dolocts Metabolism AminoAcids | 539 85 in ol homocystinuria caused by cvstathionine synrhase defrciency. Absence of megaloblasric anemra distingurshes chis condition from homocysdnuria caused by merh,vlcobalamin formation (see earlier). Thromboembolism of vesselshas also been observed in

. lraj 85.4.CysrElNVCvstNt Rezvani

Cysreine is a sulfur-containing nonesseDtial amino acid that is synrhesized from methronine (see Fig. 85-3). ln rhe presence of oxygen! two molecules of cysteine are oxidized to form cystine. The mosc common disorders of cysteindcystine metabolism, cyscinuria(seeChapter J47) and cystinosis(seeChapter 529.3), are discussed elsewhere. (MOIYBOEI{UMCOFACTOR DEFI. SUI.TITE OXIDASEDEFICIENCY ClEltlCY). the lasr srep in cysteine metabolism, sul6te is oxidized At to sulfate bv sul6te oxidase. and the sulfate is excreted in the urine (see Fig. 85-3). This enzyme requires a molybdenum-pterin comDlex named molvbdenun cofactor, This cofactor is also rlecessaiy for the function of rwo other enzymes rn humans: xanthine dehydrogenase (which oxidizes xanthine and hypoxanthine to uric acrd) and aldehyde oxrdase. Three enzymes, encoded bv three drfferent genes, are involved rn the synthesis of the cofactor The genes are mapped to chromosornesL4924,6p21.3, and 5q11. Deficiency of any of the rhree enzymes causescofactor deflciency wirl jdentrcal phenotype. Most patrents who were origrnally diagnosed as having sullire oxidase deficrency have been proven to have molybdenum cofactor deficrency. Both conditions are ioherited as autosomal recessivetraits. The enzyme and the cofactor deficiencies produce identical clinical manifestations. Refusal !o feed, vomiting, severe intractable seizures (ronic, cLonic, myoclonic), and severe developnental delay may develop wirhrn a few weeks after birth. Bilateral dislocation of ocular lenses is a common finding in patients \4ho survive the neonaral period. These children excre!e large amounrs of sullire, thiosulfate, Ssulfocysterne, xanthine, and hl,poxanthrne in their urine. Urinary and serum levels of uric acid and unnarv concentratio[ of sulfate are dimrnished. Fresh r-rrineshould be used for screening purposes and for quantitative measurements of sulfite, because oxidatron at room temperature may produce false-negative results, Diagnosis is confrrmed by measuremenr of sulfite oxidase and molybdenum cofactor in fibtoblasrs and liver biopsies, respecrively- Prenaral diagnosis is possible by performing an assay of sul6re oxidase activity in cultured amniotic cells or in samples of chorionic villi. No effective treatnent is available, and most children die in the 1st 2,vr of hfe. The prevalence of neither of the deficiencies ls known.

tion in the MTHR gene. A number ofpolymorphisms have been described in the MTHR sene.T'"!o of these(677C > T and 1298A > C) may affecr levels of plasma toral homocystein and have been studied as possible risk factors for a wide variety of medical conditions, ranging from birrh defects to vasculal disease and even risk for cancer, ProSnosrs for survival in leukemia, and risk for Alzheimer disease.To

p o l l m o r p h i . m i . w i d e l u a v a i l a b l e ,i t s p r e d r c r i r ev a l u e i n n y g i v e n i n d i v i d u a lh a s r e r t o b e d e r e r m i n e d . Treatment of severeMTHFR deEcrencywitb a combinatio of folic acid, itamin 85, vrtamin Br2, methionine supplementanon, and betain has been tried. Of rhese,early treacment with betaine seems to have the mosr beneficial eftecr. The condition is inherited as an autosomal recessivetraiti tfie genefor rhe enzl me has beenlocatedon chromosume I pl6 J and mutarion\ have been reported Prenalal iranu drsease-causrng diagnosis can be offered by measuring N{THFR enzyme activrty in cultured chorionrc villi cells or amnioc],tes, by linkage anal,vsis in informative families, or by DNA analysis of the muration Secondary hypermethioninemia occurs in HYPERMETHI0NINEMIA. liver disease, qvrosinemia type I, and classic homoc,vstinurra. Hypermethionrnemia has also been found in premarure and some full-term infanrs receiving high protein drets, in whorn it ma,v represent delayed maruration of the enzyme methionine adenosylrransferase. Lorvering the protein inrake usually resolves rhe abnormaliry Primary hypermethioninemia caused by the de6ciency of hepatic metbionine adenosyltransferase (see Fig. 85-3) has been reported in a few patients. The majority of these patrencs have been diagnosed in the neonaral period rhrough screening for homoc,vstinuria. Affected individuals wrth residual enzyme aclivrr).remain asymptomatrc throughour life despire persistent hyper methroninemia. Some complain of unusual odor to cheir breath (boiLedcabbage), A few patients with complete enzyme deficiency have had neurologic abnormaliries related to demyelination ( ntal retardarion, dystonia, dvspraxia). The gene for merhionis i adenosyltransferase on chtomosome 10q22 and several

hypermethroninemia, Secondary cystathion CYSTATHI0NIt{EMIA {CVSTATHI0NINUBIA). inuria occurs in pahents with viramin Br or Brz deficiency, liver drsease(partrcularlv damage caused bv Balactosemia), thvrotox icosis, hepatoblastoma, neuroblastoma, ganglioblasroma, or defecrr rn remethtlatron oF homocysfeine. Cystathionase defciency results in massive cystathionlnuria and mild to moderare cystathroninemia; cysrarhionine is not normally detectable in blood. Deficiency of this enzyrne is inherited as an autosomal recessivetralt and rts prevalence is estrmated co be about l/14,000 live births. Affecred subjects with a wide variery oF clinical manifestations have been reported. Lack of a consiscentclinical picture and the Presenceof cystathionrnuria in a number of normal persons suggesrthat cystathionase denciency

lrai Rezvani 85.5.TRYPToPHAN.

Tryptophan is an essential amino acid and a precursor for nrcotinic acid and serotonin (Fig. 85-5). Presumeddeiciencies of a variecy of different enzymes involved in tryptophan cacabolism have been reported, but no distinct clinical entity has yet emerged. Hartnup disorder causes disturbance in trvptophan absorption. In HARTNUP DIS0RDER. this autosomal recessive disorder,named after che 1st reporced famill there is a defect in rhe transport of monoamlno monocarboxylic amino aclds (neutral amino acids) by the intestinal mucosa and renal tubules. Mosc children wrth Hartnup defecr remain asymptomatic. The major clinical manifestation in the rare symptomatic paoenr is cutaneous photosensitivit,v.The skin becomes rough and red afrer moderate exposure to the sun! and with greater exposure, a pellagra-like rash may develop. The rash may be pruritic, and a chronic eczema may appear The skrn changes have been reponed in affected infants as young as 10 days of age. Some patients ma,v have inrermittent acaxia manifested as an unsceady, u'ide-based gair. The ataxia may last a few days and usually recovers spontaneously. Mental

thionase is located on chromosome 16.

540. PABTXI Metabolicoiserses

Protein synthesis

ln vitro

Formylkynurenine

Nicotinic acid
Figure 85 5. Pathwa)-sjn rhe merabolism of tryprophan. PKU. indicareshyperphenvlatanemia due co tecrahydrobiopterindeficiency(seel'ig. 85 ll. Enztmes: (1) tr-vptophanhvdroxylase, {2) aromadc L-amino add decarboxylaselA-qDC), (3) monoamine oxidase (MAO).

I I I

acid 5-OH-indoleacetic (5 H|AA)

development is usually normal. Two indrviduals in the original kindred were menlally retarded, however Episodic psychologic changes, such as irritabilit)', emotional instability, depression, and suicidal tendencies,have been observed; thesechanges are usually associated r,r.ith bouts of ataxia. Short starure and atrophic glossitls are seen rn some pallents. Mosr chrldren diagnosed with Hartnup disorder by neonatal screening have remained asymptomatic. Thrs indicates thac other facrors are also involved in parhogenesrsof the clinical conditron. The marn laboratory finding is aminoacrduria, which is restricted to neutral arnino acids (alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, rryprophan, histidine).Urinary excretionof proline, hvdroxyproline,and arginine remains normal. This findrng differentiates Hannup disorder from other causes of Eeneralized amrnoacrduria, such as Fanconi syndrome, Plasma concentrations of neutral amino aclds are usuaLlynormal. This seemingly unexpecred flndrng is because these amino acids are absorbed as dipeptides and rhe transport svstem for small pepcidesrs intact in Hartnup disorder. The mdole derivarives (especially indican) may be found in large amounts rn some patients, owing to bacterial breakdown oi unabsorbed rryptopnan ln the lntestrnes. Diagnosis is established by the striking intermiment nature of symptoms and the yust described urinary findings. Treatment rvich nicotinic acid or nicorinamide (50-300 me/ 24 hrr and a hrgh prorcrn dier resulrsin a tavorable respon.. in s).[lptomatic patients. Because of rhe mtefmitlenr nature of the clinical manifestations, the efficacy of thes treatmeols is drfnculr !o evaluate. The orevalence of the disorder ls estimated to be 1/30,000.Normaloutcome both Ior mother and fetus is reported in affected pregnant lvomen. The gene for rhis condition has not vel been rdentified.

4). The intermediate metabolites are all organic acrds, and deficiency of any of the degradative elzymes, except tbr the transaminases,causesacidosis; in such instances, the organic acids before the enzymatic block accurnulate in bod;r fluids and are excreted in the urine. These disorders commonly cause metabolic acido sis, which usualll/ occurs rn the 1st few days of life, Although most of the clinical lindings are nonspecific, some manifestations rnay provide imporrant clues to the nature of the enzyme deficiencv. An approach to infants suspected of having an organic acrdemia is presented in Figure 85-6, Delinirive diagnosis is r:sually established by identifying and measuring specilic organic acids in body fluids (blood, urine), by the enzyme assal and by rdenrification of the mutant gene. Organic acrdemras are not limited co defecrs in the catabolic pachways of branched-chain amino acids. Disorders causrng accumulalion of olher organrc acids include chose derived from lysme (see Chapter 85,13), those associated with Iactic acid (see Chapter 87), and dicarboxylic acidernias associated with defective fany acid degradation (see Chapter 86.1). MAPTE SYBUP URI E DISEASE (MSUD). Decarboxylation of leucine, isoleucrne, and valine is accomplshed by a complex enzyme system (branched-charn c-kecoacid dehydrogenase) using thiamine pyrophosphate (vitamin 81) as a coenzyme. This mito chondrral enzyme consists of four subunits: E1", E'p, E., nd E3. The E3 subunit is shared wrth two other dehydrogenase in the bodl namelv p;rruvare dehydrogenase and or-ketoglutarate dehydrogenase. Deficiency of this enzyme system causes MSUD (see Fig, 85-4), named after rhe sweet odor of maple syrup found in body fluids, especially urine. Based on clinical findings and response to rhramine administration, five phenotypes of MSUD have been idenri6ed. Classic MSUD. This form has the most severe clinical manifestations. Affected infants who are normal at birth develoD Door feedingand vomrting in rhe lst wk ot lite; lethargyand coma mal ensue wrthin a felr, days, Physical examinarion reveals hypertonicity' and muscular rigidity with severe opisrhoronos. Periods of hypertonicity may alternate with bouts of flaccidity. Neurologic findings are often mistaken for generalized sepsis and meningitis, Cerebral edema may be present; convulsions occur in most infants, and hypoglycemia is common. In contrast to mos! hypoglycemic states, correction of the blood glucose concentra rion does not improve the clinical condition. Rouline laboratory

85.6 o VATINE, LEUGINE, ISOTEUCINE, RELATED AND . lrai Rezvani AclDEMlAs ORcnrtc nnd David$. Eosenhlatt*
The early steps in the degradation of these three essentral amino actds, the branched-chain amino adds, are similar (see Fig. 85 *David S. Rosenbla|t contributed rhesection merhvlmalonic to on acidemia.

Chsplor r oeloctsi[ Motabolisnol AminoAcids I 541 S5

Commonfeatureg to Flelusal leed Vomiting Acidosis Dehydration Neutropenaa Hypoglycemia

Ketosis No skinmanifestations

or No ketosis mildketosis

r___-_-r
1. 3-Hydroxy-3-melhylglularic aciduria 2. AcylCoAdehydrogenase daficiency 3. HMGCoA synthetase deficiency

acidemia 1. irethylmalonic 2. Propionic acidemia 3. Ketolhiolase iciency def

Fisu.e 85-6. Ctinical approach to infancswith organic acidemia Asrerils indicare disardrsin which patients ha"e a characterisricodor (serext and Table 842). MSUD, mapte syrup urine disase.

exceptfor metabolicacidosis. findingsare usuallyunrernarkable, Death usuallyoccursin untreatedpatientsin the 1st {ew weeks or monrhs of life.

small amountsof rhem should be addedto the diet; the amount of should be ticratedcarefully by performing frequent analyses the plasma amino acids, A clinical condition resemblingacrooccursin affectediofantswhoseplasma dermatitisenteropathica very low; addition of isoleucine becomes isoleucine concentration a to the diet causes rapid and completerecovery.Patientswith MSUD should remainon the diet for the rest of their lives.Liver has rransplantatron beenperformedin a smallnumberof patients with classicMSUD with promisingresults.Thesechildren have beenable to roleratea normal diet. hrgherthan those of the orher three amino acids Urine contains The long-termprognosisof affectedchildrenremainsguarded, and valine and their respective high levelsof leucine,isoleucine, cerebraledema, and deathmay occur during Severe ketoacidosis, keioacids. These ketoacids may be detected qualitatively by in especially reagent.(0.17" any stressfulsituation such as infection or surgeryr drops of 2,4-dinitrophenylhydrazine adding a few mid-childhood, Mental and neurologic deficits are common in 0.aN HCI) to the urine; a yellow precipitateof 2,4-dinitrosequelae. IntemittntlrlSUD.In this form of MSUD, seeminglynormal chrldrendevelopvomiring,odor of maplesyrup, ataxia,lethargy, and coma during any stressor catabolicstate such as infection or surgery.During theseattacks, laboratory findings are indisform, and deathmay occr:r from thoseof the classic ringuishable Treannenrof the acuteattack of intermitrentMSUD is srmrlarro in and cuhuredfibroblasts. measured leukocytes form. After recovery, althougha normal diet is that of the classic Treatmentof the acute state is aimed at hydrarion and quick amino acids is recom branched-chain amino acidsand their metabolites tolerated, a diet low rn branched-chain removalof the in Activity of dehydrogenase patientswrth the intermirmended. form and may reach5-207o tent form is higherthan in checlassic of the normal activity. Mild lhtennediate) MSUD. ln this form, affected children after the neonatalperiod. Clinical manidevelopmilder disease are festations insidiousand limited to the centralnervoussystem. have mild to rnoderatemental retardarion(usuallyafter Patients They have the odor of 5 mo of age) with or without seizures. maple syrup and exctete moderate amounts of the branchedin charn amino acids and rheir ketoacid derrvarives the urine. lasix, or hypertonicsaline. and valineare mod concentrations leucine,isoleucine, of Plasma Trearmentafter recoveryfrom the acute state requiresa dier erately increasedwhereas rhose of lactate and pyruvate are formulasdevoidof amino acids.Synthetic low in branched-chain during an interleucine, isoleucine, and valine are available commercially. normal. Thesechrldrenare commonlydiagnosed endogenously, current illnesswhen signsand symptomsof classicMSUD may Because theseamrno acidscannot be synthesized

542 r PARTX. MotabolicDiseases occur The dehydrogenase activiry is 3-30% of normal. Since patients wirh rhiamine-responsive MSUD usually have manifestatrons similar to those seen in the mild tbrm. a trial of thiamine therapy is recommended. Diet therapr., similar ro that of classic lvISUD, is needed. Thianine-Sesponsiye MSUD. Some children wrth mild or intermediate forms of MSUD who are ueated with hish doses of thiamine havc dramaricclinical and biochemrcalmorovemenr. i AJthough some rerpond ro rrealmenr with rhiamine ar l0mg/ 24 hr, others rnay require as much as 200 mg/24 hr for at least 3 wk before a favorable response is observed- These patienrs also require drets deficient in branched-chain amino acids. The enzymatic activity in these oatie[ts is 2-407o of normal. MSUD Due to a 0efici;ncy ot Er Subunit (Dihydrolipoyl Dehydrogenasel. This is a very rare drsorder Patients develop lactic acidosis in addition to signs and symptoms simrlar ro those of intermedrate MSUD because the E1 subunit is also a component of pyruvate dehydrogenase and o-ketoglutarate dehydrogenase. Progressrve neurologic impairment manifested by hypotonia and developmental delay occurs aIrcr 2mo of age. Abnormd movements progress to ataxia. Death ma,v occur in early childhood. Laboratory findings include persistent lactic acidosis wirh high levels of plasma lactate, pyruvate, and alanine. Plasma concentrations of branched-chain amino acids are moderatelv increased. Patienls excrete large amounfs of lacrate, pvruvate, cr-glutarate, and the three branched-charn ketoacids in rheir urme. No effeccive treatment is available. Dietary resrtrction of b r a n c h e d - c h a ia m i n o r c r d s a n d r r e a L m e nrr. r r r hh i e h d o s e so f n r h i a m i n e .h i o t i n . a n d l i p o i c a c r d h a s b e e ni n e f f e c t i r e . Geneticsand Preyalenceof MSUD.All forms of MSUD are inherited as an autosomal recessive crait. The gene for each subunit resideson dillerenr chromosomes.The E1, gene is on chromo few;lears old. lo both forms, acute episodes of metabolic decompensacions may occur during a catabolic state such as an infec tion. Sen rive methods for newborn screenng have identified vet a m i l d e r n d p o t e n f i a l l ) ' a \ y m p t o m a r i ch e n o t v p e f r h e c o n d i p o tion; a few older siblings of these affecred newborns were found to have identical genotype and biochemical abnormaliries without any clinical mamfescations. Laboratory findings during the acute attacks include ketoacidosis, neucropenia, thrombocytopenia, and occasionally pancytopenia. HypocaLcemia, hyperglycemia, and moderace to severe hyperammonerma may be present in some parients. Increases in plasma ammonia may suggest a defect in the urea cycle. In urea cycle defects the infant is noc acidotic (see Fig. 85-6). Diagnosis is esrablished by demonstrating marked elevations of isovaleric acid and its metabolites (isovalerylgft.crne, 3 hydro:':aisovaleric acid) in body fluids, especially urine. The main compound in plasma is isovalerylcarnitine, which can be measured even in a few drops of dried blood on a filter paper. lvleasuring the enzyme in cultured skin fibroblasts confirms che diagnosis. Treatment of the acute attack is aimed at hydrarion. reversal of the catabolic state (bv providrng adequare caloties orally or intravenously), corre ion of metabolic acrdosis (by intusing sodium bicarbonate). nd removal of the excess rsovaleric acid. Becausersovalerylglycine has a high urinary clearance, adminisrradon of glycine \250 mglkg/24 hr) is recommended ro enhance formation of rsovalerylglycine. L-carnicine (100 mg/kg/24 hr orally) also increases removal of isovaler acid by formrng iso valerylcarnirine, which is excreted in the rine, In patients wirh s i g n i f i c a nh y p e r a m m o n e m i t b l o o d a m m o n i a . 2 0 0 ; r M r . m e a t a sures thar reduce blood arnmonia should be employed (see L h a p r e r 8 5 , 1 l ) . E x c h a n g et r a n s l : u s i o n n d p e r i t o n e a ld i a l y r r s a ma,v be needed if the just described measures fail to induce signi6canr clinical and biochcmical imDrovemcnr. Alrer recoverv

different disease-causine mutations have been idenrified in patrents with different forms of MSUD. A given phenocl,pe is car:sed by a variety of genotypes; patients from different pedi grees u'ith the classic forrn of MSUD have been shown co have mLllations rn 64enes for E1", Ern, or E2. Most paciencs are compound hererozygotes inheriting tlvo different mr.rtant allelesThe prevalenceis estimatedat 1/185,000. The classicform of MSUD is more prevalent in the Old Order of Mennonires in the Unrted States, with estimated prevalence of 1/358, Affected patients rn this population are homozygous for a specific mutation (Y394N) in the Ero subunit gene. Early detection of NISUD is feasible by mass screening of newborn infants. Prenatal diagnosis has been accomplished by enzyme assay of the cultured amniocytes, cultured chorionic villi tissue, or direct assay of the chorionic vrlli samples and by iden trfication of che mutant eeneSeveral successful pregnatr.re" have occurred in women wirh different forms of MSUD. No ill effects have been observed in the offspring of rhesepatients. Episodes of metabolic decompensations have occurred rn rhe mothers during pregnancy and the postpartum perlod. IS0VALEBIC ACl0EMlA. This rare condrtion is due to the delicrency o f r s o v a l c r yc o e n z y m e l C o A t d e h l d r o g e n a s ( s e el i g . 8 s - 5 1 . l A e Clinical manifestations rn the acute form include vomiting and severe acidosis in che 1st few days of life. Lethargy, convulsions, and coma may ensuer and death may occur if proper therapy rs nor rnitiated. The vomiting may be severe enough to suggest pyloric stenosis. The characterisric odor of "sweaty feet" may' be present (seeFig. 85-6). Infants who survive rhis acure episode wrll go on to have the chronic ntermitten! form later on in life. A milder form of the disease (chronic intefinittent form) also exists; rn rhis, the 1st climcal manifescation (vomicing, lechargy, acidosis or coma) may not appear unrrl the child is a few monrhs o. a

tine supplemenrs. Pancreatitjs (acute or recurrent forms) has been reported in survivors. Normal development can be achieved r,vith arly ano proper rreatment, Prenatal diagnosis may be accomplished by measuring isovalerylglycine in amniorrc fluid, by enzyme assay in cuhured amniocytes, or by Ldentification of the mutanr gene. Successful pregnancy wich favorable outcomes both for the mother and the infanr has been reported. Mass screening of newborn infanrs is rn use in the United Srates and othet counrfles. lsovaleric

disease-causing mutations have been identilied. The prevalence of rhe condirion is estimated from 1/52,500 (io parts of Germany) to 1/250,000 (in the United States).

MUtTtPtE CARBoXYIASE DEFtCIE'{CIES tN {DEFECTS UTIUZAT|0N

0F BlOTlt{1.Biotin is a water-soluble vitamjo that is a cofactor for all four carboxylase enzymes rn humans: pyruvate carbox_vlase, acetyl CoA carboxylase, propionyl CoA carboxylase, and 3methylcrotonyl CoA carboxylase. The latter two are involved in the metabolic pathways of leucine, isoleucine, and valine (seeFig. 8 5-4). Dietary biotin is bound co proteins; free biotrn is geoerated in the intestine by the action of digestive enzymes, by intestinal bacteria, and perhaps by biotinidase. The latter enzyme, v.hich is found in serum and most tissues in the bodr', is also essential for the recvcling of biotin in the body by releasing rt from the apoenzymes (carboxylases, seeFig. 85-4). Free biorin must form a covalent peptide bond *'ith the apoprotein of the four carboxylases to activate them (holocarboxylase). Thrs binding is catalyzed by holocarboxylase svnthetase.Deficiencies in thrs enzyme or in bio tinidase result in malfunction of all the carboxvlases and in organic acidemia.

in 0f ChaDter r Defscts ltle{abolism AminoAcids r 543 86 The orevalence of this aucosomal recessivecrait is estimated at 1/60,000. The gene for brotinidase is located on chromosome mutations have been identified in 3p25 and manv disease-causing different families. Prenatal diagnosis is possible by the measurement of rhe enzyme actrvity in the amniotic cells or by identifrcation of the mutant gene. Dueto DietaryBiotin Deliciency. Multiple Carboxyl6s;Deficiency Acquired de6ciency oI biotin may occur in infants receir.ing lotal parenreral nurrition without added biorin, in parienrs receiving prolonged antrconvulsant drugs (phenycoin, prirnidone, carbamazepine) or in children wrth short bowel s1'ndrome or chronic drarrhea who are recervrng formulas low in biotin. Excessive ingestion of raw eggs may also cause biotin defictency because the protein avidin in egg white binds biotin and makes it unavailable for absorption, Infants with biotin deficiencv develop dermatitis, alopecia, and candidal skin infections.

DEFICIENCY 3.METHYTCROTONYTCARBOXYTASE COA ISOTATED enzymes the bodythac in Thisenzyme oneof four carboxylase is (see An deliciency require biotinasa cofacror Fig.85-4). isolated
of biotin. Treatment rvich biotin (10 mg/day orally) usually results in an imDrovement in clrnical manifestatton\ and may normalize the biochemical abnormalities. Early diagnosis and treatment are of this enzvme musc be differentiaced from disorders of biotin metabolism (multiple carboxylase deficiency), which cause drminished actrvity of all four carboxylases, 3-Methylerotonyl CoA carbo:'ralase is a heteromeric enzyme consisting of cr (biocin containing) and p subunirs. Clinical manifestations are highly variable, ranging from fatal neonatal onset wrth acidosis, severe hypotonra, and seizures to asympromatic adults. In the severe form of the condition, the affected in{ant who has been seemingly normal de.'elops an acute episode of vomiting, hypotonia, lethargy, and convulsions after a ninor infection. Death may occur during the acute episode. Laboratory findings during acute episodesinclude mild to moderate acidosis, ketosis, severe hypoglycemia, hyperammonemia, and elevared serum levels of liver transaminases. Large amounts of 3-hydroxyisovaleric acid and 3-methylcroconylglycine are found in the urine. Urinary excretion of 3 mechylcrotonic acid rs not usualh' increased in this condition because the accumulated 3-merhylcrotonyl CoA is converted to 3-hydroxvisovaleric acid, Severesecondarv carnrtrne deficiency is common. The condition should be differenciated biochemically from multiple carboxylase defcrency (seeearlier) in which lactic acid and metabolites of propionic acid are present in body fluids in addition to 3-hydroxyisovaleric acid. Diagnosis rnay be confirmed by measurement of the enzyme activity in cultured fibroblasts, Documentation of normal activities of other carboxylases is necessaryfor delimtive diagnosis. Aggressive treatment of acute episodes with hydration, intravenous infusion of glucose, and alkali is recommended. These parienrs are unresponsive to biorin therapy. Parients who io earlier reporrs were found to be t'iotin fe\ponsrve were mo\[ probably suffelng from muftiple carboxylase deliciency due co biotinidase defrciency (see earher). Long-term treatmnt includes a dier rescriccedin leucine in conjuncrion with the oral administration of L-carnitrre (7 5-100 m{k{24 hr) and the preventron of catabolic states.Normal growrh and development are expected in thesepatlents. The condition is inherited as an autosomal recessivetrait. The gene for cr subunit (MCCI ) is located on chromosome 3q25-27 and rhar for the p subunir \MCC2) is mapped to chromosome 5q12-13. Mutation in either of thesegenesmay resulcin the deficiency of rhe enzyme activity. Srmilar phenoqvpe may be caused mutations rn either by different genotype. Several drsease-causrng gene have been idennfied in different families. Newborn screening programs using tandem mass specrrometry have identifred an unexpectedl;r high number of infants with 3-methylcrotonyl CoA carboxylase deficiency (1:50,000), suggesting that this condition may be one of the most common organic acidemias in certain ooDulatl()l1s.

related to che ourcome lemains unclear.

ciency. Infants q'ith this defictency may de maniiestations similat to those seen in infants

lop. clinical lth holocar-

544 I PARTX. Metabolic Diseases

546r PART r Metabolic X Disrosas Laboratory findings include marked elevation of mevalonic acid in urme; the concentration may be as high as 56,000pmole/ mole of creatinine (normal <0.3). Plasmalevels of mevalonic (as acid are also greatly increased high as 54 pmole/dl; normal <0.004). This is the only abnormal organic acid found in these patients,The levelo[ mevalonicacid tends to correlarewith the severityof the condition and increases during crises. SerumchoIesterolconcentration normal or mildlv decreased. is Serumconcentrarionof crearinekinare 1CK1 is markedly increased, Sedimentation rate and serumleukotriene-4 increased are during prol the crises, Serialexamination rhe brain by MRI reveals of gressjve arrophvof the cerebellum, Diagnosismay be confirmed b,v assayof mevalonatekinase activity in lymphocytesor in cultured fibroblasrs.No effective therapy is available,Tieatment with high dosesof predmsone improvementof the acutecrises. The con12mg/kEl24hr) causes dition is inheritedas an autosomalrecessive tuait. Prenataldiaenosis is posrible by measuremenr mevalonicacid in rde of amniotic fluid, by assay the enzymeacrivityin culturedamnioof cytesor chorionicvilli samples by demonstration lhe mutalt or of gene.The genefor mevalonate kinase(MVK) is on chromosone (Sc0T) SUCCINYt C0A:$KETOACID C0ATRAiISFERASE DEFICIENCY 1,2924. This enzymeis necessary the metabolismof ketone bodies for Pe odic Fever with Hyperimnunoglobulinemia {Mevalonic D (acetoacetare and 3-hydro:r1'butyrate) peripheral tissue (see Aciduria,Mild Form). in Somemutarions of mevalonickinase eene Fig. 85-7). A deficiencyof this enzymeresults in the underutitMVKt causemild deficiencies rhe enzyme of and producethe lization and accumulationof ketone bodies and ketoacidosis, clinical picture of periodic fever with hyperimmunogobulinemia Only a few patientswirh SCOT deficiencyhave been reported D. Thesepatientshave periodic bouts of fever associated wirh to date; the condirion may not be rare because many cases are abdominal pain, vomiting, diarrhea, arthralgiaj arthri!is, undiagnosed. hepatosplenomegaly, lymphadenopathy, and morbiliform rash The presentationis an acute episodeof unexplainedsevere (evenpetechiaand purpura) which usually start before 1]'r of ketoacidosis an infant who had beengrowing and developing age.The anacks in can be produced vaccinarion, bv minor rrauma, normalh'.About half of rhe patientspresentin the 1st wk of life or stress;usually occur every 1-2 months and last 2-7 days. and all before2 yr. The acureepisodeis often precipitatedby an Patientsare free of symptomsberweenacute attacks.The diagintercurrent infection or a catabolic state. Death may occur nostic laboratory finding is elevationof serum rmrnunoglobulin duringrhese episodes. chronrc A suhclinical kerosis usuallypergammaD (lgD); IgA is also elevated 8070 of patients.During in the sis!sbetrveen attacks,Development usually normal. is acute attacks, Ieukocvtosis,increasedC-reactjveprotein, and Laboratory findings during the acute episodeare nonspecific mild mevalonicaciduria may be present,High concentrationof and includemetabolicacidosis and ketonuria with hieh levelsof serum IgD differentrates this condition from familial \4editerand in aceroacetate J-hydroxyburyrare bloodand urini. No orher raneanfever. organicacidsarefound in the blood or in the urine.Blood glucose Tieatment of acute artacksremainssymptomaric.The condiare levels usuall)normal,bur hvpoglycemia beenreponedin har tion is inherited an aurosomal as recessire trairrmostoafients are (60'i, are either two newborn infants rvirh severeketoacidosis,Plasma amino whireand are from western European countries acidsare usuallynormal. Diagnosis can be established demonby Dutch or French).The enzymeactivity is usuallyabout 5-15% strating a deliciencyof enzymeactivity in cultured fibroblastsor of normal. The parhogenesis the condition remains unclear. of bv DNA analvsis. Severaldisease-causng mutations of the genellocated on chroTreatmentof acute episodes consistsof hydration, correction mosome12q24) have beenidentifred,but one mutation (V377I) and the provisronof a diet adequate calones.Longof acidosis, in is presentin 807o of pacrents. Long-term prognosisis usually term treatmentrvith a high-carbohydrare diet and avoidanceof good,but amyloidosir occurred a teu parienrs. has in carabolicstatesis recommended. This condition sbould be consideredin any infant tuith wnexplamed boats of hetoacidosis. The condition is inherited as an autosomaltecessive trair, The eene PBOPIOI{IG ACIDEMIAIPROPIONYT COA CABBOXYTASE DEFIfor rhis enzlme is locaredun chromosome 5plJ, and .eieral CIENCY). Propronic acid is an intermediate merabolite of mutationshave beenfound in different famrles. drsease-causing isoleucine, vahne, threonine,methionine,odd-chainfary acids, and cholesterol catabohsm. is normallvcarboxvlated methvlIt to MEVAL0NIC ACIDUBIA. Nlevalonicacid, an incermediate metabom a l o n i c c i d b y r h e m r r o c h o n d r ie n z l m ep r o p i o n vC o A c a r al a l lite of cbolesterol synthesrs, convertedco 5-phosphomevalonic boxylase, is which requiresbiotin as a cofactor (see Fig. 85-4).The acid by tbe action of the enzymemevalonate kinase(seeFig. 85enzyme composed rwo nonidentical is of subunits, and p. Biotin a 7). Basedon clinical manifestations, rwo forms o{ this condirion is boundto the cr subunic. have beenrecognized. Clinical findingsare nonspecific. the sel'ere In form of the conMevalonic Aciduria, Seyere Form. Clinical manifesrarions ditior, patientsdevelopsymptomsin the 1st few days or weeks includemencalrerardation,failure to thrive, growth rerardation, of life. Poor feeding,vomiting, hypotonia,letharg,r', dehydration, hypotonia,ataxia,hepatosplenomegaln cataracts, and facial dysand clinical signsof severe kecoacidosis progress rapidlv to coma morphrsm(dolichocephaln fronral bossing,low-set ears,downand deach. Seizures occur in =307oof affected infancs. an rnfant If ward slanringof the eyes,aod long eyelashes). Recurrenc crises, survivesthe 1st attack, similar eprsodes ma,y occur during an characterizedby fever, vomiting, diarrhea, arthralgia, edema, intercurrentinfecrionor colstipation or afrer rngestion a high of lymphadenopathy', further enlargement liver and spleen,and of protein diet, Moderate to severe mental retardattonand neuromorbrlliform rash have been observed in all patients. These logicabnormaliries suchasdystonia, choreoathetosis, uemor,and last 4-5 days and recff up to 25 times/yr Death may eprsodes pyramidal signsare common sequelae the older survivors,In in occur durine thesecrises. the milder forms, the older rnfant nay have mental retardation during acure artacks.Diagnosismay be confirmed by enzyme in assay cufturedfibroblasts,leukocytes, liver specimens by or or identificationof the mutant gene.Prenacal diagnosrs possible is by the assay the enzymein cultured amniocytes a chorionic of or villi biopsy or by DNA analvsis. Treatment of acute episodes includes hydratron, infusion of glucose control hypoglycemia, to provision o{ adequate calories, and adminisuationof bicarbonare correct acidosis. to Hyperamm o n e m i as h o u l d b e r r e a r e d r o m p t l y { s e eC h a p r e r8 5 . 1 1 ) . p Exchange transfusionand peritonealdialysismay be requiredin patintswirh severe hyperamrnonemia, Restrictionofprotein and fat intake is recommendedfor long-term management.Oral administrationof L-carnitine(50-100 mg/kg/24hr) preventssecondarycarnitinedeficiency. Prolongedfastingshouldbe avoided. One child died after routine immunizarion. The condition is inheritedasan autosomal recessive trait. The eenefor HMG-CoA lyare resides chromosomelprer-p33 and severaldrseaseon causingmutationshave beenidenrifiedin different families.The genedefect appearsto be more common in the Arabic population, especially SaudiArabia. in

Chapter r oefuclsi[ Mdtabolisnol AminoAcids r 547 85 without acute attacks of ketosis. Some affected chrldren mav hat'e episodes of unexplained se,'ere keroacidosis separated by periods oi seemingly noimal health. Mass screening of newborns- has identified milder forms of rhe condition; a few of theses infants were complerely asl/mptomatic at diagnosis. The seleriry of clnical manifestartons may also be variable wirhin a familv; io one kindred, a brother was diagnosed at 5 yr of age whereas his 13 yr old sister, wirh the same level of enzyme deficiency, was tered (10 mg/24 hr orally) to all infants during the 1st attack and until the diagnosis is established. Long-rerm treatment consists of a low-protein diec (1,01.5 dkg/24 hr) and admrnisrradon of L'carnicine (50-100 mg/kg/ 24 hr orallyr. Synrheticproteins deficienr in propionare precurvaline, methionine, and threonine) may be used sors (isoleucine, to increase the amount of dietary protein (ro 1.5-2.0 g/kg/24 ht) rvhile causing minimal change in propronate productron. Excessive supplementarion wich these proteins may cause a defrciency of the essenrial amino acids. To avoid rhis problem, natural proreins should comprise most of che diecary protein (50-75%). Some patienrs may require chronic alkaline therapy to correct chronic acidosis. The concentration of ammonia in the blood usually normalizes between attacks, and chronic trearment of hyperammonemia is not usually needed. Carabolic srates that may trigger acute attacks (rnfections, constipation) should be treared promptly and aggressively.Close monitoring of blood pH, amino acids, urinary content of propionate and its metabohtes, and growth parameters is necessaryto ensure the proper balance of the dret and lhe successof therapy. Long-term prognosis is guarded. Deach may occur during an acute altack. Normal psychomotor developmenr is possible, espe cially in the mild forms identrfied through screening programs; mosr children identified clinically manifest some degree of permanent neurodevelopmental deficit such as dystonia, chorea, and pyramidal signs despite adequate therapy. These neurologic lindings may be sequelae of a metabolic stroke occunng during an acute decomoe[sadon lseeearlier). Prenatal diagnosis is achieved bv measuring the enzyme activity in cuhured amniotic cells or in samplesof uncultured chorjonic villi, by measurement of methylnitrate in amniotic fluid, or by identi6cation of the murant gene. The condition is inherited as an autosomal recessiverrait and can be identified by mass screening of newborns. Ic is more prevalenr in Saudi Arabia (1 :2,000 co 1 :5,000). The gene for the cr subunit (PCCA gene)is located on chromosome 13q32 and chat of rhe p subunit (PCCB gene) rs mapped to the chromosome 3921-q22. Many mutations in either gene have been identified in differenr patients. Pregnancy with normal ourcome has been reporred in affected females. METHYIMAI0I{|C ACIDEMIA. Methylmalonic acid, a structural isomer of succinicacid, is normally derived from propionic acid as part oI the catabolicparhways of isoleucine, valine, rhreonine, methionine,cholesterol, and odd-chain fatt)'acids. Two enzymes are involved in the conversion of D-methvlmalonrc acid to succrnjc acid: methylmalonfl CoA racema'e, rthich iorms rhe Lisomer; and melhylmalonyl CoA mutase, rvhich converts the L-methylmalonicacid to succinicacid (seeFig. 85-4). The latter enzymerequiresadenosylcobalamin, metaboliteof vitamin B12, a as a coenzyme. Deficiency of either the mutase or its coenzyme causes lhe accumularion of methylmalonic acid and its precursors-in body fluids. A defrciency of rhe racemase has not been connrmeo. At least tr.o forms of mutase apoenzyrne deliciencieshave been identified. These are designared muttt, meaning no detectable enzyme actrvrty, and muf, indicating residual, alrhough abnormal, mucase activity. The majority of reporred patients.rvirh methylmalonrc acidemla have a deficiency of the mutase apoenzyme \mult or m r/ ). The\e patienrsare nor respon\iveto vitamin B12rherapr'. In the remarning patients with methylmalonrc acidemia, the defecr resides in che formarion of adenosylcobalamin. Defects Metabolism in olVilamin Bu (Cobalaminl. Dietar_v vitamin 812requires rntrinsrc factor, a glycoprotein secreted by the gastric parietal cells. for absorption in the terminal ileum, It is transported in the blood by 6apcocorrin(TCI) and transcobalaminII (TCII). The complex of rranscobalaminll-cobalamrn (TCII-Cbl) is recognized by a specific receptor on the cell membrane and enters the cell by endocytosis. The TCll-Cbl complex ls

and oreviously menrioned organic acids usualll persisLberueen the acureanaik,. ( T rcan and MRI oF the brain mar revealer i

r 550r PARTX Metaholic oiseases l{eonatalHypelglycemia. This is the most common form of NKH. Clinical manifestations developin the lst few days of life (between6hr and 8 days after birth), Poor feeding,failure to suck, lethargy,and profound h1'potonia may progress rapidly to a deep coma, apnea, and death. Convulsions, especially myoclonic seizures and hiccups,are common, Laboratoryfindingsrevealmoderateto severe hyperglycinemia (as high as eight rimes normal) and hyperglycrnuria.The unequivocal elevationof glycineconcentration the spinal fluid in (15 to 30 times normal) and the high ratio of glycineconcentration in spinal fluid to that in plasma (a value >0.08) are diagnostrc of NKH, Serum pH is normal; plasma serine levelsare usuallylow About 30% of affectedinfants die despitesupportiverherapy, Those rvho sun'ive developprofound psychomotorretardation and lntractable seizuredisorders(myoclonic and/or grand mal seizures). Hydrocephalus,requiring shunring, and pulmonary hypertension have beennoted i[ somesurvlvors. InlatttileilKH. These previouslynormal infants developsigns and symptomsof neonaralNKH (seeearlier) after 6 mo of age. Seizures the commonpresenting signs. This condition appears are to be a milder form, infants usuallysurvive,and mental retardation is not as profound as in the neonatalform. laboratory findingsin these patientsare rdenticalcothe neonatal lorm. Late-Onset ilKH,Mild Episodic Progressive spasticdiplegia, Form. optic atroph]'.and choreoathetotic movemenls the main clinare ical manifestations, Age of onserhas beenbetween2 and 33 yr. Symptoms delirium, chorea,and verticalgazepalsymay occur of episodicallyin some patients during an intercurrent infection. Mental development usuallynormal, but mild retardationhas is beenreported in some patienrs.Seizures have occurred in only one parieqt. Laboratoryfindingsare similar to but rtot aspronouncedas in the neonatalform. TransientNKH. Most clinical and laboracory manifestations from those of the neonaral of thrs form are indistineuishable glycinelevelsin form. By 2 to 8 wk of age,however, elevated the plasmaand cerebrospinal fluid (CSF)normalizeand a complere clinical recoverymay occur.Most of thesepatientsdevelopnorbut mental retardation has mally with no neurologicsequelae, been noted in some. The etiology of this condition is not known, but it is believed be due ro immaturity of the enz:/me to svstem. Atl forms o{ NKH shouldbe differentiated from ketotic hvoerglycinemia, o-glyceric aciduriatseelarert,and ingestion valof proic acrd.The latter compound causes moderateincrease a in blood and urinary concentrations glycine.Repeatassays of after discontinuationof the drug should establish diagnosis. the Diagnosiscan be established assay the enzymein liver or of by brain specimens by idenrifcation of the mutation. Enzyme or activityin the neonacal in form is closeto zero,whereas the other forms, someresidualactivitv is present. most patientswrth the In neonatal form, the enzymedefect residesin the P protein; the defectin the T protein accountsfor rhe rest. The enzymeassay in three patients with rhe infantile and late-onsetforms has revealed two patientswith the defectin the T protein and one in the H protein. No effective treatmentis knorm, Exchange transfusion, dietary restrictionof glycine,and administrationof sodium benzoate or folate havenot alteredthe neurologicoutcome.Drugs that counteract the effect of glvcineon neuronalcells,such as strychnine, diazepam,and dexuomethorphan,have shown some beneficial effeccs only in patrentswith the mild forms of the condition. NKH is inherited as an autosomalrecessive trait. The orevalence nor known. bur high frequency the disorder is of hai been noted in northern Finland (1/12,000).The genefor P protein is locaredon chromosome 9p22. The genefor H protein is mapped to chromosome 16p24and that for T protein is mappedto chromosome 3p21-p21,1. Severaldisease-causing mutarionshave beenidentified.Prenatal has diagnosis beenaccomplished perby Iorming an assayof the enzymeactivity in chorionic villi biopsy specimens by identifrcationof the murant gene. or (N-methr.lSARC0SIIEMlA. Increased concentrations sarcosine of glycrne) observed borh bloodand urine.but no consisrent are in clinical picture has beenattribucedto this melabolicdefect.This is a recessively inherited inborn error involving sarcosine dehydrogenase, enzymethat convertssarcosine glycine(see the to Fig. 85-8).The genefor this enzymeis locaredon chromosome 9q33q34. D-GIYCEF]C ACl0UBIA. o-glycericacid is an incermediate metabolite of serine and fructosemetabolism(see Fig. 85-8).At leasttwo forms of this rare condition have beenidentrfied,In one form, clinical manifestationsof severe encephalopathy(hypotonia, seizures, mental and motor deficits)and the laborarorylindand rngs of hyperglycinemia and hyperglycinuria were suggestire of nonketotichyperglycinemia. Thesepatientsexcretedlarge quantities of o-glycericacid (this cornpound not normallv detectable is in urine). Enzyrne studies indicated a deficiencyof glycerare kinasein one pacienrand decreased activity of o-glyceric dehydrogenase another. ln In the other form, the major findrngsare persistent metabolic acidosis and developmentaldelay, This infant excreted large amountsof p glycericacid without hvperglycinemia. enzvme The defectin this patient is not known. No effectrve rherapy is available. Resrncrion of fructose improved seizures one pacient. in TBlMEttlYLAMlNUBlA. Trimetiylamine is normally produced in the intestine from the breakdo*'nof dietarycholineand trimethvlamine oxide by bacceria. Eggsand liver are the main sources of choline, and fish is che major source of trimethylamrneoxide. Trimethylamine absorbed is and oxidizedin the liver bv uimethylamine oxidase(flavin-containing monooxygenases) trimethyto lamineoxide, which is odorless and excretedin the urine (see Fig. 85-8). Deficrency rhis enzymeresultsin massive excretionof of trimethylamine in urine. Severalasymptomatic patients with trirnethylaminuriahave beenreponed; there rs a foul body odor thar resembles tha! of a rottefl lish, which may have significant social and psychosocial ramifications.Restriction of fish, eggs, Iiver,and other sources choline (suchas nuts and grarns)in the of diet significantlyreducethe odor The gene for trimethylamine oridasehas beenmapped chromosome 1q23-q25, ro HYPEROX LURIAAND 0XAt0SlS.Normally, oxalic acid is derived mostly from oxidation of glyoxylic acid and, to a lesserdegree, from oxidation of ascorbicacid (seeFig. 85-8). Glyoxylic acid is formed from the oxidation of glycolic acid in the preoxisomes. The source of glycolic acid remains unclear.Foods containing oxalic acid, such as spinach and rhubarb, are the main exogenous sourcesof this compound, Oxalic acid canlor be further metabolizedin humansand is excretedin the urine as oxalates. Calcium oxalate is relativelyinsolublein water and precipitates (kidneysand joints) if its concenuationincreases the in tissues in
DOOy,

Secondary hyperoxaluriahasbeenobserved pvridoxine defiin ciency(cofactorfor alanine-glyoxylare aminotransferase, Fig. see 85-8) after ingestionof ethyleneglycol or high dosesof vitamin C, after administrationof che anestheticagent methoxyflurane (u'hrch oxidizes directly to oxalic acid), and in patients with inflammaroryborvel disease extensive or resectionof the bor,r'el (entetichyperoxaLarlal. Acute, fatal hyperoxaluriamay develop after ingestionof plants with a high oxalic acid conten! such as causes hl?oca1sorrel.Precipitationof calciumoxalatein tissues cemia,liver neclosis, renalfarlure,cardiacarrhythmia,and death.

Ch60ter . 0electsin Motabolism AminoAcids r 551 85 ol The lethal dose of oxalic acid is esrimated to be berween .5 and 3og Primary hlperoxaluria is a rare genetic drsorder in wbich large amounts of oxalates accumulate in the body. Two tvpes of comrnon in this condition than rn hyperoxalurra type [; the urine concains large amounts of L-glyceric acid in addition to high levels of oxalate (L-glyceric acid is not normally present in urine). Urinary excretion of glycolic acid and glyoxylic acid is not increased.The presenceof L-glvceric acid without increased levels of glycolic and glyoxylic acids in urine differentiates this type from type I hyperoxaluria. The gene is mapped to chromosome No effective therapy is available. DEFICIENCY CREATINE Creacineis synthesizedin the liver, pancreas, and kidneys from arginrne and glvcrne (Fig. 85-9) and is rransported to muscles and the brain, in lr'hich there is high creatine kinase activitl'. Phosphorylation and dephosphorylation of creatine by this enzyme in conjunction with adenosine diphosphate and triphosphate (ADP/ATP) provide high-energv phosphare reactions in rhese organs. Creatine is nonenzymatrcally metabolized to crearinine ar a constanr daily rate and is excreted rn the urine. Three eenetic conditions are known !o cause creatine defciency in rissues,Two are due to deficiency of the enzymes involved in the biosynthesrs of creatine. The enzymes are (AGAT) and quanidinoacerate arginrneglycine aminotransferase (see Frg. 85-9). Borh conditions methyltransferase (GAIIT) respond well to creatine supplementation. The third condition is caused by the defect in the creatinine transporter (CRTR) and is not resoonsir ro crearinineadminisuation. e Cliniial mani{estations of the three defects are similar, relate to the brain and muscles, and rnay appear in the 1sr few weeks or months of hfe. Developmental delan mental retardation, speech delal and serzures are common. Dystonic hyperkinecic movements are seen in severe GAMT deficiencv. Laborarory findings include decreased crearine and crearnine in blood and urine in patients with AGAT and GAMT defects. Marked elevations of guanidinoacetare in blood, urine, and especially in CSF are diagnostic of GAMT defects, Low levels of suanidinoacetate are found wirh rhe AGAT defect. Absence of ireatine and creatine phosphate (in all three defects) and high levels of guanidinoacetare (with GAMT defects) can be demonstrated in the brarn by MRS. MRI shows signal hyperintensiry of the globus pallidus. Diagnosis of AGAT or GAMT defects may be confirmed by measurement of th enzyme n the livert cuftured Gbroblascs,or srimulated lymphoblasts or by DNA analysis of rhe gene. Diagnosis of CRTR is confirmed by genetic analysis or creatrne uptake b;i libroblasrs. Treatment with creatine monohydrare (350 mg-z g/kg/day) orally has resulted in a dramatic improvement in muscle tone and overall mental develooment and has normalized MRI and elecrroencephalographic 6ndings in pacients wich AGAT and GAMT defects. It is believed that early treatment may assure normal development. No therapy rs available for the CRTR defect. AGAT and GAMT defects are inherired as aulosomal recessive traics. CRTR rs an X-hnked rrait. The orevalence of the enzvme rrhree deficrency nor known: lour patientswrrh CA\lT derecr,, is from one family) were identified among 180 insticutronalized patients with severe mencal handicap. This condition must be considered in any patienc with brain and muscle disorders, since treatment calr produce a dramatic response.

peroxrsomes(seeFig. 85 8). There is a wide variation rn rhe age of presentarion. The majority of patients becomesymptomatic before 5 yr of age. In =10% of cases, s,vmptoms de"elop before 1vr of age (neonatal oxaluria). The inicial clinical mariifestations are related to renal

as gout becauseuric acid is usually elevared in patients wirh rype I hyperoxaluria. Late forms of the disease presenting during adulihood have also been reported. Crystalline retinopathy and optic neuropath,v causing visual loss have occurred in a fe* patlenrs. A marked rncrease in urinary excretion of oxalate {normal excrerion 10-50mg/24 hr) is the most important laboratory fiading. The presence of oxalate crystals in urinary sedimenr rs rarely helpful for diagnosis because such crystals are often seen in normal indivrduals. Urinary excretion of glycolic acid and glyid is rncreased.Diagnosis can be confirmed by petformoxylic ing an say of the enzyme in hver specimens or by identification of the mulant 8ene. Medical trearment has been largely unsuccessful. In some patrents, administration of large doses of pyridoxine redu s urinary excretion of oxalate. Renal transplantation in patie s with renal failure has not improved rhe outcome in most cases, because oxalosrs has recurred in rhe transplanted kidney. Combined liver and kidnev transplanrs have resulted in a sLgnificant decreasein plasma and urinary oxalate in a few patients, and this

this condition. The most common muracion results in the mistargeting of the enzyme to the mitochondria instead of the peroxiiomes. The in vicro enzyme activi!y in these patients may reach the level found in obligate heterozygotes. In vivo function remains defectrve,however About 30% of parients with hvperoxaluria type 1 are estimaled to have this defect. Prenatal diagnosis has been achievedby the measurementof fetal hepatic enzyme activiry obtained by needle biopsy or by

dition is due to a deficiency of D-glycerate dehydrogenase (hydroxypyruvate reductase)/glvoxylate reductase enzyme in complex (seeFrg. 85-8). A deficiency the activrtyof rhis enzyme resu[|s in an accumulation of two intermedrate metabolites, hydroxypyruvate (the ketoacid of serine) and glyoxylic acrd. Both these compounds are further metabolized by lactate dehydrogenase (LDH) to L-glyceric acid and oxalic acid, respectrvely.About 307' of reporced patients are from the Saultear-rx-Oiibway Indians of Manicoba. Clinically, chesepariencs are rndiscinguishable from those with hyperoxaluria type I. Renal stones presenring with renal colic and hemarr.rria may develop before age 2 yr. Renal failure rs less

o 85.8.SrRttr lrai Rezvani

Senne rs a nonessenrial amino acid synthesized from glucose and glycine (seeFig. 85'9). 3-PH0SPH0GLYCEBATE DEHYDR0GENASE DEFICIENCY Deliciencl, of this enzyme causes deficiencies of serine and glycine in rhe body. Clinical manifestations, which are developed in the 1st few months of life, include microcephaly, severe psychomotor retar-

X Diseases 552 ! PAFIT I Met6bolic

Glucose

3-Phosphoglycerate

3-Phosphoglycerale
deficiency

I I l^

3-Phosphopyruvate Sarcosine clyoxvlate I

I"

\l
\:ryutrre Arginine ------ |

Serine.-

3-Phosphoserine

Figure 85 9. Pathways for the svnthesisof serineand cre3tine.Enzymes: 3-phosphoglycerate dehydrogen i1) (GAMT). as, (2) guanidinoacetare methyltransferdse (3) arginine:glycineaminorranslerase (ACAT).

---4 Ornithine

\ /-:\ \9/ I Guanidinoacetate

S-noenosVlmethionine 6{ YJ S-Adenosylhomocysteine
Creatine + + Creatinine I

Urine

Other findingssuchas failure to darion, and intractableseizures. cataracts,hypogonadism, thrive, spastictetraplegia,nystagmus, anemiamay also be present. and megaloblastic Laboratory findingsinclude low lel'elsof serineand glycinein plasma and very low levels of serine and glycine in CSF No abnormalorganicacid is found in the urine. Magneticresonance imaging of the brain shows significant attenuation of white matter and incompletemyehnation. of Diagnosiscan be confrrmedby measurement the enzyme activity in cultured fibroblastsand by DNA analysis. Tieatment with serine(200-600 mg/kg/24hr, orally) alone or in conjunction with glycine (200-300 mg/kg/24hr) normalizes the serinelevelsin the blood and CSF.This rreatmen!produces improvementin all clinical frndingsexceptfor the psysignificant activity subsides within a few days chomotor retardation;seizure Microcephalyimproves of therapyand may be haltedcompletely. in young affectedinfants. There is evidence indrcaterhat psyto if chomororretardationmay be prevented rhe trearmentstarrsin the 1st few days of hfe. The condition is inheritedas an autosomalrecessive trait. The gene for 3-phosphoglycerate dehydrogenase enzyme has been 1q12 and a few disease-producing mutamappedto chromosome tions have beenidentifiedin different families,Prenataldiaenoachieved DNA analysis a familywith previously by in sishasbeen affectedoffspring; administrationof serine to the mother correctedmicrocephalyin the affectedfetus as evidenced ultraby sound imagrng.The favorable responseof this condition to a simple treatment makes this dragnosis important consideraan and neurologicdefectssuch tion in any child with microcephaly as psychomotordelay or a seizuredisorder

hydroxyproline (dipeptides and tripeptidescontaining hydroxyproli[e) reflectscollagentu.nover and is iflcreased drsorders in of acceleratedcollagen turnover, such as rickets or hyperpa!alhyroidism. HYPERPR0IINEMIA. types oI this rare autosomaL Two recessive condition have beendescribed. TypeI hypetprolinemia\s dre to a deficiencyof proline dehydrogenase, and type II is due to a defect in A'-pyrroline-5-carboxylrc enzyme acid dehydrogenase (Fig. 85"10). Neither type causes any specificclinical manifestation attributableto hyperprolinemia. lncreased blood concentrations of proline (morepronouncedin rype II) and prolinuria are found in both types. Hydroxyproline and glycine are also excretedin abnormal amountsin the urine because the satuof ratjon of the commofl nrbular reabsorprionmechanismby the massiveprolinuria. The presenceof ALpyrroline-S-carboxylic acid in plasma and urine differentiates type II from rype L No for treatmentis recommended the affecredindividuals. The genefor proline dehydrogenase mapped!o chromosome rs 22q11.2 and several disease-causrng mutationshave beenidenci6ed; somemutationshave beenassociated risk with an increased of schizophrenia. Ivlicrodelerion chromosome of 22q11.2 causes velocardiofacial(DiGeorge, Shpritzen) syndrome. In a study, eight out of 15 patientswith this syndromealso had typeI hyperprolinemia. It has been suggested that patienrs wirh hyperprolinemia be screened (by FISH analysis) for presence of rnicrodeletronof chromosome22q11.2. The gene for A'pyrroline-5-carbor.1.lic acid dehydrogenase mapped ro chrois mosome:1p36, PR0IIDASEDEFICIENCY During collagen degradation, imi(suchasglycylproline) released arenorrnally dodipeptides are and for cleavedby tissueprolidase.This enzymerequiresmanganese its proper activity. Deficiencyof prohdase, rvhich is inheriredas an autosomalrecesslve ftait. resultsin the accumulationof imidodipeprides body fluids. in The clinical rnanifestations lhrs rare condirion and rhe age of at onsetare quite variable(19mo to 19yr) and includerecur-

o lrai Rezvani 85.9. PR0LINE

Proline and hydroxyprolineare found in high concentrarions in collagen. Neither of theseamino acidsis normally found in urine in the free form exceptin early infancy. Excretion of "bound"

Chaoter . Dolocts l{otabolism0l Amim Acids . 553 85 in

A'-Pyrroline5-carboxylic acrd
!-igure 85-10. Pathways in rhe mecabohsmof pro line. Enzymes: (1) proline oxidase, (2) ^lpyrroline (3) l-carboxylic acid dehydrcgenase, hydroxyproline

\.)
Glutamic acrd

Ornithine

19 Hydroxyproline Hyd.oxyprolinemia

++ A'-Pyrroline+hydroxy-scarlgoxylic acid

Pyruvic + acid

Glyoxylic acrd

rent, parnful skin ulcers, which are rypically o hands and legs. Other skin lesrons that may precede ulcers by veral years may include scaly erythematous maculopapular rash, purpura, and telangiectasia. Mosr ulcers become infected Healing of the ulcers mav iake 4 to 7 mo. Mild to severe mental and motor deficits and suscepribilityto infecrionsare also present in morr patients (recurrent otitis infection, media, sinusitis, respiratory splenomegaly). Infection is rhe cause of death. Some patients may have some craniofacial abnormalities such as ptosis, ocular propcosis, and prominent cranial sutures. Asymptomatic cases have also been reponed. Development of systemrc lupus erythernatosus {SLE) has been nored in affected children of one family; young patients wrth SLE should be screened for prolidase defrciency. iligb leuels of urinary excretion of imidodipepcides are dragnostic. Enzyme assay may be performed in eryrhrocytes or cultured skin 6broblasts, Oral supplementation wrth proline, ascorbic acid, and manganese and the topical use of proline and glycine result in an improvement in leg ulcers. These treatments have not been found consisrently effective in all patients. The gene for prolidase enzym has been mapped to chtomomutations have some 19cen-q13,11and several isease-causing been identified in drfferent families,

AclD GturAMtc . lraiRezvani 85.10.

Glutarhione (y-glutamylcysternylglycine) is the major product of glutamic acid in rhe body. This ubiquitous tripepcide is synthesized and degraded through a complex cycle called the y-glutamyl of cycle (Frg. 85'11). Because irs free sulfhydryl (-SH) group and its abundance in the cell, glutathione protects other sulfhydrylcontaining compounds (such as enzymes and coenzyme A) from oxidation. It rs also involved in rhe detoxification of peroxides, including hydrogen peroxide, and tn keeprng the cell content in a reduced stare. The common consequence of glurathione deficiency is hemolytic anemia. Glutathione also partrctpates in amino acid traflsport across the cell membrane through the 1glutamyl cycle. Three forms of 0EFICIENCY SYNTI|EIASE GIUTATHI0NE {FlG.85-11). this condition have been reported. In the severe form, whrch is due to generalzed deficiency of the enzyme' severe acidosis and massive S-oxoprolinuria are the rule. ln rhe mild forrn, in which the enzyme deficiency causes glutathione deficiency only in erynor acidosis has been throc;tes, neither 5-oxoprolinuria observed. A moderate form has also been observed rn which the hemolytic anemia is associared with variable degrees of acidosis and 5-oxoprolinuna. In all forms, patients have hemolpic anemia secondary to glutathione defictency. All forms are rare (a coral of 55 patients have been reponed).

Gldathione Synthetase Deficiency, Severe Form (Pyioglutamic Acidernia, Severe 5-oxoFrolinuria) and Modelate Form, Clinical manifestations of thrs rare condition occur in rhe 1st few days of life and include metabolic acidosis, jaundrce, and mild to mod erate hemolytrc anemra. Chronic acidosis continues after recovery. Similar episodesof life-threatening acidosis may occur during gascroenteritis or an infection or after a surgical procedure. Progressive neurologic damage manifested by mental retardation, spastic tetraparesrs, ataxla, tremor, dysarthria, and seizures develops with age. Susceptibrliry ro infection, presumably dLreto granulocyte dysfunction, is observed in some patients. Patients wirh rhe moderate form have milder acidosis and less 5-oxoprolinuria than with the severe form; neurologic manifestations are atso aDsenc. Laboratory frndings rnclude metabolic acidosis, mild ro moderate degreesof hemolytic anemia, and 5-oxoprolinuna. High concenrations of 5-oxoproline are also found in blood. The glutathione content of erythrocytes is markedly decreased.Increased svnrhesisof S-oxooroline in this disorder is believed to be due !o the conversiol of 1-glutamylcysteine to 5-oxoprolne by the enzyme lglutamyl cyclotransferase(see Frg. 85-11). y Glutamylcysteine production Increases greatly because rhe normal inhibitory effect of glutathione on the lglutamylcysreine synthetase enzyme is removed. A deficiency of glutathione synrhetase has been demonstrated in a variety of cells including erythrocytes. teatment of acute attack includes hydration, corrction of acrdosrs (by infusron of sodiurn brcarbonate), and measures to correct anemia and hvoerbilirr-rbinemia. Chronic adminisrration of alkali is usually needed indeGnitely. Administration of large doses of viramins C and E has been recommended. Drues and oxidants thar are known to cause hemolvsir and stressfulcatabolic srares should be avoided,Oral adminisrrationof elutarhione analogs has been tried wirh variable success. Prenatal diagnosis can be achieved by the measurement of 5oxoprohne in amniotic flurd, by enzyme analysis in culrured amnrocytes or chronic villi samples, or by DNA analysis of the gene, Successfulpregnancy rn an affecred female (moderate formJ with favorable outcomes for both mother and rnfant has been reported. GlutathioneSyniheiaseoeficiency, Mild Form.This form has been reported in only a few patrents. Mild to moderate hemotyric anemia has been rhe only clinical finding in these patients. Splenomegaly has been reported in some patrents. Mental devef oDment is normal: metabolic acidosis and increased concentrations of S-oxooroline do not occur Thrs condrtion is due to mulations in tle gene chat encodes for glutathione synthetase enzyme, These mutations, however, presumably render the enzyme unstable but wirh normal catalytic function. The expedited rate of enzyme turnover caused by these mutations is of no consequence for all tissues with normal protein synthesis except for erythrocltes rn which the absenceof protein synthesis results

Diseasss 554 | PABTX. Motabolic

Glutathione synthla6 deficiency . //,,''

(GSH\ _.--Glutathione \\ -Glulafi]'ylcysteinylglycine

,' Amino acid

outside the cell

Glutamyl mylcysteine

"y-Glutamyl amino acid

Lysrne ,? Histidine*Histidine nz' Prcline.' Proline- t Ornithine/

61, Glutamica( r

Figure 85-11. The lglutamylcycle. Defecrs of the glutarhione slnthesis and degradarj<,n are nored. Enzymes: (11 yslucamyl transpeptidase,l2) rglutaDryl cyclotrans ferase,(J) s-oxoprolinase, (4) lslutamyL cvsteine svnthetase, (J) glutathione syn thetase, (6) gluramjc acid decarboxylase, (7) G,{BA transaminase, suc.inic semi (8) aLdehyde dehydrogenase.

5-Oxoproline (pyroglutamic acid)

Vitamin 86 dependency

GABA

Succinic acid semialdehyde

Succinicacid

I I

t-Hydroxybutyricacid

in a serious deficiency of glutathione. Treatment is that of hemoll.ric anemia and avoidance of drugs and oxidants rhat can trigger the hemolytic process. All forms of the condition are inherited as an aulosomal reces sive trait. The gene for rhis enzyme ls located on chromosome 20q11.2. Several disease-causingmutations have been identifed in different families s-0xoprolinase 0eficiency {s-0xoplolinurial. The main cause of massive 5-oxoprolnuria is glutathione synthetase deficiency lsee earlier). Moderate 5-oxoprohnuria has been found in a variety of metabolic and acquired conditions, such as in patients with severe burns, Srevens-Johnson syndrome, homocystinuria, urea cycle defects, and tyrosilemia type I. A few individuals with moderate 5-oxoprolinuria (4-10 g/day) due to 5-oxoprolinase deficiency have been identi6ed. No specific clinical picture has yet emerged. Modera!e !o severemental retardarion has been reported in two patients. Asymptomatic individuals with the enz-vme deficiency have also been identifed, holvever. It is, therefore, not clear r-herher S-oxoprolinase de6ciency is of any clinical consequence. No treatment has been recommenoeo. T-Glutamylcysteine Synthase Defciency. Onl)' a few patients with this enzyme deficiency have been reported. The most consistent clinical manifestation has been rnild chronic hemolytic of anemia. Acure art.rck,, hemolysishave occurred after expoiure to sulfonamides. Peripheral neuropathy and progressive spin-

ocerebellar havebeennotedin tlvo siblingsin adultdegenerarion hood. Laboratory findings of chronic hemolytic anemia were presentin all patients.Generalized is arninoaciduria also present because y-glutamylcycleis involved in amino acid transport rhe in cells (seeFig. 85-11). Treatmmt is that of hemolvtic anemia and avoidance of drugs and oxidants that may trigger the hemolytic process.The condition rs rnheritedas an autosomal recesslve ttatt. (T-GTUTAMYI GIUTAIHI0NEMIA TBANSPEPTIDASE [GGTj DEFIClEl\lCYl, This enzymeis presentin any cell chathas secretorv ot absorptivefirnctions. It is especiallyabundant in the kidneys, pancreas, intestines, and liver. The enzymeis also presentrn the bile. Measurement this enzymein the blood is commonlyperof formed to evaluateliver and bile duct diseases. Deficiency this enzymecauses of elevationin glurathioneconcentrationsin bodv fluids. but the cellular levelsremain normal. Only a few patieniswrth enzymedeficiency have beenreported; therefore,the scopeof clinical manifestations has not yet been behavdelined.Mild to moderatemental retardationatrd severe ioral problemswere observedin three patients.One of the two as sisterswith this condition had normal intelligence an adult, however,and the other had Prader-Willisyndrome. in Laboratory findingsincludemarked elevations urinary concentrations glutathione(up lo 1 g/day),lglutamylcysteine,and of cysteine.None of rhe reported patients has had generalized

85 ol ChaDter | oelectsin Metabolism AminoAcids . 555 to aminoaciduria,a 6ndrng that would have beenexpecced occur in this enzyrnedeficiency(seeFig. 85-11). Diagnosis can be confirmed by measuremenc of rhe enzyme activirr- in leukocytes or cultured skin fibroblasts No effective tratment is available. trair' The The condicion rs inhetited as an autosomal recessive enzyme GGT is a complex prorein and is encoded by at least sevengenes. Laboratory studies reveal marked elevarions in 1-hydroxvbutyrrc acrd concenrrationsin the blood (up co 200-fold), spinal fluid (up to 1,200-fold), and urine (up to 800-fold). There is no acidosis. Urinary excretion of y-hydroxyburyric acrd decreases wirh age. Increased concentrations glycine may also be present of in pJasma,urine, and spinal flLrid. Diagnosis can be confirmed by measuremenr of the enzyme activi!]' in lymphocvtes. Prenatal diagnosis has been achieved by measurement of 1-hydroxybutyric acid in the amniotic fluid and assay of the enzyme activity in lhe amniocytes of in biopsy specimens of chorionic villi, Treatment has been largely ineffective; vigabatrine has produced some improvement !n ataxia end mental status in some Patlents. trait, The The condicion is inherited as an autosomal recessive gene for succinic semraldehyde dehydrogenase has been mapped mutatrons have to chromosome 6p22; several disease'causing been identilled in drfferent families. The role of 1-hydroxyburvric acid in the pathogenesis of this condition remains unclear and somewhat confusing because admrnistrationof this compound to humans and animalshas pro(GHB) has been duced someopposireeffects,1-Hydroxy-bur,vrate used illicitly as a recreationaldrug with anestheticeffecr and is one of the dare-rapedrugs (seealso Chaprer 113). Congenital Glutanine Deficiency. This uncommon disorder is Glutamine is absentin due to a deliciencyof glutamine synthase. plasma, urine, and CSF but plasma levels of glutamate remain normal. Manifesracionsinclude cerebral malformations (abnormal gyration, u.hire matter lesions),multrorgan farlure incltrding respiratory failure, and neonatal death. It may be inhericedas an autosomal lrart; the gene is mapped to chromosome 1q31.

(GABA).Decarboxylation of glutamic acid by glutamic acid decarthe main biosynthetrc pathway for GABA proboxylase (GAD) duction in the b n and other organs, especially the kidneys and the p cells oi the pancreas.Thrs enzyme requires pyridoxine

AClo 0t E8[0BS0t METABoLISM IAMINoBUTYFIC INBoRN

to chromosome 2q31. Knockour of rhe gene for CAD"' in mice causescleft palare; rhe associarionof mutacions in GAD6' gene

rvhich rs presumably caused by decreased activitv of GAD The maio clinical manifestation of thrs condition is seizures, which usually occur in rhe 1sc few hours of life and are unresponsive to conventional anticonvulsanr cherapy. Adminlsrratioo of vltamin 86 in large doses (10-100 mg/kg) usuallv results in a dramatic abnor and electoencephalographic improvementof both serzures malities. Late onset forrns of che conditton (as late as 5 yr of age) have been reported. A trial wirh vitamin 86 therapy has, therefore- been recommendedin anv infant with intracrableseizuresThe dependency is usually hfelong. Other neurologic findings such as delayed speech have been noted in some parients. Laboratory studies bave revealed increased gluramate and decreasedGABA levels in the brain and in rhe spinal fluid. of The parhogenesis this condirion remains unclear Alrhough an increase in che Km of the GAD enzyme for its cofacror (viramin 86) in the brain seems a logical explanation, no abnormality in the GAD activicf in the bram has been documented. DNA studres of rhe gene for GAD* and GADer have likewrse revealed no mutations. Linkage studies have mapped che condition ro rhe long arm of chromosome5q31,2, a locus completely different from loci of GAD genes. Treatment wich high daily doses of vitamin 85 is necessary indelinitell'. GABA Transarninaseoeficiency, This is a very rare autosomal recessivecondition that has been reported rn three infants from tu,'o different families, Clinical manifestarions include severepsychomotor retardation, hypotonia, hyperreflexia, lerhargl, and refractory seizures. Increased linear growth was present in the ofiginal report of two siblings but not in the third patien Increased concentrations of GABA and B-alanine are found i the spinal fluid. Evidence of ler.rkodystrophy u'as noled in the postmortem examination of the brain. GABA transaminase deliciency is demonsrated in the brain and lymphocytes. No effective treatment is available. Treatment rvith vitamin B; has been ineffective. The gene for this enzyme is located on chromosome

. 85,11 UREA lro Hvprnamnirolrtsrurn Gvclr r (Anetrne, CITRULUNE, Onlrutrurl lrai Rezvani
Catabolism of amino acids resulrs rn the production of free ammonia, u'hicb is highly toxic to the central nervous s,vstem. Ammonia is deroxified to urea lhroueh a series of reactions k n o r v n a s r h e K r e h s - H e n . e l e otr u r e a c y c l e ( F i g . E 5 - 1 2 t . f i t e i enzymes are required for the synchesisof urea: carbam,vl phosphate synthetase (CPS), ornirhine transcarbamylase (OTC), (AS), argininosuccinate lyase (AL), argininosuccinate synchetase and arginase, A sixth enzyme, N-acetylglutamate s,vnthetase,is also required for synthesis of N-acetylglutamate, which is an acrivator of the CPS enzyme. Individual deficienciesof these enzymes have been observed and, r'ith an overall estimated prevalence of 1/30,000 live births, they are the most common genetic causesof hyperammonemiain infants, GENETIC CAUSES0t HYPEBAMMONEMIA. addrtron to senetic ln defectsof rhe urea cycle enzymes.a marked increa.e in plarma level of ammonia is observed in other inborn errors of metabolism (Table 85-2). Ctll{l0At MANIFESTATI0t{S HYPERAMMONEMIA. the neona0F In tal period, symptoms and signs are rnostly related to brain dysfunction and are simrlar regardless of the cause of the hvoerammonemia. The affected infant is normal at birth bul beco-es sympromatic within a few days of protein feeding. Refusal to eat, vomrtinB, rachypnea, and lethargy quickly progress to a deep coma. Convulsions are common. Physical examination may reveal hepatomegaly in addition to rhe neurologic signs of deep coma. In infanrs and older children acute hyperammonemia is rnanifested by vomiting and neurologic abnormaliciessuch as ataxia, mental confusion, agrtation, irriThese manifescations may alcernate tabilitl, and combativeness.

deficiency (see Frg. 85-11) have been reported. Clinical manifestarions, which r:sually begin in early infancl rnclude mild to moderate mental retardation, delaved speech. marked hypo findrngs are oculoOther associaced tonia, ataxra, and seizuresautistic faluresrand aggressrve moror apraxia, choreoarhetosis, of behavior.Ataxia may improve with advancemenc age,

556 I PABT I Metabolic X Diseases

Benzoate
I

Glycine+ BenzoylCoA .. Glutamate ' . + Ammonia+co2+ATP

\Jnthetase dellLiency I | I 1

Phenylacetate
,

If A V,

N-Acetyl-glutamic (NAG) acid

*^+ (1)l \, I

| cps oeficiency | _J
phosphale

-I phenytacetyl glutamine

Acetyl CoA l-cl,----;".t'.phy-l + Glutamic - Glutamic acid 'y-semialdehyde acid

oTc
Citrulline

Putrescine

Citrulline

Ornithine .. +--__\ Urea I \ ^ r--------------- l(5)

I A'sininemia | {v \

Cylosol

,,.*".-\q"i:?#;;.
Argininosuccinic aciduria
. i a i fisrrcgi-ll. t t r e a c y c l e :l a r h w a y s i t r a m m o n r r d i s p o s aa n d o r n i t h i n e m e r a b o l i s mR e a c t i o n s c c u r r i n g n r h e m i t o c h o n d r i a r e d e p i c t c d n r w P l " R e a . r i o n s l o (CPSi, l2) onrthine trans shown whh i,,crruptud anoars are rhe afternarepathways for rhe disposal of ammouia. Enzyncs: (l ) carbamll phosphatesynthetase carbamylase(OTC),l])..gininosuccinjcacidsVnthetase(As)'i4)argininosuccnlicacid1yaselAL),ij)aIginase,(6)ornithine5-amlnora ( g l u r a n l e t c N A ( ; ) s y n t h c t a s c . ' H H H s y n d r o m e h y p e r a m m o n r n r a - h v p e r o r n i t h i n e m io m o c r r r u l l i n e m i a . ha .

Arginine

u.rth periods oi lechargvand somnolencetbar may progressto coma. Routine laboratory studies sholv no specifrc findings u'hen hyperamrnonemia rs due to defects of rhe urea cycle enzymes. BLoodurea nirrogen is usually low Serum pH is usuall-v normal or mrldly elevated. In infants with organic acidemiirs, hvperam monemia is commonlv associated rvith severe acidosis. Newborn inFants rvich hyperammonemiaare ofren misdiagnosed having as sepsis;rhev may succumb vr.ithouta correct diagnosis.CT may reveal cerebral edema iFig, 85 13). Autopsy is usually unrcmarkable, It is imperativeto measureplasma ammonia levelsin any ill infant q.hoseclinical manifestationscannot be explained by an obvious infection. DlAGtloSlS. The main cflterion for diagnosis is hvperammonemia. The plasma ammonia concentration in the ill infant rs usuallv >200 ptmole/I. (normal values <35 pmole/L). Al approach to the differeotial diagnosis of hyperanmonemia rn the newborn infant is illustratedin Figurc 85-14- Patienrs with a deficrency of CPS or OTC have no specific abnormalities of plasma amino acids except for increased levels of glutamine, aspartic acid, and alaninc secondary to hyperammoncmia. A marked incrcasein urinary orotic acid in patients with OTC deficiencl"

ol Chrpler85 r Deloclsi[ Motabolism AminoAci& r 557

Figure 8-s 11. Compurer axiat tomographic scans of rhe head oI hyperamnonemic encephalopathyin the composite case of ornirhine transcarbamylasede6 cjency.A, Image done on admissioDro the community hospital. B, Image done 24 hours larer denonstrates bilateral hemisphericdem, with eff.cemenr of cere Medicine 2002;81:240 ) brospinal fluid spaces.(From Brusiloe SV/: Hyperammonemic encePhalopathv.

No acidosis

I I

Obtain

Specificamino acid elevation

Nospecilic amino acidelevation

I
Obtain urine orotic acid

High

Normal elevated or

I oic--l

I
Transieni hyperammonemia of lhe newborn

I I oeticiency

Figure 85-14. Cljnical approach to a newborn infant lvirh symptonatic hyperammonemia. CPS, carbamyl phosphate synthelaseiHHH syndrom, hyperamOTC' ornrrhin uansarbamvlase NAG, N acetvlSluramatei monemra-hvperornithinemia'homocrtrullinernia;

r 55t r PAR|IX MerEbolic Diseasos Patients differentiates defectfrom CPSdeficiencv, this with a deliciency of AS, AL, or arginasehave a marked increasein the plasma level of citrulline, argininosuccinicacid, or arginine, respectively. Differentiation betweenthe CPSdeficiency and the (NAG) synthetase N-acetylglutamate deficiencymay require an assayof the respective enzymes. Clinical improvementoccurring after oral administration of carbamylglutamate, howeveq may suggest NAG synrhetase deficiency. TREATMENT ACUTE 0t HYPERAMM0T{EMlA. hyperammoneAcure mia should be treated promptly ard vigorously.The goal of therapyis !o removeammoniafrom chebody and to provideadequate calories and essentialamino acids ro halt further breakdown of endogenous proteins (Table 85-3). Adequatecalories, fluid, and electrolytes should be provided intravenously. Intravenouslipids (1 ElkglL4ht provide an effectivesourceof calories.Minrmal amountsof protein (O.25gkgl24 hr), prefetablyrn the form of essential amino acids,should be addedto the intravenousfluid to preventa catabolicstate.Oral feeding with a lowprotein forrnula \0-5-7.0 glk9lz4 fu) rhrough a nasogastric tube should be srartedas soon as sufficientimprovementin lhe clini cal condition ls seen. Because kidneys clear ammonia poorly, its removal from rhe the body must be expeditedby formation of compoundswirh a high renal clearance. Sodium benzoate forms hippuric acid with glycine (see Fig. 85-12). Each mole of berzoare endogenous removes1 mole of ammoniaas glycine,Phenylacetate conjugares with glutamineto form phenylacetylglutamine, which is readily excreled the urine. One mole ofphenylacetate in removes moles 2 of ammonia as glutamne from the body (seeFig. 85-12). Arginine adminisrrationis effectivein the rreatmentof hyperammonemiathat is due to defectsof the urea cycle (exceptin patients &'ith arginasedeficiency)because suppliesthe urea ir cyclewith ornrrhrneand NAG (seeFig. 85-12). In patientswith citrullinemia,1 mole of argininereactswith 1 mole of ammonia (as carbamyl phosphate) to form citrulline. In patients wirh argininosuccinicacidemia,2 moles of ammonia (as carbamyl phosphareand aspartate)react with arginine to form arginiacid are far less nosuccinicacid. Crrrullineand areininosuccinic roxic and more readily excreted6y the kidneysthan ammonia. In patientswith CPSor OTC deficiency, arginineadministration amino acid in is indicatedbecause arginrnebecomes esseotial an rhesedisorders,Patientswith OTC deficiencybenefit from crt1 rulline supplementarton 1200ng/kEl24 hr) because mole of crtrulline can accept1 mole of ammonia (as asparticacid) ro form arginine. Adminrsrratronof arginine or citrulline is contraindiis with arginasedeficiency. Arginasedeficiency cated in patiencs rarely occurs a rare condition jn which acute hyperammonemia as a presenting sign, In patienrswhosehyperamrnonemia sec is ondary to organicacidemias, treatmenrwirh arginineis not indicated becauseno beneficialeffect from such theraov can be expected. a newborninfant with a lsr artack oi'hyp.rnrnIn monemia, arginine should be used until the diagnosis is estabhshed. Benzoare,phenylacetate, and arginine may be administered togetherfor maximal therapeuticeffect.A priming doseof rhese compounds is followed by continuous infusion until recovery from the acutestateoccurs(seeTable 85-3). Both benzoate and phenylacetate usuallysuppliedas concentrated are solutronsand should be properly dlluted (l-2yo solution) for intravenoususe, The recommended therapeutic dosesof boch compoundsdeliver a substantial amountoI sodiumto the patient rhat should be calculatedas parr of the daily sodiumrequirement. commercial A preparation of sodium benzoateplus sodium phenylacetate is availablefor intravenoususe (MedicisPharmaceutical Corporacion, wwwmedicis.com),Benzoare and phenylacetace should be used wirh caution in newborn infants with hyperbilirubinemia because they may displacebilirubin from albumin (seeChapter 102,4). In infants at risk, it is advisable reducebilirubin to a to safelevel beforeadministeringbenzoate phenylacetate, or If the foregoing therapies fail to produce any appreciable changern the blood ammonialevelwithin a few hours,hemodial ysis or peritonealdialysisshould be used.Exchange transfusion has little effect on reducingtotal body ammonia. It should be used only if dialysiscannot be employedpromptly or when the patient is a newborn infant wrth hyperbilirubinemia (see earlier). Hemodialysis, although the most effectivemeasure removal for of ammonia, is technicallydifficr:lt to perform and may not be readil;' available.Peritonealdialysis is the most practical and expeditiousmethod for treatmentof patientsrvith severe hyperammonemia;chereis usually a dramatic decrease the plasma in ammonia level withrn a few hours of dialysis, and in most parients,the plasmaammonia returnsto normal within 48 hr of initiarion of peritoneal dialysis. In a patrent whose hyperam peritonealdialysiseffecmonemiais due ro an organicacrdemia, ttvely removesboth the offending orgamc acid and ammonia from the bodv. To curtail the possibleproduction of ammonia by rntestinal bacteria,oral adminisrrationof neomycinand lactulosethrough a nasogastric tube should be initiated very early in the courseol therapy.There may be considerable betrveen normalizalag the tion of ammoniaand an improvementin the neurologicstatusof the patient.Several beforethe infant becomes daysmay beneeded fully alert. Long-Tern Thorspy. Once rhe infant is alert, therapy should be tailored to the underlying cause of the hyperammonemia. In general,all patienls require some degreeof protein restriction (1-2 glkg/24hi) regardless the enzymaticdefect.In parients of with defects the wea cycle.chronic administrarion benzoate in of (250-500 rng/kg/2ahr), phenylacetate(250-500 mgikgl2a hr), and arginine(200-400 mglkg/24hr) or citrulline (in patientswith OTC deficiency, 200a00 ngfl<g124 is effectivein maintainhr) ing blood ammonia levelswithin the normal range. Phenylbutyrate may be usedin placeof phenvlacetate, because patient the and the family may not acceptthe latter owing to its offensive odor. A commercialpreparationof the compoundis availablefor oral use (Buphenyl,Medicis Pharmaceutical Corporation). Carnitine supplementation recommended is because benzoateand phenylacetate may cause carnitinedepletion;the clinical benefits of this compoundremain to be proved. Skin lesrons resembling acrodermatitisentropathicahave been noted in a few patients with differenrrypesof ureacycledefects, presumably due to deficiency of essentral amino acids, especiallyarginine, causedby overzealous dietary protein restliction. Carabolicstaces triggering hyperammonemia should be avoided.In patientswith CPS, acute hvperamrnonemic OTC, and AS deficiencies, attacks may administration. be precipirared vaLporate by

ot in Chalter85 r Delects Metabolism AminoAcids . 5li9 (CPS)AND fl.ACEIYI.GI.UTASYNTHETASE CARBAMYLPHOSPHATE (SEE 0EFICIENCIES FlG.85-12}DeficienSYNTHETASE MATE{NAGI cies of these two enzymes Produce slmilar clinical and biochemical manifestations. There is a wide varianon in severit,v Most commonl), rhe in the age of presenta!ion. of symptoms a comes symPtomatic durrng rhe 1st few days of affected rnfant The diagnosis ma,v be confirmed b1-performing an assal'of enzyme aclivity that is nonnally present only in che liver or bv identification of tbe murant gene. Prenatal dragnosishas been achieved by means of fetal hver biopsl' or by DNA studies of chorionic r.illi samples. An oral protein load, u'hich incteases plasma ammonia and urinary orotic acid levels, may identify asympromatic heterozygous female car'riers. A marked increase rn urinary excrecion of orotidine after an allopurinol loading test also detects obligate female carriers. Mild cerebral dysfunction female carriers. may be present in asymptomacic Treatment of acute hyperammonemic atracks and the longterm therapy of the condirion is outlined in earler pages of this chapcer. Citrulline is used in place of arginine in patients wirh OTC deficrency.Lrver transplantarion is a successfuland defrnite treatmenr for patients with OTC delicrency who have been v'ell crises. conrrolled and have avoided multipte hyperammonemrc The gene for otnithine transcarboxllase has been mapped to mutacions X chromosome (Xp21.1). N'lany disease-causing (>200) have been identified in different patients. The degree of enzyme deficiency and rhe genotype dictate the severitv of the phenorype in most cases,Mothers of affected infants are expected ro be carriers of the mutant gene, A rnother rvho gave birth to rwo affecred male offspring vas found to have normal genotype, suggesting gonadal mosaicism in the mother. (CITRUttINE(AS) SYNTHETASE DEIICIENCY ARGININOSUCGINATE Two clinically and genetically distinct forms MlAl [SEEFlG.85-12]. The classicform (type I) is of citrulUnemiahave been idencified. due to the deflciency of rhe AS enzyme, The adult form (type II) is due to deficiency of a mitochondrial transport plotein named crttrn, CTLN'l). This condrtion Typel(ClassicCitrullinemia, Citrullinemia is causedby the deliciencyof AS (seeFig. 85-12) and has vari able clinical manifestation depending on the degree of the enzyme deficiencv. Two maior forms of che condition have been identi fied. The severe or neonatal form, which ls the most common form of rhe condition, appears in the lst few days of life with sign and synptoms of hyperammonemra (seeearlier). In rhe subacute or mild form, clinical findings such as failure to thri"e, frequent vomiting, developmental delay, and dr1 brittle hair appear gradually after 1 yr of age. Acute hyperammonemia, triggered by an inrercurrentcatabolic stace,may bring the diagnosisro light. Laboratory findings are similar to those found in patients with OTC deficrency except thar the plasma cicrulline concentratron is markedly elevared (50-100 rrmes normal) in patients with citrullinemia type I (seeFig. 85-14). Urinary excretion of orotic acid rs moderarely increased; crystalluria drLeto precipitation of ororates may also occur The diagnosis is confirmed by performtng actii,it,v in cuhu.ed fibroblasts or by DNA an assay of the enz-vme analysrs. Prenaraldiagnosisis accomplishedby the assayof rhe enzyme activit], in cultured amniotic cells or by DNA analysis of cells obtained from chorionic vilh bropsv. Treatment of acute h,vperammone[lic attacks and the longterm rherapy of the condition are outlned in rhe earlier pages of rhis chapter Plasma concentration of citrulline remains elevated at all times and may increase further afrer administration of argrnine. Although prognosis is poor for symptomatic neonales, patients with the mild disease usually do rvell on a proteinrestricted diet in conyuncdon with sodium benzoare and arginine therapy. Mild to moderate mental deGcrenc,vis a common pacient. sequela,even in a rvell-treared Citrullinemia is inheflted as an autosomal recessivetrait. The gene rs located on chromosome 9q34. Several disease-causing mulations have been identi{ied in differenr families. The maloricy of patients are compound hererozygotes for two different alleles. The prevalence of rhe condrtiol is not known, (Citrullinemia Typell. CLTN 0ue Cilrurullinemia to CitrinDeficiency 2), Citrin is a mitochondrial transport protein ercoded by a gene (SLC25A13) located on chromosome 7q21.3. One of the func

byperammonemia intelspersed wirh bouts of acute h-vperam molemia have also been observed.

term therapy of rhe condicion is oullined earlier (seeTable 85-3). Parients vvrth NAG synthetasede6ciency benelir from oral administratron of carbamylglutamate. It is therefore important to dif ferentiate betrveenCPS and NAG synrhetasedeliciencies by assay

dicion is not known. {SEE FIG. OBI{ITHINE TBANSCAREAMYIASE (OTC) DEFICIENCY 85-12).In tbis XJrnked partially dominant disorder, lhe hemrzl' gote males are rno severely affected than heterozygote femalesThe heterozygous males may have a mrld form of the disease, 757o) are asymptomatrc.This is the most but the majonty common form of all rhe urea cycle disorders Clinical manifesrations in a male newborn infant are usuallv rhose of severehyperammonemia (seeearlier) occurring in rhe 1st ferv days of life. Milder forms of che condirion are commonl) seen in heterozygous females and in some affected males. Mild forms characterrsrically have episodic mamfesrations, t'hich may occur at any age (usually after infancy). Episodes of hvperam monemia (manifested by' vomiting and neurologic abnormalities

survivors; the mechanism remains unclear laboratory finding during rhe acuce atrack is hvperThe maj ammonem without an increase in any specific amino acid rn the blood. Elevatron of che plasma concenlrationsof glutamine and alanine are secondary to hyperammonemia A marked iocrease

tare in urine as gravel or stones. In the mild form, these boratory abnormalities may revert to normal between artacks. hrs form should be differenriated from all the episodic conditions of childhood, ln parcicular, lysinr:ric prorein inrolerance (see Chapter 85,13) mimics the clinical and biochemical characteristicsof OTC deficiencl', Increased urinary excretions of lysrne, ornithine, and rginine and elevated blood concentrations of citrulline, 'w'hic are salient features of lysinuric protein intolerance, are not seen in patrents with OTC deEciency.

560r PARTX. MGtabolic Diseas6r from mitochondria tions of this protein is ro transport aspartate to cytoplasm;aspartateis requrredfor convertingcitrr:llne to argrninosuccinic (see acid Fig. 85-12).Citrin deficiency causes disruption of the urea cycle. AS activity is deficientin the liver of patients,but no mutatronin the genefor AS hasbeenfound, these It is postulared thar crtrin deficiency its mutatedgeneinterferes or with translationof nRNA for AS enzymein the liver. Mutatron in the genefor citrin producestwo distinct clinical entities,The condition is reportedalmost exclusivelyin Japan. Intrahepatic Type Neonatal Cholestasis {Citrullinemia ll-Neon8tal Fotm). Clinical and laboratory manifestations,which usually starts at 3 mo of age,include cholestaticjaundrcewith mild to moderate direct (conjugared) hyperbilirubinemia, marked prothrombin hypoproteinemia,clottrng dysfunction (increased trme and partial thromboplastin times), and increasedserum lglutamyltranspepridase (GGTP) and alkaline phosphatase activiues; llver transaminasesare usually normal. Plasma corcentrationsof ammoniaand crtrullineare usuallynormal, but moderateelevations reporled.Theremay be also increases are in plasmaconcentrations merhionine, of tyrosine,alanine,and threonine,Elevationin serumgalactose levelshasbeenfound in some patlents; all enzymes involved in galactose metabolism are normal. The reasonfor hypergalactosemia not known. Marked is elevationin serurnlevel of c-fetoprotein is also present.These findingsresemble thoseof tyrosinemiatypeI, but unlike the latter condition, uilnary excretion of succinylacetone not elevated is (see Chapter85.2), Liver biopsyshowsfarty infiltration, cholestasrswith dilatedcanaliculi,and a moderatedegree 6brosrs. of The condition is usually selfJimicing and the majority of infants recoverspontaneously 1yr of age with only supportiveand by symptomatictreatment.Hyperammonemra and hvpercitrulline mia, if present, shouldbe treatedwith low-proreindiet and other (see appropriatemeasures earlier).Hepatic failure requiringliver Although the conditransplantation has occurredin a few cases. tion is almost exclusivelyseenin Japan,chediagnosis should be considered any neonatalhepatirissyndromewrth cholestasis. in Data on the long-term prognosrs and the natural history of the condition arelimrted:develooment into the adult form of the condrtion (seelater) after seueril years of seeminglyasymptomatic hiatus has beenobserved. CitrullineniaTypell, Adult Fo n {Adult-onsel Cilrullinemia, Citrullinemia Typell-Mild Form). This form stans suddenlyin a prevrously normal individual and manifestswith neuropsychiatric sympromssuch as disorienration,delirium, delusion, aberrant behavior,tremors, and frank psychosis.Moderate degreesof hyperammonemia hypercitrullinemia present. are The ageof and onset usually is between and40 yr (range to 79 yr). Patients 20 11 who recoverfrom the 1st episode will haverecurrentattacksand most will die within a few yearsof diagnosismarnly from cerebral edema. Pancrearitis,hyperlipidemia, and hepatoma are major complicatrons amongthe survivors.Medical treannenthas been mostlv ineffectivefor orevention of future attacks. Liver transplantationis the most eifectivetherapy. Several disease-causing mutationsof the genehave beenidentified in affected families in Japan. The pathogenesis citof rullinemia rype II (neonaraland adult forms) remarnsenigmatic. Although the frequencyof abnormal geneis quite high in Japan (1;20,000homozygosity), clinical condition has a frequency the of onlv 1:100.000. This rndicates numberof that a substantial homozygous rndivrduals remain asymptomattc. Only a few nonpatientshave beenidentified. Japanese major finding is mental retardation, which is associated with failure to thrive and hepatomegaly. Abnormahtiesof rhe hair characrerized drynessand britdeness of specialdiagnosric by are value.Gallstones have beenseenin someof the survivors.Acute attacks.. severehyperammonemia of commonly occur during a catabollcsrate. Laboratory findings include hyperammonemia, moderateelevationsin liver enzymes, nonspecilic increases plasmalevelsof in gluramineand alanine,moderateincrease plasmalevelsof citin rulline (lessthan that seenin citnllinemra), and markedincrease in plasmalevelsof argininosuccinic acid (see Fig. 85-14).In most amino acid analyzers, argininosuccintc acid appearswithrn the isoleucine methionineregion, which may causeconfusion in or the diagnosis,Argininosuccinic acid can also be found in large amountsin urine and sprnal fluid. The levelsin the spinal fluid are usuallyhigher than thosein plasma.The enzymeis normally presentin erythrocytes, liver, and cultured fibroblasts,Prenathe tal diagnosisis possibleby measurernent the enzymeactiviry of in culturedamniotic cellsor by identificationof the mutanr gene. Argininosuccinicacid is also elevatedin rhe amniotic fluid of affectedfetuses. Tieatrnent of acute hyperammonemic attacks and the longterm thelapy of the condition are outlmed in the earlierpagesof this chapter Mental retardation,persistenthepatomegaly with mild increases liver enzymes, in and bleedingtendencies due to abnormal clotting factors are common sequelae rhe disease. of This deficiency rnheritedas an autosomalrecessive rs rrait with a prevalence =1/70,000live binhs. The geneis locatedon chroof mosome Tcen-q11.2

ARGTNASE DEFTCTET{CY 85r2]. This {HYPEBARGTNtNEM|A) FrG. [SEE defectis inhented as an autosomalrecessive trait. There are two genetically in distinctarginases humans.One is cytosolic(A1) and is expressed the liver and er;throcytes,and rhe other (A2) is in found in rhe renal and brain mitochondria.The genefor cytosolic enzyme,which is the one deficientin patientswith arginase deliciency, mappedto chromosome is 6q23, The role of the mitochondnal enzymeis not well understood; activity increases its in patienls with argininemia but has no protec ve effect. Several disease-causing mutations have been identified in different mm tes. The clinical manifestatiomof this rare condition are ouire different from rhore ol: other urea cycleenzymedetects. The onser is insidious;the infant usually remainsasymptomatrc the 1st in years of life. A progressive few months orr sometimes, spastic diplegiawith scissoring the lower extremities, of choreoarhetotic rnovernenrs, lossof developmental milestones a previously in and normal infant may suggest degerierative a disease the central of nervoussystem.Two children were fteated for severalyears as cerebralpalsybeforethe diagnosis arginase of deficiency wasconfirmed. Mental retardationis progressrve; seizures common, are bur episodes severe oI hyperammonemia nor usually seenin are may be present. this disorder Hepatomegaly The acuteneonatal form with intractable cerebral seizures, edema, and deathhasalso beenreported. Laboratory findings include rnarked elevationsof arginine rn plasma Urinary orotic acid is moderand CSF (see Fig. 85-14). ately increased. Plasma ammonialevelsmay be normal or mildly elevared.Urinary excretions of arginine, lysine, cystrne, and but ornithine are usuallyincreased, normal levelshave also been noted. Therefore, determrnationof amino acids in plasma is a critical step in rhe diagnosisof argininemia,The guanidino (ATI (ARGININOSUCCINIC compourids {a-keto-guanidinovalenc ARGININOSUCCINATE TYASE DEFICIENCY acid, argininic acid) are ACIDURIAI The severityo{ rhe clinical and biomarkedlyincreased urine.The diagnosis confirmedby assayin is [SEEFlG.85-12]. chemical manifestationsvaries considerably,In the neonatal lng arSrnase achvrtym erytnrocytes, form, signs and symptoms of severe hyperammonemia(see Treatment consisrsof a low-prorein diet devoid of arginine, earlier)developin the ilst few daysof lile and mortaliry is usually Administration of a synthericprotein made of essentialamino high. Infants who survive the lst acute episodefollow the ctiniacids usually resulls in a dramatic decrease plasma arginine in cal courseof chesubacute form. In the subacute lare form. the or concentralionand an improvementin neurologicabnormalities.

Chaoler r oelecL in Motobolisnol AminoAcids r 561 85 order, the defect is in the transport sysrem of ornirhine from the cytosol into rhe mitochondria, which causes an accumulation of ornithrne in rhe cytosol and a defciency of ornithine inside che mitochondria. The former causes hyperormthinemia and the latter resuks in disruprron o{ the urea iycle and h} perammone mia (seeFig. 85-12). Homocirrulline is presumablyformed from the reacrion of mitochondrial carbamyl phosphate with lysine, which occurs because of the intramitochondrial deficiency of ornithine. Clinical nanifestarions of hyperammonemra may develop shortly afrer birch or may be delayed until adulthood. Acute episodes of hyperammonemia manrfesr as refr.rsalto feed, vomiring, and lethargy; coma may occut during infancy. Progressive neurologic signs, such as lower limb weakness, increased deep cendon reflexes, spasticitn clonus, seizutes, and varying degreesof psychomotor retardalion may develop if the condition remains undiagnosed. No clinical ocular findings have been observed in rhese Datients. Laboratory findings reveal marked increases in plasma levels of ornirhine and homocirrulline in addrtion to hyperammonemia. Rescricrion of protern inrake improves hyperammonemia. Ornrthrne supplementation may produce clinical improvement rn some patients.The gene for rhis disorder (SLC25,415)is located on chromosome 13q14.

gooo conlrol. 0F TBANSIENTHYPERAMMONEMIA THE NEWBOBN. Although plasma levels of ammonia in normal full-cerm infants are within normal limits, very low birthweight rnfants may have a mild ransient hyperammonemia (40-50 pmole/L), which lasts for about 5-B wk. These infants are asymptomatic! and follow-up studies up to 18 mo of age have not revealed any signifrcanc neurologrc delicirs. Severe transient hg>erammonemia has been observed in newborn infants. The maioriry of affected infants are premaLure and have mild respratory drstress syndrome HyPerammonemic coma may develop within 2-3 da1's of life, and the infanr may succumb to the drsease if treatment rs not started immediately.

o lrai HrsrtDtNE Bezvani 85,12.

Treatment of hyperammonemia sbould be initiated promptly and contrnued vigorously (see earlier). Recovery without sequelae is common, and hyperammonemia does nor recur even wirh a normal protein diet. oRNITHINE,Ornithine is one of the intetmediate metabolites of Histidine is an essentral arnino acid only during infancy. Its biosynthetic palhway in older children and adults is poorly understood. Hrstidine is degraded through the urocanic acid pathway ro glutamic acid. Severalgenetic onditions involving rhe degradative parhway of histidine hav been reported, but none has any clinical consequence.

o lvstt'tt lrai Rezvani 85.13.

The major pathway in the catabolismof lysineinvolvesits conSacdensarionwirh ct-ketoglutaricacid to form saccharoprne. charopineis then degradedro o-aminoadipicacid semialdehyde and glutaric acid. These lst two steps are catalyzed by csynthase,which has two activities; aminoadipic semialdehyde reductase; and saccharopine dehydrogenase lysine-ketoglutarate (Fig.85-15). a mrnorparhwayfor lysine degradation, lysine is In rransaminated6rst and rhen condensedto the cyclc form, pipecolicacid.This is the maior pathwa),for Dlysine in rhe body Fig. 85-15). in and for the L-lysine the brain (see Hyper$sinemia, a-aminoadipic acidemta and a-ketoadipi. acidemia are three condicionsthar are due to rnborn errorn of membolsm of lysine. Individuals wirh these conditions are usually asymptomatic.

and converts ornithtne to Putrescine (seeFig. 85-12) Two genetic disorders result in hyperornithinemia: gyrate arrophy of the re rina and hyperammonemia-hyperornithinemia-homocirrulline-

loss of peripheral vision, and postelror subcapsulal cataracts. These eyi changes start betweel 5 and 10 yr of age and Progress to complete blindness by the 4rh decade of life. Atrophrc lesions rn the retina resemble cerebral gyri. These patients usually have normal inrelligence. There is a 10- co 20-fold increase rn plasma levels of ornithine (400-1,400;rrnole/L). There is no occurrence in and no increases any other amino acids; of hyDerammonemia and creapla"ma levelsof gluramare.glutamine. lysine,crearine. re*pond partially Some paLients iinine are moderarelydecreased. to hieh dose' uf pyridoxine 1s00- I .000 mg/24 hr). Argrninep w d resrri;ted ier in cuniuncrion ith.upplemenral ysrne. roline. and creatine has been successful tn leducing plasma ornithlne concentration and has produced some clinical imProvemen !s The gene for ornithine 5-aminotransferase is mapped !o chromosome causrngmutations have been 10q26. M"ny (at least 60) drseaseidentifred in drfferent famrlies

in ACIDURIA TYPE Gluraric acid is an intermediate the L GIUTAEIC (see and tr1'pFig. 85-15),hydroxllysine, degradation lysrne of by tophan.Glutaric aciduriatype I, a disordercaused a defrciency should be drfterentiatedfrom of glutaryl CoA dehydrogenase, glutaric aciduria type Il, a distinct clinical and biochemicaldisorder causedby defects in the electron transport system (see C h a o c e r5 , 1 ) . 8 Affected infants with gJuraricacrduria ClinicatManifestations, is rvpe I may developnormally up to 2 yr of hfe; macrocephaly Symptoms hypotonia, loss of a common 6nding in theseinfancs. generalized rigiditn seizures, of head control, choreoathetosis, opisthotonos,and dystonia may occur suddenlyin a seemingly from the lsr normal infant after a minor infection. Recover-v anack usually HYPERAMMONEMIA.HYPEBORNITHINEMIA-HOMOCITRUTLINEMIA occursslowly, but someresidualneurologicabnormovements, mav especrally dystoniaand extrapyramidal inherited drs- malicies, recessively autosomal In thts {HHH}SYNDR0ME, rare

X 562 r PABT r Metabolic Disoases

Protein synthesis
o-N-acelyl-lysine

NH2-(CH2)4-CH-COOH

I ln,/

r-N-acetvFlvsine

"

Glutamic acrc cr-Aminoadipic actd 6-Semialdehyde Pipecolic ........- Piperidine-6carboxylicacid acrd

Pipecolicacidemia lx-Aminoadipic acro

(3) t'igurc 8s-1s- Parhwavsin che rnetabolismo{ lysrne ErzFnes: (1) lysine keroslutarate reductase,(2) sacchrropine dehvdrogenase, d-aminoad,pic acjd rrans(6) ftrase, (4) a-ketoadipic acid dehydrogenase, glutaryl CoA dehvdrogenase, o-anlnoadipic semialdehydeoxjdase. is)

persist.Addidonal acuteepisodes resembling 1st one usually the occur during an intercurrent infecrion. In other patients,these signsand symptomsmay developgradually in rhe 1st feu,'years of life and hypotoniaand choreoathetosis graduallyprogress may into rigidiry and dystonia.Acuceepisodes metabolc decomof pensarionwith vomiting, ketosis,seizures, and coma also commonly occur in thesepauents after infection or other catabohc states.Death usually occursin the 1st decade life during one of The intellectualabilities usually remain relaof theseepisodes. in tir..el)'normal mostpatienrs. Findings. During acute episodes, Laboratory mild to moderate metabolicacidosis and ketosismay occur Hypoglycemia, hypera m m n n e m i a ,n d e l e v a t i o n s s e r u m r a n s a m r n a la rs s e e nn ol t e e i some patients.High concentrations glutaric acid are usually of found in urine, blood, and CSF, 3-Hydroxyglutaricacid may also be present rn the urine. This frnding drfferentiatesglutaric aciduriatype I from rypeII. In glutaric aciduriatype lI, 2-hydroxyglutaric rather than 3-hydroxyglutaricacid is elevated. llasma amino acrdconcentrations usuallvwithin normal hmrts,Labare oratory findirrgsmay be unremarkable betweenattacks.Severely affected children wrthout elutaric aciduria have also been reported.In some of thesepiriencs, the glutaric acid is elevated dystonia only in tbe spinal fluid. In any child with progressive activity of the enzymeglutaryl CoA dehydrogeand dyskinesia, nase shouldbe measured leukocytes culturedlibroblasts. in or CT and MRI of che brain reveal macrocephaiy, dilated lateral venrricles, cortical atrophy', fibrosis, and atrophy of striatum (putamenand caudate). Treatnent.A lou-protein diet (especially diet restrictedin a lysine and trvptophan) and high doses(200-300 mg/24hr) of riboflavin (checoenzyme glutaryl CoA dehydrogenase) Lfor and carnitine (50-100 mg/kgl24fu orally) produce a dramatic

decreasein the levels of giutaric acid in body fluids, but the clinical effect has been variable. The addrtion of a GABA analoe thaclofen)and valproic acid to the therapeuricregimen producet improvement in some affected children, The condition is inherited as an autosomal recessiverrait. The prevalence is not known. The condrtion is more prevalent in Sweden and among the Old Order Amish population in the United States. The gene rs located on chromosome 19p13.2 and many disease-causiflgmutations have been reported in drfferent familres, A single mutat:on (A421V) accounts for all the patients from Lancaster County Old Order Amish. Prenacal diagnosis may be accomplished by demonstrating rncreasedconcentrations of glucaric acid in amniotic fluid, by rhe assay of the enzyme activit], in amniocytes or chorionic villi samples, or by idencification of the mutant gene.

(tAMtUAtPR0TE|N INTotEBANGE tYslNURtc PRoTEIN tNTotEBAITCE). This rare autosomalrecessive disorderis due to a defecc in the transportof the cationicamino acidslysrne,ornirhine,and arginine in both kidneys and intestine. Unlike patients rvith cystinuria,urinarl. excrelion of cystinejs not increased lhese in patients. About half ofthe reportedcases havebeenfrom Finland, where rhe prevalence beenestimated be 1/60,000. has to consistof refusalto feed.nausea. Clinical manifestations aver, s i o nt u p r o t e i nv o m i r i n g .n dm i l dd i a r r h e a . h i c hm a yr e s u lirn a w failure to thrive, wastrng, and hypotonra. Breasr-fedinfants usually remain asymptomaticuntil shonly after u,'eaning. This may be due to the low protein content of breastmrlk. Episodes may occur after ingestionof a high-protein of hyperammonemia diet. Mild to moderatehepatosplenomegaly', osteoporosis, sparse with moderatecentripetaladiposrq., brirtle hair, thin extremicies and growth tetardationare common physicalfrndingsin patients

Chroler95 . Dolocts Mctabolism AminoAcids r 563 in ol whose condition has remained undiagnosed. Mental development Canavan drsease,an autosomal recessrvedisCANAVANDISEASE. order characterized by spongy degeneration of the whire macter of the brain, leads to a severe form of leukodystroph;'. lt rs more prevalent in individuals ofAshkenazi Jewish descent than in otler ethnlc groups. Etiology snd Palhology, The deficrency of the enzyme aspartoa cylase leads to the accumulation of N-acetylasparric acid in the brain, especially in white marter, and massive urinary excretion of this compound. Excessiveamounts of N-acetvlaspartic acid are also present in the blood and CSF.There is striking vacuolization and astrocytic srvelling in white matter. Electron microscopy reveals distorted mitochondria. As the diseaseprogresses!the ventricles enlarge, ow'ing to cerebral acrophy. covers ClinicalManiteslations. The severityof Canavan disease a $'ide spectrum. Infants Lrsuallyappear normal at birth and may not manifest symptoms of the drseaseuntil 3-6 mo of age, u.hen they develop progressive macrocephaly, severe hypolonia) and persistenr head lag. As rhe infant grows older, dela)'ed milstones become evrdent. These children become hyperreflexic and hyper tonrc; joinr sriffness mav be encountered. As they grow older, seizures and opric atrophy develop, t-eeding difficulties, poor weighc gain, and gastroesophagealreflux may occur in the 1st yr of life; swallowing deteriorates in the 2nd and 3rd yr of life, and nasogastric feeding or permanen! gastrostomy may be required. lVIost parrents die i[ the lst decade of life; rvith irnproved nursing care, they may survive through the 2nd decade. AtypicalCanavan Disease. Some paoenrs with Canavan disease ma!,have a mild allele (Y288C), a substitution of ryrosinervich cysteine or (R71H) substitution, or arginrne u'ith histidine. Such patienrs have very mild delays and are no! suspected of having Canavan disease. The excretion of N-acecvlasparticacid is increa.ed moderately in urine, whrch rarses thi que.rrun of Canavan disease and the MRI of the brain shorvs a different image,nor global white matter drsease, increased but srgnalintensities with che basal ganglia, rvhich may be confused with rnitochondnal drsease. Diagnosis. CT scans and MRI reveal diffuse white macter degeneratron, primarily in the cerebral hemispheres, with less involvement in the cerebellum and brainstem (Frg. 85-16). Repeated evaluations may be required. N1RS performed at the time N1RI is done can show the hrgh peak of N acetylaspatrc acid, suggesting Canavan disease. The differential diagnosis of Canavan disease should include Alexander disease, rvhich is anorher leukodystrophy wirh macrocephal,v. Progression is usua)ly slorv ra Alerarder disease; hypotonia is not as pronounced as it is in Canavan disease. Brain biopsy shows spongy degeneration of the myelin livers, astrocytic swelling, and elongared mirochondria. Defi^rtrve diagnosis can be establshed bv 6nding elevacedamounrs of N-acetylaspartic acid in the unne or blood. A deliciency of aspartoacyclase can be found in cultured skin flbroblasts. The biochemrcal method is the preferred choice for diagnosis. Levels of N-acetylasparcic acid in normal urine are in only trace amounts (24 i 16 pmol/mmol crealinine), r,|.hereas patients with Canavan disease lhey are in the range of 1,440 I 873 pmol/mmol creatinin. High levels of N-acetylaspartic acid in plasma, CSF,and brain lissuecan also be derected. The acriviry of aspartoacylasein the libroblasrs of obligate carriers is abouc half or lessof the acrivitv found rn normal individuals, The gene for asparroacvlase is cloned, and mutations leading ro Lana\an disease are idenrrfied. There are tu.o mutarion\ pre. dominant in che Ashkenazi Jewish population. The 1st is an amino acid substituoon (E285A) in which glutamrc acid is subsriruted to alanine, This muration is che most frequenr and 83% of 100 mutanr allelesexamined in Ashkenazi eflcompasses .lewish parients. The second common murarion is a change from tyrosine ro a nonsense mutation, ieadi[g to a srop in the codirg (Y231X). This mutatron accounts for 13% of the 100 sequence mutant alleles, In the non-Jewish population, more diverse mutacions have been observed; the two mutarions common in Jewish

patients and may cause death Laboratory findings may reveal hyperammonemi and an elevated concentration of urinary orotic acid, rrvhich evelop only afcer protein feeding- Fasting blood ammonia and urinary olotic acid excretion are usually normal. Plasma concentlations of b l y s i n e . r g i n r n e a n d o r n i t h i n ea r e u c u a l l vm r l d l y d e c r e a s e d .u r a , sspecralll lvsine, are S,reatlr urinary lerels oi rheseamino 66i615. increased. The mechanism producing hvperammonemia rs not clear All enzymes of the urea cycle are normal. Hyperammone mia ma-v be related co a disturbance of the urea cycle secondary to a deEciency of arginine and ornithrne. In patjents rvitb c1'strnuria rvho also have defects in the transporc of l,vsine, arginine, and ornirhine in both intestine and kidneys hyperammonemia is not observed. Piasma concentrations of alanine, gJutomine, serine, glycine, proline, and citrulLne are usually increased. These may be secondaryro hyperammonemiaand are not abnormalicies specific to thrs disorder. N{ild anemia and increased serum levels of ferritin, laccic deh,v-

ated from hyperammonemia due to urea cvcle defects (see females with OTC Chapcer 85,11), especrallyin heteroz,vgous de6ciency'.Increased unnary excretion of l,vsrne,ornithrne, and arginine and elevated blood levels of cicrulline are not seen in

mented with citrulline (3-8 g/day) has produced biochernrcal and

the management of acute pulmonary conplications The gene for l,vsinuric protein incolerance iSLCTAT) is mapped mutations to chromosome 14q11.2 and severaldisease-causing have been identified in different families, Pregnanciesin affected morhers har.e been complicared by anemia, thrombocytopenia, toxemia, and bleeding, but offspring have been normal.

O DTSEASE} AgD 85,14. ASPABTIC (CAI,IAVAN

K. Reuhen Matalon
N-acet,vlasparricacid, a derivacive of aspartic acrd, is synthesized tn the brain ard is found In a high concentrarion, similar to that of glulamic acid. Its function is unknown, but excessiveamounts of N-acetylaspartic acid rn urine and deficiency of the enzyme aspartoacylase !hat cleaves the N-acetyl group from N-acetylaspartic acid are associaled rvith Canavan drsease.

564r PART r Mtabolic X Diseares

Scriver CR, BeaudecAI. Valle D, et al (eds): The Metabolic and Moleculat Basisof Inheited Disellse,8th d. New York, McGraw-Hill, 2001. \0aisbren SE, Albers S, Amato S, et al: Effec of expanded nenborn screening for biomedical genetic disorders on ch d outcomes and parental stress. I A M A 2003:290:25 64-2 572. Phenylalanine Blau N, Koch R, Matrlon R, et al: New de"etopment in phenylkeronuria and tetrahydrobioprrin rescarch. Mol Genzt Mektb (S"ppl 1) 2C)05;851 1-156. Blau N, SeriverCr Nr,r' approachesro trear PKUt l{ow I arc wel Mol Geflet Merab 2O04i81:1-2. Crone Mr, van SpronsenFJ, Oudshoom K, et al: Behavioural fac.ors related to mtabolic control in parients with phenylkerofltia. I lnherb Metab Dis 2O05;28$27437. Desviat Lr, Perez B, Belanger-Quintan, A, et al: Tetrahydrobioptr;n respon siveness: Resulrsof the BH4 loading tesr in 31 Spanish PKU patienrs and correlation with their genc't:fie. Mol Geflet Metab 2004j83:157-152. Gassio R, Fuste E, Lopez-SalaA, er al: khool performance rn early and contrnuously createdphenylke.ontlrrr..Pediatr Neurol 2005;33:267-27 1. Koch Rr Maternal phenylketonuria: The imporcanceof early control during pregnancy.Arch Dts Ch'ld 2005;901114-115. Koch R, de )a Cruz F, Azn CG, t al: The maternal phenylketonuria collaborative study: New devlopmenrs and the needfor new stratgies. ?edidtids 2 0 0 3 ; 1l 2 ( S u p p l ) : 1 5 1 3 - 1 5 8 4 . kvy HL, GuJdberg B Guttler F, et al: Congenital hearr diseasein maternal phenylkeronuria: Repon {rorn the matemal PKU collaboracive studv. Pediafi Res 2001;49:636-4 42. Matrlon R, Koch R, Michals-Matalon K, er al: Biopterin responsivepheny lalanine hydroxylase defr.\ency.Cenet Med 2004;627-32. Munrau AC, RoschingerW, Habich M, er al: Tetrahydrobiopterin as an alrer nrtiv treatmnt for mild phenylkeronuria. N Eflgl J Med 2002;347:2122-2132. Segwa M, Nomura I Nrshiyama N: Autosomal domhant guanosinerriphos' phate cyclohydrolase I deficiency (Segrwa disease). Ann Nearol 2003;54:S32-545. Waisbren SE, Hanley W Lera HL, et al: Outcome at age 4 years in o{fsprrng of women wrth maternal phenylktonuna: The maternal PKU collaborative study. JAMA 20OO;283:756-762. Waher JH, $ghite FJ, Hall SK, et al: How practical are recommendarionsfor dietary control in phenylketon[ia? La/'.et 2002;350:55-57. Tyrosine Cerone R, FantasiaAR, CastellanoE, et al: Prgnancyand tyrosinaemia type . I Inherit Metab DE 2002i5:317-318. Crone J, Mostinger D, Bodamer OA, er al: Reversibiliry of ci-rrhotic regenerative liver nodules upon NTBC trearment in ! child with ryrosinaemiatype l. Acta Paediatt 2003;92:625-628. Dionisi-Vivi C, Hoffmann GF, Leuzzi V, et a| Tyrosine hydroxylasr deficiency with severe clmical course:Clinical and biochernicalInvestigationsand optimizarjon of therapy..l Pediitr 2000t136:560-562. ELlaway CJ, Holrr}e E, Standing S, a al: Outcome of tyrosinaemia type ll1. J lnherit Metdb Dis 200l;2+824-832, Furukawa Y Updare on dopa-responsivedystonia: Locus hererogenertyand biochemicaffearures.Ad, Ne,rcl 20O4i94:127-138. Hefd PK: Disorders of tyrosine catabolism Mol Genet Metab "f 2006;88:103-r06. Mag.a MJ, Cunawardena ND, Hahn SH, et al: Quantirative determination of succinylacrionin dried blood spots for newborn screeningof tyrosinemia qp< L J Mol Genet Metab 2006t88tr6-?1. Macsar MS, SchwarrzTL, Hinkle D, er a| Tyrosinemia typ II: Nine casesof ocular signs and symprom$ Am I Opbthalmot 2001.t132:522-527. Madan V Gupta U: Tyrosinaemia type I with diftuse planrar keratoderma And self-mutilation. Cli, E p Dermatol2006t3L154-56. Moller LB, Romstad A, PaulsenM, et al: Pre- and postnatal diagnosisof tyrosine hydroxylase defrcietrcy. Prenat Diagn 200 5t25:67 7-67 5. Phornphutkul C,Introne !0J, PerryMB, et al: Natural history ofalkapronurir. N Engl J Med 2002;347:2111-2121.. Russrll'Eggin I: Albinisfl, Ophthabnol Clin North Am 2001;14:533-546. Schiller A, Werers RA, Steenbrgen GC, et al: Long-term course of L-dopa responsivdystonia caused by tyrosine hydrorylase deliciency.Newology 20M;6J:1524-1526. Techakrtriroj C, Cunningham A, Hooper PF, et al: High protein dret mimics hypertyrosinemia in newhon infants. ! Pediatl 2o05t1461281-282.

Fieure 85-16. Axial T werghted MRI of a 2 yr old patienr with Canavan d i s e a s eE x r e n s i v eh i c l i e n i n g f t h e u h i t e m a n e r i s s e e n . . r o

people are rare. A different mutation (A305E), substitution of alaninefor glutamic acid, accountsfor 40/ of 62 mutant alleles in non-Jewish patients.Wirh the diagnosis Canavandisease, it of is important to obraina moleculardiagnosis because will lead rhis to accuratecounselingand prenatal for the family, If the mutations are not known, prenataldiagnosis relieson the level of Nacetylaspartic acid in the amniotic fluid. In AshkenaziJewish patients,the carrier frequencycan be as high as 1:36, which is closeto that of Tay-Sachs disease. AshkenaziJewishindividuals may needto be screened Canavandisease, for No specifictreatment is available. Treatment and Prevention. Feedingproblemsand seizures should be fieated on an individual basis.Geneticcounseling, carrier testing!and prenataldiagnosisare the only methodsof prevention.Injection of liposomes genewas introduced to the venwith the human aspartoacyclase tdcles of two children with Canavandisease, The resultsof this gentherapy have no! beenencouragrng.

General Crombez E, Koch R, Cederbaum S: Pitfalls in newborn screeniq. I Pediatr 2005;147:r19-120. Holtzman NA: Expanding newborn screenng. /A MA 2003;290:26O6-2608. McKusick VA: Online Mendelian lnhentance in Man (OMIM), Available ar www.ncbi.nlm.nih, gov/entrez/quryfcg?db-omim Morioka D, Kasahara M, Takada Y, et al: Living donor liver transplantation for pediacricpadents wjth inheritable merabolic disodlrs. Am I Tlansplant 2QO5;1r:27 5417 63 . polrcy for prorecNa|owicz M: Newborn screening-Setting evidence-based rron. N Engl l Med 2005;353:857-870. Schulz A, Lindner M, Kohlmuller D, et al: Expanded newborn screeningfor inbom efiors of metaboLismby electrosprayiomzation-tanden mass spec tromtry: Results, outcome, and impltcarions. Pediatrics 2OO3;l1l 1399-1406.

ChEptsr85 r Delocls ir Metabolism ot Arnino Acids r 565 Bodner LeideckerA, WendelU, SaudubrayJM, et al: Branched chain L-amino alter orthotopic liver acid metabolism in ctassicalmaple syrup urine disease tJanspl^nj3tiotr. I l,'hetn Metab Dis 2000;23:805-818

of Tomita Y, Suzukj T: Gnecics pigmenca.y disorderc. Am I Med Cenet C Se,nn Med Genet 2004;131C:75-81 Vrn SpronsenFJ, Bijleveld CM, van Maldegem B! wiiburs FA: Hepatocel lular carcinoma in hereditary ryrosinemia cyPeI desprre2-(2 nitro-4-3 trrPediatr I fluoromerhylbenzoyl)-1,3-cyclohexanedione treatment. G astrcentetol Nul'' 2005i40:90-93 Methionile Carmet R, Green R, Roesnblaft DS, Watkins D: UPdate on cobalamin, folate' and potymorphisms Hematologj Am and homocysteine.Generic diseases SocHema I Educ Program 2003;62-,37 Larvson-Yue A, Levy HL: The use of betaine in the tratment of elevated homocysteine. Mol Csrlet Metab 2006;88:201)07 .l I ee SJ, Lee DH, Yoo H\v, er al: Idenri$carion and funcrional analvsisot cvsrarhionine beta synthasegene mutations in patienrs with homocvsrinuna J H&m G enet 200 5 i5 01648-6 5 4 PD, i al: Identification ofthe SeneresponLerner- sJP, Tnone JC, PaweLek merhylrnalonicaciduria and homocysrinuria,.rlc rvpe Nat Cenet sible 2006;38:93-100. Morel CR Scotr, P, ChristensonE, et a| Prenatal diagnosisfor severemedyl entetrahydrofolatereductasdficiencvby tinkage anatvsisand enzvmaoc ^ss^y.Mol Genet Metab 2005;85:115-120. SelzerRR, RosenbtattDS, Laxova R, Hogan K: A erseeffect of nitrous oxide in a chitd with 5,10 methylenerertahydrofolate ductasedefciencv.NE@ J Med 2003;i49:45-50 IS, SibanrS, kclerc D, rWeisberg er atr Characrenzationof mulations i' severe nerhylenetetrahydrofolate reducr:se deficiency reveals an FAD rsponsive m:utation.Hun MBt 2003;21:509-520 Topaloglu AK, SansaricqC, SnydermanSE: Influence of metabolic contro growth in homocystinuria due ro cystarhionine p-synrhase deficie Pediafi Res 200 1i49 :7 9 6-7 98 Ueland PM, Holm, PI, Hustad S: Bta,n: A key modutacor of one-carbon metaboLism and homocysreine status Cli, Cbm Lab Med 2005;43: 1069-L075. pregVilasecaMA, CuarceroML, Marrinez de SalinasM, et aJ:Two successful nancies in pyridoine-nonresponsive hornocysrinuria.,f lzDerit Metub Dis 5-777 . 2004l'27:77

tarhionine beta-synrhase(CBS) deficincy Am I Med Cenet 2002|.108:

s7-63.
deficiency. Inheit Metab Dis 200724:437447tathionine beta-st'nthase J Cysteine/Cystine, Tryptophan Karakas E, Wilson HL, Graf TN, et al: Structural insights jnro suifire oxidase defrd.en.y. Biol Chen 2005;280:lJ 505-3 35 l5 J Kleta R, Brnardini I, Arcos Burgos M, et al: Molcular basis of the Harrnup Mol Genet Metab 20O5;84:225. dtLsordet murations iD the molvb Leirnkuhler S, CharcossetM,latour P,et al: Ten noveL denum co{actor genesMOCSI and -MOCS2 and rn "nro characterizatron of a MOCS2 mutation that abolishesthe binding ablhry of molybdopterin H s y n r h a ' e . a z z G p 4 p t2 0 0 i ; l l ' : t 6 5 - 5 7 0 Tan V/H, Eichler FS, Hoda S, et al: lsolated suJfireoxidase deficiency:A case report with a novel mutation and reviw of rhe hrcrarufe. Pediat/lcs 2O0 5;llt5:7 57-7 6ri. Valine, Leucine, Isoleucine, and Relared Organic Acidemias Acquaviva C, BenorstJR Callbaur I, et al: N219Y, a neiv trequnr mDraoon among zal forms of merhylmalonic aciderniajn Caucasjanpatienrs ElrJ Hu,fl Ceflet 2007,,577-582. Anikster Y, Klera R, ShaasA, et al: Type III 3-methylglutaconicaciduria (optic atrophy pJus syndrome, or Cosceffopric arrophy st'ndrome):Idenri6carion of the OPAI gene and ns founder m'rrarion in Iraq; Jews.Am J Htm Genet 200169:12 L8-1214 Barshop BA, Khanna A, Domino heparicrransplantarionin maPle s)'fuF urine N d\sease. Engl J Med 2005;353:2410-2411 Barrh PG, Valianpour F, Bowen VM, et at: X'linked cardioskeletalmyopathy and neurropenia (Barth syndrorne): An update. An I Med Cenel 20Q4;126 A:349-i 54. Baumgatner MR' Molecular nechanism of dornrnant expression in 3merhylcroronyl CoA carboxatase deEcrency. Inhe t Metab Dis 2005; ,f 28:301-309-

2002;140:261 263. c T D a n t a ' M F , S u o r m a l a , R a n d u l p hA , e r a l : I M e t h y l c r o t o n y l - C o A a r b o t l lase deficiency:Mutation analysis rn 28 probands, 9 svmproDadc and 19 Hum Mutut 2005;261164. derectedby newborn screeninP, Desviat LR, Perez B, Perez-CerdaC, et al: Propionic acidemia: Mutacjon updareand tunctional and srrucrural eflectsofthe varianr alleles Mol Getet Metab 2004.8328-37 . ctinical D'Osualdo A. Picco P. Caroli F. er al, MVK murarions and associaced fearures in kalian patients affecred rvirh aucoinflammatory disorders and recurrent fever. E,r.l HLln Cenet 20OSi1Jt3'14-32O. L n c e n a u e R , v o c k l e y I , W i l l a r d l . t a l : A ( o m m o n m u r a r i o ni s a ' s r x r a r e d r witb a mild, porennally asymptomatic phenorypin patients wrth iso"aleric acidemia diagnosed by newborn screnine. A,fl J Hum Gmet 2O04;7 5:11i6-1't47. l I - u k a oI s c r i v e rC R , K o n d o N . e r r l : T h e L l i n r c a p h e n o t . p ea n d o u t c o m eo f mirochondriai acetoacetyl-CoAthiolax deficienc).(beta ketothiolase or T2 deficiency)in 25 enzymaricallyprovd and muBrion-de6ned patients. Mol Genet Metrb 200t i72tL09-lr4 Harding CO, Pillers DA, SreinerRD, et al: Porendal for misdiagnosisdue to (c6lcl rn lack of combined rnerhytmalonicaciduria/hyperhomocysteinmia the neor, rc.I Petitatol 2003 i23:384-3 86. Hoffrnann B, Hetbling C, Schadewaldt P, lWendelU: Impact of longrtudinal plasma leucine levels on rhe intellectuat ourcome in patjents w,th classic MSUD. Pedt t/ Res 2006t59:17-20. e e H o u r e n5 M . F r e n k e J , R ' j k e r \ G l . e t d l : T e m p e r a r u r d e p e n d e n co f m u r a n t l mevalonatekinase activq as a parhogenjcfacror jn hyper{gD and periodic fever syndrome. Hzz Mol Geflet 2002t2213115-3174. HymesJ, StanleyCM, V/olfB: Mutarion in BTD causins biotinidasedeficiency Hutk Mutat 200111*37 5-3131. Kavser M: Disordrs ofktone production and udliz tion. J Mol Genet Metdb 1006;87:281-283. Koeberl DD, Millington DS, Smnh r0rE,er al: Evaluation of 3-merhylcroronylCoA carboxylasedeficiencydetectedby !andem massspectrometrynewborn sqernhg. J lflherit Metab Dis 200326:25-35. Lerner-Ellis JB Gradinger AB, Watkins D, er al: Mutation and biochemical analysisofpatients beLonging th trl B complementarionclassofvitanin to Br:-dependent methvlmalonrc aciduria. Mol Genet Metab 2006.87: 219,225. Lonso N, Fukao ! Slngh R, er al: SuccinyfcoA:3 kecoacid transferase ISCOT) de6ciencyin a new parient homozysous for an R217X mumdon. / Inheit Metnb Dis 2004;27:691492. Mardach R, Verity MA, CederbaDmSD: Clinical, parhological, and brochemicai studiesin a patienr wirh prcpionic acidemia and fatal cardiomyopathy. Mol Cenet Metab 2005:85:286 290. Morel CR Scotr P, ChJistensen er al: Prenaral dragnosislor severemerhylE, eneteuahydrofolatereducrasedeficiencyby linkage analysisand enzyrnatic assalJ. Mol Cenet Metdb 2005;85:115-120. tvlorel CF, watkins D, Scott B et al, Prenatal dragnosis ior mechylrnalonic acidemia and inborn errors of vimmin B,r metabolism and transport. Mol C enet Metz b 200S;86:1 60-17 1. Morrone A, Malyag,a S, Donari MA, et al: ClinicalEndings and blochemical and rnolecular analysis of lour patienrs with holocarboxylase synthense deficiency. A,n I Med Genet 20r)2;lrr:70-78. Morton DH, Stfauss KA, Robinson DL, er al: Diasnosis and creatmenrof maple syrup disease: study of 36 parienrs.Pedidtrics 2002t1o9:999-70o8 A Modinger D, Muhl A. Suormala T, et el: MolcuLarcharacterizationand neuropsychological outcome of 21 patienrs wnh profound biorinidase defi ciency derected by newborn screening and lamily srudies. F.w J Pediatr 2003;162:545-S49. Nellis MM, ksinski A, Carlson M, er al: Rladonship of causarivesenetic mutations in maple syrup urine diseaswirh rheir clinical expression.Mol G e,et Me tab 2003\80:189-19 S. Prasad C, Nurko S, Borovov.l, Korson MS: The importance of gut molility in the metabolic control of propionic acidemia. ./ Pedzatr 2004;144:532-.535. Prietsch V Mayateper E, Krastel H, et aL Mevalonate kinase deficiency: Enlarging the cljnical and biochemical spectrum. Pediatics 2003t11r. 258,261. Sass JO, HofDann M, Skladal D, et al: Propionic acjdemia rvisited:A Dorkshop report. CIis Pedi4, (Phila) 2004;43:837-84J. ValianpoDr 4lx/aners RJA, Overmars H, er at: Cardiolipin deficiencv in Xlinked cardioskeleral myoparhy and neutropenia (Barth syndrome,

566 r PABT r Metobolicoiseases X MIM 302050):A stud,v culturedskin fibroblasts. Pedia 2002;1411 in J 729-733. VarvogliL, Reperto GLI, Waisbren et al: High ccgnirive SE, ourcome an in adolescent with ,r'4r merh)'lmalonic acidenia.An J Med Ge et 20OQ\ 96 192-195. Y/olfNI, Rahman Claycon Zschocke Mjtochondrial S, PI' Hluc-CoA sl,n J: rhase deliciency: Idencificalion trvo {urrherparjents of carrfing ttro novel m[Janons. ] Pedidtr2003,162.2/-9-280. [.ur \0organLC, Niles K, TironeJC, et aL The spectrum murarions m r of in
me vl'naloni. acidemiaand jdenrification of a comnon Hispanic mut.tion and haplorype. Hrn Mutat 2006;2t-:3143. Yoriluji T, Muroi J, Uematsu .{, et al: Living relared Jiver transplantation tbr neonatal-propionic acjdemia.I Pediatu2.000;13V572 574. Glycine Almeida LS, Verhoeven NM. Roos B, et atr Creatine and guanidinoacerate: Diagnostic markers for inborn erro.s in creatine biosynrhesis and cransport. Mal Genet lvletd b 2004;82:2 \ 4-21,9 . Caldeira Araujo H, Smir U/, VerhoevenNi.f, et al: Guanidinoacerare rnethyluanslerasedeficiencyidentified in adulrs and a child wifh mental retarda tlon. A,t1I Med Cenet A 2005i133:122-127. Cochat P, Nogeeria PCK, Mahmoud lVA, et al, Primarv hyperoxaluria in jnfants: l!{edicoethical and economic issnes.I Pediatr 1999;135:746750. Darnpue CJ: Molecular etiologr of primary hyperoxaluria rype 1: Ne\,! directions for trearrnent.Am J Nephd 2005t25:303-3 t0. Dinopoulos A, Varsubara Y, Kure S: Arypical vrriants of nonketoric hyper gl_vcinemia. MoI Ge,er Metab 2005t86:61-69. Hoover Fong JE, Shih S, Van Hove JL, et al: Natural hisrory of nonketotic h y p e r g l y c i n e m iia 6 J p a t i e n . s N e , r / o / o s ]2 0 0 4 ; 5 3 : 1 8 4 7 - 1 8 5 3 . n . JamiesonNV European PHI TranspJantationStudy Group, A 20-vear experience of combined liver/kldnev transplantarion for primary hyperoxaluria (PH1): The European PH1 transplanr regisrry experieDceI984-2004. Am I Nephrcl 2005i251282 289. Mitliner DS: The prirnary hvperoxalurias: An algoflrhm for diagnosis,Arn / N ephrc I 2005 ;Zrl 5 4-1,60. Rosenberg EH, Atmeida LS. Kleefstra ! et al: High prvalenceoI SLC6A8 deficiency in X linked mental retardarion. A,n I Han Genet 20O4;7 5:97-10 5 Sellner L, Edkins E, Greed L, Lewis B: Derection ol mutations in the glycine decarboxylase gene in prtients ivilh nonkerotic hvpergl-vcinaemja.,VIol -171. Cenet Metab 20Os184:767 StroinberserC, Bodairer OA, SrocklerJpsirosluS: Ctinical characteristics and diagnosric clues in inborn efrors of creatine metabolism. J Inhetu Merab Dis 2O03;26:299-308. Verhoven NIU, Salomons GS, Jakobs C: Laboratory diagnosis of defectsof crearine biosvntheslsand uansport Clt Cbin Acta2005;361:1 9. Serine de Koring TJ, Klcmp LW Serlne-deficiency syndromes. Cutr Opin Nearcl 2004;171197 204. de Konins TJ, Klomp LW! van Oppen AC, er at: Prenatal and earl).postnatal (eatment in 3 phosphoglycerate dehydrogenase deficiency. Lracer 200413 64:2221)222. PolLitcRJ. Sharard N.fJ:T.eatins rare inborn errors o{ metaboLism.Lrr.ef 2004i364:2158-2160 Proline ForLino A, Lupi ,A.,Vaghi P, t al: l.Iu|ation analysis of 6ve new parients affecred by prolidase deficiency: The lack of enzyme activir-v c.uses necrosisLike cell death in culrured fibroblasts. Hum Cenet 2002,'l1ll 314-t22. Lupi A, DeRrso A, Torre SD, et al: Characcerizationof new PEPD altele causing prclidase denciency in r\r'o unrelated patientsi Natural-occufrent mutations as a tool ro investigate structure funcrion rclad'onship.I Hum Genet 2004;41500-506. Gluramic Acid Cordon N: Succinic sernialdehvdedehydrogenasedeficiency TSSADH) (4hydroxybutyric aciduria, gamma hydroxvbutyric a.ciavti^\ Eul I Paediatr Neutul 1004;8:261J55. Haberle J, corg B, Rutsch R et al: Congennal glutamine deficiencywith gJu' r a m r n cs y n r h e t a sm u t a t i o n s . E z A l l M ? d 2 0 0 5 ; 3 5 3 : 1 9 2 6 - 1 9 3 3 . N e N'ledinaKauwe LK, Tobin AJ, DeMeirleir I- et al: 4 AmLnobutyrare aminorrans(GABA fansarninaseldefrcienc\l.I ferase Inbetu Metdb Dis 199922414427. Njalsson R: Glutathione synrhetasedeficiency. Cell Mol Life Scz 2005i62: 1939-194S. Njalsson R, Ristoff E, CarlssonK, et al: Genowpe,enzymeactivirl'! glutrrhione level, and clinical phenotype in patienrs wirh gLutathionesyntherasedefi .iet\cv. Hum Cenet 2005 tr16384-389. Pearl FL, Gibson KN{: Ciinical aspectsof rhe disorders of GABA netabolism in chrldren. Crzr Opm Newol 2004i171107-113. Pearl PL, Cibson KN.I, Acosta MT, et al, Clinical spedrun of succinic senialdehyde dehydrogenase deiciencr. N'errolr;gy 2 0O390.74 73-7417. Ristoff E, Larsson ,{: Oxidative stressin inborn errors of metabolism:kssons Irom slutathione deiciercy. J Inheit Metnb Dis 200225:223-226 Wong CG, Bottislieri T, Snead OC III: GABA, samma-hydroxybur_vric acid. and neurological disease. Afln Neurcl 2003\54s3-512. Urea Cycle Anadions G, Ierardi Curro L, Kaplan PB, et al: Ornithine transcarbam_vlase deficiencl and pancreatnis I Pedia, 2001l'1381123-124. Arvio P, Arvio N,l: Progressrve nature of aspartylglucosaminuria. Arta Paedi dtr 2002191255-257 Brusilo\r' SW: Hlperamnonenic encephalopathl Medicifte (Bdhimole) 2002\811240 249 . Cronbez EA, Cederbaun Slr: Hyperargininemia due to liver arginase deficienct. Mol Cenet Metal' 2005;84:2:13-251. EnsenauerR. Tuchman M, El YoussefM. et al: I\'Ianagemenr and ourcome of neonatal-cnsetornithine transcarbamvlase deficiencyaollowing liver rrans' planration ar 60 days of liIe. Mol Ceset Metdb 200J;84:363-355. Gropman AL, Ba6haw ML: Cognitive outcome in urea cvcLedisorders. nfol G enet Metab 2004;81 tS 8-S62. 5 Habede J, Koch HC: Generic approach to prenaral diagnosis in urea cycle detec$. Prcnat Diagn 2004;24r378-383. Honlen SP, McCouan TC, Goertzen TC, er al: Isolated hcparocyre trans ptantation rn an infant with cycle disorder. Pediatrics 200i;L1.L:1262 L267. Kaiser Kupfe. l!{I, Caruso RC, Valle D: Gvrare arrophy of the choroid and retira: Further experience{'irh long"term reduction of ornithine levels jn children. Arrn Ophtbabnol 2002t120:146-15 3. KaiseFKupfer lvll, Caruso RC, Valle D, ReedCF: Use of an arginine-resrricred diet to slow progressionof visual loss in patients rvith gyrate atrophv. Arcb I Ol, hthdltuol 2004i \229 82,-9 4. Kleijer U1, Garrisen VH, Linnebank lvl, et al: Clinical, eDzynadc, and mole cular geneticcharacterizationof a biochemicatvariant type of argininosuccinic aciduria: Prenatal and postnatal djasnosjs in five unrelated farnilies. / 9-410. Inberir Metub Dts 2C02;25:49 Kofman SH, Kanaza{'a N, Abu-Ljbdeh B, et a): Hyperornirhinemia, hvper ammonemia, and homocitrullinuria syndrome \r1th evidenceoi mitochon d r i a l d y s f u n c r i o n u t o a n o v e l S L C 2 5 A 1 5( O R N T / ) s e n e m u t a r i o ni n a d P a l e s t i n i a na m i l y . r N e l l r o S c r2 0 0 4 ; 2 1 8 : 5 35 8 . f l / t.rnnebankM, TschiedelE, H3berle J, et al: Argininosuccinarehasc (ASL) de6ciency: Murarion anal).sisin 27 patients and a compLeted st.uctur of the human ASL gene H n Cenet 2002t171:350-3s9. LfcBride KL, Llitler G, Carier S, er at: Developmental outcomes with early orthotopic liver uansplanration for inlants {.ith neonatal-onserurea cycle defecrsand a female patiencivith late onserorniihine rranscarbanylasedefi4 c;ency.Pedidtr i.s 2O0 :I 74 :e523-e526. Morioka D, Kasahara \,I, Takada Y, et al: Current rule oi 1i"er transplanration for the treatment of urea cvcle disorders: A review of che trrtrLdwrde English lirerature and 1l cases ar Kyoto Universir): Lircr Tlanspl 2 0 0 5 ; 1 1r:3 3 2 - lJ 4 2 . Nagasaka H, Komatsu H, Ohura T, et aL:Nitric oxrde syntheris in ornithine transcarbamvtasedeiciency: Posslbleinvotvement of lorv no svnthesis in clinical manifestarionsof urea cycle defect. / Pedidtr 2004\145:259 262. Nicolaides P, Liebsch D, Dale N, er al: Neurological outcome of patienrs with deiciency. Arcb Dis Child 20018654-56. ornirhine carbamo,vlrransferase Picker JD, Puga AC, Lery HL, et al: Arginase deiiciency rvith ledral neonatal expression: Evidence for rhe glutamine hyporhess of cerebral edema. / Pediatt 2003;r 42349-3 52. Robininath T, Costello DJ, Lynch I et al: FataLpresentationof o.nithine transcarbarnylase deficiencyin a 52'vear-old man and farnily studies./ lnrel,t Metab Dt 2004i27:285 288. in SahekiT, Kobayashi K, Iijima M, er al: Metaboiic derangemenrs deficiencl' carrier H"pdtol Rr of citrin, a ljver-typemitochondrial aspartare-glutamare 2005;33:181-184. SahekiT, Kobayashi K, Iijima M, et al: Adutt onsectvpe II cnrulline'nia and idiopathic neonatal hepatitrscausedby citrin deficiencv:InvoLvement the of

r of in Chaptr . Defects MotobolismLipids 567 86

asparraregtutamatecarrier for urea synthesisand maintenanceol rhe ura

year follo*-tp. I Inhent Metab Dts 20O4;27:787-196 ScagliaF, O'Brien WE, HenrvJ, er al: An integraredapproach rothe dia osis and prospectivemanagementof parrial ornithine rranscarbanvlase ficiency.Pedia*rcs Z0D2;109:150-152 conferenceior rhe man of Summar M, Tuchman M: Proceedings a consensus

prolonged periodsof starvalron,and during periods of reduced illnessor increased energv caloric intake due to gastrointestinal expenditureduring febrile illness.Under these conditrons,rhe body switchesfrom using predominantly carbohydrateto pre acidsare alsoimportant fac dominanrly as icsmajor fuel. Facry skeletalmuscle and are the preferred subsrrate fuelsfor exercising factl' acidsare completelyoxidized for the heart.In thesetissues, ro carbon dioxide and water The end products of heparrc fatry acid oxidarion are the ketone bodies p-hydroxybucyrate
These cannot be oxidized by che liver but and serv as important fuels in peripheral tissues, particularly the brarn. Genetic defects have been identified in nearly all of the known steps in the fatry acid oxidation pathway; all are recessivelyinherited (Table 86-1). Clinical manifestatiozs characterisncally involve lhe tissues with a high p-oxidation flux including Iiver, skeletal, and cardiac mr:scle. The most common presentation is an acute episode of life+hreatening coma and hypoglycemia induced by a period of fasting due to defecrive hepatic ketogenesis.Other manifestations include chronic cardiomyopathy and muscle weakness or exercise-induced acute rhabdomyolysis. The fatty acid oxidation defects can be asymptomatic during periods when rhere is no fasring scress.Acutely presenrrng drseasemay be misdiagnosed as Reve syndrome or, if fatal, as sudden unexpected infant death, Facty acid oxrdation disorders are easily overlooked becausethe only specific clue ro the diagnosis may be the frnding of inappropriately low concentrations of urinary ketones in an infant who has hypoglycemia. Genetic defects in ketone body utilizauon may be overlooked because kecosis is an expected finding with fasting hypoglycemia, ln some circumstances, clinrcal manrfestations appear to arise from toxic effects of fatty acid rnetabolites rather than simply rnadequate energy production. These include disorders (LCHAD, CPT-IA, SCAD, TFP; see larer) in which the presence of an affected fetus (homozygous) increases rhe risk of a life-threatening rllness in che helerozygote mother, resultrng in acute fatty liver of pregnancy or preeclampsia r,'v'ith HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Malformations of the brain and kidne;rs have been described in severe electron rransfer flavoprotein (ETF), ETF dehydrogenase (ETF-DH), and carnitine palmitoyltransferase-2 (CPT-ll) deficiencresthar might reflect ir utero toxiciry of farly acid metabolites. Progressive retinal degeneration arrd chronic progressive liver drsease have been identifred in LCHAD deficiency. Newborn screening programs using ta[dem mass specrromerry (MS/MS) detect characterisric acylcarnicines seen in many of these disorders and permir presymptomatic diagnosis. Screening programs have provided evidence thar all the fatry acid oxidation disorders combined are among the mos! common inborn errors of metabolism. Figures 85 1 and 86 2 outline the steps involved in the oxidation of a rypical long-charn fatty acrd. In the carnitine cycle,Iatty aclds are transported across the barrier of the rnner mitochondrial membrane as acylcarnrtine esters. !(Iithin che mitochondla, successiveturns of the four-srep p oxidation cycle convert the coenzr,nteA (CoA)-activated fatty acid to acety'l CoA units. Two to three different chain length specific isoenzymes are needed fbr each of these p-oxidation steps to accommodate the differentsized farty acyl CoA species. The electron rransfer pathway carrres electrons generated in the 1st P-oxrdation step (acyl CoA dehydrogenase) to the ele.trorl ttufispolt .hdin for adenosine triphosphare (ATP) produccion, while electrons generated from che third step (3-hvdroxyacyl CoA dehvdrogenase) enter the respitatetry chain ac the level of complex 1. Most of the aceryl CoA generated from hepatic p-oxidation flows through the pathway of ketogenesis to form p-hvdroxybutyrare and acetoacelale.

Caserepons from 15 causedby citrin defrcjenc,v: ral inuahepatic cholestasis

Metab 2004i81:585-59L.

o'rccome. Pediatl 1997;131:44G-443. I Lysine Bjugstad KB, Goodman SI, Freed CR: Age at symptom anset predrcts sever ity of mocor impajrment and clinical outcome of glutaric aciduna tvpe I .f Pediarl 200O\l 37:681-6 86. earlv despLte Kolker S, Rarnaekers VI, ZschockeJ, er al, Acure encephalopathy rherapy in a padenr wirh homozvgosny for E365K in the slutamyL coen gene.I Pediatu20O1t138:277279 zvme A dehydrogenase Palacjn M, Bertran J, Chi aron J, ec al: Lysinuric Prorein intolerance, lvlechanisms of parhophysioloEy.Mol Genet Metab 2004;81:527-S37. SperandeoMB Annunziara P, Ammendola V, er al: Lysinuric prorein intoleF ance: Identification and functional analvsis oI mutations ot rhe SLC7A7 gene.Hum Mutat 2005;'25:410. Strauss KA: Cluraric aciduria rype 1: A cJinicjant vlew oI progress. Brarz 2005;128:697-699. Strauss KA, Puffenberger EG, Robinson DL, Morton DH: Tvpe I gluraric aciduria, pan 1: Natural hiscory of 77 p^tienrs An I Med Gnet C Semin Med C enet 2003;121138-51. Aspartic Acid Leane P. Janson CG, Bilianuk L, ec al: Asparroacylasegene transfer to rhe mamnalan central nervous system wirh lherapeutic imPlications for A C a n a v a nd i s e a s e . r a N e u r c l 2 o 0 0 t 4 8 ' 2 7 3 8 . N{ataton R, Mjchats K: Molecuiar basis of Canavan disease.E1i I Paedidtl Neurol1998t2t6976. l,latalon R, \{ichals-Matalon K: Spongy degeneratjonof rhe brain, Cana"an Biochemicatand molecular findings frozt Bios.i 2000lj:301-311 disease, rric SurendranS, Bamforrh FJ, Chan A, et al, Mitd elevationof N-acerylaspa acid and macrocephaly: Diagnosricprobtem./ Clld N2nol 2003;18B09-812 possibtegeneotype-phenotype correlatrons Tacke U, Olbrich H, Sass JO, et at: in children wirh mild clinical course of Canavan dlte^se Neurcpedidtl'cs 2005;36:252-25i. Topcu M, Erdem G, SaatsiI, ec al: Clinical and masneric resonancermasins featuresof L 2 hydroxygluraric aciduria: Report of three casesin comparison with Canavan disease. Chil,1 Neurol 1.996;11:373-377 I Yalcinkaya(1, Benb; G, SalomonsGS,et al: Atypical MRI findinss tn Canavan A disease: parienr wirh a mtld colrse. Neuropediarl;rr 2005;36:316-339

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(leconlpensaflolif cxposccl suf6ciert peli()dsof irrr nrerabolrc to iesring. MC I)uring acutc cpisocles,hypogl-vcc'mra is A C D Findin(Js. M E D I U M H A I N C Y I O A E H Y D B O G I NIA S TA D ) D E T I C I E N C Y Lahoratory C ltrc rs nsualll prcscnt. Plesma enrl urirrary l<etoneconceorrati()lls M(lAD clcficicncr thc rnostconrmon fhe ieftv acid o\i(l,rof 'l he cffecrirnost inappropri:rrclvlor.r {hyp6ks161ic hypoglycemia),Bccauscol rhe shor,r'sstrone, a f()un(ler tiorr rlisorclers. ,Jisorder acrdernie patieDf havc il l()rrll\,vcsrcrn Europei]lrilncestrv.1nd rhe major rclati\.ch\ pokct{)nemii, there js litrle or no metaLrolic irv of paricnrs are homozvgous krr a sing,lec()mrlon orisscrrsc Tcsrs of lircr iLrnctiou ruc atrnorrnal, widr cle\rti(nrs oi livcr blood ernnronia, and prolonp,ed enzymes iAI l. ,\S'l), eLcvatecl nutariol! en,,\-(i trensirion :rt cDNA posirion 9il-5thar chalges prothrombin 1Pf) arrl pertiei tlxornhoplastin ti rcs LPTT).I ivel e d l v s i n ef o g u t a L n i r c r ( l: r r r s r d u c3 2 9 i K l 2 9 t - ) . prcscnr in rhe hiopsl, at finles of rcufe illness shows rnicrovcsjculrr or ClinicalManilestahDIs,{fiecred pafrenr\ usuall-v [)uring mecrovcsicular dLre accurnulatjon. lsr 3 nro I rr of liic rlith episodesoI acure rllnessrrrggcrcd by scearosis to trigl,vcerlde and slmp fastingstrcssor dt tiurcsoi:rcLlteilltess,uriLrarvorganrcacid prcprolong,c.lf,rsringlasring longer rhan 12-16 hr. SigLrs prog,rcss 6lcs by gls chromirrogr.lphy/rnass spectronctlv shorv indppro to rorns in.ludc vonlitilrg end lerhargv,u'hrch rapicLlv priateLy lrrv concenrrationsof keroncs and clcvaccd lcvels of co]rra or seizulesand cardiorcspirarorycollapsc. SuddcLturex pectedintaDf death mal occur. I'hc livcr mav bc slightly enJlrged rlrcdiuDr-chain clicarLrrxl.licacitls ladipic, suberic. ilr)d sebacic ecicls) rvirh far rleposition.Affacks are rare until rhc infant is beyorrcl thar dcri!e ironr microson.rl an.1perorrsonrrl onrcgl rrri ,Jueto nrore lrequenr lceddanon o{ iarrl acids l)Lasmaand rissuc corceDtfations ol total rhe lst few months oi liic, presurnably .irr itinc ;rrc rcduced () lj .50lzu normal. and the liaction of ol irrgsar a younger:rge.Affeoed oider intinrs are ar higher risk of total esrerifierl cirnrfine is increased This pattcrn ()t lccondarv illnessas rhc,vbcgin nr iast thlough the rright or ale erpose.l tcr PrcscLrra- carnitine dcficicncyis secn in alrnost all thc frtty acjd oxrdrti()n iasting strrss rllrring an rntercurrenrchrlJhood iLlness. clcfcctsand fcflccfscl)rr)pefltionl.crnrcn incrcascddcvlcrrnirinc tion in rhe irt clrvs of lifc has bccn rcporrcd irr rrcq.bornsthat Sig lcvcls end frcc c^rnirinc rlensport lt the plesrnanrenrbr:rrre. r,vcrcfastcd ilradrerrently belirre successhrl bleast ieerfillg.Diegirr are bccn r](rcrrrncnrccl prrcvir;LrsJv riiclllrt e\ccpfr(ns to fhis r-Lrle rhe llesmd rncmbrlnc crrnj nosis ol Nl(-AD hls occasjonall-v (irA hcllrhl tcerage antl acLulr indivirluals. indrcirting tlrrr even Iinc rrdnsporfer (IPTIA .lrd p h-vdrox-v-13-urcthyLglur,rrvl dcficrencies. prrticnrslvho h.rvc been asymptomatic iu inaencylrc strll .rt risk C.oAl svrrth:rsc iH\.iC

DEFECTS p-0Xr0ATr0N tNTHE CYCTE

ot Chapter . Delects Metabolism Lipids r 569 86 in free tatty acid (C16'palmilate) Long-charn Carnitine Plasmamembrane

Lcaclrctrl:le

Outer mitochondrial membrane

brane bv carnitine/acylcarnitinerrandocase (TRANS). and rhen reconvcned inro , ton8 chain fany acvl CoA bv carnitine palmrtoyltransferase"IlICP I) !o (VLCAD/LCADi leads to tbe prodLrctionof (C15-l0i 2,3 eDoylCoA. Trifunctional protein (TFP) undergo p-oxidarion. r;ery long chaln acvLCoA dehydrogenase (3'OH-ACD), a|d P ketorhiolase (thiolase) Acervl CoA, (hvdrataset, 3 OH-hvdrox,vacyl CoA deh;rdrogenase conrains rhe acriviries of enoyl CoA h,vdrarase \{ediurnFADH. and N,iiDH are produced. Medium, and shorr-chain faay acrds (C8-.+l can enrer rhe Inrrochondnal matri\ independenrof rhe carnitine c-vcle. (SCHAD) are required CoA dehydrogenase (MCAD), short-chaiu acyl CoA dehydrosenrsclSC,{D). and shorr chain h,vdrcrv ac-vl chain acyl Q,A dehvdrogenase Acecyl CoA can rhen enrer rhe Krebi tl CAI cycle. Electronsare rranspoir.d fro'1 FADti ro rhe respirak).y chain via the eJecrrontrnnsfer flavoprore,n (h-TF)and (ET}--DH). NAI)H mrers rhe electron ra'rspo( chain through compLexL Acervl CoA can be converred into rhe eledron ugnsfer 0avoprorein dehydrogenase (HMCI) CoA bv 0 hvdrcx,'-0 merhvlglutaryl CoA svnthase(HNl(; GiA svnthase)and rhen r,bekerone body acetoacerate thc acrion b-v h_vdroxymerhylsltrrar_vl of p hydrory'p-merhl lgluraryl CoA lvrse (HMG CoA lyase)

Dtagnoscicmarkers include increasedplasma Cro, Crl,o, and ylglycines C101 acylcarnitine specresand increased urinary glvcines. including hexanovl-, suberyl- and 3-phenylpropio Newborn screening programs using tandem mass spectrometry can diagnose presymptomaticInfants based or the detection oi in the abnormal acylcarnitines 6lter paper blood spots. In many cases,the diagnosis can be confirmed by finding the common A985G mutacion.A secondcommon mutalion. T199C, has been in acylcarnitrnes nervborn detecredin infants with characterisric screening tesrs. lnterestingll, this allele has not been seen to date in symptomatic N{CAD patients; ic may represent a miLd mutatron. Treatrenl. Acure illnesses should be promptl]' treated \r'ith inrravenousfluids containing 107" dexrrose to treat or prevent and !o suppresslipolysisas rapidly as possiblelsee hypoglycemra Chapter 92). Chronic therapv consistsof avoiding fashng. This

simply adjustingrhe dier to ensurethat overnight usually requrres fascingperiods are limiced to <10-12 hr Restncting dietary fat or treatment wilh carnitine is controversial. The necessityfor active theraDeuticintervention for individuals u.ith the T199C murarion has not yet been esrablished. Prognosis. to 257. of unrecognized Up patienrsmay die during rheir lsr attack of illness.There is frequendv a histor,vof a previous sihhng dearh due ro unrecognized Some MC,{D deficrency. patienrsmay develop permanenrbrain injurv during an attack of profound hypoglvcemia. The prognosis for survivors rvithout brarn darnage is excellenr because muscle weakness or car Fasting tolerdiomyopathy does nor occur in MCAD deficiency, ance improveswith ageand the risks of rllness decreases. many As as 509. of affected patienrs have never had an episode; therefore, testing of siblings of affected patienrs is imporrant to derecl asvmDtomatrc familv members.

570 I PABT r MetabolicDiscases X VEFY IONG CHAIN ACYI. COA DEHYDROGENASE OEFIiVI"CAD) CIENCYVLCAD deficiency u'as olginally termed LCAD de6ciency be{ore rhe existence of the inncl mirochondrial membrane bound VLCAD lvas knorvn.,A.ll paticnts prevrouslv d i . r g n o s ea . h a v i n g| ( \ D , l r 6 . i e n . ' h a v . \ ' L t \ D e n z v m cd e F J cienc,v.No patients with isolated LCAD dcliciency have been describedand the rolc o1 LCAD i human fattv acid oxidarion is u r k n o w n . P i t r e r r t ' ' , t r r h \ r l L A D r l e h c i e n c ta r r u . u c l l r r n o r r severely afiecced than rhose with MCAD dcficiencl', prcsenting earlier in infanc]'and having more chromc problems rvirh muscle ,,r;cakness episodesof musclepain and rhabdomyolysis.Caror dromyoparhymay'be presentdurmg acute attacksassociated rvirh fasting. The left vencricle may bc hypertrophic or dilated and show poor contractility on echocardiograph,v.Sudden unexpected death has occurred in several patients, b$r most lvho surviled !he initial eprsode shorved improvement, including normalizatron of cardiac functjon. Other ph1'srcal and routine laboratory learures are similar to those of -\.ICAD deficiency, including secondary carnirine deliciency'- The urinary' organic acid pro6le shows a nonkctotic dicarboxylic aciduria. Increased levels of (161, dicarboxylic acrdsmay be noted in the urine. Diagnosisma,v be suggested an abnormal acylcarnitineprofile n'ith plasma or b,v blood spor C1111a6ac-vlcarnicine species, but che specificdiagno sis requires assay of enz,vme activities of VLCAD in culrured frbroblasts or direct mutarional analysis of thc VLCAD gene. Treatment is based primarily on avoidance of fasts for >1012 hr. Continuous rntrallastrLc feedingis usefu)in some patientsACYTCOAOEHYDSOGENASE SHORT_CHAIN DEFICIENCY {SCAD} A small number of paticncslvith tu.o clear null mutaoons in the SCAD gene have been described u.ith variable phenor,vpe.Mosc paticnts classifred as being SCAD deficienr have been shor,vn ro have polymorphic DNA changes rn the SCAD gene and high residual activity. lhe ru<r common polymorphisms are Gl85S and R147Vi Currenth, it is believedthat rhcseare susceptibility changes, rvhich require a 2nd, as vet unknor-r.rt,genetic mutatiorl !o express a clinical phenotype. These indrviduals do nor preselt rvith hvpoketoric hypoglycemia. Skeleral myoparh,v secms to pre dominate. br:r a consistent clinical ghenot,vpe has not hccn iden ri6ed. Some patients have severemetabolic acidosis.Ncurologic signs are present in most patientsr although mildly aftccted indi viduals mav be asympcomatic. Diagnosisis indicated by elevated levelsof butyr,vlcarnirine blood spots or plasma and increased on excrerioi of urinary erh,vlmalonic acid and butvrvlglycine.These metabolic abnormalities are most pronounced in paoents wJch null murations and variably presenrin parrenrs u'ho are homozygous for the polymorphisns. Confirmacion of dragnosisrequires mutacion analysls.Some of the clinical featuressuggesc toxic a perhapsowing to accumulationof short chain farty ity s,vndrome. acid merabolites.One reported parienc had nornal ketogcncsis, irnplving chat there is no irnpairmenr of longer chain farrv acrd oxidation. Treatment is lirnitarion of fastrng strcss and dierary far. IONG_CHAIN3-HYDROXYACYT COA OEHYDROGENASE ITCHADI/ TRIFUNCTIONAT PROTEIN (TTP} DEFICIENCYMITOCHONDRIAT LCHAD deficienc,vis the second most common of the fatty acid oxidanon disorders.The LCHAD enzymeis part of a mitochondrial crifuncrionalprorein (TlP), which also contains two other stcps in B oxidation, long chain enoyl CoA hvdrataseand long protein composed lr chain p-kerorhiolase. rs a hetero-occameric of 4o and 4J3chains that dcrive iron disnncr contiguous gcnes wirh a common promoter region. In somc paricnrs, onlv the LCHAD acivity of the TFP is affected (LCHAD dedcienc,v), rvhereasochershave deficiencies all three acriviries(TFP dcf of cienc,v).Clinical manilestations include rtracks of acute hypoketoric hvpoglycemia similar ro MCAD deficiencv;patients oflen r1 shou' e1'161s... m.rc severedisease,inclucling cardiomyopath,r',

Palnitate

v
Cr5 CO-CoA
I

Y C15-CO carnitine I n n e r i t o c h_ - .d- _ _ _ _ ___ I _ T B.A N_ _ __ _ _ Canitine m on rial I__^ S Cycle ;;;b;;_ Cj5 CO-carnitine

lcPr-1

Eleciron Transfer ranspon *charn

cer.,

C1s CO-CoA

ErF-DH ErF rno-.1 ^"" ^^^ Electron

-- rao14

R -CH2-CH:CH-CO-CoA

V R -CH2-CHOH-CH-CO-CoA

I uyoratase
13-Oxidalion Cycle

*.j NAD s_oFt_nco z+ NADH

R - CH2-CHO-CH2-CO CoA ncetvtCoA--y' t Thiolase '
C1s-CO-CoA

Acetyl CoA<--1 C11-CO-CoA nceVrcoe --{ Ca-CO-CoA A CoA<--1 Acetyl C7-CO CoA Acervl - CoA<-4 v Cs-CO CoA Acet/ Con+{ Ca-CO-CoA con.-{ Acetvl Acetyl CoA coA synthase I HMG f Ketone -->' Leucine -+ Hydroxymethylglutaryl CoA Synthesis i Acetoacetate

,J

I uuc coo'y"""

i
{ 13-Hydroxybutyrate

o o f i g u r c l t 6 - l P n t h w a r o f n i t o c h o n d r i a L x r d a r x r n f p a l m r r a t c i, r v p i c a l 1 6 carkrn Longchain firly alid. Fnz)'lne sleps irt{rt1r tarnitinc palmrtorltr:ns r f t r a s e ( C P T ] I a n J 2 , c a r r i t m c / e c l l c e r n i n n e. r n s b c a s ei T R A N S I . e l e c t r o n t r a n s { e rf l a v o p < , r e ( F T t ) , E T F d e h } d r o g r n a s cE T } - D H t . r c v l t : b A d e h y n i d r c s c D a s e A ( l D ) , e n o v l C o A h y d r a t a s t l h v d r a r a s c ). l - h y d n ) \ - v c y J C o A a l ( c l e h v d r o g e n a sie O H A C D ) , p - k c t o r h i o l a s et h L o l a s e ) , h _ v d r o x B m e t h l l ' l l P glutarrl CoA iH\4c CoA) syntlase, and lvase.

of Chapter r oefeclsin Metabolism Lipids | 5tl S6 carnitine threshold or in vilro by assav of carnitine uptake using cultured 6broblascs or lvmphoblasts. Mutations in the organic carion/carnitine transporler (OCTN2) underlie this disorder. Treatment of chis disorder with pharmacologic doses of oral carnitine (100-200 mg/kg/day) is highlv effective in correcting the cardiomyoparhy and mlrscle weakness as well as any impairment in fascing ketogenesis. Muscle total carnitrne concentrations r e m a r n< 5 o z o l n o r m a l o n l r e a l m e n t CAEI!ITINE PAIMITOYLTRANSFERASE_IA {CPT_IA} DEFICIENCY Several dozen infancs and children have been described wrth a deliciency of the liver and kidney isozyme of CPTIA. Clinical manifestations include fasting hypoketotic hypoglycemia, occa sionally ';r'ith markedly abnormal Iiver funcrion rests and, rarell', The heart arld skeletalmusc]eare not rvith renaltubular acidosisinvolved because the muscle isozyme is unaffected. Fascing urinary organic acid profile shows a hypoketotrc Cr-Cr: dicarbox;rlicaciduria but may be normal. Plasma acylcarnione analysis demonstrates mostly free carritine with r.ery littLe acylated carnitine. This observarion has been used to esrablish CPT-IA diagnosis on newborn screening by tandem mass spectrometr)', CPT-IA deliciency is the only fatty acid oxidation disorder in rvhrch plasma total carnitine levelsare elevatedco 150-200% of normal. This may be explained by the fact rhat rhe inhibitor,v effects of long-chain acylcarnitines on the renal rubular carnrtine rransporter are absel! in CPT-L{ deficiency. The enzyme defect can be demonstrated in cukured fibroblasts or lvmohoblasrs. in LPT.IA deficiency the fetus has beenas'ociaredwrth icute farry liver of pregnancy rn the mother in a single case report. Treatment is similar to rhat for N{CAD defciencl' with avoidance of situatrons where fasting ketogenesrsis necessary. TRANSTOCASE CARNITINE_ACYTCABNITINE {CACI) DEFICIENCY This defect of tie rnner mitochondrial membrane carrier prorein for fatcy acylcarnirines blocks the entry of long-chain fatqv acrds inco che mitochondna for oxidation. The clinical phenotype of this disorder rs charactenzed by a severeand generalized impair ment of farty acid oxidation. Most neu'born patrenrs present *.ith acracksof fasting-rnduced hypoglycemia, hyperammonemia, and cardrorespiratorycollapse.All symptomatic newborns have had evidence of cardiomyopathy and muscle $eakness. Several pacienrs with a partial rranslocase deficiency and milder disease wirhout cardrac involvemenc have also beeo idenrified. No discincciveurinary or plasma organic acids are noted, although increased levels of plasma long-chain acylcarnitines are reported. Diagnosis can be made using cultured fibroblasts or lyrnphobLasts. The human genehas beencloned, and mutarions have been identilied in affected parienrs. Treatment is similar to rhat of other farty acid oxidacion disordersPATMITOYTTRANSFERASE_II CARITIITINE {CPT_II) DEFICIEIIIGY ThrCC forms of CPT-II defrciencv have been described. The antenatal presenlation of this drsorder rs associated wirh a profound enzyme deficiencl and neonatal death has been reported in several newborns with dysplastic kidneys, cerebral malformations, and mild facial anomalies- A severe deficienq' of enzyme activity is assocrated w'ith an infantile-onset form. This form shares all the clinical and laborarory features of CACT deGciency. A milder defect is associated with an adult presentation of episodic rhabdoml'olysis. The 1st episode usually does not occur until late childhood or early adulchood. Attacks may be precipitaced b,v prolonged exercise. There is achrng muscle pain and myoglobrnuria that mal be severe enough to caus renal farlure. Serurn levels of creatine kinase are elevated to 5,000 100,000 UiL. Fasting hypoglycemia has not been described, but fasring may contribure to attacks of myoglobrnuria. N{uscle biopsy shows rncreaseddeposition of neutral fat. The myopachic Dresenration of CPT ll deficiencv is associated with a common

mav also be associared\l'ith malernal lllness. 'ireatmenr is similar to that for MCAD or LCAD/VLCAD deficiencn thac is, avoiding fasring stress. Sorne invescigators have suggested thac dietary suPplements wirh medium-chain trrglycacid (DHA) may be useful Liver eride oil and docosahexaenoic tlansplantariondoes nor ameLoratechemetabolic abnormalicies. DEHYDBOGENASE }HYDROXYACYI._COA {SCHADI SHORT_CHAIN y few patrents with rhis inborn error have been DEFICIENC frve patients with proven mutatrons of SCHAD described. have been reported. Four cas in three families wirh recessive mutarions of SCHAD presen d with episodesof hypoketotrc hypoglycemra that was shown to be due lo hyperinsulinism ln contrast !o patients wlrh other forms of fatty acid oxidation disorders, these cases required specific therapv for hyperinsulinism to avoid recurrent hypoglycemia. A Sth child presencedwith fulminant hepatic failure at age 10mo and was compound hererozygous for two different SCHAD mutations. Orher reports include a child wrrh attacks of fascing h,vpoglycemia and myoglobinr,rria associated wrth deficiency of SCHAD in muscle but not in cultured fibroblasrs, three children with fatal liver disease, and an rnfant wbo died suddenly and unexpectedly. Thrs variable phenotvpe may be due lo genetic heterogeneitv.Specific me bolic markers for SCHAD deficiencv have not yet been ide i6ed, making this a particularly dif6cult diagnosisco establish.

IN CABNITINE CYCLE DEIECTSTHE

PTASMA MEMBRANE CARNITINETBANSPOBTDEFECT {PEIMARY CABNInNEOEFICIENCY). Primary carnitine deficrencyis the only gene c defecr in rvhich carnirine de6ciency is the cause, rather than he consequence,of imparred fatcl' acid oxidation. The mosr colrlrlron presentalio is progressive cardtomyopathy wirh or h a w i r h o u t s k e l e r am u ' e w e a k n e s s e g i n n i n g t l - 4 ' r o f a g e . A l smaller number of patients may present rvith fasring hypoketotic hypoglvcemra in the lsr yr of life before the cardromyopachl' becomessymptomatic. The underlying defect involves the plasma membrane sodium gradient-dependent carnitlne uansporter that is present in heart, muscle, and kidney. Th:s transporter rs responsible botb for maintainioe intracellular carnitine concenrratrons 20- to 50-fold trigher than plasma concentracions and for renal conservallon or carnlrlne. Diagnosis of the carnirine cransporter defect is aided by rhe fac that patients have extremely reduced carnitine levels in plasma and muscle (1-27o of normal). Hereroz,vgoteparents have plasma carnitine levels =50% of normal. Fasting kerogenesis may be normal becauseliver carnitine transport is normal, but ir may be irnpaired if dietary carnirine intake is interrupced. The fascing unnary organic acid profle may show a hypokecocic dicarbox,vlicaciduria pattern if heparic fatty acid oxidation is impaired, but it is orherwise unremarkable. The defect in carnitine transporl can be dem,rnstrated clinicallr by severefeduction in renal

572 r PAnTX I Melaholicoiseases mutanon 5113L. An intermediare form of CPT-II deficiencv oresents in intanc)/early chrldhood wirh fasrrng-inducedhepanc failure, cardiomyopathy, and skeletal my'opathy with hvpoketo!ic hypoglycemia but does not have the severe developmental changes seen in the neonatal presentation. This pattern is more like that seen in VLCAD de6ciency and management is identical. Patiencs are generally heterozygous for one of the severe rnutations and one of rhe milder mutations. Diagnosis of all forms of CPT-II deficiency can be made by demonstrating deficient enzyme activity in rnuscle or other tissues and in cultured 6broblasts. Mutation analysis rs available.

IIEFECTSKETOTIE ItI UTILIZATIOI{

The ketones P-hydroxybutyrateand acecoacerate rhe end are products of hepatic fatt;t acid oxidation and are important as metabolicfuels for the brain during fascing. Two defectsrn utilization of ketonesin brain and other peripheral tissuespresent as episodes of "hyperketotic" coma, with or without nypoglycemra. SUCCIYI-COA:ilKEI0ACID COA TBAIISFEBASE {SC0T} DEFICIENCYSeveral parients with SCOT deficiency have Deen

reported. Characeristic presentation is an infanc q'irh recurrent episodes of severe ketoacidosrs induced by fasting. Plasma ac,r'lcarnirine and urine organic acrd abnormalities do not distinguish (ETf) TSANSFEB FTAVOPROTEIN AND ETECTRO ETECTBON TRANS. from other causesof keroacidosis. Tieatment of eoisodesreouires FER FTAVOPROTEII{ DEHYDROGENASE infusion of glucore and large amount' of bicarbonateunril mera{ETF{H I DEfICIENCIES {GI.U. TARIG TYPE MUTTIPTE 2. ACIDURIA ACYLCOADEHYDROGTNATION bolically stable, All patienrs exhibit inapproprrate hyperketoneETF DEFICIENCIES). and ETF-DH funcrion to transfer elecrrons mia even between carabolic episodes. SCOT is responsrble for inco the mitochondrial electron rransoort chain from dehvdroactivating acetoacelate in peripheral tissues using succinyl CoA genation reacrions caralyzed VLCAb. MCAD. and SCAD,as by as a donor to form acetoacetyl CoA, Deficient acrivity can be well as glutaryl CoA dehydrogenase at least four enzymes demonsrrared rn brain, muscle, and fibroblasts lrom affected and involved in branch-chainamrno acrd oxidation. Deficiencies of patients. The gene has been cloned, and numerous mutations ETF or ETF-DH produce illnessthat combinesthe featuresof have been characteflzed.

II{ DEFECTSETECTROII INAilSFER PATHWAY

Andresen BS, Dobrowolski SF, O'Reillt, L, et al, Medium chain acrfCoA (MCAD) muratrons identified by MS/MS-basedprospecci"e dehydrogenase screeningof newborns differ frorn rhose observedin patients wrrh clinical svmptoms, Idenrificarion and charactrizarionof a new, prevalent mutarion thar results in mild I{CAD deficiencv. Az Cenet Htm I 2001i68:1408-1418. Bonne{onrJP, Djouad, 4 Prip-Buus C, et al: Carnitine palmitoyltransaerases 1 and 2: Biochemical, molecular and medical aspects. Mol Aspe.ts Med 2004;25:495-520. Clayton Pl Earon S, Aynsley Green A, et al: Hyperinsulinism in short-chain L 3-hydroxvacyl-CoA dehvdrogenase deficiencyreveals the impcrtance of beta-oxidation in insulin secretion.I Clin Inuest 2001;1081457465. Den Boer MEJ, Dionisi-\ricj C, Chakapani A, et ai: lviitochordrial tilunc' cional protein deficiency,A severe fady acid onidation disorder wirh cardiac and neurologic rn"olvenent. I Pediatr 2003i142r684-s688. Den Boer MEJ, Wanders RJA, Monrs AAM, er al: Long-chain 3-hvdroxvacyfcoA dehydrogenase de6ciencl.:Clinical presentarion and follow up of 50 paienl.s PeAdtri.s 2002;109:99-104. tslpelegON, Hammerman C, SaadaA, et al: Antenatal presentarionof carniIt tine palmitoylrransterase deiclency.Affi J Med Geftet 2001'102:183 187. Fukao I Mrcchell GA, Scng XQ, ec al: Succinyl-CoA:3-ketoacidCoA uans ferase(SCOT): Cloning oI th human SCOT sene! te{dary structuraLmodeling of the human SCOT monomer, and characrerization of three IN SVNTHESIS PATHWAY DEFECTSKETOTIE pathosenic muradons. Geaomics 2000i681144 151. GregersenN, Andresen BS, Corydon MJ, et al: Mutation analysis in miroCoA {HMG F-HY0R0XY-p-METHYTGT.UTARYT. CoA)SYNTHASE chondrial fany acjd oxidation defects:ExemplJfiedbv acyt-CoA dehydrogenasedeficrencres, with specialfocus on genotype-phenorvpe HMG CoA synthase is the rare-limiting step in the relationship. DEFICIENCY Hun Mutat 2001t181169 189. conversion of acetyl CoA derived from fatty acid p-oxidation in Klose DA. Kolker S. Heinrich B. ec al: Incidence and short rerm outcome of the liver to kerones. Severalpatrents with this defect have recently children rvith symptomatic pr*entarron of organic acid and iany acid ox;' been identified. The presentation is one of fasting hvpoketotic dation djsorders in Germ^ny. Pediat/ics 2002t110:1204 1210. hypogJycemia withor:r evidence of impaired cardiac or skeletal in Mathur A, SimsHn, Gopahkrishnan D, et aL,MoJecularheterogeneiry very' muscle function. Urinary organic acid profile showed only a long-chain acyl-CoA dehydrosenase dedciencvcausing ped,atric cardiomy'19999911337 hypoketotic dicarboxylic aciduria. Plasma and tissue carnitine oparhy and sudden death. Cir.ulatioh 1343. levels are normal, in contrast to all the other drsorders of fatty Shekhawat PS, Marern D, StraussAW: Fetal fatty acid oxidacion disorders, acid oxidarion. A separate synthase enzyme, present in cytosol rheir eifecr on maternal health and neonatal outcome, Impact of expanded newborn screening on their diagnosis and management. Pedntr Res for cholesterol biosynrhesis, is not affected. The HMG CoA syn2005;57:78R-85R. thase defect is exoressed onlv in the liver and cannoc be dernonStanley CA, Bennett MJ, Mayatepek E: Disorders of mitochondrial fatty acid strated in cultured fibroblasts, The gene has been cloned, and oxidation and related merabolic path.*ays. In: Fernandes Saudubmy J-M, J, mutations in rhe affected patients have been characterized. AvoidVan den Bergh C, Walter JH (eds).Inborn Metabotic Djseases:Drasnosrs ing fasting is usually a successfultreatment. and Trearment4rh edidon: Heidelberg:SpringerVerlag,2005 pp. 175-188. Wllcken B, Haas M, Joy P, et al: Ourcome of neonaral screeningfor medrum p-HYDR0XY-P-I/IETHYLGLUTA8YL See COA TYASE 0EFIGIENCY chain acyl-CoA deh-vdrogenase deficiency in Ausualia: a cohorr study. Lancet 2007359:3742. Chaoter 85.6.

impaired fany acid oxrdation and impaired oxidatron of several amino acids.Completedeliciencies either protein are associof illnessin rhe newborn period, characterized ared with severe by acidosrs, hypoglycemia, coma, hypotonia, cardromyopathy, and an unusualodor of sweatyfeet due co isovalerylCoA dehydrogenase inhibition. Somealfectedneonateshave had facial dysmorphia and polycystic kidneys similar to that seenin severe that toxic effectsof accumuCPT-II deliciencl',which suggesrs lated metabolitesmay occur in utero Diagnosiscan be made from the urinary organic acid pro6le, corresponding blocksin oxidation which showsabnormalities ro and acids), of fatty acids (etbylmalonace C6-C,6dicarboxylic lysine (glutarate),and branchedchain amino acids (rsovaleryl , Mosr severely affected isobutvryl-,and q-methylbutyryl-glycine). infants do flot survivethe neonatalDeriod. Parlraldrhcrencres L ll' .rnd t rF-DH oroducea disorder ol f M t h a rm a ' m r m r c C A D d e 6 c r e n c lr o r h e r j l d e r a t r ya c i do x i o m Thesepatientshaveatracksof fasringhypoketotic dation defects. coma. The urinary organic acid profile revealsprimarily elevacions of dicarboxylic acids and ethylmalonate,derived from Secondarvcarnitine de6 short-chain fartv acrd rntermediates. ciencyis present. Somepatientswirh mild forms of ETF/ETF-DH deliciencybenelit from treatmentwith high dosesof riboflavin, which is a cofaclor for the pathway of electrontransfer.

DEFICIENCY. Chapter 85.6. See P-{GT0TH|OLASE

of Chapter r Defects Metabolism Lipids r 573 86 in

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Flrrv Actos LoNG CHATN 0F 86.2. DtsoRorRS VERY

a

PEROXISOMAI DISORDERS
'fhe are genetiaallt derermined clisorclcrs pcroxisomal diseases rhc catLsed !o either by rhc faiLr.rre f()rrn or maiLrtarrr pero\Ls()nrc

nror'c ircquentll and prcscnt e ulder in chiidhood ard r>ccurrecognrzed rhe past in rlngc of phelotvpe rhen h:s becLr [Tl0l-0GY l'eroxisonral drsordersare subdivided Into t\\'o n].jor c a t e g o r i e( l a b l e 8 6 2 ) . s In categorvA, the pcroxisomalbiogenesirdisorders(PBD), rhc basicdefcct is rhe failure ro irnport one or morc protetls inro fbe orsanellc- ln category Il, defeccsaffect a single peroxisonral protcin 1he peroxisorrc is prcsenttn all cellscxcepr natLrrc er\ rrrgancllesurroLrnded e singlc by drrocvtes.rud is a srLbcellul;rr membrlnc; >51) peroxisr:rmalcnzYmes erc identificcL Sorne c z!nrcs ere rnvolved in the pro(luctron dnd dcconposLtiorr()f others nrt conceruedwlfLr liPid ald rrnrno hldrogcn pcr<>xide; ircid metabolsn. N4osrpcroxisonralenzy cs irrc I sr sl nrhesrzed aurl enter tltc cyrorn their Inatllre forrn,rn lree prrlyribosornes plasrn.Proteirtsthat arc destirledfor the perorisorneconfarn spe (PTS). N'losf peroxi\orrrirI cilic perox;somc targeting seqLrences :rr rnarrix proterns contain PTSI. a 3-amino .rcLdsequrencc rhc rhir i\ carboxyLtermilus. PTS2 is an rrrlno-ternlindl seqLrcnce rrt cricical for the xnport oi elzvnlts rnvt>lved phsnalog,cn rntl branchcd-charn farty lcid nr.'raltolisnr. llDport oi pr(rtcins involves a complcx serresot rellcrons thar rnvolves at least l.l

jlt-linkd 81 adr00leukodyforhy B2rAcyl[oA def( oxi(id5eency ona enzyme deficienr/ 8l:BrFLrn(i B4:Peroxsolra defrc rholase enry 85[ a5iir Sebum dsease B6:2ethllary n(emase l [0A den[ien(y 87i AP uansferaie Df dry dPnoenq 88:A CHAP ly lynthase defi(iei(y 89:lvlevalonk a(duda 810:6lutrk type a(iduria I EllHIEro$luia type 812 a5emia A(ata

ttlZYME B: DEFECs 0F SlL6l.E PEno)($oliAt

distnrct proteins. These proteins are referred t() as perorins cncodc.l by PF.X gcnes IaLrle86--i sumrnarizesrhe /'lX geles rhrrr irrc delectivein hunrar discasesrarcs. tPlDEMl0L0GY. Excepr for X-linkccl odrcnoleukodlstrophy (Xll6-2 are autosonal Al.L)), elLfhe peroxlsomal,:lrsorclers TaLrle rlr rcccssirctraits- X AII) is the rnosf comiroll pcroxisorrraldisor d c ( r t r r h a n c s t i m a t c d r c i d c n c co f 1 / 1 7 , 0 0 0 T h e c o r n b i n c d n c i i i derce ol the other peroxrsomal djsorders Ls esfirrated fo be t/i0,000. PAIH0t0GY Absenceor reduction il rhc number of peroxisones is parhognonrortic disordersof peroxrsone broqenesis. nrosr tor hr disorrlcrs,rhcrc irre mefilbrinoLrssacsthar confain perorisomal integr-ll nrcrrbralc proteins. rvhich lack che norrnal complcmenr oi nntrir protcins; these lre pcr()\isonre "ghosts." Parhologic charlges rre observedin nran! ()rt!:lns and include proiound and ch.rr.rcrerrsrrc defecrs in neuronal migrdtioni micronodultf cir

PTROTIN# (HARACTTRISTI( l
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574 r PART r Mehbolic Diseases X Patientsrvith neonatal ALD shor.r'ferver and, occasiooally, no dvsmorphic features.Neolatal seizuresoccur frequenrly. Some is degreeof psvchomorordevelopmenr present;function remains in che severelyor proioundl,v retarded range, and developmenr mav regress afrer 3-5,vr of age, probabl,rrfrom a progressive leukod,vstroph,v. Sel'eralpatienrs are now in a stable, albeit disabled, sate in their 3rd or 4th decade. Hepatomegaly, impaired liver function, pigmelrary degencration ofthe retina, and severely impaired hearing are invariabl,vpresenf.Adrenocorricalfuncrion is usuallv imoaired. but overt Addison diseasers rare. Clhondrodvsplasiapunctata dnd renal cysts are absenr. Patientswith infantile Refsum disease have survivedto rhe 2nd decadeor longer. Thev are able to walk, afthough gair may be ataxic and broad based. Cognicive funcrion is in the severcl-v hcaring loss and pigmenretarded range. A11have sensorineural tarv degenerarion the retina. They have moderatel,vd,vsmorof phic fearuresrhat nal include epicanrhalfolds, a flar bridge of ears. Earlv h.lpotonia and hepatomegaly the nose, and lo.rv-ser rvirh rmpaired function are common. Levels of plasrna cholesteroL and high and lou'densitl' lipoprorein are often moclerarel,v puncrata and renal cortical cvsts are reduced.Chondrodvsplasia absenr. Postnlortem studv in infantile Refsum drseaserer.eals mrcronodular lir.er cirrhosisand small hvpoplasricadrenals.The brain sholvs no malformations, except for severebypopLasia of the cerebellargranule layer and ec()pic locati{)nsof the Purkinje Ldyer The mode of iohenhnce is aucosocells in the moleclrLar mal rccesslve-

Pe'odio4les I0rcduredflumber ab5ent in (aala5e(''tosol n

lnireased eKretion urioary

punctata;corneal rhosisof the liverl renal cyscs; chondrodysplasia clouding, congenital cataracts,glaucoma, and recinoparh,v; con geniral heart diseaser and dysmorphic fearures. PATH0GENESIS. is Lkelv that all pathologic changesare secIr ondarl co che peroxisome defect. N'tultiple pero)(isomal enzymes fail co function in the PBD (Table 86 4). The enzymesthar are diminished or absent are s)-nthesized buc are degraded abnormalll. fast becausethey mav be unprotected ourside ot the peroxisorne.It is not clear how defectiveperoxisome funcrions lead parhologic manifestatrons. to the rvidespread The PBD are associated t'ith geneticall,v deternined import defects. The PBD have been subdividedinro 12 complementarion groups. The molecular defeccs have been defincd in l0 of these (seeTable 86 3). Thc pattern and severityof pathologic gror,rps features var-vrvirh the nature of the tmporr defeccsand the degree to rvhich import is impaired. Thescgcnc dcfectslead to disorders that were named before rheir relationship to lhe peroxisome \{'as recognized. namell', Z,elhl'cgcr s,vndrome (ZS), neonatal adrenoleukodystrophv(NALD), infanrile Refsun disease(lRD), punctara (RCDP). The 1st three and rhrzomelicchondrod,vsplasia are no\\' considered form a clinical continuum, with to disorclers ZS rhe mosr ser.ere,IRD rhe leasr severe, and NALD itcermedi ate. The,v can bc caused b,v 11 diiferenr gene defecrs, u'hich invoh'e mainly rhe inporr of proteins that contain the PTSI taron cannot be distingLrished the basis gecing srgnal;thc genedefects variesv'ith the degreeto ofclinical ieatures.The ciinical ser.eriry imporr v'hjch prorein import is impaired. Mutations thar aboLish

reraincd, leads to the somewhat mildet phenotypes.A defect in PEX7, r'hich involves the import of proteins that utilize PTS2, rs associatcdwith RCDP -PEX7 defects rhar leave imporc parsome of u'hich with milder phenotypes, ciallyintact are assocrared resembleclassicRefsum disease. The geneticdisordersthar involve single peroxisomal enzymes usualJyhave clinical manifestationstha! are rnorc rcstricted and

relaccd to thc biochemical defect. The primar,v adrenal insuf6of cienc,v X Al-D is caused b,v accumulation of ver,vlong chain fatty acids iVLCtA) in rhe adrenalcorrex, and the peripheralneuropath,v in Refsum disease is caused b,v rhe accumulation of phy r r n r . . r . i d i n 5 . h t t a n n c e l l sa r r J m l r l r n . Nervborn rnfancsr.'r.rth PBD with Milder or AtypicalPhenotypes.

Facialappearance(high forehead, unslanring palpebral lissures, hrpopJasricsupraorbital ridges.and epicanrhalfolds; Fig. 86 31, and e,ve abnorweakness and hyporonia,neonatalseizures, severe glaucoma,comeal clouding, Brushfieldspots, malities (cacaraccs, Bccausc of chc pigmenrary rccinopatht-,arrd nerve d,vsplasia). hvpotonia and "mongoloid" appearance.[o*'n svndrome may be suspected. lnfants rrrrh Zelhveger s,vndromc rarelY live more than a ferv months. More than 90ot" shou' poscnatal grorvth failure. Table ll6--5hsts the rnain clinical abnormalities.

Iigtrr. ll(. I lilrr tatients $irh Zellu'eger cerebrohepatorcnal svndrome. and h,vpoptasia nrpmorbit.l ridges of Note thc hlgh forehead,ep'icrnrhalfo1ds, and rnrdiace (t-ourtes! of Han\ Zellweser. N{Di

Chapter t oeleclsin Metabolisrn Lipids s 575 86 ol srLrvrved rhe -5rhclecade. to Delects ir PEX7, which rnost conrronlv lead ro dre I{CDP phenotype. rnirv.rlso lead ro a mjlclcr phenorl pe rvrrh cLinicaL manlfest.lti()ns sinrilar ro those of clirssi cal Reisurn drsease iph,vranovlCoA hvrlroxvlasede{icicncv). P n R h r z o n r e l C h o f l d r o d y s p l a s ira c t a t a H C D P ) h i s d i s o r d c ri s ic I T cher.rcrerizecl rhe preserrce stippled ioci of calcification by of wirhrrr rhe h,vrline carrilagc and is associatcd rvith cfi,varling, carar.rcrs i72'llol.and rrulr;.lc rnalformationsdue to contrac[ures. carnlage rhat is a Vcrtcbral bodics hrvc'a coronal clcft lilled Lr,v result of an ernbrl,onrc rrrest, l)rsproportiorrafe short stirturc (Iiig. 86-4i). Radr' .rffcctschc proxinral parts of fhc cxrrcnrrti.-s oLrgic.lbnormaLiries consrsrof shorteLrrni{ the proxunal linb of boLres, rnetaphlsealcupping. tnd drsturhedossilicationiFig. 86 '1lli. Height, u'eight. irnd hc.rl circumfercncc are lessrhan the 3rr1 percentile, and thesechildrcurc levcrcl) rcrardedmcncalb'.Skin changessuch as those observediLr ichrhyosliorm erythroderma afc lrcsent in =2.5!6 of fitrtnts. 'l lsolatedDelectsol Peroxisonral FattyAcid 0xidation. hc disordcrs lrbclcd R1 through tli isec Tablc S6 2) cech invoLveole of rhrce enzl.rnes involverlrn per<>xisomal farrv acrd oxidanon.'fheir c l r r i c a l n e n i f e s t a t r o l s r c s c r n b l er h o s e o f t h c Z c l l w c g c r s 1 n clronrc/rconaralALD/Inienrile Rcisum disccsecontinuum; thev cirrrbe clisrirrgurshecl h onr disordersoi pc.r'orisonre biogenesis by lel-.or.rnrrvtcsts. Dciccts oi biiuncrionel cnzvmc erc c()rnnron rnrl dre found in =li'li, ()f patrenrr rvirh rhe lellweger svl tl rlme/neora tal ALL)/irridnfile l{elsunr disease phenor,vpe. Pirricr)ts wirh isoldtccl L (.oA oricl:rscdcficicncv have a somc..\ $+it nrilder phenot,vpc fhrrt rcsernblcs thar of nconatal ,i\LD. ls0latcd Defects of PlasmalogenSynthesis. Plasmakrgens are l L p i d ;i n w h i c h r h c l s r c a r b o n o i g l , v c c r oils l i n k c d t o a n a l c o h o l rrrth.r th.n a iacry acid Thcy rre synthesized chrough a compler serreroi leactions, rhc lst two steps of rvhich ale cefrllzed bl thc peroxisomaL enz\mes dihydroxvacetonc phos|h:rte alkyl ()i trrrtsieraseaiJ s\nthrsc. L)eliciencv elfhef oi fhese enz\.rnes r L r . lr n l t i r n L r l l , s . - l c r d ' r , , r f r ( r ' \ ' r \ l c l ' r r . . l i n r . a l l r r inclisrirrgLrisha ir onr rbe peLorrsornirl ble rrnport rlisorclerRCL)P ThLs letrcr disorder is crru\ed b_v dcft-ctin PFX7, thc .cccptor a krr pcr()\i\onrc targcrirrqsclluelce 2 lt shares the severeclefi crencr of plasnaloeers \vrth disorders B.trand 85 but. in arldi-

ABI'IORMAT FTATURE |l ghfore|le,rd Flal ori:pui Large Bnel \lide fon eis). iLriun5 o o S hla w dtrd l r d q e s Low/bro,rd bridqe naa Eocalthus Hgha,{hed dte F Exiernr earilefolmrty llcrognalhia lieCundant lrfne(k skinfold Erushhed rpots [a]a.arl/( (orneJ ordy Gaucotu p q A b n o l m a i r e rrn ,m e r r d t $ n Optc pa ds( llrr SeveE hypo:ord A b n c n a l M ctrs p o n 5 e f u Nypcrsllexa crareflexa Poolucklnq Gavaqe iieding :pripiisezrles liyihomorcfretrrd,rton ,mpt hearlnq red fystaqmus

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Some prricnts u'idr PtsD drsordcrs have milder ancl rr\pic:lI phcnortpe:,. lhev rral prcsent with periphcrel netlroPith) {rl vision, or cafaracfsrn chilrlhootl.adrr rvirh retinop:rrh,-. iurparrecl to lescence, rclultltood enrl heve bcen dragnoscd hare Ch.rrcot or Sonrc parieors hare l\.larieToorh diseaserrr Llshcr svndrc>rne.

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hrzonlclL. .hondrod!s 'hortenrlg of the pro\ rosc, hvpcr ons,n. .rn.1 rhe nrnrkd slrorre. ng

rt tlic rhouLder .rjrl oi rhc humcrur arrd eprphvseal 5rttlnq e l b o r v ; o , n t s . i C o u r : r ' r o t l o h n ] ' ] .I ) o , s r . \ ' l l ) r

576 r PARTXI MetabolicDiseases 'l rion, has defecrs of phytanrc oxidatit>n. he fact rhat disordcrs 84 and 85 are associrtedu-irh the full phenrxlpe of RCIDP sugis geststhat e delicrency plasmakrgens sliEcrenr ro producc irof enzyme iphvtaLroyl(ir,i\ ClassicRelsumDisease.Ihe defectrve is iocalized to the peroxisorte. Thc nranifestationof oxidase) classicRefsurndisease includesimpalred vision irom retinirispig merrrosa,ichchyosis,pelipherll n.uropathy, irrarir. and, occasionaLly.cardiac arrhyrhmias. ln conrrast to rnfanrile Refsum drsease, cogritiue funcrion is rrorrrdl and there are rro congenital malforrnarions.(lLassic Refsum diseaseofrcn does not rnanifcsc unol youLrg adr.rlthcx>d, bur visual disturhancessuch as nighr blindness,ichthyosis,and peripheralneuropadry nray rlreaclv be is present in chrldhood and adolescence. Earll cliagnosis impor tallt lrecauseinsritution of i phvfarlic acid resrricrrd dier can rcvcrscrhc pcripheral neuropadrvand prevent the p()grcssio of Thc classi rhe visLral and ccntr'alrrcrvoussysternmanifcsterions. rrav :rlso bc causcd hv dciccrs in cal Rcfsum discascphcnoc-vpc PI..X7. 2-MethylacylCoA Hacemase Deliciencf- Ihis clisorderis caused by en enzvme clelict that lcrds to thc accunrrrlationol the .r.ndbi.le branched-chain fattv acids (ph,vtaricand prisranrcacicLl acids.Paticnrsprcscntwith adult typc pcriphcral ncuroparhvand <:i may also havc li!r,lne[tdry degenerati<>n rhe rerrDa IAIIORAI0RYFlN0lNGS. Laboracorl cestsfbI pcroxrsonraldisor of ders cen bc vicwcrl ar rhrcc lcvcLs cornllcxirv. Disortlet? This can l-evel1: Docsthe PalrentHavea Peroxisomal he resoh'ed bv noninvasivc tcs[s that a.c generallv availablc (fable Eri 61. -\4ersurenrent plasrnaVI CIFArs thc nrost corn of rnonlv used assay Wbereasphsna VLCFA levelsarc ele!ated ii rhis rhe mn[,\'paticnts lvith peroxisomal chsorclers, is n<x:rJrvays are VLCFA casc.The most irrpt)rtant excepfLons RCL)P.in "vhich lcr.elsare lormaL, but plasma phyranic acid lcvcls arc incrcascd ald rcd l>loodccll plasmalogenlevelsare reduced.In sorneofher peroxrsomal drsorders, thc biochcmicirl abnormaliries are strll and nrore resfricfed.Therefc:re, panel o1 testsis rcconrrnended a phsnrr lcrcls of Vl-(lFA ald of phvtanic, pristanic, ancl inciLrdes in pipccolic acids ancl levels of p)asmalogerrs red blood cells Tandenr Lrass sfectronrctry techniqucs also permit c<;trvcnicnr . q u a n t i r i r t i ( )o i b l l c : r c i d s i n p l a s m aa n c lu r r L r eJ h i s p a n e lo f t e : i r s n b]ood in(l pernirs cau bc pcrfi)rmcd on 2 nr[. samplesof ven<>us rnd ornal results deteccion oi nrosr pcroxisomal chsorclers. nakc thc prcsenceof a peroxrsomaldisorder unlikclr'. Disoder] [euel ti Whfit ls lhe PreciscNotureol the Peroxrsonlal Table 86 6lists thc main biochemicalabnormalitiesin rhe varior.rs peroxisomal disordcrs. Whcr combined u'Lththe clinical presen rnenrionedpalel of testsis ofrerrsutficientto iderr tation, thc jLr5t tit,v the precise narure of the defect- ElcvarL'dplasma VL(-FA levels permir thc frccise diaglosis of X ,AI l) ir rrralepctients. plasoralogcnlevels combired -\4arked reduction of err,throc,vrc in lr-ith clevared plasma phytanic acid perrnrtsprccrscdiagnosJs a patierrr !vidr thc clinical features of RCL)lr. Classic Refsunl disease can be di.rgnosedbl demonstration oi rncrcascdplasrna phyranic acicl corrbincd rrith normaL or rcrluced levels of priscrnic acid levels,rvhile in D bifunctional enzrrne deficiencl aLrd the leveJs prisranrcand of 2 merhylacv CoA raccrnasc dcficiencl', of phyranrc acid rle bodr incrcascd.Preciseiclenri6cation some studresirr culperoxisonal disordersmay r'equiremorc cxccnsil'e for rhe driferenriarured skin libroblasts. This mal bc rcqrLrrcd tion of PBD trorlr dcf-ectsin biiunctjonal elz,vne. In PBf), rhe pacierrc's perorisomcs irrc absenr and catalaseis rD rhe solultle fraction, whcrcas in bifunctronal enzvmedefecr!peroxisomcslrc present and catalase is in the particrrlatc fracriol. libroblasr stLrclies requircd ro idcntifv rhe nature of rhe rnoleculardelect are lvarranred sturlicserc clinjcaLlv in PBI). V'hether such specialrzed Pr'cciscdclinjrion of rhe depenclson indrvic|.ralcircurnsranccs. defecr Ln a probard may improre the precisicn of prcnatal diagnosis in at risk prcgnancics,alci ir rs requrred for carrier derection. It is also oi value il ;ertirrg progrrosis. Prccisc

Aqe degendel-:t t(rcas r[rea5ed fcreasedabrorma Eitem Vamby deireased nrftased 0efta5ed DerEa5eC D$r..aseC lytosoli. Ferox iblent lmmunoqn(im,r(ry 50me5 [omplelllettalton 5e 'abh86-l DNA seeTabh86-1 Rhizcmelc Ph5ma P h / t i n ( a ( i d lnfta5ec N0mal {hondrody5pla5a VLTFA pun(ata oqeI Decreased RBls Plasma level5 fibtublan5 Plalrralcgen 5ynihe5i5 De(reased c De(rea5el PhIan accoxidaton Pf,Yl ONA deteo n(rcaied X Inked ALDhemuy,Jon Pa5ma fibftrbla5i5 kver VLIFA c](idaton Derrea5ed vLIFA mrrn,lrearrvrtl Ab5e[f70% ALDP ,4tarimutit,of DNA Pla5ma VL[FA Varable naed!e in85 X lnkedAlD e!el5 Vardble ircredse o 90% nererozyq0rc iil'obiJ6 !L[FA mmunoreartvity Varable dP(rease ALDP ,1ffO1nutatior DNA jncea5ed Pa5ma VL(FA Bfunctona enzyme

DISTASI ISSAY Zelvq{ersyndrome Pa5ma Neonatdl adreno el*odystmphy lnfanth diseaie ReBum

FINDING ]/L(FA ( add Pnytan ,nctea5e0 Aqe dependentin{rca5e

ft 5tanacd c Ppmliracrd Be & d evel5 NB(e, Pasmaoffn v(FA er'e 5 Fibrobia5E VfFA oxddtion olen Fla5na 5yntieri5 pr(anl( on Fh!,1dni{. oxdat |cdlizatioi Gtaia5e

dete(

Phytan(add DT t iod nan Srearid5 VLFAievels Pr r a(dDxdatoD 51an ase [ata loriization Inryme

nctr5ed nateaSed palten rfc,ra5e4,rbnormdl fftaied De(rcaied plclen D-bifurctrona l]efirenq n('a\gd n(r,.a5ed Dereised A.f ftA liiCa5r defu(t lnrreaied lncreaied, a patlem ibncrfl 0ereaged h,leih)" ftA oridase acy dehal lndeaied Decr..a5eC (oA cen.y Ph)'lancyl dcfi

AryftA oxdaie deh(ien(y

Phrma Vt(IA eve FbrobranJ /L(FA s

Vl(FA oxcation Enzyme 1:oA cd 2'Vetrrlary Pbirnr Pr5tanild racemai,! thicdr deliaen(y PrL$rLL(aaid c{iditloi FibrobLarts Enrlme

l:a5:i( ReEum d5edie

Pliina
d5tJ Fbrob

ard Phfani( P r s t ic a ( d n Inr/me

AtD,adren0hLrhd\qr0rhyYtifA rer 0i9i"anfaqa.d5

characterizarorr is of prognosric value iir patjcnrs wirh PFXl antl a bout detects. Thrs deiecrrs prcscntin =60?i of PBD paricrrrs, hali of thc PI:Xl clefe*s have rhe G843D allele,which is associ urilclerphenotypethan is lound in other ulqcl1r'idra signrficanrly mutatron5. Detqct? Table 86 3 shoq.sthat chc LcvelS:What ls the Molecul;rr m<>lecular defectsin rrosc of the PBD har'c bccn dcfincd. Dclinirion of rhe rnoleculardefect in the probalcL,rvhich is rolr'ofiered for in scvcrallaborarories, essential carner rlefectiot and spccds rs prenatal clr agnosrs. tests that DIACN0SIS Ihere arc scvcral noniuvasivc laLrorator,v o1 pcrnrir prcciseand earlr ciiagnosis pelorrsonral disordcrs lsee -fhc the fronl Iable 36 5). chalLeng,e PBD is to clriferenriate in thc largc varictv of orher conditions thrt cerr causc hvpotonia,

r 86 ir Chapter t Delects MotabolismLipids 57t ol

seizures, failure to thrive, or dysmorphic features. Experienced clinicians can readtly tecognize classic Zellweger syndrome by its clinrcal manifestations. PBD patrents often do not show the full clinrcal spectrum of disease and may be identifiable only by laboratory assays.Clinical fearures that mav serve as indicatrons for rhese diagnostic assays include severe psvchomotor retarda tion; weakness and hypotonia; dvsmorphic features; neonatal seizures; retinopathn glaucoma, or cataracts; hearing de6crts; enlarged liver and impaired liver function; and chondrodysplasia ounctata. The Dresenceof one or more of these aboormalities increases rhe li[elihood of this diagnosis. Arypical mrlder forms presenting as peripheral neuroparhy have also been described. Some patients wrth the isolated defects of peroxisomal farry acid oxidation (group B) resemble those wrth group A disorders and can be detected by the demonscratton of abnormally high levels of VLCFA. Patients with RCDP must be distinguished from patients with olher causesof chondrodysplasiapunctata ln addition to warfarin embryopathy and Zellweger syndrome, rhese disorders include the milder autosomal dominant form of chondrodysplasra punctata (Conradi-Hunermann syndrome), which is characterized by longer survival, absenceof severelimb shortening, and usually inract intellectl an Xlinked dominant form; and an Xlinked recessiveform assocrated with a deletion of the terminal Dortion of the short arm of the X chromosome. RCDP is s pected clinically because of rhe shortness of limbs, psychomo r retardatioo, and ichthyosis. The most decrsrvelaboratory tes s the demonstration of abnormally low plasmalogen levels in red blood cells and an impaired capacity to synthesize plasmalogens in cultured skin fibroblasrs. These biochemical defecrs are not present in orher tvpes of chondrodysplasia punctata. Chon drodysplasia punctata may also be associated s'ith a defecr of 3$-hvdroxysteroid-As,Atisomerase,an enzyme involved in biosynchesisof cholesterol, COMPLlCAT|0NS.Patienrs wich Zellweger cerebrohepatorenal n r y n d r o m eh a v e m u l r i p l ed i s a b i l r n e is v o l r i n g m u s c l et o n e .\ w a l lowing, cardiac abnormalities, liver disease,and serzures.These conditions are treated symptomaticall-v, but the p.ognosis is poor, and most patients succumb in the 1sr few months of life- Patients owrng to compre5sionaI wirh RCDP may develop quadriparesis rhe base of the brain. PBEVENTI0N. Chapters 83 and 84. See The most effective therapy is the dietary treatment TBEATMENT. of classic Refsum diseasewith a phytanic acid-restrrcted die!. For patients with rhe somewhat milder variants of rhe peroxi has been achieved some import disorders,considerablesuccess with multidisciplinary early incervention, including physical and occupational therapl hearing aids, alternative communication, nurrition, and support for the parents. Altbougb mosr patients continue to function in the profoundly or severelyterarded range, some make signilicant gains in self-help skills, and several are in srable condition in their teens or even early 20s. Srudies to mitigate some of the secondary biochemical abnor malities include the oral administration of docosahexaenoic acid in a dosage of 50-100 mg/24 hr eirher as the ethyl ester or in rhe

GENETIC C0UNSEIING, the peroxisomaldisorders, All except prenatallyin the lst or hyperoxaluriatype 1, can be diagnosed for 2nd trimester.The tests are similar to those described post(see natal diagnosis Table86-5) and usechorioric villus sampling havebeenmonitored, or amnioc)tes. More than 300 pregnancies have beenidentifredwithout and more than 60 aflecredferuses diagnosrrc error Because the 257orecurrence of risk, couples with an affectedchild must be advisedabout the availability of prenalaldiagnosis. Heterozygores be identi6ed X-ALD and in can in rhosedisordersin which the moleculardefecthas beenidentified (see Table86-3).

(X.TINKED} ADRENOTEUKODYSTROPHY
X-ALD is a genetically determrned disorder associated with the accurnularion of saturated VLCFA and a progressive dysfunction of the adrenal cortex and central and peripheral nervous svstem white matter. ETI0L0GY The key brochemical abnormality is the tissue accumulatron of unbranched saturated VLCFA. with a carbon chain length of 24 or more. Excesshexacosanoicacid (C26:0) rs the most striking and charactenstic feature. This accumulation of fatty acids is caused by genetically deficient peroxisomal degra darion of fatty acjd, The kev biochemical defect involves the impaired function of peroxrsomal hgnoceroyl CoA ligase, the enzyme lhat catalyzes the fornation of the CoA denvative of VLCFA. The gene that rs defective (ABCDI ) codes for a peroxF somal membrane(ALDP). More than 400 distinct mutations have been idenrified, and most familes have a mutation that rs "privare" (unique cothat kindred) and are updaredon the websice http://wwwx-ald.nl. The gene has been mapped to chromosome Xo28. The mechanism by which rhe ALDP defect leads ro VLCFA aciumularion and the pathologv of X-ALD is unknovvn. EP|DEM|0L0GY The mrnimum incidence of X-ALD in males is 1i21.000. and the combined incidenceof X-ALD males and heterozygous females in the general population is estimated to be 1n7,000- All races are affecred. The various phenotypes often occur in members of the same krndred. PATH0L0GYCharacteristic lamellar cvroplasmic inclusions can be demon',rrated with the electron mic.osc,rpe in adrenocortical cells, tescicularLeydig cells, and nervous system macrophages, These inclusions probably consist of cholesterol esrerified with VLCFA. They are most prominent in cells of rhe zona fasciculata of the adrenal cortex, which ar 1st are distendedwith Jipid and later arroPny. The nervous system can display two types oI lesions. In the severe childhood cerebral form and in the rapidly progressive adulr forms. demyelination is associated with an inflammarory responsemanifesied by the accumulati.rn of perrra.cr.,larlym: phocytes that is most mtense in rhe pariero-occipital region. In rhe slowly progressive adult form, adrenomyeloneuropathy (AMN), che main finding is a distal axonopathy rhat affects the long tracrs in the spinal cord. The inflammatory response is mild or absent. PATH0GENESIS. adrenal dysfunction is probably a direcr conThe sequence of the accumulatron of VLCFA. The cells in the zona fasciculata are distendedwirh abnormal lioids. Cholesterolesteri6ed wirh Vl-.Cl'A is relativell resirtant io adrenocorlicotropic hormone (ACTH)-stimulated cholesterol esrer hydrolases, and this limits rhe capacity to convert cholesterol to accive sreroids. ln addition, C26:0 excess increases the viscosity of the plasma membrane and thrs may interfere with receptor and other cellular functions.

in tbe peroxisorne, There are anecdotal reports of ctinicaL improvement. The oral admrnisrracion of choLc acid and chenodeoxychoLc acid in a dosage of 100-250 mg/24 hr, wirh the aim of reducing the levels of presumably toxic brle acid intermediares, may be effective.

570 r PARTXr Meraholic Diseases There is no correlation between the neurologrc phenotype and the nature of the mutation or the selrrity of the biochemical defecc as assessedby plasma levels o{ VLCFA or berween the deeree of adrenal involvemenc and nervous svstem involvement. lhi severiryof the illnerr and rare of progressioneorrelarewith the lnlensltt/ of the inflammatory response, The inflammatory response mav be cytokine mediated and may involve an autoimmune response triggered in an unknorvn way bv rhe excess of VLCFA. A CDI lipid anligen has been implicared..Nlitochondr ral damage and oxidatrve stress also contribute. Approximately half of the paciencsdo not expenence the inflammatory response. A modifier gene that sers the "rhermostar" for the rnflammatory response is postulated. CtlNlCAt MANIFESTATI0NS. There are five relatively distrncr phenotypes, three of which present in childhood r,r.ithsymptoms and signs. In all the phenotypes, development is usually normal in the 1st 3-4 yr. In the childhood cerebral {orm of ALD, sy-mptoms are 1st noted mosl commonly betweenthe agesof 4 and 8 yr (21 months is the earLest onser reoorted). The most common initial manifes tations are hvperactivicl', rvhich is often misraken for an artention deficrt disorder, and u.orsening schooI performance in a child u ho had previotLsly been a good student. Auditory discriminarion is ofren impaired, although tone perception is preserved. Thrs may be evidenced by difficulty in using the telephone and greatly impaired performanceon inrelligence testsin items that are presented verball,v.Spatial orienration is often impaired. Other rnrtial symptoms are disturbancesof vision, acaxia,poor handu,'rrting, seizures,and strabismus.Msual disrurbancesare often due to involvement of the cerebral cortex, which leads to variable and seemingly inconsistent vrsual capacit;', Seizuresoccur Jn nearly all palients and ma).representthe 1st manifestatronof the disease. or Somepatientspresentrvith increased inrracranialpressure with unilareral mass lesrons.lmpared cortisol responseto ACTH stim ulation is present in 857o of patients, and mild hyperpigmentation is noted. In most pariencs uith this phenotype, however, adrenal d,vsfuncionis recognized onlv afrer the condition is diagnosed because of che cerebral s,vmptonrs. Cerebral childhood ALD tends to progress rapidly with rncreasing spasticity and paralysis,visual and hearing loss, and loss of abilirv ro speak or su'allow. The mean rnrerval berv'een the 1st neurologic symDcom and an apparentl,v vegetative state is 1.9 yr Patients ma1' conrinue m this apparently vegtalivestate for 10 yr or more, Adolescent ALD designatespatients rvho experience neurologic symptoms betweenthe agesof 10 and 21 yr The manilesrations resemble chose of childhood cerebral ALD excepr that progressron is slower About 10% of patients present acuteJywith scatus epilepticus, adrenal crisis, acute encephalopath,v,or coma. Adrenomyeloneuropathy 1st manifesrs in late adolescence or adulthood as a progressive paraparesis caused by long tract degeneration in the spinal cord. Approximately hali of rhe palienls also have rnvolvement of the cerebral \,\.hltematter The "Addison only" phenotype is an important and under diagnosed condrtion. Of male patients with Addison disease,25% may have the biochemrcal defeccof ALD. Many of rhesepatients have intact neurologlc systems,\*ereas others have subtle neurologrc signs, Many acquire adrenomyeloneuroparhv in adulchood. The term "asymptomatic ALD" is applied ro personslvho have rhe brochemrcal defecr of ALD bur are free of neurolosic or -deiecr enducrine disrurhancqs,Nearly all personr wirh the gene eventually become neurologrcalll' symptomatic- A few have remaned asymptomatic even in che 6th or 7ch decade. Approrimatelv 50'o of female heterozlgotcr acquire a \vn drome rhat resembles adrenomyeloneuropachJ is mrlder and but of later onset. Adrenal insufficiency is rare. FINDINGS. IAB0BATORY AND RADI0GRAPHIC The most specific and rmportaor laboratory finding is rhe demonstrationoF abnor mallv high levels of VLCFA in plasma, red blood cells, or cul tured skin libroblascs. The test should be performed in a laboratory that has experience with this specialized procedure. Positive results are obtained rn all male patients with X-ALD and in =85% of female carriers of X-ALD. Mutation analysis is the mosr reliable merhod for che identificatronof carriers. CT and MRl. Parienls ',vrth childhood cercbral or adolescent ALD show cerebral *hite matter lesions that are characteristic rvith respect to locatjon and attenuahon parrerns on MRI. In 807o of parienrs, the lesions are svmmetric and rnvolve the periventricular whire matter in the posrerior parietal and occipi tal lobes.About 50% sholv locacionof a earland of accumulated c o n t r a s rm a t e r i a la d j a c e n fa n d a n t e r , o .i , , t h e p o r t e r i o r h r p o This zone corresponds rhe zoncs of denselesions(Fig. 86-.5,4). to

Fisure86-i. ,4, Conuast enhanced t abnor C malitics in adrenoleukodrsrophy IALD) $'jrh q'pical parietcoccipital location, shor.ing s1n metric biJareralhypodenseinactive zones (HO). The enhancing active periphery zone of h,vpo, densirv is demarcarcdby arrt*rs Conpare rhe anterior zone of hvpodensry (drrouheads) wnh that on the MRI in B. CC, corpDs caLlosurn. ts, MRI oi the same pattern and area shown b,vCf NIRI T2 r,r'eighted nnage shows a high-intensity signaLoi rhe abnormall,vbrighr parieto-occrpital white matter. Subcordcal involvement is betrer identified on MRL Separatron oI acrive zones ma_vbe bener apprecJated C! becauseboth by inacrive and acrive zonesare seen ar high srgnal areasorr N'IRL k is assumed.hou'ever,that such najor disdndions afforded hy CT rt'ill also be demonsrrablewhen IV enhancement(prramas netic enhancement) becones readilv availaore. Nore e },lpoden\e involverne|r of CT 1anor,heads^nd dttotus in A) .ompared !$rh rhe well resolvedlesioDson MRI in B (From Kumar AJ, RosenbaumWE. Naidn S, et al: Adrenoleukody srrophy: Corresponding N{R irnaging srrh CT. Radi alogt 19 I /',165 :497- 504.)

86 in Chapter r Defects Mol.holismof Lipids I 579 incense perrvascular l1'mphocytic infiltracion where the blood brain balrier breaksdown. In 127o of patrents,the inrtial lesions are irontal. Lnilateral lesionschat produce a mass eftect tuggestive of a brain lumor may occur. MRI provides a clearer delineation of normal and abnormal white matcer rhan does CT and by CT (Fig. 86-58). 857o of patientswith the evels of ACTH in plasma and a subnormal nse of cortrsol levelsin plasma following inrra venous injectron of 250 pg of ACTH {Cortrosvn) 0lAGN0SlS The earhestmanifesAND 0lFFEBENTlAt DIAGN0SIS rations of childhood cerebral ALD are diflicult to disringuish from the more conrmon artentron deficir disorders or learning discircumstances. The nonverbal IQ has been found to be of predictive value, and transplant is not recomnended in patients w'ith nonverbal IQ significand,v below 80. Unfortunateh! in more than half the patienrs who are diagnosed becauseof neurologic symploms, the illness rs so advanced tha! they are not candldates for transplant. Consideration of BMT is most rele\.anl in neurologically asymptomatic or mildly involved patients. Screening ar-rrsk rela tives of svmpromatic palients idenrilies rhese parients most ftequenrly. Screening by measurement of plasma VLCFA levels in patienrs wrth Addrson disease may also idenrif,v candidaces for BivIT. Because of rrs rrsk (10-20% mortality) and the fact lhat up to 50% of untreated patrenrs with X-ALD do not develop inflammatory brain dem,veLinatron, transplant rs not recom mended in patients who are free of demonstrable brain involvemenc. The MRI rs also of key rmportance for the crucjal decision of *'hether transDlan! should be oerformed. MRI abnormalicies precede clinically evidenr neurologic or neuropsychologic abnorrnalitres. The brain MRI should be monitored at 6 mo to 1 ,vr intervals in neurologically asymptomaric boys and adolescenrs becrveenthe ages of 3 and 15 yr, If the MRI rs normal, BN'IT is not indicated. If brain MRI abnormalties develop, the patient should be evaluated ar 3 mo intervals to determine if the abnormalicy is progressive, in combinacion rvith careful neurologic and neuropsychologrc evaluacionl and if earl,v progressive nvolvement is conlirmed, transplanr should be considered.Magnectc resonance \pectroscopl improver the capacil\ lo derermine whether rhe brain involvement is progressive. It is nor knolln whether BN{T has a favorable effect on the noninflammatorv spinal cord involvementin adults with the adrenomyeloneuropa thy phenotype. Lolenzos oil Therapy.The administration of Lorenzo's oil to asymptomatrc boys reduces the rrsk of developing the childhood cerebral phenocypeby a factor of two or more. Lorenzo's oil (4:1 mrxture of glyceryl trioleate and glycer,vJtrierucace) combined rvich a dietary regimen is recommended for neurologically asvmDtomatic bovs rvho have a normal brain MRI and are younger than 8 yr'old, but must be supervrsed carefully. Adrenal funcrion and brain MRI must be monirored. Patients v'ho develop progressive lvlR[ abnormalities are evalualed for hemaropoietic stem cell cransplant wheo changes are still m an early phase. Lorenzo's oil has not been shown to alter disease progressionin patientswho already have cerebraIinvolvement. OtherTherapies.lnterferon-p and immunosuppressive therapies have not been found to be effective. Therapies r.ith lovasratin and with 4-phenylbutyrare have been proposed and are betng rested in clinical trials. Gene rherapy has shown promise in cultured cells and the mouse model of X-ALD buc is not yet available for human trial. Supporlive Therapy.The progressive behavioral and neurologrc disturbances associated with the childhood form of ALD are exrremely difiiculc for che famill'. ALD patienrs require the establishmenr of a comprehensive management program and partnership among the family, phvsician, visiting nursing staff, school authorities, and counselors,[n addrtron, parenl support groups are often helpful (United Leukodystroph,v Foundatron, 2304 HighJand Drive, Svcamore, IL 60178). Communicacion with school authorities rs imporrant becauseunder rhe provisions of Public Law 94-142, children with ALD qualifv for special services as "other health impaired" or "multihandicapped. " Dependingon rhe ra!e of progression the disease, of specialneeds mrght range from relatrvely lowlevel resource se ices within a teaching regular school program to home- and hosprtal-based programs for children who are not mobile. Management challenges vary with the stage of rhe illness. The early stages are characterized by subtle changes in affect, behavior, and attention span. Counseling and communication u.ith school authonties are of prime importance. Changes in the sleepwake cycle can be benefited b.v the ;udicious use ac night of

tarion during the neonaralperiod. Cerebral forms of ALD mav presen! as increasedintracranral pressureand unrlateral mass lesions.These have been misdragnosed as gliomas, even after brain biopsy, and severalpatients have received radiotherapy before the correct dragnosis was made. Measuremen!of VLCFA in plasma or brain biopsy speci mens is rhe mo.r reliabledifferenriaringtesr. Adolescentor adult cerebral ALD can be confused with psychiarric disorders,dementingdrsorders,or epilepsy The 1scclue to the dlagno s of ALD mav be rhe demonstration of whicc mafter lesions y CT or MRI; assaysof VLCFA are conlirmarorl'. ALD canno be distinguished clnicaLly from other forms of Addison drsease;it is recommended that assaysof VLCFA levels be oerformed in all male Datients\,rth Addison disease Al-D parientsdo not usually have anribodiesto adrenal tissue in their plasma. An C0MPI-ICAT|0NS. avoidablecomplication is the occurrenceof adrenal Jnsufliciencl'. The most diflicult neurologrc problems are those relatedIo bed resf,contracture,coma, and swallowrng dis turbances.Other complicarions involve behavioral disrurbances and injuries assocrated with defeccs of sparial orientation, impaired visron and hearing, and seizures. TREATMENT, Corticosteroid replacement for adrenal insuf6cienc;, or adrenocorticalhypofunction is efleccive(seeChapter -576).It

Bone marrow transplantation Eone Marrow Transplantation. (BMT) benefits parients who shov early evidence of th inflammacory demyelinarion that rs characteristic of the rap lv progressive neurologic disability in boy and adolescents rvirh the cerebral X-ALD phenotl'pe, BMT is high risk procedure, and with great care, The mechanism of patients must be selecced the benelicial effect is incompletely understood. Bone marrow-derived cells do express ALD! the protein rhat is deliciencin X-ALD; =507o of brarn microglial cellsare bone marrow denved. It is possible that replacement of affected cells bv cells that conrarn lhe normal gene changes the brain mtlteu suffrcientl;; ro correct the brain merabolic disturbance. The favorable effect may also be caused by modificarion of the brain inflammatorv response. Five co 10 yr follow-up of boys and adolescents who had earlv cerebral involvement has shot'n stabilizacion and, in some instances, rmprovement. On the other hand, BMT has not shown favorable effecrs in patients who had already severebrain involvement and may accelerate disease progression undet these

r 580r PABTX Metabolic Disoaros sedatives such as chloral hydrate (10-50 mg/kg), penrobarbital (2-3 mglkg). {5 me/ke), or diphenhydramine As the leukodysuophyprogresses, modulation of muscle the tone and support of bulbar muscular function are malor condoses(5 mg bid to 25 mg cerns.Baclofenin graduallyincreasrng qd) is the most effectivepharmacologicagent for chetreatment of acuteepisodicpainful musclespasms. Other agenrsmay also be used,wrth careberngtaken to monitor the occurrence srde of effectsand drug interactions,As the leukodystrophyprogresses, bulbar muscular control is lost. Although initially thrs can be managedby changrngrhe dier to soft and pureed foods, mosc patients eventually require a nasogastrictube or a gasrrostomy. At least one third of patients have focal or generalized anriconvulsant seizures that usuallyreadily respondto scandard medications. GENETIC At{D Geneticcounselinsand COUNSETING PREVEI{TI0N. primarv and secondary prerentionof X-ALD are of ciucial should be offered to all importance.Excended family screening at-risk relatives symptomaticparients;one program led to the of identificacron more than 250 asymptomatic affectedmalesand of 1,200 women heterozygousfor X-ALD. The plasma assay permits reliableidentificarionof affectedmalesin whom plasma VLCFA Levels increased are alreadyon the day of birth. Identification of asymptomatic male5 permits instirution of steroid replacement therapy when appropriateand preventsthe occurrenceof adrenalcrrsis,which may be fatal. Nloniroring of brain of MRI also permits rdentiEcation patientswho are candidates chance for BMT at a stagewhen this procedurehas chegreatest in of success. PlasmaVLCFA assavis recommended all male patientswith Addison disease. X-ALD has beenshown to be the causeof adrenal insufliciencyin >25% of boys with Addison disease unknorvncause. of Identi6cationof women heterozygous for X ALD is more drfficuk than that of affectednales. Plasma women, VLCFA levelsare normal in 1-f-20% of heterozygous errorsin senetic and failurero norerhishasled ro serious c,.runseling. Vl CFA levels normalborh in plasmalnd cultured lf are resultsis reducedbut skin frbroblasts, the risk of false-negative nor eliminated.DNA analvsrs Dermitsaccuraterdentilicationof carriers,providedthat the mutarion has beendefinedin a family for member. and is cheorocedure recommended the identification of heterozygous wbmen. Mucation analysis is available on a seffice basls. can be achieved by Prenaraldiasnosisof affecced male fetuses or measurement VLCFA levelsirr cultured amniocvres chori;f onic villus cells and by mutation analysis.lVhenever a new pacientwith X-ALD is identified,a detailedpedigreeshould be constructedand efforts should be made to identilr all at-risk female carriersand affecredmales.These investigations should by attention to social, be accompanied careful and sympatheric emotional,and ethrcalissues during counseling.
PreussN, Brosius U, Biermanns M, er al: PEXI mutarions in complementanon group 1 of Zellweger spec m patLentscorrelate rvirh sevenq. of disease. Pediatr Res 2002;51,:706-714. SteinbergS, Chen L, We, L, Moser A, er al: The PEx gene screen:Molecular diagnosis of peroxisome biogenesisdisorders in rhe Zellweger syndrome spe.JJtm. Mol Genet Metab 2004.83252163. Valter C, Goorjes J, Moojjer P.{: Disorden of peroxisome biogenesis due to mutations in PEXI: Phenorypes and PEXI proteln levels Am J H tft Geftet 2OO1;69:3 548 . peroxrsomesand phy Wanders RJ, JansenGA, Skjeldal OH: Refsum disease, tanic acid oxidationi A review I Neurooathol Exo Neu/ol 2001;60:1021-1031. Adrenoleukodystrophy (X-Linked) BezmanL, Moser AB, Raymond cV, er a| ,{drenoJeukodystrophy: Incidence, new Duration fare, and fesulrs of extended family screening.Azn Nezro/

200r;49:5r2-517.
Boehm CD, Cuttins GR, LachrermacherMB, et al: Accurate DNA baseddiag nostrc and carrier resring for X linked adrenoleukodvstrophy.Mo/ Ge,?. Meab 1999;66:128-136, Kemp S, Pujol A, V/rrerham HR, et al, Xlinked adrenoleukodystrophvmutation database: Rote in diagnosis and clnical correlations. Hun Ml.iat 2 0 0 1 ; 1 8 : 4 9 9 - 55 . r Moser AB, Krirer N, Bezman L, et al: Plasma very long chain fatw acids Jn 3,000 peroxisome disease patients and 29,000 concrcls. Ar'n Neutol 1999;45:100-110, Moser FIri(, Los DJ, Melhm ER, er al: X linked adrenoleukodyscrophy: Overvrew and prognosrsas a tunction ol age and brain magnetic resonance irDaging abnonnali.y: A srudy involving f72 parients. Ne"rcpediatri.s 20O0;3r:227 -239 . Moser HW, Raymond GV Dubey P, AdrenoleukodysFophy: New approaches to a neurodegenerative disease.,JAMA2005j294:3131-3134. Moser H\v, Raynond CV, LD SE, er al, Follow-up of 89 lnrenzo's Oil treared asymptomaric adrenoJeukodysrrophy parients. Arch Neurol 2005j62:l073-1080. peters C, Charnas LR, Tan Y, et ai, Cerebral X linked adrenoleukodystrophv: The inte.national hematopoietic cell transplanlation experiencefrorn 1982 t o 1 9 9 9 .B l o o l 2 0 0 4 ; 1 0 4 : 8 8 1 - 8 8 8 . SrephensonDJ, Bezman L, Raymond GV Acute presentarjon o{ childhood adrenoJeukodystrophy. Newopedia*i.s 20003r:293-297. Van Geel BM, AssiesJ, Haverkon EB, et al: Prosressjonof abnorrnaliriesin adrenornyeloneuroparhy and neurologicallv asymptomatic X-linked adrenofeukodystrophy despite treatment ivirh "Lorenzot oil." J Newol Ner/osarg Psychiatry 7999,67:290-?99.

86.3. orsoR0EBs LlpopfiorElN 0F MEtrsor-rsnr lNo o William Neal TRAt'rsPoRr A.

EPIDTMIOTOGY BTOOD LIPIDS AND OF CARDIOVASCUI-AR DISEASE
The relationship betweendietary fat consumprionand plasma cholesterolwas demonstratednearlJ' a century ago. ! ell-fed Americans had higherratesofcoronary heart disease {CHD) than Eurooeans who subsisred limited rations. The Seven on Dostlr.ar and ethnicdifferences -ountries Studyof geographic, socialclass, rn CHD around the world found strong associations between intake of saturatedfats, plasmacholesterol, and mortal average level ity from CHD. In 1950, the mear total blood cholesrerol \e'as 220 mg/dl. By 1991, cheleveldeclinedro amongAmericans a mean of 205 mg/dl-. ln 1977, the Cooperative Lipoprocein Phenorl'prngStudy showed chat ther is an inverserelationshipbetweenHDL and CHD. Clinical trials of dietary and drug inrerventionsdirected during the cowardmodulation of cholesterollevelswere begLrn 1970s, ultimately providing rhe basis for screeningand treatment standards as promulgated by the National Cholesterol

Peroxisomal Disorders Baumganner MR, Poll-The B! Verhoeven NM, et al: Clinical approach to inherited peroxisornal disorders: A series of 27 pztients. Ann Ne rol 1998;44:720-7 30. Ferdinandusse Yliantrila MS, Gloerich J, et al, Mutarional speccrurn DS, of bifuncnonal protein deiciency and structure based genotype phenotype A,r1 I Hr'11 Geset 2006t78:112-124. anAlysis, Maninez M. Pineda M. Vidal R. et a| Doco$hexaenoic acrd-A new therapeutic approach ro peroxisomal-disorder patients: Exprience with two cases. Nerlolos] 1993t4 t1389-1397 NIoser HW: Genorype phenorypecorrelarionsin disordersof peroxisone bioMol Genet Metab 1999;68,316-327. &enesis. Modey AM, Brites P, Gerez L, et al: MDrarional specuum in lhe PEXT gen and funcrional analysis of mutanr alleles in 78 parients with rhizomelic chondrodysplasiapuncrat^ rype 1. ,1m J tu1ft Genet 2002;70:612424.

ol 86 in Chaptei r Delects Metabolism Lipids r 581 Educarion Program (NCEP). l'urther refinement of the molecular basis of lipoprorein merabolism has better characterized phenotypic aboormalities and more directed inrerventional sffategte none is so clearlv influenced Of all ommon chronic diseases,

ETOOD LIPIDS AIHEROGEI{ESIS AITD

Numerous epidemiologicsrudres have demonstratedthe associa tion of hypercholescerolemia, reierring to elevated total blood cholesterol, rvith atheroscleroric disease.Advances in clinical labfor oratory rechniqLres measurement of orher selectedlipoprotein parricleshave increasedour understandingof the role of blood lipids in relation to hearr disease.The ability co measure subcomponents wirhin classes of lipid parhcles, as $'ell as markers of rnflammation, have further elucrdaredthe processof athero genesis and plaque rupture leading to acutecoronary syndromes. affecrs primarily the coronary arteries but also Atherosclerosis often involves the aorta, arreries of the lower extremities, and carotid arteries. The early stage of development of alherosclerosis rs chought ro begin with vascular endothelial dysfunction and intima rnedia thickness, which has been shown to occur in preadolescent children with risk factors such as obesity or familial hvpercholes terolem,a. The complex process of penetration of the intimal lining of the vessel may be due to a variety of insults, including the presenceof highly toxic oxrdrzed LDL particles. Lymphocytes and monocytes perterate the damaged endothelial lining, rvhere tbey become macrophages laden wrth LDL lipids and then become foam cells. Such accumularron is counterbalancedbv HDL partrcles capableof removing liprd deposics from tbe vessel wall, Fundamental to plaque formatron is an inflammatory process(elevatedC-reaciiveprotein) involving macrophages and che arrerial wall. The deposition of lipid withrn the subendochelial lining of the arterial wall appears macroscopicallyas fatty A screaks, r'hich may to some degreebe reversible. later srageof plaque developmenr involves disruption of arterial smooth muscLecells stimulated by rhe releaseof tissue cytokines and growrh facrors. The atheroma is composed of a core of fatty subfrom the lumen by collagenand smoorh muscle stanceseparated (Fig. 85-5). Growth of the atheroscleroncplaque mav result in rschemia of the tissue supplied by che arcery, Chronic inflamma tion within the atheroma, perhaps caused by infectrous agents such as Chlamydn pnebmonite, results rn plaque inslabiliqv and subseouen! ruoture. Placelet adherence leads to clor formation at the sire of rupture, resulting in myocardial infarctron or a cereDtovascularevenl.

male gender, though it is increasrngly apparent that hearr disease is under recognized in women. Tobacco use confers a twofold higher liferime nsk. Sedentary activiry and high intake of saturated fats, leading to adrposity, increase risk through differences in the plasma levelsof hpoproreinsthat are atherogenic Famil,v history is a reflecnon of the combined rnfluence of lifescyle and Risk of premature genetic predispositionro earlv hearc disease. with posirive family historJ is 1.7 trmes heart disease associated hieher rhan in families with no such histor,v. The pathogenesis of atherosclerosis begins durrng childhood. Korean and Vietnam war casualties rvere noted to have surprrsinglv advancedtafty streak .rnd plaque formati.,n rn rhe coronarr arieriesand aona. The lohn' Hopkinc PrecursorrStudv demonsrraced that white male medicaL students with blood cholesterol levels in the lowest quartile showed only a 107o incidence of CHD three decades later, whereas those in the highest quartile had a 40% incidence. The Pathobiological Determinants of Atherosclerosis Youth (PDAY) Srudy demonstrateda signi6in canc relarionship berween tbe weight of the abdomind lat pacl and the extent of atherosclerosis found at autopsy on subiects 15-34yr of age. The Bogalusa Heart Study of >3,000 black and whire children and adolescentshas provided the most comprehensive longitudrnal data relaring the presence nd severicy of CHD risk facrors wirh semiquantiliable severi of arhrosclerosrs, The "feral origins hvpotbesis" is basedon rhe observationthar babies born wrth lorv birthweight have a higher incidence of heart disease aduhs-EpidemiologicstudiessupPorrthe idea that preas natal and earlv poscnatal conditions mav affecr adult health starus. Children *'ho are large for gesratiooal age at birch and exposed to an intrauterine environment of eirher diabetes or maternal obesicy are at increased nsk of eventually developing type lI diabetes, rhe "metabohc syndrome" (insulin resistance, obesrty, CHD). Breasc-feeding preterm infants confers a longterm cardioprotectivebenelit 13-16 yr laret. Those adolescents 'w.howere breasr-fed as infants had lower C reactive prorein concentratiors and a 141" lower LDL to HDL ratro compared to those fed infant formulas, Poverty is also associated wirh numerous negative health oLrtcomes. The Younq Hearts Proiecc in Northern Ireland has shown rhat behavioral ;isk factors are influenced bv socioeconomic status. and they are well established by adolescence,even rhough no biologic differences are apparent.

PTASMA LIPOPROTEIN METAEOTISM O AIf TRAI{SPORT

Abnormalitres of liooorotein metabolism are associatedwith diabetes mellitus and premature arherosclerosis, Lipoproteins are soluble complexes of lipids and proteins rhar effect transport of fat absorbed from the diet, or syorhesjs by the liver and adipose

Adventitia
fisurc 86-6. The early stage oI developrnent of atheroscle.osis beglns rvrrh penetrarion of rhe incimal lining of rhe vessclbv innamDitory ceLls Deposrtion of lipid {jthin the subendothelial Lrnrngof the artcrial *'all e"entualty leads ro drsruprion o{ smoochmusclecells co form an sthero matous hpid core thar impitges on the lumen. Chronic inflanmation leads ro plaque instabilitv, setring rhe srage for plaque rupture and complete occiusion oi the vessellumen by clor lormahon

Monocyte/ Macrophage

lntima

Subendothelial layer Endolhelium Lipid core

Tunica medra

582 r PABT . MetabolicDiseases X

E i

and reversecholesterol Figule 86'7. The exogenous, endogenous, pathways. The exogenous parhway transports dietarl far from rhe small intesnneas chylomicrons to rhe periphery and the liver The endogenous pathway denores the secretion of verl low densiry lipoprotein (VLDL) from rhe liver and its carabolism ro inrermediaredensity lipoprotein (IDL] and lo$ density lipoprotein (LDL). Trigiyceridesare hydrolyzed frorn rhe VLDL particle bythe action oflipoprotern lipase(LPL)in rhe !ascular bed, vielding free fatty acids (FF.\s) for utilization and storage in muscLe and adipose trssue.Hish-densiry lipaprotein (HDL) merabolism is responsible for the transporr of excesscholesterol from the perlpheral cissuesback to rhe liver {or excrerion in the bile. Nascent HDL-3 particles derived from the Lver and small intesdne are esteriied to more macure HDL-2 parricles by enzyrne mediacedrnovemenr of chvlomicron and VLDL into the HDL core, n'hich is removed Irom the circularion by endocvtosis.

Dietary facis transported from tissues, utrlizationand storage. for the smallintestine chylomicrons. Lipids synthesized the liver by as asvery low densrtyhpoproteins(VLDL) are catabolized interto mediatedensity lipoproteins(IDL) and low-densitylipoproreins (LDL). High-density lipoproteins (HDL) are fundamentally rnvolvedin VLDL and chylomicronmerabolismand cholesterol free fatty acids(FFAs)are metabolically uansport, Nonesterified active lipids derived from lipolysis of triglyceridesstored in adiposetissuebound to albumin {or circulation in the plasma (Fie.86-7). and choLipoproteinsconsrstof a centralcore of triglycerides (CE)surrounded phospholiprds, lesterylesters by cholesterol, and proteins(Fig. 85-8).The densityof the several of classes lipoproteinsis inversely proportional to the rario of lipid to protein (Fig. 86-9).

(Table86Constiruentproteinsare klown as apolipoproteins for 7). They are responsible a variety of metabolicfunctions in role, includingcofactorsor inhibitors addition to thefuscructural of enzymaticpathways,and mediatorsof lipoprotein binding to ApoA is the major apoliprotein of HDL. cell surfacereceptors. ApoB is presentrn LDL, VLDL, IDL, and chylomicrons.ApoB100 rs derivedfrom the liver, whereasapoB-48comesfiom the ApoC-I, CJI, and CJII are small pepcides imporsmall intestine. Likewise,apoE,which rs presenr tant ir lriglyceridemerabolism. in VLDL, HDL, chvlomicrons, and chylomicronremnants,plays an important role in the clearance triglycerides. of

1.20 1. 1 0 Phospholipid

HDL

E
Uuerterified choleslerol
'a c o

1.06 1.O2 1.006

APOB-100 1.00 510 Low-DensityLipoprotein

Figure 86-8. Schematicmodel of low-density lipoprotein (LDL). Lipoprotein consistsoI a central core of cholesrerylesrers,surrounded by phospholipids, cholesrerot.and Drorein.

20

40

80

1,000

Diameter, mm
Figure 86-9. The densir-v the severalcLasses lipoprotein is inverselyproof of portionat ro th ratio of lipid to protein. As lipid is less dense rban protein, irs rhe more lipid contained in the parcicle increasesrts size and decreases density. HDL, high-densir.v lpoproteinj LDL, lorv-densiq' lipoprotein; IDL, intrmediate density lipoprotein; VLDL, very low densitl lipoprotejn.

85 in Chapter . Defects Metabolism Lipids r 583 of

LIPOPROTTINI|llomoo15 a [hyom ]n remfan$

$unc
lrte$ ne [hylomkonr Livetifienine VLDI

ttDrDl
Llt HDt

!tDr
[iwr, VLDLthylol|]i(ont intenine

SlZt(nm) i301,200 10 1t0 l0-80 25-35 1825 5)0

DtNtlIY(9/rrLl <095 <t 01106 095-10C6 r 11x-r 019 1019 061 1 I 125 lr0 I

PR()IAN ,:l 6"8 7,10 'tl )1 t2 57

(oMPO$Tn % LIPIO 98-ts

9l% 90 9l 89 19 4l-68

AP0umPRoTgt{5* ( ,i ,t I , i,Al,A ,Alv,8 4 B48,t I J . [I , t , t ] 3100 a ,a l-,r- I,A-r\r t,I D,t

'i po!rteB.rn! q Df ertn 0E of ! n !?ry denritv lQopote ale ft{, h qh.lenl ryl p0prctn lDl, rFrmed dmr ly l Fpnir n;LDl,0w,le$ ty I poprrt n]VLDt, lo,,v

(0IETARY) tlPIDS All dietarv iar rvith 0F TRANSP0BT EXOGENOUS crrried thc exceprion of ruedium-chaintriglycendesis cflicieLlrLt

tissuc. Free fattv acids are oxidized. resterifiedfbr storage as

the chylolnicron, apo(i parrrcles:rrerecirculatedLrackto HDL coltribr.rriol of apoE from lll)L to the re rlilnr Thc subsequcnr

ot sroragein rnuscleand adiposerissue.Hvdrol,vsrs =80% of the TG presencin VLDL perriclesproducesIf)l- partrclescontaining .ur equal amounr of cholesteroland TCI- The remarningrentnanc IDI- is conr.ertedto I I)L h)r deliverr ro pcripheral tissuesor ro ro rhe liver. ApoE is artachecl the reulnant IDI- particle ro allo{' incorporacion inro rhe l-r-so l.inding to the celLand srLbsecluent of some lndividLralswith deficienc,v eicher apoE2 or hepatic IDI- in rhc plasma. trigl'ceride lipase (HT(iL) accuntulere I DI particlesac.olrnt for =709i, oi thc plasma cholesterolin of normal jndividuals. l.Dl reccprorsare presentoD the surfaces Lre.rrly cells. N'losr LDL rs taken up b,vthe liver, and rhe rest all such as the adrenalglands and is rrrnsported ro peripher'al tissLrcs gonrds iol steroid synrhesis.Dlslipidcmia is grearlv rrfluenced bi LDL-R activirv The cificiencvu'irh rvhich VLDL is converterl l t r r r rI, D l r s . r l . oi m p n r t , t nrrr rt r p r . h , ' n t e o s r a s i ' . TRANSP0RT. hcparicsecretion HDLAND REVEBSE CH0LESTER0t As of hpid parricles into che bile is rhe onll mcchirnisrnbv u'hich cholesterolcan be removcd fronr rhe hodv. lransporr of excess cholesrerolfrom the peliphcral cclls rs a r.rtall,v importent iunction of IIDL. HDL is hcavil-v laclen q.rth apo,A. conraining I rvhrch rs nonarherogenrc contrast to B llp()proir lLp.opr,rceins, rcins (iholescerol-por)r nirsacntHDI- parricles secrefedby thc HDL-2 parlrter end small inrestire are esteriiiedto more nratr.rrc ecyLtransriclesbv rhe actiorr of rhc cnzvnc lecirhin-cholesrerol rnorernenrof chvlomicrons nrrd tcrasc (L(lAI). u'hLchf.rcrlitares esters VLDL rnto the HDI corc. HDL-2 mav trarsfer choLesrcryl nredilted bv cho)estcrylester rransfer bacl to lpoB lipoproreiLrs proteir (CE1P), of the cholcsteKt-rich parricle nay bc rcrnoved irrm rhe plirsnrahy endocytosis. complering reversccholesrerol (defic icnc,v f apoA-I) or sec rrrrrl sport. Low I ID L rnai be gerreric o plasna TCi. ondar. to increased

meal, an exception being lndividuals with a disorder of chrLomi is cron rnetabolism.Posrprandialhvperlipidemra a risk frcror ior Abnormal transport of chvlomicrons and therr arhrrosclerosis. in nrav rcslrLt their absorpfion in() rhe blood ves.cl.vlll ren'rnants bv of causecl rhe rngescion CF-bl macroPhlges,rhe as foam ccLls. oi carliesrsrirgcin rhe developrnenr fatt,vsrreaks T tlP EN T B A N S P O R T 0 F D 0 G E N 0 U S l D SF B O M H EI I V E B ' f h e k r r r n r of tion and secretiorr VLI)1 frrrm the liver dnd irs carabolisnrrrr IDL and I-DL parrcles des.ribe lhe eldogenous lipoprorcirr n path\\'ay.Fatq- aciclstrsecl tbe hepatrclbrmation ol !'l Dl rrc

ancl ir consrstsof trglyccricles,cholesrervlesrcrs,phospholipicls. and apoB 100. Nascent parncies oi \rLD[- secrccd into rhe circulatit>ncombrne .r'ich lllo]iprorei Vl-DI particle is dctermineJ l.tr prcsent, prrrgrcssivel,v shrinklng rn the :rctiorl oi l.PL. yielding frcc

HYPEBLIPOPROTEINEMIAS (TABLE HYPERCHOLESTEBOTEMIA 86.8)

(FH).FH is a monogenrc ruroso FamilialHypercholesterolemia nal co dominarrrdisordcr cluseclb,vrnurarionsaffectingthe LDL

e5lerolemi,r imi ia hypercho 100 imiial,lele(veApoB Autosomr hyp.orch0l5tercleitD rcces5i\ a Sltoiteroem enE hlyqen ahypedohneo (ombined hyperlipldem a(t(HL) tunlla fa llal m 4$betalipoproteinemia (Freder(kson fuflrdlrh.v (runernia I om ) rype (Frc,ieftkson1V) type Fami qpertrIyre.idemia al (FredericKon gy.eddemia fumi alhyperlr type Vl rpase( fu dlhecirc def eicy mil

L}L L]L Llrl LDL

LDt LDL,TC tDt,r.G

rctT 161 16tt

VtDL

Tendon xanthorna5,I|Jt Tendon xanthomas,I|1D Tendon xaflhomrs,l-|1D .Iendon )(dnrhomas,IHD tfD (rlD periphera ardisea5e iubaeruplive xanthoma5, va5cu p,rncredt xanth0,Ta5, en0meqaly, I 5 hep,rtorp irupnve l(l]i hnlh|rmast{HD i|])

AD AD

11!04 tltai]il < N.llll,i)0-i) <ti I,llll:l. ll t il ! '

AD AD AD AD AF

t//lu t/'I],]clt
'/"ll0,llll:l '/5ll

< r ill!',l la

AD,iu|05omadonnant,Afa!Io9m.rResve]LH!,r0r0|']riedl|df3R]LJi,0wnell5ly|pDEm,I6,lf)f

r oiseasss 584r PARTX Metabolic

(hererozygous Figure 10. Achilles tendonxanthoma 86 familialhypercholes(FromDurrington Dydipidaemia. terDlemia). P: Lan.et 2O03;j6Z7l7-731.1

receplor. ft is characterized by strikingly elevated LDL choles terol, premature cardiovascular disease, and tendon xanthomas. Molecular studies have identified five classesof mu!ations affecting the ability of LDL cholesterol to bind with the LDL receptor Of the nearly 800 murations described, some result in failure of syflthesisof rhe LDL receptor (receptor negative) and orhers cause defecrive binding or release at the lipoprotein-recepror rnterface. Receptor negative mutations result in more severe phenotypes than recepror defective mutations. HomozygousFH. FH homozvgotes inherit two abnormal LDL recepror genes! resulting in markedly elevated plasma cholescerol levels ranging between 500 and 1,200 mg/dl. Tnglyceride levels are normal to mildly elevated, and HDL levels may be shghdy decreased. The condition occurs rn 1/1,000,000 persons.Recep tor negative palents have <2o/o rrortr].al LDL receptor activir,v, whereas those who are receptor defective may have as much 257o normal activirr and a bener prognosi(. The prognosrs rs poor regardless o{ the specific LDL receptor aberration, Severe atherosclerosrs involvins the ao.tic roor and coron.rryarreriesir pre\ent by early ro mid-;hildhood. Thesechildren usually present with xanthomas, which may cause thickening of the Achilles tendon or extensor tendons of the hands, or cutaneoLrslesions on che hands, elbows, knees, or br:trocks (Figs, Famil,v 85-10, 86-11, and 86-12). Corneal arcus mav be presenc.

Figure 86-12. F,ruptive xanthomata Dn ertensor surftce of forearn. lFron Durrington P: Dyslipidaemia. Lakcet 2003;362:717-731.)

Fisure 36-11. Srria palnar xanrhomata. (From Dulljngron daemia Lancet 2003;362:7L7-7 37.)

P: DysliFi-

history is informarrve becausepremature heart diseaseis strongl,v prevalent among relatives of both parents, The diagnosis may be confirmed bv measuring LDL recepcor acivity in cultured skin fibroblasts. Pheoo4prc expression of the disease may also be assessedby measuring receptor activity on the sulface of l)'mphocytes bv using cell sorting technrques. Untreated homozygous patients rarel_rsurvive !o adulthood. S;rmproms of coronarv insufficiency may occur; sudden death is common. LDL apheresisto selectively remove LDL particles from rhe circularion is recommended for many children and has been shown to slow the progression of atherosclerosis. I-iver transplantation has also been successfulin decreasing LDL cholesterol lerels. but complicarions related ro immunosuppression are common. HMG CoA reductase inhibitors are ofren effective depending on the specific class of LDL receptor defecc presenr. Combination therapy with ezetimibe, selectively blocking cholesterol adsorption in the gut, usually results in further modest decline in LDL levels; it has largely replaced tbe use of bile acid sequestra11ts. Heterozygous FH. Heterozygous FH rs one of the most common single gene mutations associared with acute coronary syndromes and atherosclerotic CHD in adults. Its prevalence is =1/500 individuals worldwide, but the frequeoc,v may be as high as 1/250 in selected popularions such as French-Canadians, Afrikaners, and Christian Lebanese due to the founder effect of unique nex. mutatio11s. Heart disease accounts for more than hall oi all dearhs in Western society, The pathogenesis of CHD is both environmen-

Chrlter 06 | Dolocls in mdabolism ol LiDids r 685

An estimated10 million peoplehave FH worldwide. Symptoms of CHD usuallyoccur at the meanageof 45-48 yr in males,and later in females, a decade

I oarenta hypercholesterolemia. ' do Plasmalevelsof LDL cholesterol not allow unequivocal by by 20-30 mg/dl. This medicationhasnot beenevaluated coninhibitors trolled clinical trials in children.HMG CoA reductase of have becomethe drug of choicelor treatmentof FH because risk profile, There and their remarkableeffectiveness acceptable with this classof drugsin children is sufficientclinical experience ro documentthat they are as effectivein children as adults, and hepaticenzymes and myositisare no greater the risks of elevated than in adults (seebelow). ApoB-lm {FIIE}. FDB is an autosomaldomiFamilialDefective FH from heterozygous nant condition that is indistinguishable triglyceridesare normal, LDL cholesterollevels are increased, adults often develop tendon xanthomas, and premature CHD occurs.FDB is caused mutation in the receptorbinding region by of apoB-100,rhe ligand oI the LDL receptor,with an estimated cultures.It is usuallycaused frequency 1/700peoplein Western of by substitution of glutamine for arginine in position 3500 in apoB-100,which resultsin reducedability of the LDL receptor thus impairing its removalfrom the cirro bind LDL cholesterol, FDB from laboratory testingcan distinguish culation. Specialized except in researchsettings,since FH, but this is not necessary, treament is the same. This rare conAutosomal fiecessiye Hyprcholstsrolemia {ARH}, by dition, caused a defectin LDL receptormediatedendocltosis hypercholesterolemia with severe in the liver, clinically presents at levelsintermediateberweenthose found in homozygousand presentamong SarFH. It is dispropoJtionately heterozygous to dinians,and is modesdyresponsive treatmentwirh HMG CoA reductase inhibitors. condition characterA Sitosterolgmia. rare autosomalrecessive intestinal adsorption of plant sterols, sitosized by excessive terolemia is causedby mutations in the ATP-binding cassene for transporter systemwhich is responsible limiting adsorption of plant sterolsin the small intestineand promotesbiliary excrerion of the small amounts adsorbed,Plasmacholesterollevels resultingin tendonxanthomasand premay be severely elevated, Diagnosiscan be confumed by measurmature atherosclerosis. plasmasitosterollevels,Treatmentwith HMG CoA ing elevated reductaseinhibitors is not effective,but cholesteroladsorption inhibitors such as ezetimibe and bile acid sequestranlsale effecrive.

Holland. The diagnosiswithin well-definedFH families is pre-

ability of FH, verified by molecular genetics,is derived frorn a U.S. population cohort and may not be applicableto other counttles.

(LDL-C 155rngidl). Treatmentof childrenwith FH should beginwith a rather rigorous low-far diet (seelater). Diet alone is rarely sufficientfor levels (LDL-C blood cholesterollevelsto acceptable decreasing <130 mg/dl). The Expert Panelon Blood CholesterolLevelsin Children and Adolescents (National Cholesterol Educarion

586 r PABT r MetabolicDisoases X small effects of many genes are impacted b; environmental rnfluences (diet), Plasma cholesterol levels are modescly elevated; triglvceride levels are normal. Polygenic hypercholesterolemia aggregates rn families sharing a comrnoo lifestyle but does not follow predictable hereditarl' pafterns found in single gene lipoprotein defects, Treatment o( children with pollgenic hvpercholesterolemia is directed tou.ard adootion of a healrhv liFescvle: r e d u c e d o t a l a n d \ f l t u r a t e df a t i o n r u m p t r o r r n d a t l e a r t I h i , ' f t a physical activitl, dail;'. Cholesterol lowering medication is rarely necessal)'. their parents is ofcen a problem, but small incremencal steps are more likely to succeedthan agglessive w.eighcJosssrrategies.It is verv importanc that the child's caregivers partrcrpate in the process. Plasma rrigl,vceridelevels are usuall,v qurte responsive co dietary restriction, especially reducrion n the amount of srveetened dnnks consumed. Blood cholesterol levels mav decrease by

HYPERCHOI-ESTEROIEMIA WITH HYPERTRIGTYCEBIDEMIA (FCHI). is an autosomal familial Conbined Hyperlilidemia This

dorninant condition charactenzed bv moderate elevation in plasma LDL cholesceroland trrgll.cerides, and reduced plasma HDL cholesterol. ft is the most commol primary lipid disorder, occurnng rn =1/200 people. No single metabolic aberration has been identilied linking FCHL wich atherogenesis, but it is rvell documented thac =20o/. of individuals who develop CHD bv o 0 ' r o i a H e h a r e F C H L . f a m i l r h i s r u r ' ' , f p r e m a r u r eh e a r r diseaseis t,vpically posrtrve; the formal diagnosis requirs that at leasct$o lirsr-degree relatives have evidence of one of three r.ananrs of dvslipidemia: (1) >90th percentile pLasmaLDL cholesrerol; (2) >90th percentiLe I-DL cholesteroland trigllicerides; and (3) >90tb percentile rngl,vcerides. Individuals su.irch from one phenotype to another. Xanthomas are not a feature of FCHL. Elevated plasma apoB levels rvith increased small dense LDL particles support the diagnosis. Chrldren and adults with FCHL have co existing adiposi4., hypertension, and h,vperinsulinemia, suggesting the presence of the metabolic syndrome. Formal diagnosis of this multipler s,vndrome as defined bv the NCEP's Adulr Treatment Panel III {ATP III) idenrifres six major components: abdominal obesicl', atherogenic dyslipidemia, h1'pertension, insulin resistance w.ith or wirhour impaired glucosetolerance,evrdence vascularinflamof mation, and hvpercoaguabiliryIt is escimated thar 30% of over weight adults fuliill criteria for rhe diagnosis of metabolic syndrome, including rwo rhirds of those rvith FCHL. Hispanics and South Asians from rhe Indian subcontinent are especially \ u \ c e p it h l e . The mechanisms associating visceral adiposity with che nerabolic s,vndnrme and type II diaberes are not full,v understood. A plausrble unifying principal is that obesiry causes endoplasmic tetrculum scress,leading to suppression of insulin receptor signaling and thus insulin resiscanceand heightened inflammatory response. Hor,! this relaces to atherogenesis is unclear lt rs assumed that hypcrcholesterolemia and, rvith less certainty, h-vpertrigl;-ceridenia confer risk for cardiovascular disease in patients wrth FCHL. When features of rhe metabolic syndrome are ncluded in logistic models shared enologrc fearuressuch as increasedvisceraladiposir,vbecomeapparent. Visceral adrposity increaseswith age and its importance in chrldren as a risk facror for heart disease and diabetesis Lmired by the relative paucrtyof dara. Though longicudinalmeasurementof lvaist circumference and rhe presence incra-abdomrnal as decermined MRI is of fat bv being conducredin tbe researchsetcng, body mass index (BMI) remains the surrogate for adipositv in the pediatric clinical sertlne. The metabolic syndrome is a dramatrc illustrarion of che interaccion oI generics and rhe environmenc. Geletrc susceptibilit,v is essenrial an exolanation tbr Drematureheart diseaseLn indias viduals rvith FCHL. Unhealthy lifesq,rle,poor diet, and physical inactivity contribute ro obesitl and atrendant features oi the metabolic syndrome, The cornerscone of management is lifesc_vle modificatron. This includes a diet low rn saturatedfats, trans fats, and cholesterol, as well as reduced consumption of sirnple sugars- Increased dietary rnrake of fruits and vegetables is importanr, as rs t hr of moderate phvsical accivitv darly. Compliance among children and

(FDBL, Fanilial Dysberalipoproteinernia Typelll Hyperlipoproteinemia).FDBL is causedby mLrtations the genefor apolipoprotein in E (apoE), rvhich when exposed co environmental influences such as high fat, high calonc diet, or excessrvealcohol inrake, results in a mixed rvpe of hvperlipidemia. Patients cend to have elevated plasma cholesteroLand trigl,vceridesro a relativelv similar degree. HDL cholesrerolis rypically normal in conlras! !o orhet causes of hvpetriglyceridemia associated u.ith low HDl,. This rare disorder affecrs=1/10,000 personsApoE mediatesremovaLof chylomicron and \rLDL remnants from the circulation bv bindine to heparrc,uriace receptorsThe poll m.rphic apof g"n" .*pr.i,.\ in three isoforms: apoE3, apoE2, and apoE4. E4 is che "normal" allele present in the majority of rhe population. The a1xtE2 isoform has lower affnic,v for the LDL receptor and its frequencv is =7%. About 1% of the population is homozygous for apoE2/E2, che mosr common mutarion associated with FDBL, but onl,v a minority express rhe disease.Expression requires precrpitating iJlnesses such as diabetes, obesity; renal drsease,or hvpothyroidism. Indir.iduals homozygous lor apoE4/E4 are ac rr:k for lare-onset Alzheimer disease. \Iost parrencsr.irh FDBL present in adulthood wirh distinctrve xanthomas. Tuberoeruptive xanthomas resemble small grapelike clusters on the knees, burtocks, and elbows. Promrnent orangeo rellow drscoloration f the crea'e' ol rhe handstpalmar xJnthomas)is also rypically present.Atherosclerosis, often presenting with peripheral vascular disease,usuallv occurs in che 4rh or 5rh decade, Children ma;'' present u.ith a Less discinctrverash and generally have precipitatrngillnesses. The diagnosis of FDBL is established by lipoproteJn elec trophoresis, r'hich demonsttates a broad beta band conraining remnant Lpoproteins.Direct measuremenr VLDI- by ulcracenof trifugation can be performed in specialized lipid laboratories. A VLDL/total triglyceride ratro >0.30 supports the dragnosis. ApoE genotyping for apoE2 homozygosity can be performed, conlirming rhe diagnosis in rhe presence of the distinctive ph1'sical frnd ings. A negativeresuk does lro! necessarily rule out che disease a \ o t h e r m u r a t i o n \ i n a F ' , f m a v c a L r \ ee \ e n m o r e s e r i o u ' i manilesrations. PharmacoLoeic treacmenco1 FDBL is necessarvto decreaserhe l i k e l i h o o do f . i r p , o - r L ' . a t h e r o \ c l e r o \ ir n a J u l r \ . H M C ( o A s reductasernhrbitors,nicotinic acid, and fibraresare all effecrive. FDBL is quJrc responsive recommendeddietary rescriction. to HYPERTRIGIYCEBIDEMIAS. familial disordersof crielvcerideThe r i c h l i p o p r o t e i n ,r n c l u d eb , r t hc o m m o n a n d r a r e v . r r i a n r ,o l r h e Frederickson classification sysrem. These include chylomicrone(tvpe IV), and chemore mia (rypeI), famrhal hypertriglyceridemia severe combined h,vpertriglyceridemia and chylomicronemia (t,vpe V). Hepatic lipase (HL) deficiency also resulrs Ln a similar combined hyperlipidemia. tamilial Chylonicronernia I Thrs rare sinsle {Type Hyperlipidemia}. g e n ed e l e c t ,l i k c f a m i l i a l h l p e r c h o l e s t c r o l e m iia , d u r r ' , m u i a ' tions a{fecting clearance o{ apoB-contaimng lipoproteins. Defrciencv or absenceof lipoprotein lipase (LPL) or its cofacror apoC-ll, which facilitates lipolvsis by LPL, causes severe elevarion oi crigllceride nch plasma chylomicrons. HDL cholescerol levelsare decreased. clearanceof theseparticJesis markedlv As dela,ved, rhe plasma is noted to have a rurbid appearanceeven after prolonged fasrrng(Fig. 86-13). Ch,vlomrcronemia causedby LPL deficrency is associated wlrh modesr elevation in trigly'c erides. u.hereas rhis is not the case rvhen rhe cause is deficienc or

n in Chapter36 Delecls Metabolism Lipids( 587 of c\ac\!i\ c corrsLtrn|i oi io(1.1 i{Jn ifr(l ()thcr \!r'cctcrlccl clrinkr, as it r i c ( ) 1 i 1 r ( )rIo e n . ( ) L l n f rp a o p l c\ h ( r ( l . r n L \ L r p e r s i z cd r i L r k s r l d o r r r r u l r p l c l 2 o z r ' r r r so i : t c e r c n c . l r L r j n k .J . r i l r ' ( l c s s e n o n f t h i s o levclsas rvell i]l l)r.r.f.c'()itcn resLrlrs drrnritre fa Lirr trigl-vceride .'.i \\'crghf .lrrron!l those who .trc oltcsc. llDL cLlrlcstcrol levels \ \ r l f r n J t o r i s ca s l l \ ' l l s t a L r i l i z c s hvperlipidenri. inclu(le l)cilirtric dise:rsesdssocirteJ *itI h g h r p o t h rr o i ci s r l , n e p h r o t i c\ v r r c i r o r r r a .i l i a r v a r r e s i a , l , v c o g e n T.rv'Sechscliscitsc. si's\ror :,rtc diseirse, Nienrann-l\ck cliseitsc. hepanris, lrtcl artorcxie Lrervosa fcl)ric lIl-\LrservtherndtosL]s! i l . r l , l Ll r > l { ) ) . (.crreLnmedicariors cxircerhrtehrpcrliprderlrr, irclrdur!i rsorrerinoin l,Accutanci.rhiezrLlcJiur crics, ()r.tl cof frirccfrrvcs! rrcroidr, j3 blockers. rrrnrurlo\Lrppressits. xnd protease nhrl-.Ltors rse(l in thc trcaoncnr ol HI\i Ire.rrnrcnrof hyl-ertrgLrccrirlcnri,riLr chrlclrcrrrereh re(luircs nrcrll..rrioLrLrnlesslcvcLs >1.00()rrril,/dl- persist aftcr diefar,v drafes. accompaDiedbl r.!tri!tr(nr of iars, sugars, l1nal..rfLroh\ incrc,r.cd physicaL acti\'ltv. ln \uch eascs.rhe airr rs to prcvent of .l-rr\orles pdDcrextitis.Ihe uornnton Lrsc librates and niacirr of rr r.lulrs u,irh hvpelniglr.endenria is rrot rccommendedin chilrrhrhrtori rre rcasonilbLy eflectivc in Llrcn H\'lCi (loA reclucrasc more etpe Iruerrrrg tr'igl,vcerrde lerels. rrd thcrc is coLrsidcrlbl,v ncnec docuurcncingthe sirtcrr irrrd cificecv t>f this class of Jipid lorr crin!, rneclicatiorrs .hllJrcr in Hcpatic Lipase0elicrerrcy Hcpirric lrprsc rledciencyis a very rilr. irrrrosomdlrecessrtecouclition caLrsingele\,ation iD both t.i.r\nri cholesterol rn.i rrii{lrccrJeJ. Hcparic lipase ilJl.) in rrilr,rl,zcs rriglvceridesrncl phos]'holiprcls Vlf)1, remnanrs r r n c l L ) 1 . p r c v c n t i n gr h e i r r o r \ c r \ i ( ) r r n r L D L . l l l ) 1 . c h o l e s t e r o l , rhc lcrc s rcnd to be ucrelscLl .lrrher d1.1n decreascd, suggestirrg ililgnosrs. I-ahorarory conlifmafr()f lt,-'srablishedbt nreasuring i i l l : r c t i v i t y n h c p a r i n L z ep l r s n r r r O I S O R D L B S H D TM E T A B t I S M OF O PflrnaryHypoalphirliproteireoria Isoi:rtccl lou HI)1. cholesterol ()t s .r i.lrrilr.rl condition rhrt oircn follorvs a patterrr sullir,cstive ru:,rsoLD:rI domtnlnr irlherrt.rnce hut lri]v occur indepc Llcnt oi of irrnrlr hrstorf. It is rhc nrosr coDrnorr (lisorcler HDI- mctalroli:nr k rs rlefinecl HDI cholcsrelrl <ll.)fh pcrccnlle lor gcndcr' ris

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a [ r s c r r t a ] - . ( ) Clll . B o r h a r c i r u r o s o L r e l r a c c s s l v e a o n d i f l ( ) r r \ \ \ ' i ! h i I \ f r c q u e n o o f - 1 . 1 1 . ( l ( 1 0 . 0 0 t 1I.e d i s c a s e L r s L r i r l lp r c r c r r r \ ( i L L r i n g r chrlclhootl u'ith rrcute pirncrc.rtiris. FirLLptJr'canthorrrits orr thc i l r l s ! k c c s , a n L l L ) L l r ( ) a l ( 5t l l i t r l . ) e p r e s c n t . a l 1 ( l t h c f c n r i l ! [ r r

p o r t a r l v c D o o s s ! s r c | l r r r ] i l \ i l L r l l x r c r t !t o l e l f l t i n t a k e , i l r l d , l ( l l l l l l l israrion of fish oils rlrir\ .1lso bc bencficial

T ria F a n i l i a t H y p e r t r i g l y c e n d e n( F l j T G , y p e l V l l y p e r i i p i d e m r a ' r r t l i { T ( i i s r r . l u t o s o m r jd o n r r n e n r l i s o r t l e o f L r l l L n o $r c t i o l o S \ . n t L r i c h o c c L L ri s . - l . r . i i ) 0i n d i v i d L r r l ;I.r i . c h l r a c t c r r z c .Il' r l l c l r tiorr oi pLasrrra rrighcericlcs>'l(Jrh l-.crccntilc i2.5(l-l.0lli) rrrq,'ctl (l .qcl.()ltcrr acc()nrF;rrr;('{l .ljghr r'levarjonill plasrllrrc lolts i'r lna.llc\t Llnnl .r(1L1ll rerol irnd l<>rv H[)[-, l:]l l(i docs rrot Lrslrellv chllclrtn- lrr hoocl. though ir 1s cxprerse.l irr =10')i, ol eiiecrccL ()gcrrrecolltfesf to F(-l ll,, l H'I (, is rror thought ttr bc highlr .rthcr Lrr It is rnosr likely causecl d.ic.ri!c brcekdorvnof Vl L)l ' or less

HYPMCHOTTSTEROLEi$IA -lpctiyrcdrjm l-HT(i shoLrldl-'c.lr. degrcc relativc wirh h!pcrrrLgl\'.:tridcmra.

rrPlfr!r:itni'cme i ii.e!ti5ri re ll Lrq5:prcqeneonqllnx del, tqret0,ilr05p0t HYPTRTRIGTY(ERIDEMIA 01:!tl l!oeldrar.'te5

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icl'on levcls oi c rr lornicrons ils wcll es Vl-l)l l'.rrticlcs (ljreclcr c cr r l p c \ r ) r r r r \ o c c a s i oi l l t b c c r t c o r r n f e r cT l .i g , l l c e r i . llc r c l . . r r r ' i sr s o i t c n > 1 , 0 0 0n r g / t l L .I h e , - 1 i s c , r r e i r r . ' l v c e n l c h l l d r e r rI'r rc o r r f r - a stt( J c h v l o r n r c r o r r c r ni il r c L l . r i . k s ( ) rtr! P c l ) , I l ' l - o r r l ( ) ( . l l oifcrl dcvcl{rPcrrrfr \r dcficiencl is ror pfeseur Thc\e L..rtrcnrs , * t x i l r f h o n l r s i r r a c l u l r h o o r l .h c r - c a s y p c I V h v p e r t r t g , h eic lrc r l l i , r indivi,JLrllsclo nof Acure pirrcrc.rritis rnrt be dre frc\cnfrrrs \ i l l n e s s .A s w i t h o d r c r h yp c rt r i g l ' c e r r d e r n i ' r e,x c c s s i \ c . 1 l . o h ( ) l fLrcrilIr catl e\rccrbafc thc diseescc()nsul]lptionrncl e.rr-ogcn Secrrnclalv c.rusc:oi rrltrsicrrr hvpertriglvccridertiirshorrltl ltc rf x l u l c c l o u t b c f i r r cn r i r k L n g ( l r d c r r ( r so s t H T ( 1 . A c l i c rh i g h i r r

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ilr()ttt criJenri.t. Adolcscerts iur!l adulrs rhoulcl bc qtrcstiorrcLl

I 588r PAnTX Melabolic oiseases and age with normal plasmauiglyceridesand LDL cholesterol, r00hether is assocrared it with more rapid athetosclerosis unceris tain. It appearsto be relatedto a reduccionin apoA-I synthesis and increased catabolismof HDL. Secondary causes low HDL of cholesterol,such as the metabolic syndrome,and rare diseases such as LCAT deficiency and Tangierdisease must be ruled out. FamilialHyperalphalipoproteinemia. is an unusual condiThis tior conferrirg deceased risk for CHD among family members. Plasmalevelsof HDL cholescerol exceed80 mddl. Familial ApoA-lOeficiency. Muration\ tn rhe apoA-l genemay result in complereabsence plasmaHDL. NascentHDL is proof duced in the liver and small intestine. Free cholesterol from peripheral cells is escerifiedby LCAT, enabling formation of marureHDL particles.ApoA-I is required for normal enzymaric functioningof LCAT. The resultantacctrmulation free cholesof terol m rhe circulation eventually leads to corneal opacities, planar xanthomas, and prematureatherosclerosis. Somepatients, however, nay havemurationsof 4poA-1that result in very rapid catabolism of the protein not associatedwith atherogenesrs, despiteHDL cholesterol levelsin the 15-30 mg/dl range. TangicrDisease.This is an autosomal co-dominanr disease associated wrth levelsof HDL cholesterol mgldL-It is caused <5 by mutationsin ABCAI, a protein thar facilitaresthe binding of cellular cholesrerolto apoA-L This results rn free cholesterol accumulation in the reticuloendothelialsystem manifestedby tonsillar hypertrophy of a distinccive orange colo! and hepatosplenomegaly, Intermittenr peripheral neuropathy may occur from cholesterolaccumulationin Schwanncells. Diaenosisshouldbe suspected childrenwirh enlarged in orangeronsil* and extremelylow HDL cholesterol levels. (IGAT)Deficiency. FamilialLecirhin-Gholesterol Acyhransterase LCAT interferewith the esterification choMutations affectrng of lesterol,tberebypreventingformation of mature HDL partrcles. Thrs is associated with rapid catabolismof apoA-I. Free circulating cholesterol the plasmais greatly increased, in which leads to corneal opaciries and HDL cholesterol levels <10 mgldl, PartialLCAT deficrency known as "fish-eye"disease, is Complete deficiency causes hemolyticanemiaand progressive renal insufflciency early in adulthood. Thrs rare disease not thought ro is cause premature atherosclerosis. Laboratory confrrmation is esterification basedon demonstration decreased o{ cholesterol in rlre prasma. EstelTranslerProtein{CETPI Cholesteryl Defciency.Mutations involving the CETP gene are localized to chromosome16y21. CETP facilitatesrhe transfer of lipoproteins from mature HDL ro and from VLDL and chylomi-ronpanicles. thus ulrimately regulatingthe rate of cholesteroltranspon to the liver for excretion in the bile. About half of matureHDL2 particlesare directly removedfrom the circulation by HDL receptorson the surface of the liver.The other half of cholesteryl esters the coreof HDL in exchangewith triglyceridesin the core of apoB lipoproteins (VLDL, IDL, LDL) for transportto the liver Homozygousdeliciency of CETP has been observedin subsetsof the Japanese population with extremely high HDL cholesterol levels (>150meidL). ASS0CIATED GONDlTlOlls WITHtOW GHOIESTER0t. Disordersof apoB-conrarning lipoproteins and intracellular cholesterol metabolismare associated with low plasmacholesterol. Ahetalipoproteinemia. rare autosomalrecessive This disease is caused rnutationsin the geneencoding by microsomalrriglyceride transferprotein necessary the cransfer lipids ro nascent for of chylomicronsin the smallintestine and VLDL in the liver This results in absence chylomicrons, VLDL, LDL, and apoB,and very low of levelsof plasmacholesterol and triglycerides. malabsorption, Fat diarrhea,and failure to thrive presentin early childhood. Sprnocerebellar degeneration, secondary viumin E deficiency, ro manifestsin loss of deep tendon reflexesprogressing ataxia and to lower extremiry spasticity by adulthood. Patientswirh abetalipoproteinemiaalso acquire a progressive pigmenledrednopawith decreased thy associated night and color vision and eventual blindness. The neurologicsymproms and retinopachy may be mistaken for Friedreichataxia. Differentiation from Friedreich by ataxia is suggested the presence malabsorptionand acanof thoc;tosis on peripheral blood smear in abetalipoproteinemia. Many of the clinical manifestations the disease a result of of are malabsorption fat-soluble vitamins,suchas vitaminsE, A, and of K. Early treatmentwith supplemental vitamins,especiaJly may E, significantly slow the development of neurologrc sequelae. Vitamin E is normally transportedfrom the small intestine the to liver by chylomicrons,where it is dependent the endogenous on VLDL pathway for delivery into the circulation and peripheral tissues. Parents of children with abetalipooroteinemiahave normalblood lipid and apoBlevels. Fanilial Hypobetalipoproteinemia. Familial homozygoushypois betalipoproteinemia associated with symproms very similar to thoseof abetalipoproteinemia, the rnheritance but patternis autosomal co-dorninant.The disease causedby mutations in rhe is gene encodingapoB-100synthesis. is disringuishable lL from abetalipoproteinemia that heterozygous in parentsof probands have plasma LDL cholesteroland apoB levels less than half normal. There are no symptomsor sequelae with the associated heterozygous condirion. The selective inability to secrere aooB-48from rhe small intestine resulls in a condition resemblingabetalipoproteinemia or homozygous hypobetalipoproteinemia. Sometimes referredto as Andersondisease, failure of chylomicron absorptioncauses rhe steatorrhea and fat-solublevitamin deficiency. The blood le"el of apoB-100,derivedfrom normal hepatocyte is secretion, normal in this condition, Smith+enlH)piE Syndmme Patientswith SLOS often {SLoS). have multiple congenital anomaliesand developmentaldelay causedby low plasma cholesteroland accumulatedprecursors (Tables85-11 and 86-12).Family pedigreeanalysis has revealed inheritance Dattern. Mutations in the its aucosomalrecessive DHCRT1t dehydrocholesrerol-Areducrase) generesulrin de6ciencyof the mrcrosomal enzymeDHCR7, which is necessary to competethe linal step in cholescerol synthesis. is not known It why defecrsin cholesterolsynthesis result in congenitalmalformations,but as cholesterol a major componentof mvelin, neuis

86 in ol Chapter r Defects Melabolism Lipids | 589 cholesrerollegg volk) and pr>ssibly includessupplementaldictar-v jnhibirion to pre!ert rhc svnthesis roxic of H\lC; CoA reductase prccu15ors proximal to thc cnzyrnarrcblock. IIERVIX's sYsT[TI CEI{TML konral hypopla5ia obe En ventride5 arqed Aqmesi5 (allo5um olrDlpus (ereblhr hypopasia Holopm5en(ephdly CANDIOVASOI.AR cana Al',rrrventli(ular atr a deh(t se(Undumsepla duclu5 o5u! %tent arte llembranou5 spplal vertdolar defeo URINARYTNACT ff apLrsia ReMl hypoplasia rord(al Renal (y5t! fiydmnephrosis llretecl icalion dup GASTnotrT6TllllL Hirschsprung di5ed5e PylofC ieno5s ReiBctofy 45motifily progc55ive livel disedse nondolenatc l:ho16lafi( and PUullot{AnY hypoplasia Pulmonary obation Abnomal fi.lDofttt{E Adrena insuffrdenry
of d 6f: ko. PadD, klLE R, foffmann nhdli sodeE dd?]ko bi6,nlh{n \AnpedidrE l:f\l,tl1l 111

METABOLISM CHOI.ESTEROL DISOBDERS INTRACELLUTAR OF disThis aLltosomalrecessivc Xanthomatosis. Cerebro(endinous rvith tendon xanorrlcr presentschnically in latc adolescence ft fhorrls. cttaracts, and progressrve neurodc.qenerarion. is shunted of ceusedL-vtissueaccumLrlation bile acLdrnternrediates resulting from nlutations rn the ecne fol sterol into cholestanoL -Ihrs 27 hrdrox,vlase. enzymc rs neccssarlfor normal mirochonclrrals"nrhesis bile acidsiLrtbe liver. Early trcatmenrwirh chen of oJeoxrcholic acid reduces cholesrerol lcvels aLrd prevents the of de-velopment sy.rnptoms. Ester Sl0rageDisease(CESD), Wolman Diseaseand Choleslerol Thcsc autosomal recessive disordersare caused by lack of lyso_ sonral acid lipase,Afrer LD[- cbolesterolis incorPoratedinto lhe cell bv endocytosis, ir is deli"ered lo lvsosornesu'here ic is because of hydrol'zed b,v lysosomallipase.Failure of hycLnrlvsis conDlere absenceof the enztme causesaccumularion of choles teryl csters vvithin thc cells, Hepatosplenornegall,steacorrhea, aLrdfarlure to thrive occur during early infancl, lcading ro death hr, rhe age of 1y'r. ln CESD, a less severeform rhrn Wolman acid lipase acrvicv, discasc,rhere is lou but derectable 'fhrs DiseaseTypeC is a disordcr of inrracelLu Niernann-Pick Ier cholcstcrol transporf charac[erizcd b,v accuntulation of .hrlc.rcr,'l anJ 'phrngonrtcl'n n lh. (cntrJl ncrt',ut anJ Death froru this autosomal recessive rcticuloendorhelial s-vsten1s. ncurologic disease r:suallyoccurs bt adolescence. AND AD0LESCENTSTabte PATTERNS CHILDREN lN ||POPR0TE|N ll6-li, derived primaril,v irorn the Lrpid ResearchClinics Populanon Studies, shoo.s thc disrnbution of Jipoproccinlevels in Anencan youtb at various ages. lbtal plasma cholesterolrises r.rpidh lionr a mean of 6i3mg/dl ac birrh co a level approxi nrarcLr rwice fhar by rhe end of the neonaral ptri'rd. A very gradu:rl rise in cotal cholesterol level occurs unfil puberty, nt rvhich rine the mean levcl reaches160 mg/dl, Total cholesrerol during pubertv. in malcs due to a snall decrease falls cransicnrly to in HL)L cholesterol.and in femalessecondar,v a slight fall in LDL cholesterol.Blood cholesrerol[e'.elsrrack rcasonablyl'r'ell in as individuals age, High blood cholesterolrendsto aggregace fanilies. a reflecrionoi eeneticaDd environmentalinfluences. Ar :rcceptableroral iholesteroLanrong children and adolescents is <170 mg/dl,; borderline is 170-199 mg/dl; and high >200 Lr/dL. An acceprable LDL cholesterolis <110 mg/dl; bor

somcrvhathigher frequencyin Hispanics and lolver Lrcideoccin indrvidualsof Airican descenr.

cholesrerollevel is <20 g/dl. vival rs unlikel,v*'ben the pLasma Laborirtor-v neasutcment shoLrld be performed bv ga chr,r for as macography, standardrechniques lipoprotein assa-v cludc rvhich nav vield ialsc -"naut.rrr"ltt oi cholesterolPrecursors, rnay nor preseurunril late chiJd positive result. N4ildercases cardiacand Pheoorypicvariancerangesfr<)mmicrocephal,v. malforniarion, and ruultiplc organ sysremfailure to onll dysmorpbic teatures and mild Jevelopmental delav Treacntenc

TOTALTFI6UGNDE
l:ord 14 yl Male [imale

roTrl cHor.t$tnot fioDr)

95TH 5rH 4) 84 MTAN 75TH 9OTII 95TH sIH 103 11 68 t/0 1/3 168 116 r7t t7l 168 176 r90 r88 181 r90 188 191 t8l 198 201 200 r89 191 242 205 l9l )01 61 68 64 68 6t 59

UPoPnfiHil tof,i-oEilst 0{0tEsTrR0t

-ttxStTY Gfl UP0PftorEttl 0t0ttsrEflot

95fi 60

l4 29 t4 28 l2 33 l9 38 l6 56 t 6l 7) t8 7l 68 lq 58 74 14 85 88 85 85 95 /0 101

MTAN 75IH MTH 95TH 5TH IOTH 25TH - 5 0 1l 79

99 112 85 126

114 155 112 156 125 155 111 124 160 125 r60 ll8 r8 r5l 159

5 9yr lvlale fumdle yr l0-14 lvale fumah yr l5-19 Mae Fema e

9l r0{ 91 9l 94 96

r0l 5
r09 |0 109 l

t17 12J

129 r40

t8 t6

42 t8

49 4/

56 5l

14 /3

94 lll 10.4 r20 r25 fl2 143 126

14 40 46 5t 111 tn v 1 1 6 B 6 ] 7 q 4 5 5 2 7 0 lrl )9 J0 117 J0 t5 1,1 l8 l9 4l ^6 t 61 t4

'Note diftercnt pe(flt le5 ?rcllFdmr|iDi.h0eltem dar l1,16,d|d]inIa|)q?seaft0n'(5[wtl0ran,udk5D0laWrDl1'|l'ePRfEf.?Ji!d'NNp!bLkalirnM80]527Wi'hil1!l0n'0(l1aI0rrhi|fF5dH$h[l9&

590| PABTX. Metabolic Diseases derlJne110-129 mg/dl; and high >130 mg/dl.. HDL cholesterol should be >40 mg/dl. tions for those children with hypercholesterolemia can be safel;, applied at chrs stage of neurodevelopment.

Bt00D GHOLESTER0I SCREENINc. NCEP's Expert Panelon Blood Cholesrercl Levels in Children and Adolescenrs established suidel i n e ' ,i o r c h o l e , , r e r o l e a \ u f e m e nr h a r w e r e p r . r b l i s h eid 1 9 9 l . m r n The panel recommended a sele.tiue approach to screening based on the follo\a1ng critena:

Saeen dildren adolescents parcntr grandparentt do(umented and whore or have coronary arterydiseare theaqe beforc of55yr. (alories conrum.dfatrhoold ex(eed oftotal(aloder at not per 1096 conrumedday. Screen offspring a parcnt has the of who been found hav.a blood to dolegterol of level (alorie! (onqrmedratlnted should exeed oftotalcaloriet day. per ar fat not 1lD6 >240 mg/dt. (holcrtercl ihoold linited <300 Total intake be to ng/dlper day. Smen(hildnn adole(entsforwhomfamilyhistory and ir unobtainable,pattkuladythosewith other fadors, rir* The American Academy oI Pedrarrics and rhe American Hearr Assocration (AHA) have endorsed rhese criterra. Application of these criteria will result in the screenins of 2J7o of American y o u l h . r e p f e \ e n r i n t h o \ e m o s t l r k e l l r o h a l e a f a m i l i a lb a r i s l o r g their hypercholesterolemla. predicted 597" of children wirh A elevated levels of blood cholesterol will avoid detecrion because of che lack of universal screening, and rherein lies the source of

RISKASSESSMENT AND TBEATMENT HYPERTIPIOEMIA. OF NCEP recommends nsk assessmen! based on LDL choles ol levels (Fie. 8 6 - 1 4 ) .t h e f o l l o u . u p i n t e r v a l n d m o d i f i c a r i o n d i e r i s d e r e i a mioed by the sevelry of dyslipidemra. Borderline hypercholesterolemia {LDL 11,0-129 ngldLl should prompc iniriation of lhe child on the AHA Step I diet:

>240 mgldL is considered by some to be coo insensirjve and difficult to apply. The rationale is basically sound, lhough admirredly the guidelines are fraught rvith problems of compliance. lf familv hisrory of n'idespread premature arherosclerotic heart disease ts obtained, offspring are Jndeed at signilicandv greater risk of dyslipidemia than children without such family' history..The converse applies to children who do not fulfill criceria for screening; they are not likely to have a suong genedc predisposition ro heart disease. The 59% of children with hypercholesterolemia not d e r e c t e d 1 i l i n i . i a n ' f o l l o w i n g r h e g u i d e l r n e a r e I i k e l vr o h a v e b s only modest elevacion of cholesterol due to environmental influences such as diet and sedenrar)' lifstyle. Primary prevention strategiesapplicableto the population as a whole include daily physical activicy and a diet low in saturated fats. Children and adolescents for whom there may be consideration of using cho lesterol lowering medication rvill nearly always be correctly iden t r F e db 1 i o l l o w r n gc u r r e n rg u i d e l i n e ' . Early dragnosrsand treatment of individuals rvho are at risk of premature CHD because of genetic susceptibrliq is an important public health strategl It is esrimated that no more than 2070 of people with heterozygous familial hypercholesterolemia are diagnosed, and <10% are being adequatelycreared. detailed stud_v A frorn the United Kingdom has established the cost-effectiveness of "cascade screenng," which means tracking and tesrrng family members of FH probands. Ic is even more cost-effective to screen vounger people becauseof more life yars gained attet preventrve ffeatment. It is well documented that many parents are unaware of their o$.n cholesrerol levels, making the use of that criterion problematic. The evidence that cholesterol screening of children may cause psychological harm to the child is less than compelling, as is the concern that universal screening mighc lead to overuse of cholesterol lowering medrcation, The n'orrisome eprdemic of chrldhood obesity, approaching 50% in some disadvantaged high risk populations, supports broader screening to identif). those with the metabohc syndrome- A fasting lipid profile rarher tban nonfasting total blood cholesterol measurement is indicared if screening is beiog conducted because of obesity as a risk facror

Instruction regarding avordance of other risk lactors for hearr disease such as tobacco use should be provided. and the child sh<'uldbe reevaluated I yr. in Persrstenceof elevated LDL cholesterol >130 ms/dL indicates the need for more comprehen\ile elaiudtion an life.rvle modi fication. Hrstory and physical examrnarion nd .rddrri.'nal Iaborarory tests aimed at rulng out scondar,v causes of hyperlipidemra (see Table 86-10) should be performed. Other family members should have blood cholesterol screening. If rhe LDL cholesterol level does not achieve the rmnimal eoal of . | ]0 mgidl. the AHA Step ll drer *hould be recommended, his I diet allows lhe same average fat consumption of no more than 307" of total calories, bur restricts saturared Iats to <7-87o of toral alories and cholesrerol intake to <200 mg/day. Follolr-up lab c ts, meastrremenr of height and weight for the calculation of body mass index (BMI), and dieta._vhistory should be scheduled at 3-6 mo intervals. The 2004 revision of the NCEP ATP III raised rhe mrnimal acceptable leveLof HDL cholesterol from 35 mg/dL to 40 mg/dl-. If low HDL cholesrerol Js present, counseling directed roward weight management, tobacco avoidance, and daily physical activitv shor:ld be orovided. No restricrion of fac or cholesterol is recommended for infants <2 yr of age becauseof rapid grorvth and development, especiallv rnvolving the cenlral netvous systemand the possibiliq of developing failure to thrive. Overfeeding should be drscouraged, however, as, increasingly, infants and toddlers are exceeding u,'eight for height standards published by the U.S. Centers for Disease Control and Prevention- The myth that "a bigger bab,v is a healthier baby" persists.

not specrfy the age at which at-risk children should be tesred. Five -yearsof age is a reasonable age !o screen since dietary intetven

of poor growth or compromised nutritional status. The prospecrive, well-controJled Dietarv Irtervention Srudy in Children (DISC) compared chrldren consuming a low-far Step I diet with sublects consuming che "Lrsual" dier, containing 33-34o/" ol calories as fat and 137. as saturated Iat. No differences between groups wlth regard to height, weight, micronurrients, or psycho logic well being were observed. Children on the lor-fat diet had lower LDL cholesterol levels. The Commrtee on Nutrition oI the American Academy of Pediatrics suggeststhat as children >2 yr consume fewer calories from far. thev should ear more grain pioducrr, {ruirs. regerablej. low-fat milk produclsr beans, lean meats, poultry, frsh, and other protern-rich foods. Low-carbohydrate, high-fat diets have become popular in the lascdecadeas a means to achieveweighr redr.rction.Unlimiced fat intake is strongly discouraged, as is unre stricted sugar and carbohYdrate consLlmption. Carbohvdrates should comprise --55% of calories, achieved b,v consuming complex carbohydra!es such as pasta, cerrain vegetables, potatoes, le8umes,and whole grain cerealsand bread.

86 in ol Chapter r oelects Metabolismtipidsr 591 BiskAssessmenl High Posilive Family History Parental ol CVD BloodCholesterol Premalure or

Repeatlipoprotein analysis wilhin5 yr. Provideeducationon recommended eatingpattern and risk factor reduction.

ligurc liL l1. llow chart of chssLiicalion, educatiol, .rnd f<,lli,w up oi chilclren b.rsedon r,'|l . lor de-sr' l,noororer l Dl "'r, d l e v e l s . C V D , c a r d i o v a s c u l a r i s e a s e ;H D L . h i g h ' d c n s i t -l!i p o p r o t c i n .( F r o r nV i l L r a n s C L . S H a g m a nL L , D a n r c l s R , e r a l : C a r d b v a s c u l a r henkh io chi(dhoorl. Cir.:rlarr)" 1001i106: 1 , + l - 1 6 t ))

Repeat lipoprotein analysisand average prevrous measurements

Risk factor advicel ProvideSlep-OneDiet and other risk factor intervention. status in one year. Re-evaluate

(history, evaluation Do clinical physical lab exam, tests) . Evaluate secondary for causes. . Evaluate familial tor disorders. members Screen family all Intensive clinical intervention: diett Step-One, Step-Two then SetgoalLDLcholesterol: . Minimal: <130mg/dL . l d e a l< 1 1 0 g / d l : m
"lf low HDL cholesterolis deiected,then patientsshouldbe counseledregardingcigarettesmoking' low saturatedfat diet, physicalactivity,and weighl management(if overweighl). if nsk >10 yr old and withLDL-C> 190 mg/dL(or >160 mg/dLwithadditional factors), tFor patients shouldbe considered intervention diet does nol achievethe goal, then pharmacologic

hypertension,Thc Narional Associarion for Sport and Ph,vsical EdLrcatior (NASPE) recommendsrhat children should accun,ulare ar leasr 60 minutes of age-appropriatephysical aclivit,von nlost days of rhe week. Extendedperiods (>2 hr) of daYtimejnac tivif\r are dlscouraged,as is >2 hr of televrsionand other forms of scrcentrme, The NCEP Experc Panel 86-14and 86-151, DrugThelapy(Tables recommendsrhat considerationhe for rllhiidrenand Adolescents frozen vegctablesarrd soups should be selectedfor lorv sodiurn conrent,

fion, at leasr 6 mo, has not achieved therapeDticgoals Dtug rherapv should be consideredrvhen:

the entjrc iamilv rarher fhan cn ildjvidual child -r\ regular tirne

' LDL cholesterol >190 rcmains mg/dl 'LDLdole(erolremains>16{mg/dLandthereitaPotitivefemilyhietoryofple (CVD)before ofage twoormore fot are ot othet fadols (VD dsk di0va(ular diseare 55yt present vigorour modif(ation. attemptt lifestyl. at afler These arbitrarv but sensibleguldelinesare basedo[ lhe slatis-

aclrvity emong oLlr youth is conlributing The rise jn sedentar,v

592t PABTXr Metabolic oiseases

MECIIANISMAOION OF |1MC rcduxa!e toA inhibftoE i5tarn5) Bie d 5eq,testants: a( iiole5lranine [ohntpc l,iccln acd c ii|ft arid dedvt,ve5: 6emfbroz F5ho5 ft ohnerc abiorption inhrbit|)|l fuelamibe

['lDt(ATt0t{ tlevated L0l Flevaied tDL

Jt eiterolandV|DLrynthesis 1|1 ar|( rc(eflcB LIL TB andexrrelon J Hepar synthees rVLDL

STARTT 6 D05t 5-80 qhr rq g y 4-12 Ca' g 5 4 C l ay Jrl]2,000 rd m! 600 bd mq I 10 daily _a lCl|rg daily

'l

rPr

Ekv?teil L0i TPVatPd IG !levared16 EPVated;6 te,/ated LDL

JVLDL produdion J VL)L

(hr] J lnrcnina ab5orptio[e5lerol t!l-low denriu D0rrft lxp'olantLfL, n pa5e,iG,Iq}teide]VtDt,lrrylowdmsiry FpDler are encouDtered and family history oi early cor-onarvdiseascis prevalenrCorsiderable experiencc with drug therapl. rn childrcn and

cacy. ID fhe pasr. rhe mainst;lv of drug rherapl was bile acicl sequcstrartts sLrch cholesFralninc and cholesripolbecaLlse as thc,v rverenot sysrcrricalll' .rhsorLred. hrterruption of the enrerohepatic crrcLrlatiorr Lri]eacrds promotes svDrhesis thc lir.cr oi nelv oi in bile:rciclsfronr cholesterol. Gastroinrcstinal side efficrs and testc fe\ultcd in lessrhan desirablecornplrance. e\renrvheDthere \,vcrc t e u . v i a b l eo p r o n s . HN'lG CoA rerluctase inhibrtors,knorvn as statins,are rcmark abl,v cifecrive in lorvering LD[, cholcsrcrol levels and rcducrng plaque inflanlmation, thereb,v rcducilg rhe likelihood of a sudden DRUG s|lE AftD 0nIYPE tFfE(T 0r rfrrfi coronery event iLr an at-risk adult lr'irhirr u,eeksof srarting the sIAT[iS medication. As a class, they u'ork I't blocking the intrahcpetic ikn Rarh biosynthcsis cholesrerol, ol fherebvstimullting the proclucrionoi penpheral Nervo!5 5y5iern Lcss .oftentorioi,r dLtudaia, of eep head&he, nlote Lf)L recel)rors thc ccll lLlrface.The N(IEP ATP aclvo on neilr0pa(ny cafes rllgrcssivc lorvcring ol l-DL ro <70 rng/cll in indivicluals qhl Lver Hepilil 0bppetiie,we csr3nd'roeaie5serum s,lo55 iI rvith knowr coronary he:rrt discese. This informarion is rclcrant '"l rotrdrrhras.\_0 f'periffer,' .ppq n o[_1" |,^4Io because childrcn u'ho iulfill crrterrafor considcratronof cholesncmallan!le terol lowering rnedicanon!\rll allnost alwai,s hrvc inheflreclrhc pdn, GJ$mintetr,r( na Ab0ofitlndl mii5ea, diairhea pd condrfi(u ironr ()ne pnrcnr Not urfrequentll', rvhcn pro"iding lMus( e5 4(5ale n cfwedknel5, (u5Lraly 5er,Jin myorri5 wrth fleatine > i{nase 1,000 rhabdrrny0y5 r|rna u/L), sw th furlure care lor ll1echild. questjonsco re up abont screeningancl trcac(ol/artatn,5 yndrome lmmune5y5tem Lupu5like !"r!ana1rn,0r n) ll!va5ta ment of parents or grandparcnts.Statins are equallv cficccivcill Pmtein bindrng D i rf i f p db i l l T 0 f1 ! " d r r l L ! ' d \ l d r r , r : a : r . l i l v d ' r d r n l children, capableof lou'ering I-DI cholesterollevelsb,r half wl-ren . BITIA(IFBINDING RESIIIS necessar,v. Ihey also effect nlodesrreduction in rrigl,vccridcs and l;astro nleii0a rra( Abdomnalfulns5s,nau5ea,tlas,(on(ipaton,hemo4hoidl,ana incortsistent incrcase in HI)l cholesrerol. Sratins have been istLrre, &tiatlo aid!e( tul1ltdmi0 absorlii0n I 5hed of shown to impr(rve intirne-nrcrliathicknessin crrotid irrteriesin
ljver Metabcic5yrtem yiiirnin in(hiden D -b flp l M d \ p _ r o - 1o r r J r ' ' ped , d l r o , ! i ; t h , d n [ e e r d " . c r by(0nr0m trealmpnt aitatin taFI vrih (greatpr In(Ieaiesln lr!iy(eridei 5emm of=10% rn(ed5es in patem5 hypet ycerdemia) g with .eldlfalLr f rpprr' oDr r a(d0.i h !h ldrFo p".i" ..,\,,.f d1d kholesfycmine) Einding 0fwafan,dl!ox thaidedruret(' n, thymxine,rciins

failLrre, should bc rakcn into considerationbcforc prescribiDgfhe drug. Thcre has beel no evidenceto datc, ho,"vever, rhar compli, catrons are aLr,v rnore lrcqucnt in children than in adLrlts.ancl lhffo yle5 skeLeralnrLrscle discorriort seens r() bc sornervhat less of a 0ruq nieraclionr problern. Stiltrnsare concraindicarcd pdtienrslvith acti!c livcr in (llseaseand during prcgnarrcv alrd lactarion. Childrerr should t(oTtNt(ACrD prur{1r5, have liver enzyrnes nlolirored rcgularll, ancl creatirc plr(rsphok 5ki Flu5hrng,dry lkin, i(hthyosis, arantho5i5cn! niqr Eyes [on]unctivt,!,ryJtoddredema,ndldetaihment ma(u ret inasc (CPK) measnredii musclc ache or weaknessoccurs I iver Re5pihll)ry tra(t Na5arJIufline5l erzv rcs car be allowed to rise rhreeioldbcfore discoltinuing rhc (Ular Heart 5,.pra\,entraIhythrn aj drug. It should be reernphasized rhrr children rvirh nroclcstclc 6afonlestinatmat |Jerf icors tbur, bowsl flroveme0$ otdiarhei vations in cholesrer()1, sLrchas that sccn in polvgelic h_vpercho |1 rrith Lver i id rn(ei9e seruTn amLn0irdnsfenses,hepatiti narrsea lcstcrolemia,are nor candidatesfor stetins as a rule becauscof anCIa(LcUe thcir side effet profile. l/lusces lt4yorilh ()thcr cholescerol Lly0q!:Ir1i {in(dene lou'ering medicariols such as r'ricofurrc acid j|$en -\h \iJhpn pd,tp,t. lt4elabolic $tha.dbae,t. ancl fibrareshave heen used far lcss often iu chrltlrer thrn bile lnLfea5eof n ierLlm aiid 10% ur( acid scqucstrants and stxtins-Nicorinic acid has been useclselecfIBRATES tivcly in children u'rth rrarked hvpcrtriglycendeLriaar risk for 5kn Fash (a5trointen tholgh dictary resfrlcrionof complcx srrgars pain(rnaryqemFbrozi),ch0eslerolacute pancrearifis, faltECt 510mrrh rpiet,ab,roitna and cirri)oh)drates usrrallv resulrs in significant lo,,verug of ln( 5aiuftted bie,inrreareof n galsmne dence I l% (rna 6en lcudnary tcrl fteclile dy5fun(1i0n doibote) ny rriglycericle Ler.cls. Nllxe5 Myos w ti impa rendlfun.llon t5 rd F.zctjnibe is useful in the pediirtric popularron beceuscof irs Pblma nterfercncev/nh ofwarldnn, xnq 0rctein5 bindinq Equ redudron inll.e ei6cacr' and low side effect pro6le. F-zctirnibc reduces plasma dose wdrfarin-10% of by l.l)t- cholesrerol bloci.ingsrerolabsorprionin elteroc,vtes. bv Thc Lvef urrcdsed amnoiran(era5e5 5e'um is drrrg, nratketecl an adjuLlctft) starins$,hen adulr subjectsarc as fomhop! RdDtuq rrcrmFfi i,iid iorder fntl/#e, 1999t1.115l2 0f d , 498 nor achievingsufficienrblood lipJd lorrerirrg \\,ith stauns irlonc.

r in ol Chader . oefects MetabolisrnLipids 593 m usedasmonotherapyin children Largeclinical trials of ezetimibe reports thereare sufficient Nevertheless havi not beenconducted. of effectiveness this the in the literature documenting impressive medicationu'iihout worrisomeside effectsthat the clinician can of clinical manifestations rhe lipid alterationsand characteristic lysosomalaccuTable 86-16). Progressive storagedisorders(see in mularion of glycosphrngolipids the cenrral neflous system whereasstoragein visceralcellscan leadsto neurodegeneradon, pulmonaryinliltraskeletalabnormahrres, leadto organomegaly, The storageof a substratern a tion, and other manifestations. tissueis dependent its normal distribution in the body. on specific Diagnosticassays the identificationof affectedindividuals for enzymaric activit' In isorelyon the measurement rhe spectfic of lated leukocltes or cultured fibroblasts, For mosr disorders, and prenataldiagnosisare available;a specarrier identifrcatron generic The is to counseling. charcrficdiagnosis essential permrt required enzymes of that encodethe specific acterization the genes for sphingolipid merabolismpermit the developmentof theralherapy' peuticoptions,suchasrecombinant enzyme replacement as well as the potential of genetherapy.Identilicationof specihc prena!aldetection, mutationsimprovesdiagnosis, disease-causing For somedisorders(Gaucherdrsease), and carrier identificatron. correlations it has been possibleto make genotype-phenotype genetic counand rhatpredicr disease severiry allow morePrecise excep! for X linked seling. Inheritance is autosomal recessive Fabrydisease. most frequently preGM1 GAt{Gtt0SlD0SlS. GM1 gangliosidosis in br-rt sentsin early infancy (type 1 disease) has beendescribed patientswith a juvenileonser(type2). Both are autosomalrecessivetraits; eachresultsfrom the deficientactivity of F-galactosi3 dase,a lysosomalenzymeencodedby a geneon chromosome (3p21.33). rs by Althoughthe disorder characterized pathologic accumulation of GM1 gangliosidesin the lysosomesof both accumulationis mosl neural and visceralcells,GM1 ganglioside markedin the brain. In addrtron,keratansulfate,a mucopolysacrn in charrde, accumulares lirer and rs excreted the urine of genehas parientswith GM1 gangliosidosis. The p-galactosidase mutationscausingeither type 1 or beenisolatedand sequenced; have beenidentified. rvpe 2 disease 'ihe clinical madfestationsof the infantile form of GM, gangliosidosis(type 1 disease) may be evidenr in rhe newborn as edema, and skin eruptions (angiokerlrepatosplenomegaly, in atomata),It most ftequentlypresents the 1st 6 mo of life with psychomotottetardelayfollowed by progressive developmental A dation and the onset of tonic-clonrcseizures. wpical faciesis nasal a ears,frontalbosring. depressed characterized low-ser bv bridge, and abnormally long philrrum. Up to 50% of pacients and have a macular cherryred spot. Hepatosplenomegaly skeleof tal abnormalities similar to chose the mucopolvsaccharidoses, of including anterior beakingof the venebrae,enlargement the By sellaturcica,and thickeningof the calvarium,are present. the end of the 1st yr of life, most patientsare bhnd and deaf, with rigidimpairrnentcharacrerized decerebrate by severe neurologrc itv. Death usually occurs by 3-4 I'r of age. The juvenile-onset (type 2) is clinically distinct, r'ith a form of GM1 gangliosidosis variable age at olset, Affected parientspresentprimar y with ataxia, dysarrhna,mental refalneurologicsymptomsinclLrding may sur\ive Deterloration slowi pafienr( is darion. and spasticity. chroughthe 4th decadeof life. Theseparientslack the visceral and skeletalfeaturesseentn involvement.facial abnormalicies. There rs no specificffeatment for either form oI type 1 disease. GM1 gangliosidosis, in should be suspected The diagnosisof GM' gangliosidosis infanrs with typical clinical featuresand is confirmed by the activrty in demonstrationof the deficiencyof p-galactosidase Orher disorperipheralleukocytesor cultured skin fibroblascs. ders that sharesomeof the featuresof the GM1 gangliosidoses tvpe I), I-cell include Hurler disease(mucopolysaccharidosis (NPD)typeA, whrchcaneach disease disease, Niemann-Pick and enzymatic by of be distinguished rhe demonsrration their specific deiiciencies. Carrrersof che disorder are detectedbv the measuremenrof the enzvmaticactrvitv in white blood cells or cul-

<L30 mg/dl or, more ideally,<110 mg/dl. There is no reasonto for push LDL levelslower as is recommended high-risk adults'

2004tl60421429 D e l o n s h \ , O s e L , s r a m o s i l . e t i l : f f f c a c y a n d s a f e wo f ' t a t i n t h e r a p vr n Crcularion hvpercholesterolemia. wirh familial .ttitai.n 2002;1Q6:2231-2237. obesitv screeningin Demerath E, Muratova V SpanglerE, et al: School-based ral Appalachia.Preu Med 2003;37.553-560. J Durringron P, Dyslipidaemia. Lancet 2003;362:717 37 coadminiscoldberg AC, Aditi S, JLL, et at: Effcacy and safety of ezecimibe A tered with simvastarinin Patinrswirh Primary hyPercholesterolemia: ranMavo Clift Pto' domized, double-blind, placebo controtted vl:.l 20O4t79:520-629crundv SN{. Hansen B, Srnith SC, er al: Clinrcal managemenroI metabolic syndrome:ReporcoI rhe American Heart Association4'{anonalHeart, LunB, Itlood Instrtute/American Diabetes Association Conference on kientific IssuesRelated ro ManagemerJ:.Circul|tioll 2004;109:551-556 risk in familH ins PN, Heiss G. Ellison C, et al: Coronary arrerv disease cornbrned hyper)ipidemia and famitiat hvPrtriglyceridemia, A case control comparison irom the National Hean, Lung, and Blood Insricure

Gmet 2004;66:483487. Merkens LS, Connor WE, Linck LM, et at: Effecrsof dietarl cholesterol on plasma lipoproterns in Smith-lmli-OPitz syn&ome Pediat Res 32. 2O04l,56:726-7 Raitakari OT: Arrerial abnormalities in children with familial hvpercholesftrcmi?, Lan et 2004\363:342-343 Sinshal A, Cole TJ, Feffirll M, et al: Breast milk feeding and lipoProrcin born pretermr Follow up of a prospectiverandornized profile in adolescents st)d\. Lan et 2O04i363,1571-157 8. wiesman A, Hultn BA, de Groot E, et al: Effcacy and safetvoI stat rherapv in children wrth familial hypercholesterolemia,fAMA 2004;292: 1-331

and M. Margaret McGovern 86.4.LlPlDosEs. J, Bobert Desnick

each drsorders are diseases diverse lipid storage fhe lvsosomal leading hydrolase of de6ciincy a lysosomal due to an inheriLed particular sub_ to che lysosomalaccumulationof the enzyme's and of strate(iable 85-15). With the excePrion Wolman disease cholesterolester storage disease,the lipid substratesshare a common structurethat includesa ceramidebackbone(2-N-acylby are sphingolipids derived .ohineosine) trom whichrhevarrous phorphorylcholine. oneor moresiahc or of subrriuLion hexose", acid residueson the terminal hydroxyl gror:p of the ceramide

5S4

PABT X

Metabolic Diseases

ft(]MEN(LATURE MUOLIPIDOSTS l u r o l ) o 5 e,!l r r d 5 E i i e d l rlu.ord.r5i Llj5tudo llr4e: p i uao $!! t

TNZYMI DFIIO q ,'[Aaeiyrr05ar ]hcjphotrrn!L:ri$ l+l ry /i AieiI,lr(Diarf y Jfl];l]hotr:riarri5c L+l

l+l

i+) (+)

SPtlll'lG0LlPlD0StS fubr/Cie25e d Gad(1c5d;\e fdderdrase tetaTt iiie 6i datl]ra d.rJ t s a a a c r o s L lCsLa d r ? ar! d 6^r,g:qq .idcris Faaictosiar\i (T;y 6Mrgirg 05dcsi5 5irh5 drseaeq!ardh0'i lexcsarn nida5aJA I ari P 0r5edsei (' u.c(ercbm5il.5. [,rucher rlpe ourcrerubrc5 i 5.' iaurl.:rlyp3 durocePl]rl]\d;!! N e n d n)r r ( r ) - p .i = A & B ) .a:e )Prr fq0mle r,,lcta.hrcn.: | .Ll.di5trph! Ary sullirta5. A p 6; airi]iertr'lddr.. UPtDST0RAGE Dt50n0tnS N l e r d nP ( k l F L 1 = i & D ) n l !io man disea!e (p'cd |olir{ n05,5,infdnth ItrntayJox flantal ('i0 d pofLrn !,h:e fiinte(lanskl nir Be5rhlr!i5[y) a?r0 ipofL.( !.iuvenie d r,(r iSpieFr?yef' 'rcqt) ri G m di p o l u l r n c r j . ; d(rr i j , f u r / j nfrrelu;rahr cnr,o ran5p()rt Ai il piie ([.N]i Pa iol !r1r1: oE5tnre fl frh p..nid (l:L\l) Papt3iin in5erjlire fue ( tr,irni5 t nhiCi-N5l.lrke) 1 ( i L N T l . a ra i a L \ , 6 ) h ii protein lLfll,rembrane (lN4, prabablyerD1rerroLr! t r5parryJianr nare !

{+;

i+i

]r + +
I

1+ 1+) (+) l+)

#

(+l + 1+l + + +
.

+ +

(a)

+ +

1+) l+) + l+ + 1+i i + N + t (+) i*) (-) +

(+l

l+) l+l
(+)

0LtGosA(ftARtD05ts
qur ArpJrlylE Lrici:m a Furc!rdoit 3 i{;nioidor ! )[i ndErd 5ear? lir fti51 5ii ccisI

0 lVafn,rldJjs d-lfAcetilqi icrjrn r ii,e 5r;rda5i 5r;rdar.'

nrrtlsln,

1+l 1+l l+t l+l +

+ + +

+
f . -

l+) +

+ rn.re.lt+,me_ p iisnl,[+1, n:rnrtrr fi'rilllg ile: n_ad5fi(t r.u n l tA(.,i t.tiim riq)r;rt |,1td1?dflNof-dn[:tilh.0$L,l5(hNk!],etaJido,eL]]0,d4/il,

tur-e(lskin hhrobLastsrprenatal dragnosis is rccourplishc.l by (leterlninationoi thc cr)zvDa acfir.it,v ctrlrurcd.rrlrlocr tes or nc in .horioric \rllrI t i i 1 l l 1 i , i t r i : r i r ' l S r L l l l S ! 5 h e ( i N 4 1 a r g l i l l s i c l o s . ' s l r L c hI a r I g i c Sachsdiscese.rrrI Sandhoff discasc:clch risults irorn th(- Llcfi ctenc! ol [3 hcrosarrriDiclaseacriv]tv end t hc 1r-sosorrel ac(urlrLr|rLron (i\'12 galgiiosides, pirticulirlr rrt rhe ccnnal or nervoLrs s\stenl. Eorh disorders have becn ci.rssifierl rnto irtilrtile-, jrLvenile. and adulf onser fi)frns barcci on fre aqe at onset flnd clinical fcanrres. B llerosaminicl;rsc ().cLlrs rs ttv() isoz-vrues: hcxosarnirritlase r,r'hich cornposcrlof ole u and A, is B one li s b nir, an.l B herosarninrclase rvhich hrr t.r,o J3sub, ll, Lr ifs. F Hexosamiljrlasc dcficicncl lesLrlts from nrirr:rtiorrs thc i n subul)itard causcs'lrri,Sirchs clisease, rvhcre:rs nrurrrrions tlre rr of B srbuLritgelc rcsult ir the rle6cielc,v both p lrcrosr lrinril:rscs A ald B :rnd ceuse Sandhoff diseasc. Borh rre aLrfosonr.rl rccc! silc rr:rits, u,rrh T.ry-Sachs discasc harrng a preclilccrionrl rhe

.\rhkelazi jcwish popLrlunon, wherc rhc cerrier tiequcncv is r Lrour1/25 l\'1orerhan i(l rLrtarols have beel iclentifiedint(rsr.rre :tssr) .r.rtcd rvirh rhc iLrfenriLc forurs oI cliseasc.lhr.ec rrurrtiors irc.oLrnr >.lSll; of nrutarltallelesarnong Ashkc razi ]crvishcar for r icrs of la.v-Sachs discirsc. rrclurlng one allclc assocrarecl lvrrh rhc lclrrlt olser forrr. \'ftLterLons that carrse the subacutcrrr chroLrrc krrnrs result il enzy.nre enzrrrrrtic aerrvi l)r()tcinswifh residrLal t r ' , . t l r c I . \ , , " r r r 1 . ' . r ' r r c l r trc, , i r r h s r r t r r r . , l r , d , r . r * . h l)arcrts rvith rhe irlannlc form of Ta1'Sachs.listasc hrr.. clinical manilestationsrn rLriercy of loss .ri not()r skll1s,rncreasecl s(rrtle re.tction. and rllecular paLloratrclretinal chcrrv red spots i u i s c cT a b l e8 6 1 6 ) . A f i e c t . ' J n i a n L s s u a l l ,r, l c v e l r pn o r r n a l l yr , r r n l 4 j rno oi erc rvhcn decreased evc corltocl lt1ld aD exi!,ftcrxteLi sr.rrrlcrcspor;c to noise thyperacusis) erc lroted. Macr-ocephaly. nor rssociaredlvirh hvrJftrcephalus, nrry rlevelop.ln rhe Lrrd ur ol lrle. seiztrres requlrine rnlicorvu)sant rherapv dcvclop. \cLr rodegencratioris fclr'rrlcss,wirh Jearh occltrlng by rhe agt'o14

in ChaflErt6 r Dstocts Met.bolismol Lipids . 595

p
g a l - NAcgalla NANA

Neuraminidase --------> + gal- NAcgal ceramide

Polysialogangliosides

T
PC-ceramide Sphingomyelinase gal -

A B-Hexosaminidase i|ooars S8ndhofi,and others)

- glc-ceramid 9al I NANA

I Gmganglioside neuraninidase
I *
glc-ceramide

disease Niemann-Pick

p-galactosidase Lactosylceramide gangliosklosis, K.abbe disease

given wrth the name Flgure 86-15. parhways in the maabolism of sphingolipids found in nervous tissues.The name of the eruyme caralyzing each reaclion is is defect or deleccs Siven in lhe nearest of the subsrrace acredon. Inborn errors are depicted as bars crossing cbereacdonsarrouts, ar'd the narne of the associated a compound. 6on. The gangliosidesare named eccording to che nomenclarureof Svennerholm.Anomeric configurations are gtven only ar the largest staning NANA, N-acetvlneuraminic acid; PC, phosphorvlcholine cal, gabc;s] glc, glucose;NAcgal, N acerylgalactosamine;

with alaxia and form initially presents or 5 yr. The iuvenile-onser with a macula! cherry red dysaithria and may no! be associated spo!. are of The clinical manifestations Sandhoffdisease similar to

beforethe initiation of pregis nazi Jewishdescent recommended nancy to identify couplesat risk. Thesestudiescan be conducted A by the dererminationof the levelof $-hexosaminidase aclviry to or in peripheralleukocytes plasma.Molecular studies identify the exact molecular defect in enzymaticallyidendfied carriers should also be performed to permit more specificidenrification m of carriersin the family and to allow prenaul diagnosis at-risk couples by both enzymaticand genotypedeterminations.The has of disease beenmarkedly reducedsince incidence Tay-Sachs programsin the Ashkenazi the introduction of carrier screening may be possibleby meapopulation.Newborn screening Jewish markers. suring specificglycosphingolipid liptdosischaris This GAUCHER DISEASE. disease a multisystemic and skeletal acterized6y hematologicproblems,organomegaly, involvement, rhe laner usually manifestingas bone pain and

cartrer disease, A and B determination,Indeed, for Tay-Sachs in screening all couples which at leastone memberis of Ashkeof

596r PARTXr Motabolic Diseases

c r p p p p fuc- gal- NAcglc- gal- glc- ceramide l" I

NAcgal BloodgroupA glycosphingolipid .t-galactosaminidase NAcglc- gal-glcceramide

fuc- galt^

NAcglc- gal-glc-

q-galactosidase -ceramide fuc-gal-

gal

diseaso I Fabry I group glycosphingolipid Blood B

I etooosrouposty""-:-i,j::3flfJ:
galNAcglc- gal- glc-ceramide g-galactosidase

NAcAal- gal- gal-glc-

'

ceramide

A and B _Lq-hexosaminidase gangliosidosis GM2 (Sandhoff )

I cnmsroe

NAcglc

T
I

GMIgangliosidosis

gal-

glc-ceramide

-]jj"'""rT!I
galgalTrihexosylceramide a-galactosidase ---_l glc-ceramide gatl--------------r-

8)

gangliosidosis, GMa certain types

gtc-ceramide p-galactosidase Lactosylceramide gangliosidosis, GM1 Krabbedisease

ganglioside GM3 neuraminidase NANA d g p gal-glcceramide

glc-ceramide

Sphingomyelinase Pc-ceramide--_-_-] l--------------+ceramide Niemann-Pick disease

+ sphingosine fattyacid

drseas"1 IT",b",

Figure 86-16. Parhways in the degradarion of sphingolipids found rn visceral organs ,nd red or whire blood cells. Seealso the legend for Figure 86-15. Fuc, fucose;h-Acglc, l-- acetylglucosamine.

juvenileor Norrbotcnianform. All are aurosomal recessive traits. Type 1, which accou tor 99lo of cases, a striking predilecnts has tion for Ashkenazi of Jews,with an incidence about 1/1,000and a carrrerfrequencyof 1/18. Gaucherdisease resultsfrom the deficientactivrtv of the lvsosomalhydrolase, acid p-glucosidase, which is encodedby a gene locatedon chromosome1q21-q31.The enzymaticdefecrresufts in the accumulationof undegraded glycolipid substrates, particularly glucosylceramide, cellsof the reticuloendolhelial in system. This progressivedeposition results in infiltration of the bone marrow, progressive hepatosplenomegaly, skeleral and complications. Four mr:tadons-N370S, L444P, 84insG, and IVS2account for =957o of mutanr allelesamong AshkenaziJewish patients,permittingscreening this disorderin this population. for Genotvpe-phenotype correlations have beennoted, providingthe molecular basisfor che clinical heteroseneity seen in Gaucher disease rype l. which has a wide rangeof ieverityand agear onset, Patientswho are homozygousfor the N370S muration

tend to have later onset, with a more indolent course than patients with one copy of N370S and another common allele. Clinical maoifestations of type 1 Gaucher diseasehave a variable age at onset, from early childhood to late adulthood, with most sympromatic patients presenting by adolescence. At presentation, patients may have bruising from thrombocytopenia, chronic fatigue secondary to anemia, hepatomegaly with or without elevated liver function test results, splenomegaly, and bone pain, Occasional patie[ts have pulmonary involvement at the time of presentatron. Patients presenting in the 1st decade frequently are not Jewish and have growth retardation and a more malignant course. Other parients may be discovered fortuitously during evaluation for other conditions or as part of routine examinations; these patients may have a milder or even a benign course. In symp[omatic padents, splenomegaly is progressive and can become massive, Most patients develop radiologic evidence of skeletal involvemenr, includrng an Erlenmeyer flask defotmiry of the djsral femur. Clinrcally apparenr bony involvemenr,which

. ir of ChaDter . D.tects ile{.holism Lipids 597 06 diagnosisis available by dererminationoI enzyme activity in chorionic villi or cultured amniotic fluid cells, Treatment of patients wirh Gaucher disease type 1 includes therapy,with recombinanracid l3-glucosienzymereplacement dase (imiglucerase).Most extraskeletal symptoms (organoby megaln hematologic indices)are reversed an initial debulking by infusion dose of enzyme(60 IU/tg) administered intravenous every other week. Monthly maintenanceenzyme replacement improvesbone structure,decreases bone pain, and inducescompensarory growth in affected children.A smallnumberof patients which is curarive have undergone bonemarrow transplantation, but resultsin significantmorbidity and mortality from the prolimited. cedure,making the selectionof appropriatecandidates Although enzymereplacement doesnot alter the neurologicprogressionof patientswith Gaucherdisease types2 and 3, it has patientsas a palliativemeasure, particularly beenusedin selected in type 3 patientswith severe visceralinvolvement.Alternative to the trealments,including the useof agentsdesigned decrease syrthesis of glucosylceramide chemical inhibition of gluby coslceramide synthase, are being evaluatedand efforts are also under way to developgenetherapyfor type 1 disease. (NPD}. NEIMANI{-PICK DISEASE The original descriptionof NPD was what is now known as type A NPD, a fatal disorder of infancy characterized failure to thrive, hepatosplenomegaln by and a rapidly progressive neurodegenerative coursethat leadsto form death by 2-3 yr of age. Type B is a non-neuronopathic form in observed childrenand adults.Type C is a neuronopathic that resultsfrom defective cholesrerol transport.All the subtypes are inherited as autosomalrecessive rraits and displav variable (see clinicalfearures Table86-15). NPD types A and B result from the deficientacrivity of acid sphingomyelinase, lysosomalenzymeencodedby a gene on a The defect results in chromosome (11p15.1-p15.4). enzymatic 11 the pathologc accumulation sphingomyelin, ceramidephosof a pholipid, and other lipids in the monocyte-macrophage system, of the primary pathologicsite.The progressive deposrtion sphingomyelin in the central nervous sysremresultsin the neurodegenerative cou$e seenin type A, and in non-neuraltissuein the manifestations type B, including progressive of systemic disease geneis lung disease someparients.The acid sphingomyelinase in sequenced, a variety of mutationsthat causetypesA and B and NPD are known. The clinical manifestationsand course of rype A NPD is by at unrform and is characrerized a normal appearance birth (ahhough rhe newborn period is sometirnescomplicated by prolonged jaundice). Hepatosplenomegaly,moderate lymphadenopathn retardationare evidentby 6 mo and psychomotor regression deathby and of age,followed by neurodevelopmental age,the lossof motor function and the dete3 yr. Wirh advancing rioration of intellecrual capabilities progressively are debilitating; and in later stages, spasdcityand rigidity are evrdent.Affected infanrs lose conract wirh their environment.In contrast to the stereotypedtype A phenotype, the clinical presentationand courseof patientswith type B disease more variable. Most are in of are diagnosed rnfancyor childhood when enlargemenr the liver or spleen,or boch, is detectedduring a roucine physical examination. At diagnosis,type B NPD patients usually have evidence mild pulmonary involvement,usually detectedas a of diffuse reticular or finely nodular infiltration on the chestradiograph, Pulmonarysymptonrs usuallypresentin adults.In most patients,hepatosplenomegaly particularly prominent in childis hood, but with increasinglinear growth, the abdominal procuand becomesless conspicuous,In mildly berance decreases affectedpatients,the splenomegaly may not be noted until adultmanifestations. hood, and rheremay be minimal disease pulmonarydiffusion caused ln somerype B parients,decreased by alveolarinfiltration becomes evidentin late childhoodor early affectedindividuals adulthood and progresses wirh age.Severely

A disease. charwirh Gaucher of Fisure86-17. Cellsfrom thespleen a pacient with glucocerebroside. spleen is shownengorged cell acteristic

lieence are normal. -The pathologic hallmark of Gaucher diseaseis the Gaucher cell in the reticuloendothelial system, particularly in the bone marrow (Fig. 85-17). These cells, which are 20-100 pm in diameteq have a characteristic wrinkled paper aPparance resulting from che presenceof irltracltoplasmic substrate inclusions. The cytoplasm of the Gaucher cell reacts strongly positively with the periodic acid-Schiff stain. The presence of this cell in bone martow and tissue specimensis highly suggestiveof Gaucher disease,although it also may be found in patients with granulocltic leukemia and myeloma. Gaucher diseasetype 2 is much lesscommon and does not have an ethnic predilection. ft is characterized by a rapid neurodegenerative course with extensive visceral involvement arld dearh within the 1st 2 yr of life. It presents in infancy with increased tone, strabismus, and organomegaly. Failure to thrive and stridor caused by laryngospasm are typical. After a several-year period of psychomotor regression, death occurs secondary to respiratory compromise. Gaucher disease type 3 presents as clinical maniIestations that are intermediate [o those seen in rypes 1 and 2, with presentation in childhood and death by age 10-15 yr. It has a predilection for the Swedish Norrbottnian population, among which the incidence is 1/50,000. Neurologic involvement is present but occurs later and with decreased severiry compared with type 2 disease.Type 3 disease is further classified as types 3a and 3b based on the extent of neurologic involvement and whecher there is progressive myotonia and dementia (rype 3a) or isolated supranuclear gaze palsy (type 3b). Gaucher disease should be considered in the diflerential diagnosis of parients with unexplained organomegaly, who bruise easily, have bone pain, or have a combination of these conditions. Bone marrow examination usually reveals the Presence of Gaucher cells. All suspected diagnoses should be confirmed by determination of the acid p-glucosidase activity in isolated leukocrtes or cultured fibroblasts. The identification of carriers can be achieved by enzymatic assa5 wirh confirmation of results by molecular resting in most Jewish families. Testing should be offered to all family members, keeping in mind that heterogeneity, even among members of the same kindred, can be so gleat that nonsymptomatic affected individuals may be diagnosed. Prenatal

598 r PAnTX r Mebbolic Diseses may experience significant pulmonary compromise by 15-20 yr of age. Such pacients have low PO2 values and dyspnea on exertion. Life-threatening bronchopneumonras may occur, and cor pulmonale has been described. Severely affected patients may have liver involvement leading to life-threatening cirrhosis, portal hypertensron, and ascites, Clinicall,v significant pancytopenia due to secondary hypersplenism may require partral or complete splenectomy; this should be avoided if possible because splenectomy frequently causesprogressron of pulmonary disease,which can be life-threatening. In general, type B patients do not have neurologic involvement and have a normal IQ. Some patients wirh type B diseasehave cherry red maculae or haloes and subtle neurologic symptoms (peripheral neuropathy). Type C NPD patients often present with prolonged neonatal yaundice, appear normal for 1-2 yr, and then experience a slowlv progressive and variable neurodegeneratlve course. Their hepatosplenornegaly is less severerhan tbat of patients with types A or B NPD, and the-v may survive into adulthood. The Lrnderlying biochemical defect in type C patients rs an abnormality rn cholesterol t.ansport, leading to the accumulalion of sphingomyelin and cholesterol in their lysosomes and a secondary parrial reducrion in acid sphingom,velinaseactivi!y (see Chapter 8 6 . 3) . In type B NPD patients, splenomegaly is usually the 1st man ifestation detected. The splenic enlargemenr is noted rn early childhood; however, in l'ery mild disease, tbe enLargement ma,v be subtle and deteccion may be delayed untrl adolescenceor adulthood. The presence of the characceristic NPD cells in the bone marrow aspirates supports the diagnosis of type B NPD. Parients \.rth type C NPD, however, also have extensive inliltration of NPD ceLls in the bone marrorv and, thus, all suspected cases should be evaluated enzymatically to confrrm the clinical diagnosis by measuring rhe acid sphingomyelinase acrivity level in peripheral leukoc,vtes,cultured fibroblasts, or lymphoblasts, or a combination of rhesecells. Parients with tvpes A and B NPD have e w m a r k e d l l d e c r e a s e ld v e l s( l - l 0 " i , r . w h e r i a s p a r i e n r s i r h r u p e C NPD have someu.hat decreased acid sphingomyeJinaseactivilies, The enzymatic identification of NPD carriers is problemaric. In families rn which the specific molecular lesion has been iden tified, ho\a.ever,family members can be accurately tested for heterozygote status by DNA analysis. Prenatal diagnosrs of types A aod B NPD can be made reliably by the measurement of acid sphingomvelinase activif_y irt cultured amniocytes or chorionic villi; molecular analysis of fetal cells can provide the specific diagnosrs or serve as a confirmatory test. The clinical diagnosis of qvpe C NPD can be supported by the demonstration of filipin stain positivicy in cultured libroblasts and./or by idendfying a speci6c mutation in rhe NPC gene. There is no specific treatmert for NPD. Orthotopic liver transplancation in an infant with type A disease and amniocrc cell transplantation in several type B NPD patients have been atrempted rvirh little or no success.Bone marrow ttansplantation in a small number of trpe B NPD patients has been shown to be rn successful reducing rhe spleen and liver volumes, the sphingomyelin content of the liver, rhe number of Nlemann-Prck cells in the marrow, and radiologically detected infiltration of the lungs. ln one patient, horveve! liver biopsies taken up to 33 mo post transplantation showed only a moderate reduction in stored sphingomyelin. To date, lung transplantation has not been performed in any severelv compromised patient with cype B disease, although two patients who underweflt whole lung lavages with variable results have been reported. Future prospects for treatment of rrpe B diseaseinclude enzyme replacemenr and gene therapy. Treatment of rypes A and C disease is presently precluded by the severe neurologic involvement, FABRYDISEASE, This condition is an inborn error of glycosphingolipid netabolism characterized by angiokeratomas (relangrectatic skin lesions), hypohidrosis, corneal and lenticuLar opacines! acroparesthesias,and vascular disease of the krdnel', hean, and/or brain (seeTable 86-161. The drseaseis an X-linked recessrve trart tha! is maflrfested in affected males and has an estimated prevalence of =1/40,000 males, Later-onset affected males with residual c-galactosidase A activity may present with cardrac and./or renal diseaseincluding hyperrrophic cardiomyopathy and renal failure. Heterozvgous females for the classrc phelotype can be asymptomatic or as severely affecred as the males, the vari abihtv due to random X-i[activation. The disease results flom the delicient activity of cr-galacosidase A, a lysosomal enzyme encoded by a gene located on the long arm of the X chromosome (Xq22). The enzymatic defeccleads to the systemic accumulation of neutral glycosphingolipids, primarily globocnaosylceramide, particularly in the plasma and lysosomes of vascular endothelal

tion, leading to the major diseasemanifestations. The CDNA and genomic sequences encoding c-galactosidase A have identilied more than 200 differenr mutations in the d-galactosrdaseA gene that are responsible for this lysosomal storage disease,including amrnoacid substitutrons, gene rearrangements, and nRNA splicrng oetecls, Affected males with the classic phenotype have the skin lesions, acroparesthesias, hypohidrosis, and ocular changes, whereas males wrth the later onset phenotypes lack these frndings and present with cardiac and/or renal drsease rn adulthood- The classic angiokeratomas usually occur in childhood and ma,v lead to early diagnosis, They increase in size and number wirh age and range from barely visible to several mm in diameter The lesrons are puncta[er dark red to blue-black, and flat or slightly raised. They do not bJanch with pressure, and the larger ones may show shght hyperkeratosis. Characteristicall]', the lesions are most dense between the umbilicus and knees, rn the "bathrng trunk area," but may occur anywhere, incLrding the olal mucosa. The hips, thighs, buttocks, umbilicus, lower abdomen, scrotum, and glans penis are common srfes, and there is a tendency toward symmetry. Variants without skin lesions have been described. Sweating is usually decreased or absent. Corneal opacities and characteristic lenticular lesions, observed under slit-lamp examr nation, are present in affected males as well as in =707. of asl'mptomahc heterozygotes. Conjunctir.al and retinal vascular tortuosity is common and results from the systemic vascular tnvolveme11t. Pain is the most debilitating symptom in childhood and adolescence. Fabry crises, lasting from minutes to several da-vs, consist of agonizing, burning pain in the hands, feet, and proxi mal extremiries and are usuall,v associated with exercise, fatigue, fever, or a combination of these facrors. These painful acroparesthesias usually become less frequent in the 3rd and 4th decades of hfe, although in some men, they may become more frequent and severe.Attacks of abdominal or flank pain may simulate appendicitis or renal colic. The major morbid symptoms result from the progressiye involvement of the vascular system. Early tn the course of the disease, casts, red cells, and lipid inclusions with characteristic birefringent "Maltese crosses" appear in che urinary sediment. Proteinuria, isosthenuria, and gradual deterioration of renal functron and development of azotemia occur in the 2nd through 4rh decades. Cardiovascular findings may include hvpenension, left ventricular hvpertroph,v, anginal chest parn, myocardral ischemia or infarction, and heart failure. Mrrral rnsufficiency rs the most common valvular lesion. Abnormal electrocardiographrc and echocardiographic findings are common, Cerebrovascular mani festations result from multifocal small vessel rnvolvement. Other features maf include chronic bronchitis and dyspnea, lym phedema of the legs without hypoproteinemra, eprsodic diarrhea, osteoporosls, retarded growth, and delayed puberry Death mosr often results ftom uremia or vascular diseaseofthe heart or brain.

ol Chatter86 . Delscb in Metabolism Lipids r 500 Before hemodialysis or rena transplantation, the mean age at death for affected rnen was 1yr' Later onset cardiac varianis with resrdual u-galacrosidase A activiry have cardiac diseaseand may have mild proteinuria but usually have normal renal func tion for age, Thi cardiac manifestations include hyperrrophy of the left ventricular wall and interventricular septum, and elechic abnormalities consislent *ith cardiomyopach,vtrocardiog had hypertrophic cardiomyopathy or myocardial Others ha and prenatal diagnosisare possibleby deteridentificationsrudies mination of the enzymacicaccivity. SCHIN0tERDISEASE. This is an aLrtosomal recessrveneurodegeneratrve disorder that results from the defrcienr accivitv of q-Nand acetylgalactosaminidase the accumulation of sialylated and (seeTable 86-15). The asialoglycopeptides and oligosaccharides gene for the enzyme is mapped to chromosome 22 (,22913.1-1.3.2), The diseaseis clinically heterogeneous,and t',,r'o major phenotypes have been identr6ed. Type I diseaseis an mfanlile-onset neuroaxonal dystrophy. Affected infants have normal development for the 1st 9-15 mo of life followed b,va rapid neurodegenerarive course that resuhs in severe psychomotor retardaoon, corcical blindness, and frequent myoclonic seizures. Type l[ drsease characterizedby a variable age al onset! mrld retaris dation, and angiokeratomas. There is no specific therapy for eicher form of the disorder, The diagnosis is by demonstration of the enzymatic deficiency in leukocytes or culcured skin fibroblasts(MLD). This is an autosomal METACHR0MATIC LEUK0DYSTR0PHY recessivewhite matter disease caused by a deficiency of arvlsulfatase A (ASA), which is required for the hydrolvsis of sulfaced gl,vcosphmgolipids. Another form of MLD rs caused b,v a deficienc;r of a sphingolipid actrvator protein (SAP1), rvhich is required for che formation of rhe subsffate enzyme complex. The deEciency of this enzymatic activiry results in the white marter storage of sulfated glycosphingolipids, which leads to demyelination and a neurodegenerative course. The ASA gene is on chromosome 22 (22q13.31qter);specificmutations are knou'n to fall inro rwo groups rhat corlelate with diseaseseverity, The clinical manifestatiors of tbe late inlantile form o{ MLD, which is most common, usually presents between 12 and 18 mo of age as irritabilitJ', inabrlity to walk, and hyperextension of the knee, causinggenu recurvatum. Deep tendon reflexesare diminished or absent. Gradual muscle wasting, weaknss! and hypo tonia become evident and lead to a debilitated state. As the diseaseprogresses,nystagmus, myoclonic seizures,optic atroph;', and quadriparesis appear,wirh deachin the 1scdecadeof life (see Table 86-16). The iuvenile form of the disorder has a more indolent course with onset rhat may occur as late as 20 yr of age- This form of the diseasepresencsas gait dJsturbances,mencal deterioration, urinary inconrinence, and emotionat difiicultres. The adult form, which presents after rhe 2nd decade, is similar to the juve nile form in its clinical manifesrations, althou8h emotxtnal difficulries and psychosis are more prominent features. Dementia, seizures,diminished reflexes, and optic atrophy also occur in both rhe juvenile and adult forms. The pathologic hallmark of MLD rs che deposition of metachromatic bodies, which stain strongly positive with periodic acid-Schiff and alcian bLue, in rhe whrte matter of the brain. Neuronal rnclusions may be seen in the midbrain, pons, medulla, recina, and spinal cord; dem,velination occurs in the peripheral nervous syslem. Bone marrolv ttansplantation has resuhed in normal enzymatic levels in peripheral blood buc no clear evidence for clinical efficacy in terms of che neurologic coursei supportive care remains the primarv rntervenuon. The diagnosis of MLD shor,rldbe suspectedio patients with the clnical fearures of leukodvstrophy. Decreased nerve conduction velocities,increasedcerebrospinalfl uid protern, metachromatrc deposics in sampled segments of sural nerve, and metachromatic granulesin urinary sedrmenrare all suggestive MLD. Confir of marion of rhe diaenosis is based on the demonstracion of the reducedactivity of ASA in leukocyces cultured skin libroblasts. or Sphingolipid activaror protein deficiency is diagnosed by measuring the concentrauon of SAP1 in cultured fibroblasts using a specific antibody to the prorein. Carrier deteccion and prenatal diaenosis is available for all (orms of the dtsorder.

angiokeracornasof the scrotum (Fordyce disease)or from angiokeratoma clrcumscriptum. Aogiokeratomas identlcal to lhose of Fabry disease have been reported in fr.rcosidosis, asparryJglycosaminuna! Iate-onsecGMr gangliosidosis, galactosialidosis, crN-acetylgalactosaminidase deficienry, and sialidosis. Latel onse! variants have been rdentified among chronic hemodialysis pacients. Like the cardiac variants, these renal varianrs lack the early classic manifestations such as the angiokeratomas, acro paresthesias, hvpohidrosis, and corneal opaclties The dragnosis of classic and variant patients is confrrmed biochemicall,v by the A ct-galactosrdase activit,v of demonstrarron markedly decreased in plasma, isolated leukoryces, or cultured fibroblasts or lymphoblasts. Heterozygous iemales may h e corneal opacines, isolated skrn A lesions, and intermediate activi s of cr-galactosidase in plasma or cells. Rare female heterozvgotes may have manifestarions as severeas rhose in aifected males. Asymptomatic at-rtsk females in families affected by Fabry disease, however, should be optiby the direcr analysis of their family's specifrc mally diagnos mutarion. Pre tal detection of aftected males can be accom plished bv che demonsrration of defrcient o-galactosidase A activity or the family's specrfic Sene mutarion in chorionic villi obtained in the ls! trimester or in cultured amniocltes obtained by amnrocentesisin the 2nd rrimester of pregnancn Fabry disease can potentidlly be dececred newborn screening. was once nonspecific and limired Tieatment for Fabry drse

of 1mg/kg er.ery other week. disorder caused This is a rare autosomal recessrve FUG0SlD0SlS. by the deficrent accivity of c fucosidase and the accumulation oi fucose-containrng glycosphingolipids, glycoproteins, and

type, with the most severely affected patients presentng rn the 1st yr of life with developmental delav and somatic fearures similar to those of the mucopol;rsaccharidoses. These features rnclude frontal bossing, hepatosplenomegall', coarse facial features, and macroglossra. The central nervous system storage results in a relentless neurodegenerative course, with deach in childhood- Patients lr'ith milder diseasehave angiokeratomas and longer survrval, No specific therapv exisrs for the disorder, which can be diagnosed bv the demonsrration of deficrent cr-fucosidase activity in peripheral leukocytes or culcured fibroblasts. Carrier

m0 r PARTXr MctabolicDiseases MUITIPLESULF SE DEFICIENCY This is an autosomal recessive disorder that results from the deficiency of three enzymaric acdvities: arlrlsulfatasesA, B, and C. Sulfatides, mucopolysaccharides, steroid sulfates, and gangliosides accumulate in the cerebral cortex and visceral tissues, resulting in a clinical phenotype with features of leukodysrrophy as well as those of rhe mucopolysaccharidoses. Severeichthyosis may also occur. Carrier testng and prenatal diagnosis by measLrrement ofthe enzymaric activities can be performed. There is no specific treatmenr for multrple sulfatase deficrency other than supportive care. KRABBE 0ISEASE. This condition, also called globord cell leukodysrrophn is an autosomal recessive fatal disorder of infancy. lt results from che deficiency of the enzymatic activity of galactocerebrosidaseand the whire matter accumulation of galacrosylceramide, which is normally found almosr exclusively in che myelin sheath. The galactocerebrosidasegene is on chromosome 14 (14q31), and specificdisease causing mulalions are known. The infantile form of Krabbe disease is rapidly progressive and patrerts present in early infancy wich irritability, seizures, and hypertonia (seeTabJe85-16). Optic atrophy is evident in the lst yr oI hfe, and mental development is severely impaired, As the diseaseprogresses,opcic arrophy and severe developmental delal' become apparent; affected children exhibit opisthotonos and die before 3 yr of age. A second, late infantile form of Krabbe disease also exisrs and patients present atter the age of 2 ;'r Affected individuals have a diseasecourse similar to thar of the earll, infantile form. Bone marrow cransplantation has been attempted in several patrents wirh later onset disease but without signifrcanc results, Umbilical cord blood transplantation of presymptomatic parients in the 1st 2 mo of life results in ensraftmenr and normal blood galactocerebrosldase levels. Developrnental milestones, cerebral myelination, and cognitive funcrion up co 3 yr of age have been near age-appropriate expectatrofls. Nonetheless, some patien!s demonsrrate mild ro noderate language delays and mild to severe gross motor deLavs.The diagnosis of Krabbe diseaserelies on the demonstration of the specrficenzymaric defrciencv in u'hite blood . e l l s , , , rc u l t u r e ds k i n f i b r o b l a s t r C a r r i e r i d e n t i f i c a r i o a n d p r e . n natal diagnosis are available. FABBER DISEASE. This is an aulosomal recessive disorder that results from the deficiency of the lysosomal enzyme ceramidase and the accumulation of ceramide in various tissues, especially rhe joints. Symptoms can begin as early as the 1sr yr of life with painful jornt srvellingand nodule formation (Fig. 85-18), which rs sometimesdiagnosedas rheumatoid arrhritis. As che disease progresses, nodule or granulomatous formation on the vocal cords can lead to hoarsenessand breathing difficulties; failure to thrive is common, In some patients, moderate central nervous systemdysfuncnon is presenr(seeTable 86-16). Parientsmay dre of recurrent pneumonias in their leens; there is currently no specific therap,v-The diagnosrs of this disorder should be suspected in patienrs who have nodule formacion over the loints but no other lindings of rheumatojd arthritis. In such patrenrs, ceramidase activrt,v should be determined in cultr-rredskin fibroblasts or white blood cells. Carrier deteccion and Drenatal diaqnosis are available.

Figurc 86-18, Forerrm of an 18 rno old girl wich Farber disease.Note the painful joint sweiling and the nodule formarion. The infanr rvas suspected of having rheumatoid arthritis

There usr.rallyis hyperliprdemia. Hepatic dysfunction and Iibrosis ma,v occur. Calcification of the adrenal glands is pathognomonic for the disorder. Death usuallv occurs wirhin 5 mo. Cholesterol ester storase disease is a less severe disorder that may not be dragnosed un;il adulrhood. Hepatomegaly can be the only detecrable abnormaliq., but affected individuals are at significant risk for premature atherosclerosis. Adrenal calcilication is not a feature. Diagnosis and carrier identification are based on measuring acid lipase actrvity rn leukocyres or cultured skin fibroblasts. Prenaral diagnosis depends on measunng decreasedeozyme levels in cultured chorionic villi or amniocytes. There is no speci6c therapy available for either disorder, although pharmacologic agents io suppress cholesterol synrhesrs, rn combination lvith cholestyramine and diet modilication, have been used in patients with cho(seeChapter 86.3). lesterolescerstoragedisease

WOIMANDISEASE CHOI.ESTEROL STOBAGE AND ESTER DISEASE

(CESD). These are autosomal recessivelysosomal storage diseases that resulr from the deficiency of acid lipase and the accumulanon of cholesterol esters and triglycerides in hrstiocytrc foan cells of most visceral organs. The gene for lysosomal acid lipase is on chromosome 10 (10q24-q25). !(/olman disease !he more severe is clnical phenotlpe and is a fatal disorder of infanc,v.The clinical features of che disease become apDarert in the 1st rvk of life and include failure to thrive, relentliis vomiting, abdominal disten (see Table 86-16). tion, steatorrhea,and hepatosplenomegaly

Charrow J, Andenon HC, Kaplan P, et al, Enzyme replacemenrtherapy and monitorins for children wirh rvpe r Caucher d,sease:Consensusrecom mendations I Pediatr 2004;144:112 120. Clark JTR: Naiiarive revier': Fabry disease. An lflten Med 2007;1461 425433. Desnick Rl, Brady R, Barranser J, er al: Iiabry disease,an under recogr zed multi systemic disorder: Experc recommendadans ior diagnosis, manage ment, and enzvme replacemenr therapy. Arz lnten Med 2003.138: t38-345. Elstein D, Abrahamov A. Hadas Hrlpern I, et al: Cauchcr's .lisea,\e.Ldncct 2 0 0 1 ; 3 5 8 : 3 2 4j 3 7 Escolar ML, Poe N{D, Provenzale JM, et aL:Trarsplantarion of umbilicafcord blood in babies with inhntile Krabbet disease. N Ehgl I Med 2005i20:2069-2080. Johnsor V/G: The clinicat specrrum of hexosamrnidasedeiciency diseases. Newolosy 1981i3r tl4 53 1456. Kaplan B Andrson HC, Kacena KA, Yee JD: rhe clinicaLand dcnographic characrerisrics nonncuronpathic Gaucherdisease 887 children ar diagof in nosis Arch Pedidtl A.lolesc Med 20O6;16U603-608 Meikle PI, Ranien E. SimonsenH, et al, Nervborn screeningtor lvs(xomal srorage disorders: Clnical evalDation of a rrvo tier straregl Pedidrr.s 2004i114:909-916 Mistry PK, Abraharnov A: A practical approach ro diagnosisand manasement of Gaucher'sdisease.Baillieres Clin Hdenatol I997;I0:8] .-8l8

r It ol Chapler r oelectsir Metabolism Carbohydrates 601

SchuchmanEH, Desnjck RJ, Types A and B Niemann Pick drseaseln Scriver CR. Beaudet AL, Sty rWS.er al leds)t The Metabolic and Mole.ulat Bases of lnherited Dsease, 8rh ed. New York, Mccraw Hill, 2001 Wilcox wR, BanjkazemiM, Guffon N, et al: Long rerm safetv and efficacvcf enzyme replacement therapy for Fabry djsease. Am I Hun Cenel 20O4t7 5-74. 5;6

. M. Mar$aret McGovern 86.5 Muc0LlPt0osEs. J. andRobert Desnick

and pseudo-Hurler polyI-cell disease (mucolipidosis II [MLl!) dystrophy (mucolipidosis III IML-IU) are biochemically related' rare autosomal recessive disorders that share some clinical fea-

activities. The enzyme that catalyzes the lst step, the UDP-N-

enzymatic levels in cultured skin fibroblasts. Direct measuremenc of the phosphotransferase accivitv is possible. Prenatal diagnosis and carrier identificaoon studies are available for both disorders by measurenent of lysosomal enzymaric activities rn cultured cells. Neonatal screening by tandem mass spectroscopy may detect I-cell disease. l-CEtt DISEASE. This disorder shares many of the clinical manifestations of Hurler syndrome, although there is no mucopolysacchariduria and the presentadonis earlier (seeTable 86-16). Some parienls ave clinical features evident ar birth, including coarse facial fe ures, craoiofacral abnormalities, restricted joint movement, and hypotonia. Nonimmune h1'drops may be present in the fetus. The remainder of patients present in the 1sr yr wich severe psychomotor retardation, coarse facial features, and skeletal manrfestations that include kyphoscoliosrs and a lumbar gibbus. Parients may also have congeniral dislocation of the hips, inguinal hernias, and gingival hypenrophy. Progressive, severe psychomotor retardation leads to death in earlt' childhood No lreatment is available. Pseudo-Hr-rrlerpolydystrophy PSEUD0-HURtEFP0tYDYSTR0PHYis a less severe disorder than I-cell disease,with later onset and survival to adulchood reported. Affected children may present around the age of 4 or 5 yr wich joint stiffness and short starure.

Carbohydrate synthesis and degradation provide the energy required for mosr metabolic processes.The importanr carbohydrates include three monosaccharides-glucose, galactose, and fructose-and a polysaccharide, glycogen. The relevant brochemical pathways of these carbohydrates are shown in Figure 87-1. G|,rcose is the principal substrare of energy melabolism, A conrinuous source of glucose from dietary mtake, Sluconeogenesrs, and glvcogenolvsis of glycogen maintarns normal blood glucose levels. Metabolism of glucose generates adenosine triphosphate (ATP) via glycolysis (conversion of glucose or glycogerr to pyruvate), mitochondrral oxrdative phosphorylation (conversion of pyruvate to carbon dioxide and water), or both, Dietary sources of glucose come from ingesting polysaccharides, primarrlv starch and disaccharides, including lacrose, maltose, and sucrose. Oral intake of elucose is rntermirtent and unreliable, Glucose made de novo from amino acids, primarily alanine (gluconeogenesis) contribures to maintarning the euglycemic state, but this process requires time to be acrive. The breakdown of hepatic glycogen provides the rapid release of glucose, which mainrains a constanc blood glucos concentratlon. Glycogen is also the primarv stored energy source rn muscle, providing glucose for muscle activity during exercise. Galactose and fruc!ose are monosaccharides rhat provide fuel for cellular metabolism; their role is less significanc than chat of glucose. Galactose + rs derived from lactose (galacrose glucose),which rs found in milk and milk pruducrs.Calactoseis an imporrant energl 'ource rn rnfanrs, but it is 1st merabolized ro glucose. Galactose (exogenous or endogenously synthesized from glucose) is also an important component for cenain glycolipids, glycoprotetns, and glycosaminoglycans. The dietary sources of fructose are sucrose (fructose + glucose, sorbirol) and fructose itself, lvhich is found in fruits, vegetables, and honey. Defects in glycogen metabolism rypically cause an accumulation of glycogen in the tissues, hence rhe name g/lcogen storage disease lTable 87-1). Defects in gluconeogenesisor rhe glycolytic pathway, includng galacrose and fruccose metabolism, do not resulc in an accumulation of glycogen (see Table 87-1). The defects in pyruvare rnetabohsm in rhe parhv-ay of rhe conversion of pyrr-:vate to carbon dioxide and water via mrtochondrial oxidarive phosphorylarion are more often associated rvirh lacric acidosisand some tissueglycogenaccumulation.

. . DTSEASES SToRAGE 87.1 Gr-vcocrr and Chen Priya Kishnani Yuan-Tsong S.

The disorders of glycogen metabolism, the glvcogen storage diseases (GSDs). result from de6ciencies of various enzymes or transport proleins in the pachways of glycogen metabolism (see Fig. 87-1). The glycogenfound in thesedisordersis abnormal rn quanrrq; quality, or borh. GSDs are calegonzed by numeric rype in accordance with the chronologrc order in which these enzymatic defects lvere identified. This numeric classification is still widely used, at leasr up ro number VlL The gJycogenstorage diseases can also be classi6ed bv organ inr.olvement and clinical manifestations into liver and muscle glycogenoses (see Table

ings include corneal clouding, retinopathy, and astigmatism; visual complaints are uflcommon (see Table 85-15). Some patients have learning disabilities or mefltal retardation. Treatmenr, which should include orthopedrc care, is symptomaric.

87-rJ.
Glucose-6There are more than 12 forms of gl,vcogenoses, phosphatase deficiency (type l), lysosomal acid cr-glucosidase deficiency(type Il), debrancherdeliciency(type III), and liver

6mr

PABTXT Metabolic Diseases

Debrancher

GSa=z csb
./'o*'

UDP-Glc

Galactos

1-P UridvllEnslerase

ll

otc-o ase

---__-_--. --- ,--_-_--t+ Phosphohexoseisomerase Fruclose_1,6 +J phosphotrucbkrnase o t p n o s p n a s er r F-1,.6-P, F-1-P<- Fruct l l +'l Aldolase Aldoiase 5.\G lyceraldehyde r ' <Glyceraldehyde-3-P Dihydrcxyacelone-P Phosphotrioseisomerase tl dehydrooenas ll Glyceraldehyde-3-P l,3.Bisphosphoglycerale kinase f{ ehosphostycerate 3-Phosphogiycerate Phosphoglycerate mutase ll 2-Phosphoglycerat

Glucose

fiBure E7 t- Parhlvav related to glyco gen storage dlseases and galactoseand tructose disorders GSa, aclive elvco gen synrhetase; CSb, inactLvefl,vcogen svntherase;Pa! actLve phosphorvlaser Pb, inactive phosphorylase;I'aI. phol phorylase a phosphatase;Pb(a. active phosphorylase kinase;PbKb, inacfive b phosphor,vlase kinase; G, glycogen, b rhe primer for glrogen synrhesis; UDP, uridine diphospharc; CLUT-2, glucose rransporrer 2; NADA,'ADH, nicoti namide-adenrne drnucleotide (l.Iodi fied from Beauder AR: Gly.ogen Kl, cr al slorage disease ln Isselbacher lcdsl Haltison s PtinctpLesof Internal Medi.ine, 13th ed. \ew York, McGraw-Hill, 1994 Rcprcduced \r ith permission ot The McGrarv-Hrll Companies.)

1+ Enoiase
Phosphonolpyruvale I Pyruvatekimse I Lactaledehydrognas _ Pytvale . Laclale .

*----Z'-\-

phosphorylase kinase deficiency (t-'-peIX) are the most common that rypicallv presenr in early childhood; myophosphorylase de6ciency (type V, McArdle disease)is the most common in adolescenrs and adults. The frequenc,vof all forms of GSD is =1/20,000 live births.

involved and may manifest as renal dvsfunction in type I and myopathy (skeletal and/or cardiomyopathy) rn types Ill and IV, as rvell as in some rare forms of phosphorylase kinase deficrency.

TYPE GLYCOGEN I STORAGE OISEASE iGLUCOSE,6"PHOSPHATASE 0RTRANSL0CASE DEFICIENCY, GIEBKE VON DISEASEI. I CSD Tvpe
i. caused hv rhe absenceor deficiencr oi gluco'e-o-ph,r'phata'c activity in the liver, kidney, and intestinal mucosa. It can be divided inro trvo subtypes: type Ia, in vr'hich the glucose-6phosphatase enzyme is defeccive;and rype Ib, in u'hich a translocase that transports glucose-5-phosphate across the microsomal membrane is defeccive. The defects in both tvpe la and rvpe Ib lead to inadequate hepatic conversion of glucose 6 phosphare ccr glucosechrough normal glycogenolysis and gluconeogenesis and make affected individuals susceptible to fastrng h,vpogl,vcemia. Tvoe I GSD is an autosomal recessivedisorder. The srructural gene for git cose 6 phosphatase is located on chromosome 17q21; the gene for rranslocaseis on chromosome 11q23. Common mutarions responsible for the disease are koown. Carrier detec

TIVER GTYCOGENOSES
The GSDs rhat principally affect the liver include glucose-5phospharase deficiency (type I), dehranching enzvme deficiency (type Ill), branching enzvme deliciency (t,vpeIV), liver phosphorvlase delicienc,v(t),pe VI), phosphorylase kinase deficiency (type IX, tbrmerly rermed GSD VIa), glycogen s,vnrherasedelicienc,v (type 0), and glucose transporter-2 defect. Because heparic carboh,vdrare merabohsm is responsible for plasma glucose homeoscasis, rhis group of disorders typically causes fasting hypogl,vcemiaand hepatomegalv. Some (rvpe III, tvpe IV, tvpe IX) caD be associaredu.ith crrrhosis- Other organs can also be

Chapter 87

D e f e c t si n M e t a b o l i s m f C a . b o h v d r a t e s o

0t50nDER5 L|vEn GtY(06E1.105t5 Type/Common Name 1.1\r,rn I erk tc lla/(or forber or

BI5I( OEFECTs

(urlrctt Pflt5tNTATj0N

(O/IIMENTS

a LriD5e 6 plrojcha.i5t 6-pl05chal? 1]t;5e trani a ucoie debranthefieF( enrl lyprird mL5c:e q i ; m !c . 1 , 5 l u ( 0 5 1 f t ! e l er L Y sd e b E n dd e l c e n a y , n o m . r aatv mi( een,ymi ty Erir.trg en2/,ie L! e ' p h o 5 p h o r y a 5 c kna5 Pf05phoryase e 6 /oqen!ynrhetaie I i6!tT ll 6 i.ose sporter rrd

0 VlAfda5ef ll er5 y l9ii !n{! PlLrjpho i5e k fa5e dPir 6li.cqenryr thelir5e rnq tan(cn B1: 5yndron-'

bloci rrarda0on,hepailrmeqd a;e :r,n,rrh l, hlpoglyen evrteC E5ftrcl,triq ur d(?le,(ra /c4de,anc i i( d eveh nnd 0l dnii !;nea5tipeh tr:haddr[00a rE5 neutroEnia npr re(] nerLnpf rdr0n llL hepJtcrrre_cal)'!rcvJth ru5(ewakre55, rrrrdaton :h dfl]nd eve5ver h]'poqy:em;,lylenpdema,elevsieolranlamina5e .nprcvewlm,rqe rymptcn; L y a5 t f r p l c f55 na s nl l p e l a ; f 0 m ue 5 y m o l o m 5 r id ? I

hlpo_q'yi?F] a [ormon,sererc l 0 %o l l l p e/ fornon,ntrmedate it/ 0fiypc!t(er a seve

l5%rlripe

proEe5\ Rlr neLfomu5iula, er!t varanl! f. ure -hr",a,h/iroronr;, I0 repalcriela!;5p errome,qdly, w r atl l ve5 a r f i h c i 5 l d e 5 , d' l y " e f o r c 5 l h y I ) , e l e v a r e d r ea n 5 a n r n r 5 e q yioqef05i ycnB.lyper [3.:,Denrqn n lJ hyiroq rpderia, kel0sl5 anc N.,p,Iomegdl,r qF f : o r m c f , b e no y ( t l e0 5 ! Heoatrn{r}n idi'rp0E kei[ icrD,lyffripide b,dnd \ Yer hypoqlycem [eto5i5 Dftredsed qy(ogen a,a 5tcre [aryr,irn1qdo\r5 ?fdf?tque,fa5tn! nesj .LlLld pancreas.and n lv.tk,lrel,, o :LtT I eipressed t o , r er - r , r . r .p ^ p p : ' . o r e q ) i l r ! )4 . e f a r ntetIn.. rpa and rti dydun(i0r rd q ur0se qaact05e atorr

6LYC06tt{05ts MUs(tr Typ./(ommon ilame

(icd Ardd q r(osdase ra ta5el k( A.do q uto5dd5ed |li tasel na A ( d oq J r i 5 l d s e ( i ( d l a 5 e l yjcScma melnDIaft al50taLe0 n irlole I ILAMPl) prore llVPa( \'ated r k'r?5e l \l)'opno5prorybr PIr!phlrfruftk n!!e Phir5phoqlycerdle k f a5e \l rubur 0tph05rhoq .nutare te lie'dle Mrub!rrcf 3ctate detyCmgemre urdylranft E5e 1-pf aalarlo5e o$hate i,rhftkndJe qa]:tlcre 4 d llIdrne pftspMie epTlera5e

(a,l0meg.t/'y0rlonrr,llep,rlorieit,rlt0n5elJTth 6 ro 0n5a l'1pp:rhI ab: .i rdonlcparh)"i thidhcod rdr nsuli(en(yicnleradulthood l'1!0palh\1re5pGor! fllrertropn i G(lrJm/ipdtrl (adr0lr y0rirt, flyce(lphL: fatgabi nxersed t,v :xer(!eI0ler;,ra,rrJ5ia(Irmp5 i e . F . 0 h . r , i r 0 [ Pl d ] d e 1 d . r/ o 0 l ' br ' o As ilir?,] wrrl' A lw r t i y c e t
1' . r1q("r-r-t J ."

qi]L t

Ddnon dl5edSe P R K A [e h ( e n q c] !/t1:Adle \il/T::ui Pho$hoql)'cerdtele']i?rq_ I nd!e mrraje enrl Phojphcql/aerdt ceh( nqsriiedeh:i?niI La(ire dehid DISORDtRS GAIACTOST avrth deh(1e1:y Gala(mJern t?15ferne dehferar Gid(okxaie il03 G?fftlzed d pi05r.dte !,lbilcie +epir!G5c efc! Cei( FNUOO5E DISORDERS truo.riLrri l55en.d

t0 i0m|Iaf,iird0r5pctor)"trc eading dedl]r Dy r yr age a F e 5 d ie? i y r e ( t l y rn F e j d , re n 4 re d a ( Y U d i { Farc,Inked Arlosoral ndnt Con: []mrai ralep',"i1]minan(e Pre$lentJipane5s Ashkenarle$l dnd in Rdre,X Inked FJre oltyotpalrentsA[ (znAme:ria,r ma arc Jre (an pateIlirifd lc have Afr Amercn fiilCe, synflcmJ B qr varant ei!s Abeniqn alsc

/.dtdi,dr'1d,d.'d.di.:

iatardr5 icd nq5 a ! r rri. trdf5fera5e en(lwlrh t 0nalfind ofhrpcmn lejii ;fd nerYicrafnet Llxna ! iLrbstan(e eiJi AC.re I fg,rwe;r mJqy rom ! \epatr( .lle ure.n fai ahrcni.:fd thrre,

3enon )roqnc5 {l.h truitose 5q00d rcitrctiorl d ta5tnc tcc0proq105r,avc Rai?

dcare FrJiroir-l-plosc[ale,r rl] H e i e d . r i l l r u f trs e e r i n c e 0t GtU(0Nf Ntsls off DtSonDERS enq deh( F((ore I 6 drpho5phatd5e 0 pyevate crblxl 1iiedehtieltl Ph0sphoef MITABOTISM Of PYRUVATE DISONDERS (0n dihldrcqer;se pet defe.t ryruvile Grbrrlirccefief.l ry vaie lerpifttor)" I d.fet5hx dit!e dl; cros!horili:orjea\!) I MTTAEOTISM DIsOROERS IN PTI'/TO5E r;n!aldcb5e deF(re1ay ltner?Je deh(re1iy 1bo5e phcrphaLe ; slrita5e L xtu o5e Trif!alloaie RbirPr ixc5phare 5ornerdse

j a,apner,aodl]j [p iodr hypoqlt(en Fru.r$E 1,6-dphctph;Ieie a,fd,ure thlve tD Hipnq Piosphoenclpyruvale.itortkrna5e yirn i, fapdlcmPga i iripoton PyrLViredehydruqenr5e fltv;tP car00rya5e (crnp ItoV:mafy toooldra er rl DllA nurar!fi

y drr recnai, r ld itiorrt, a(t,cardo5is,psyclornotor\fon(cn'mon to[] o lhrnrt,d.fert]i rkei !eie.a'ati ir r c L l r c a l c n h,rl J r ec l f r r ' e , n dl Rare,dut,isona ve ie(eri )ilte;lacc\'e Mtochoxdria fherit1t: Hei..raqpfec05 \!itl multi5)51:m ent nvclven

rEluanq tr"in;nie Urne fr radon/,rpathy La (r h0sri:iil ure feur0pdthy Proqresgrrl?r(cena?phdll]parhldrrorerplerd

B er l n Attcilma fies5lve

u'rfh rhe I)N'\_l-'ased .1rc fion and Prendlll (Li3Bn()srs Lr()ssrble rhev arld lacuc acidosisr il the ueonatal periud rvirh hr prri:lvccmia

hcpatomegelt: to an.l l proruherantabdomentLrati; .1ue nlassive and heart are rhc krdrevs ere also eniargcd,lrrlcfcJs the spLeen n o r m al .

Thc Lriochemical hallrnarks of rhe discascerc hypoglvcerni:r, lacnc acrrlosrs, hypcrrrriccnria. ,urci hvperlipicJerlia. Fl-vpogLycernra lacric aci.losiscaLr rlevelopeffer l shorr fast. Hyper and rarclv clcvelops beforc uriceLriais prcscnrin voung children; guLrr Dcspitc rnerked hepatoLregaLy, 1it,cr lransanrirtasc rhc f.Lrbertr. letcl. erc usuall,vnorLn.rlor onlr slighdv clcvarcd. lntenurtccnr is dilrr hea nra,voc.Llr tthe Llecherrisrn urrknorvn) liasy bruisiul-t :rnJ eprstaris ilrc c(nrn()r1 .rrJ rr-e essociatcdrvirh n prolortged blceding rrme as u ;esulr rrl inrp.rircil l'l3rclef aegrcgirtionand e.ihesion.

Disases 6lN r PARTXr Metabolic The plasma may be "milkv" in appearance as a result of a striking elevauon of rrrglyceride levels. Cholesterol and phospholipids are also elevated, but less promrnently. The lipid abnormaliry resembles type IV hyperlipidernia and is characterized by increased levels of very low density Lpoprorein, low-density lipoprorein, and a unique apolipoprotein profile consisting of increased levels of apo B, C, and E, wirh relatrvely normal or reduced levels of apo A and D, The histologic appearance of the Iiver is characterized by a universal distention of heparocytes by glycogen and far. The lipid vacuoles are particularll' large and prominent. There is litde associaredfibrosis, All these findings apply to both rype Ia and wpe Ib GSD, but type Ib has addrtronal features of recurrent bacterial inlecrions from neutropenia and impaired neutrophil funcrion. Oral and intestinal mucosal ulcerarron and inflammatory bowel diseaseare common. Excepronal casesof rype lb wrthour neutropeniaand type Ia with neulropenra have been reported. Although tvpe I GSD affects rnarnly the liver, multiple organ systems are involved. Pubert,v is often delayed. Virruallv all females haye ultrasound lindrngs consiscent with polycystic ovaies; other features of polycystic ovary syndrome (acne, hirsutism) are not seen. It is uncerrain whether rhis affects longterm ovularion and fertilicy. There have been mutiple reports of successfulpregnancy in adult rvomen with GSD I. Symptoms of gout usually srart around pubertl' from long-term hyperuricemia. Secondary co the hpid abnormalities, there is an increased nsk of pancreatitis. The dyslipidemia, together with elevated eryrhrocyce aggregation, predlsposes these parients to atherosclerosls. Premature arherosclerosis has rtot yec been clearly documented except for rare cases.Irnpaired platelet aggregation and increased anrioxidatrve defense to prevent lipid peroxrdation may function as a Drotective mechanism to helo reduce the risk of atherosclerosis, Frequent fractures and radiographic evidence of osteopenia are common; bone mineral content is reduced even in prepubertal patiencs. By the 2nd or 3rd decade of life, mosr patienrs wirh rype I GSD exhibit hepatic adenomas that can hemorrhage and, in some cases, become malignant, Pulmonary hypertension has been seen in some lons term survivors of the drsease. Renal disiase is another complication, and most pacients with type I GSD l,/ho are >20 yr of age have proteinuria. Many also have hypertension, renal stones, nephrocalcinosis, and altered creatimne clearance. Glomerular hyperfiltrarion, increased renal plasma flov; and microalbuminuria are often found in the early stagesof renal dysfunction and carl occur before the onset of pro teinuria. ln younger patienls, hyperfiltration and hyperperfusion may be the only signs of renal abnormalities. With the advancemen! of reflal disease, focal segmental glomerulosclerosis and interstitial fibrosis become evident. In some patierrtsj renal funccion has detenorated and progressed to failure, requiring dialvsis and transplancerion. Other renal abnormalities include amyloidosis, a Fanconr-like syndrome, hypocitraruria, hypercalciuria, and a distal renal rubular acidification defect. Diagnosis.The diagnosis of rype I GSD rs suspectedon the basis of clinical presentacron and the laboratory findings of hypoglycemia, lactrc acidosis, hyperuricemia, and hyperlipidemia. Neutropenia is noted in GSD Ib pacienrs, typically after the 1st 2-3 yr of lile- Administracron of glucagon or epinephrine results in litde or no rrse in blood glucose level, buc the lactare level rises significantly. Before rhe glucose-6-phosphatase and glucose-5phosphate rranslocase genes were cloned, a definitive diagnosis required a liver biopsy. Gene-based mutation analvsis now provides a floninvasive $'ay of diagnosis for mosr patients with types Ia and Ib disease. Taealmenl. Treatment is desrgned to maintain normal blood glucose levels and is achieved by continuous nasogastric infusion of glucose or oral administration of uncooked cornstarch. Nasogasrnc drip feeding can be introduced in early infancy from rhe rime oi diaenosis. It can consist of an elemental enteral formula

or contain only glucose a glucose polvmer to provide suffrcient or glucoseto maintain normoglycemiadurrng the night. Frequenr feedings with high-carbohydrate contentare giveoduring the day. Uncooked cornsrarch actsasa slow-release form of elucose and can be introduced a doqe t.6 g/kgevery4 hr foi rnfants ar of <2 yr of age.The response young infants is variable.As the child of grows older, the cornstarchregrmencan be chaogedto every 6 hr at a doseof 1.75-2.5g/kg of body werght,Because frucrose and galactose cannotbe converted directlyto glucose GSD type in I, thesesugars restricted the diet. Sucrose are in (tablesugar, cane sugar,orher ingredients), fructose{fruit, juice, high fructosecorn s;rrup),lactose(dairv foods), and sorbitol should be avoidedor limited, Due to thesedietary resrrictions, viraminsand minerals suchas calcium and viramin D may be deficientand supplemenration is required to preveflt nutritional deficiencies. Dietary therapyimproveshyperuricemia, hyperhpidemia, renal funcand tion, slowingthe developmenr renal failure. Thrs therapyfails, of however, normalze blood urrc acid and lipids levelscompletelv ro in some individuals,despitegood metabolic control, especially after pubeny,. The control of hyperuricemia can be further augmenred by the use of allopurinol, a xanthine oxidaseinhibitor. The hyperlipidemiacan be reducedwith lipid-lowering drugs such as HMG-CoA reductase inhibitors and fibrate (seeChaoter 8 6 1 M i c r o a l b u m i n u raa .e a r l y n d i c a t oo f r e n ad y s f u n c r i on . in i r l i rype I disease, treatedwith angiorensrn-converting is enzvme (ACE) inhibitors. Citrate supplementscan be beneficial for parienrs with hypocitraturia by preventing or ameliorating nephrocalcinosrs development urinary calculi. and of In patients with r1'peIb GSD, granulocrte and granulocytemacrophage colony-+timulating factorsare successful correcrin ing the neutropenia, decreasingthe number and severiry of bacterial infections, and improving the chronic inflammatory boweldisease. Orthotopic liver transplaltation is a potential cure of type I GSD, but the inherenrshort- and long-termcornplicarions leave this as a treatmnrof last resort, usually for patientswith liver malignancn muhiple liver adenomas,merabolic derangemencs refractory !o medical management, and/or liver failure. Large adenomas(>2 cm) that are rapidly increasingin size and/or numbermay requirepartial hepaticresecuon. Smalleradenomas (<2 cm) can be treared wirh percutaneous ethanol injection or transcatheter arterial embolizatron. Beforeany surgicalprocedure, bleeding the srarus must be evaluated and good meraboliccontrol established. Prolongedbleeding times can be normalizedby the use of intensivejnlravenous glucose infusion Ior 2448 hr beforesurgery. Useof l-deamino(DDAVP) can reducebleedingcompli8-o-argininevasopressin cations. Lactated ringer solution should be avoided because rt containslactateand no glucose, Glucoselevelsshould be maintained in the normal range throughout surgerywith the use of 107o dextrose. Prognosis. Previously, many patientswith rype I GSD died at a young age, and the prognosiswas guarded for chosewho survived.The long-rermcomplications occur mostly in adultsu'hose disease was not adequately treatedduring childhood.Early diagnosis and effectiveEeatmenthave imoroved the outcome:renal di*ease and lormationof heparic wrLhporenrial risk adenomas for malignant rransformationremaln seriouscomplications. TYPEIII GIYCOGEN STOBAGE DISEASE {DEBRANCHER DEFICIENCY tlMlT DEXTBINOSIS). III GSD is causedby a deficiencyof Type glycogen debranching enzyme activity. Debranching enzyme, togetherwith phosphorylase, responsible completedegrais for dation ofglycogen.!(hen debranchrng glycoenzymeis defective, gen breakdown is incompleteand an abnormal glycogenwich short outer branchchainsand resembline limit dextrin accurnulares. Deficiencyoi glycogen debranlhing enzvme causes hepatomegaly,hypoglycemia,short stature, variable skeletal myopathy, and variable cardiomyopathy.The disorder usually

' in ol ChaDter r Dolects Metabolism Ca.bohydroles 605 87 involves both liver and muscle and is termed tvpe IIIa GSD. In =157. of patients, the disease appears to involve only liver and patients show symptoms and signs of neuromuscular disease.The initial diasnosis has been confused with Charcor-Marie-Tooth disease.Polycystic ovaries are common; fertilrt,v, however, is not reouceo. Hypoglycemra and hyperliprdemia are common. In contrast to rype I GSD, elevation of liver transaminase levels and fasting ketosis are Drominent, but blood lactate and uric acid concen trations are usuallv normal. Serum creatine kinase levels can be useful to identify patients with rnuscle involvemenr; normal levels do nor rule out muscle enzyme deficiency. The adminrstration of glucagon 2 hr after a carbohydrare meal provokes a normal increase in blood glucose; after an overnrgh! fast, glucagon may provoke no change in blood glucose level. Diagnosis. The hisrologic appearance of the liver is character-

has been seen in some patienrs with GSD lII. Parienrs with mvopathy and liver symptoms have a generalized enzyme defect (type IIla). The deficient enzyme activity can be demonsrrated not only in liver and muscle, buc also in other tissues such as heart, erythrocl/tes, and cultured 6broblasts

weaknes. and waslinS. Myopathy does not follow Droaressive any-parricularpatrern of involvementl both proximal and distal -uril"t ,t" involved. Electromyography reveals a widespread mvopathyi nerve conduction srudiesmay be abnormal. Venrricular'hypenrophy is a frequent finding, but overt cardrac dvs funcdon is rare. Hepatic symptoms in some patients may be so mild that rhe diagnosis is not made until adulthood, when che

n I

btype asslgnmenr in the maioricy of patienrs. Dietary management is less demanding than in type nts do not need to restnct dietary inrake of fructose

rhan recommending a high-protein diet and an exercise plogram. Liver transplantation has been performed in pariencs with endstage cirrhosis and/or hepatic carcinoma.

(BRANCHING ENZYME DEFI. DISEASE TYPE GLYCOGEl{ IV STOBAGE DlSEASEl Deficienc,v 08 ANDERSEN AMYLOPECTIN0SIS, CIENCY,
of branching enzyme activity results in accumulatior of afl abnormal glycogen with poor solubiliry. The disease is referred to as type IV GSD or amylopectinosis because the abnormal glycogen has fewer branch points, more q. 1-4 linked glucose units, and longer ourer chains, resulting in a structure resembling amvloDectlnTyF IV GSD is an autosomal recessivedisorder The glvcogen branching enzyme gene is located on chromosome 3p21. Mutations responsible for rype IV GSD have been identified, and their characterization in indrvidual patients can be useful in predicting the clinical outcome. Some mutations are associacedwith a good

develoPmenrin a patint wrrh tvpe IIIb glycogen nt has debrancher deficrencvin livs but normal hvpogtvcemia,and growth d, he had hepatomegalv, he no lonsef bad hpatomegalvor hvpoglvcemia' s normal He had lro muscle weaknssor atroph,vi this is in contrast to rvpe IIIa parints, in whom a progressivemvopathv rs

mosr common and classic form is characterized by progressive cirrhosis of the Lver and is manifested in the 1st 18 mo of life as hepatosplenomegaly and failure to rhrive. The cirrhosis progresses to portal hypertension, ascites' esophageal varices, and liver failure that usually leads to death b-v -51'r of age. Rare patients survive without progression of liver disease A neuromuscular form of the disease has been reported. Patients may present at brrth wirh sevete hypotonia, muscle atrophn and neuronal involvement with death in the neonatal period; others may present in late childhood wirh myopathy or

I 606r PARTX Melaholic oiseases cardiomyopalhy;or present as adults with diffuse central and peripheralnervoussystemdysfunctionaccompanied accumuby lation of polyglucosanbody drsease the nervoussystem(soin calledadult polyglucosanbody disease). adult polyglucosan For disease, leukocyteor nervebiopsyis needed establish diagto the nosisbecause branchingenzymedeficiency lrrmtedto those the is ttssues. Diagnosi$. Tissuedeposrionof amylopectinJikematerialscan be demonsrrated liver, heart, muscle, skin, inrestine,brain, in spinalcord, and perrpheral nerve.The hepatichistologicfindings are characterized micronodular cirrhosis and fainrly srained by basophilicrnclusions the hepatocl.res. inclusions in The consistof coarsely clumped,storedmarerialthat is periodicacid-Schiffpositive and parcially resistant to diastase digestion. Electron mrcroscopy shows,in addition to the conventional and p glycoa gen parcicles, accumulationo{ the fibrillar aggregations that are typical of amylopectin.The drstirct staining propertiesof the cytoplasmicrnclusions, well as electronmicroscopicfindings, as could be diagnostrc. However,polysaccharidoses histologic wirh featuresremrniscent type IV disease, of but without enzymacic correlation,have beenobseryed. The definitivediagnosis restson the demonstrationof the deficientbranchingenzymeactivity in liver, mu..1., cultured skin fibroblasts,or leukocytes.Prenatal diagnosis possibleby measunng enzymeactivity in cultured rs the amniocytes chorionic villi. or Treatnent, Thereis no specific treacment type IV GSD.Liver for transplantationhas beenperformedfor patientswith progressrve hepaticfailure, but because is a multisystem ir disorderinvolving many organ systems, long-term success liver transplantathe of tion is unknown. of liver glycogenoses. additronto live! enzyme In activitycan also be delicientin erythrocytes leukocyces; is normal in muscle. and it T1'pically, 1-5 yr old presents a with growth retardarionand an rncrdental finding of hepatomegaiy. Cholesterol, rnglycerides, and liver enzymes mildly elevated. are Ketosismay occurafrerfasting. Lactateand uric acid levelsare normal. Hypoglycemiais mild, if present.The response blood glucoseto glucagonis normal. in Hepatomegaly abnormalblood chemistries and graduallybecome normal with age.Most adulcsachreve normal 6nal height and a are usually asymptomaricdespite a persistent phosphorylase kinase deficiency. Liver histologic appeatance shows glycogendistendedhepatocltes.The accumulatedglycogen(p particles, rosette form) hasa fra;,'ed burstappearance is less or and compact than the glycogen seen rn type I or type III GSD. Fibrous septal formation and low-grade rnflammatory changes may be oresenc. fhe strucruralgenefor the common liver isoform of rhe phosphorylase kinasesubunit,liver crsubunrtis ort the X chromosome (rrl- at XpZZ.2). Mutations of this geneare known.

AUTOSOMAL IIVERANO MUSGTE PHOSPHORYTASE KINASE DEFIGlEilCYSeveral patientshave beenreported with phosphorylase kinasede6ciency liver and blood cellsand an autosomalmode in of inheritance.As with the X-linked form, heparomegaly and growth retardationapparentin eady childhood are rhe predominant symptoms.Somepatients also exhibit muscle hypotonia, I(/hen measured a few cases, in reducedactivity of the enzyme has beendemonstrated muscle. in Murations causine auto:oma lly rransmined lrverand rnut.|" nhosphorvlase kinaiedeficiency are for-rnd the autosomalp subunitgeneof rhe PK gene(chroin mosome 16q12-q13). (I.IVER TYPEVI GTYCOGEN DISEASE STORAGE PHOSPHORYTASE DEFIGIENCY, DISEASE). HERS There are few patients with docuAUT0SOMAILIVEBPH0SPH0RYLASE KINASEDEFICIENCY Thrs mented llver phosphorylasedefcrency. Such patients have a form of phosphorylase kinasedeliciencyis due to mutarronsin benrgncourseand presentwith hepatomegaly and growth retarthe testis/liver isoform of rhe7 subunit of the gene(TL, PHKG2). dation in early childhood. Hypoglycemia,hyperliprdemia,and In contrastto the benigncourseof XJinked phosphorylase krnase hyperketosis usuallymrld if present. are Lactrcacid and uric acid defrciency, patienrs wich mutatrons the PHKG2 genehavemore in levels are normal. The heart and skeletal muscles are not severe phenotypes wrth recurrent hypoglycemia and often involved. The hepatomegalyand growh retardation rmprove developa progressive liver cirrhosis.PHKG2 maps ro chromowith age and usually disappeararound puberty. Treatment is some 16p12.1 and many disease-causing mutations are known svmptomatic. high-carbohydrate A diet and frequentfeedingare IOr tirls gene efiectirern preventing hypoglycemia; mosr palientsrequireno specifictreatment. GSD VI is an autosomal recessive disease. ilUSCtE-SPECltlC PH0SPH0RYLASE KINASE DEFICIENCYA few Diagnosisrestson elzyme analysisof the liver biopsy.The liver cases of phosphorylase krnase deficiency restricted ro muscle are phosphorvlase gene (PYGL) is on chromosome74q21-22 and known. Patients, both male and female, present either with has 20 exons.Many mutationsare known in this gene,a splice muscle cramps and myoglobrnuria with exercise or with prosite mutation in intron 13 has beenidentifiedin the Mennonite gressive muscl weakness and atrophy. Phosphorylase kinase populatlon. TYPEIX GI.YCOGEN STOBAGE DISEASE KII{ASE {PHOSPHORYTASE CYl.This disorderrepresents heterogeneous a group of oses, Phosphorylase,the rate-limiting enzyme of glycogenolysis, activatedby a cascade enzymaricreactions is of kinase. The latter enzyme (n, has four subunics p, 16), each encodedb;' differentgenes differentchromosomes differon and entially expressed various tissues. in This cascade reactionsis of stimularedprimanly by glucagon. This glycogenosis could be the result of any enzymedefciency along thrs pathlvay; the most common is the deficiency phosphorylase kinase. of The numenc classiflcarion phosphorylase of kinasedefrciency is confusing,rangingfrom rype VIa to VIII to IX. It is advisable to refrain from sucha designation and to classifythe variousdisordersaccordingto organ involvementand mode of inheritance. X-tlNKEDUVEBPHOSPHOBYLASE KINASE 0EFIGIENGY Xlinked liver phosphorylase krnasedeficiency the most common form is
activit't is decreasedin muscle but normal in liver and blood cells. There is no hepatomegaly or cardiomegaly. The structural gene for muscle specifrc form q subunlt (crM) is located at Xq12. Mr-rtations of this gene have been found in male patients with this disorder. The gene for muscle l subunit (1M, PHKG1) is on chromosome 7p12 (29). No mutations in this gene have been reported so far

PH0SPHORYI-ASE 0EFICIENCY KINASE tlMlTEDT0 HEABT. These patients present with cardiomyopathy infancyand rapidly in progress heartfailureand death.Phosphorylase to kinase de6ciency is demonstrated in the heart with normal enz_vme activity rn skeletal muscle and liver. Diagnosis. Definitive diagnosis of phosphorylase kinase de6ciency requires demonstration of the enzymatic defecr in affected tissues.Phosphorylase kinase can be measured in leukocytes and erythrocytes, but because the enzyme has many isozymes, the diagnosis can be missed withour studies of liver, muscle, or heart tn certain rnstances, Tteatment. The treatment for liver phosphorylase kinase deficiency includes a hrgh-carbohydrate diet and frequent feedings to

r 60t of 8? i[ Chapter | Detects Mel.bolistn Calbohydrates with a comcan latter enzyme deficiencres alsobe assocrated these pensacedhemolysis,suggestinga more generalizeddefect in glucose metabolism. (tYS0S0MAt ACID 1,4-Gl-Ucr DISEASE STORAGE WPE ll GtYCOGEl{ also Pompe disease, POMPE 0ISEASE}. DEFICIEI{CY, C0SIDASE is referredto as GSD type II or acid maltasedeficiency, caused This enzymedefect resultsin lysosomalglycogenaccumulation in multiple tissuesand cell types, with cardiac, skeletal, and affected. The disease smoothmusclecellsbeingthe most serrously as by is characterized accumulationof glvcogenin lysosomes, opposed to its accumulation rn cyroplasm in the orher glycogenoses. disorderwith an rnciPompedisease an aurosom recessive is denceof =1/40,000 live births. he genefor acrd q-glucosidase hare mutations l-q25.2. Multiptepathogenic rson chromosome been identifredrhat could be helpful in delineatingche phenocomsitemutation(IVS1-13T-"G), types. An descent. enrsof caucasian monly see a e disorderencompa\ses rangeuf Clinicat

lase kinase deficiency other than healt transplafltation. DEFlCltttloY{GSD0}. Deficiency of hepacic ctYcOcEN SYIIIThErASE glycogen synthetaseleads to a marked decreaseof glycogen srored in the li"er The patients Present in infancy with early-morning (before eating breakfast) drowsiness, pallor, emesis, and fatrgue and sometimis convulsions associated with hypogll'cemia and

-fteatmett consists of frequenr cated on chromosome 12p72.2 eals, rich in prorein, and nighttime supplementation wich uncooked cornstarch. HEPATIC GIYCOGEI{OSISWITII RENAT FAIIICONI SYNDROIIIE

hepatomegall', appearance,"feeding difficultres, macroglossia, followed by dea from carand a hypertrophiccardiomvopachy diorespiratoryfailure or respiratoryinfectronusuall by 1yr of (late-onset forms) is charage.Juvenileand adult-onsetdisease cardiacinvolvementand by of acterized a lack or absence severe proximal The clinical picture is dominatedby slowly progressive with truncal involvementand gteater involvemuscleweakness ment of the lower limbs than the upper limbs. The pelvic girdle, paraspinalmuscles, and diaphragrnare the musclegroupsmost progressiol,patlentsbecome conaffected. With disease seriously and require artrficialventilation.The initial fined co wheelchairs manin symproms somepatientsmay be respiratoryinsufficiency orthopnea,and exermornrflg headache, ifestedby somnolence, tional dyspnea, which eventually lead to sleep-drsordered breathingand respiratoryfailure. Respiratoryfailure rs the cause morbrdrtyand mortality in this form of the disease. of significant The ageof death variesfrom early childhood to late adulthood, progressionand the extent of dependingon the rate of disease muscleinvolvement. resDiratorv levelsof setum creTheseinclude elevated laborrtoryFindings, and atine kinase,aspartate amrnotransferase, lacratedehydrogenase. In the infanrile form a chest x-ray showing massive Electrocarrs cardiomegaly frequentlythe 1st symptomdetected. diographicfindings include a high-voltageQRS complex and a revealsthickening of shortenedPR interval. Echocardiography both ventricles and/orthe intraventricularseptumand/or left venricular outflow tract obstruction.Muscle bropsyshowsthe presence of vacuoles thac stain positively for glycogen; acid phosphataseis increased,presumably from a compensatory Electfon mi(ro\copy re\eals increase lysosomal of enzymes. glycogenaccumulationwithin the membranoussac and in rhe revealsmyoparhic featureswith cytoplasm.Electrornyography excessive electricalrrrirability of muscle frbers and pseudomySerumcreatinekrnaseis not always elevated otonrc discharges. on in adult patients.Depending the musclesampledor tested,the may not be musclehrsrologicappeara[ceon electromyography abnormal.Ic is prudent to examinethe affectedmuscle. nosrs of PomPe id cr-elucosidase. skin fibroblasts,

and small meals with an adequate caloric intake may Implove grol\,'th.

MUSCTE GTYCOGEI{OSES

r 6mr PARTX Metabolic Disaasas dried blood spots,leukocyces, blood mononuclearcells usng or mahose,glycogen, 4-methylumbelliferyl-a-D-glucopyranoside or (4MUG) as a substrare, Deficrency usually more seyere rhe is in infantile form than rn the juvenile and adult forms. The skrn fibroblast assayis usually preferredto musclebiopsy because it is lessinvasiveprocedurewith rhe advantage maintaininga of ce line for future use and providing information on residual enzyme activit)'. Blood-basedassayshave the dvantage oI a rapid turn-around time. A musclebiopsy can yi d fasterresults and provide addrtronalinformation about glycogencontent and site of glycogen storagewichin and outside the lysosomes of musclecells.A mayorlimitarion of a musclebropsyin late-onset patientsis the variablepathology and glycogenaccumulationin differentmuscles and withrn muscle6bers;musclehistologyand contentcanvary depending the site of musclebropsy. on Elycogen There is also a risk from anesthesia. Prenatal diagnosisusing amniocytesor chorionic villi is available in the fatal infantile form. Treatmentoptions were once limited to supportive or care. Clinical trials of enzymereplacement therapy (E beenpromisingand ERT with myozymeis available for treatmentof Pompedisease. Recombinant acid cr-glucosidase is capableof improving cardiac and skeletalmuscle functions (Frg.87-3). For patientswith the late-onset form of rhe disease, a high protein diet may be beneficial.Nocturnal ventilatory support, when rndicated,should be used.It has beenshown to improve the quality of life and is parricularly beneficial during a period of respiratorydecompensation. GIYCOGEI{ SIOBAGE DISEASES MIMICKING HYPERINOPHTC CARDI0MY0PATHY. Deficrencies lysosomal-associated of membrane protern 2 (LAMP2, also called Danon disease)and AMPactivatedprotein kinasey2 (PRKAG2)result in accumulationof glycogen the hean and skeletalmuscle.Thesepatientspresenr in primarily as a hypenrophic cardiomyopathy, bur can be distinguishedfrom the usual c sesof hypertrophiccardiomyopathy due to defecrs sarcome prorein genes their electrophvsioln by logic abnormalities,particularly ventricular pre-excitationand conduction defects.The onset of cardiac symproms,including chest pairi, palpitation, syncope,and cardiac arrest, can occlrr betweenthe agesof 8 and 15 yr for LAMP2 defrciency', younger than the averageage for patients u'ith PRKAG2 deficiencl which is 33 yr, The prognosisfor LAMP2 deficiencyis poor with progressiveend-stageheart failure early in aduhhood. Cardiomyopathydue to PRKAG mutations is compariblewith long-term survival, although some patients may necessitate the implantarion of a pacemaker and aggressive control of arrhythmias. TYPE GIYCOGEfl V STORAGE OISEASE PHOSPHOBYTASE IMUSGTE DEFICIENCY, MCARDTE DISEASE). rs causedby rhe deficiency This of muscle phosphorylaseacrivity. Lack of this enzyme limits muscle ATP generation by glycogenolysis, results in glycogen accumulation, and rs the prototype of muscleenergydisorders. A defrciency myophosphorylase of impairs the cleavage glucosyl of molecules from the straighrchain of glycogen. erance with muscle cramps/pain. Two rypesof acLiviry rend ro causesymptoms:brief exercise grearintensiry such as sprintof ing or carrying heavyloads;and lessintensebut sustained activiry suchas climbing starrsor walking uphill. Moderateexercrse, such as walking on level ground, can be performed by rnost patientsfor long periods.Many patientsexpetience charactera istic "secondwind" phenomenon. they slow down o pause If brieflyat the lst appearance musclepain. rhey can esr.rme of exercise wrth more ease, Due to the underlying myopathy, these patients may be at risk for statin-inducedmyositis and rhabdomyolysis. About half repon burgundy-colored urine afrerexercise, which is the consequence exercise-induced of myoglobinuriasecondary to rhabdomyolysis. Intense myoglobinuriaafter vigorousexercise may causeacute renal failure. In rare cases, elecromyographic findings may suggest inflammatory myopathy and the diagan nosiscan be confused wirh polymyosiris. The level of serum creatinekinase is usually ele.\'ated rest at and increases more after exercise.Exercisealso increases tl-re levelsof blood ammonia, inosine,hypoxanrhine,and uric acid. The latter abnormalities attlbuted to accelerated are recyclingof muscle purinenucleorides owingto insufficient ATPproducrion.

Pre-treatment

Post-treatment

Fisure 87-3. Chestx-rav and musclehistotogy findings oi an infanrile-onset Pompe diseaseparient before fnl and after fEl enzyme replacementrherapy.Nore rhe decrease in heart sizeand musle slycosen wirh rhe rherapy.(Mod, i6ed Irom Amalfitano A, Beneur AR, Mone R?, et al: Recombinant human acid alpha-glucosidase enzyme therapy' for Lnfannle gtycogea storage disease type II: Results of a phase VII cljnical trial, Genet Med 2001i3:132-138.)

. 6m in of 87 Chaptei r D.lects MetaholismCalbohydiates disorder.The gene for Type V GSD is an aulosomal recessive (PYGM) hasbeenmappedto chromosome musclephosphorylase glucoseinhibits lipolysis and rhus deprivesmuscle of because In fatty acrd and ketone substrates. contrast,parientswirh typ glucose V drsease merabolize derivedfrom either can blood-borne glucose;indeed,glucoseinfuliver glycogenolysis exogenous o! tolerancein type V pattents.(6) There is sion improvesexercise phenomenon of because the inabilno sDontaneous second-wind ity to metabolizeblood glucose. Two rare rype VII variants occur. One variant presentsin described, infancy with hypotonia and limb weaknessand proceedsro a rcise test offers a rapid diagnostic myopathy rhat leadsco death by 4 yr of age rapidlv progressive Lack of an mecabolicmYoPathY. sc by The other variant presentsin adults and is characterized a blood ammonia s and exaggerated in lixed muscleweaknessrather than cramps slowly progressive, and suggesta defect rn elevationsindicate muscleglycogenosis and myoglobinuria. the conversronof muscle glycogen or glucoseto lactate. The To Diagnosis. establisha diagnosis,a biochemicalor hisroabnormal ischemrcexerciseresponseis not limrted to type V of GSD. Other muscle defects in glycogenolysisor glycolysis chemrcaldemonstrarion the enzymaricdefecrin the muscleis of of of producesimilar results(deficiencies musclephosphofrr-rctoki- required.The absence rhe M isoenzyme phosphofructokiin nasecan also be demonstrated blood cellsand fibroblasrs. mutase, or kinase, phosPhoglycerate nase, phosphoglycerate There is no specificffeatment,Avoidanceol screnuTrcatment. lactatedehydrogenase). ous exerciseis advrsable!o prevent acute attacks of muscle MRI) allows for ri"gn.tr. t".onuttc" imaging (31P Phosphorus crampsand myoglobinuria. evaluationof musclemetabolism Patientswith rhe nonrnvasive pH in type V GSD have no decrease incracellular and haveexcesin sive reduction in phosph<xrearine responseto exercise The ENERGY IMPAIR. WITH OTHER MUSCI.E GTYCOGEI{OSES MUSCTE evaluationof muscle. shouldbi confirmedby enzymatic diagnosis MENI Six additional defects in enzymes-phosphoglycerate mutation R49X in exon 1 is found rn 907" A cbmmon nonsense fruc mutase, lactate dehl'drogenase, kinase, phosphoglycerate of white patients,and a deletionof a singlecodon in exon 17 is tose-1,6-biphosphate aldolaseA, musclepyruvatekinase,and ppatrenrs. Other common mutatronsrn found in 51% ofJapanese enolase in the pathway of the terminal glycolysis----cause (G204S exon 5 and K542T in exon 14) make DNAin whrres symptoms and signsof muscleenergyimpairmentsimilar to those possrble and carrier tesringfor McArdle disease baseddragnosis of typesV and MI GSD. The failure of blood lactateto increase fbr the 2 populations. is ln response xercise a usefuldiagnostictesrand can be used to pleventsthe svmpexelcise Avoidanceof strenuous Treatmeni. from disorders of lipid ro differentiate muscle glycogenoses to is regularand moderateexercise recommended toms; however, II mecabolism, such as carnrtinepalmitoyl transferase deficiency improve exercisecapacity. Sucrosegiven before exetcise can which and very long chain acyl-CoA dehydrogena deficiency, dier A -"ik"d1y i-ptou. tolerancein thesepatients. high-prorein also causemusclecramps and myoglobinur Muscle glycogen has and muscleendurance creatinesupplement been may increase levelscan be normal in the disordersaffectingterminal glycolyshownto improve musclefunction in someparients.Longeviryis the sis and assaying muscleenzymeacrivity ts neededco make a not generallyaffected. Avoidanceof There is no specifrccreatment, definire diagnosis. strenuouserercisepreventsacute attacks of musclecrampsand (MUSCTE PHOSPHOFRUCDISEASE STORAGE TYPE GTYCOGEN VII myoglobinuria.Avoidanceof drugs such as statins,and maligType VII GSD rs caused nant hypenhermiaprecaulionsfor patientsundergoinganestheTABUT DISEASEI. DEFIGIENGY TOKINASE sia should be followed.

. METABOTISM IN 87.2. DEFEGISGATACTOSE and Yuan-Tsong Chen PriyaS. Kishnani

rhe Milk and dairy productscontainlactose, major dietarysource producesfuel for celof galactose. The metabolismof galactose h-rlar metabolismthrough its conversionto glucose-L-phosphate (seeTable 87-1). Galactosealso plays an important role in rhe glycolwhich include glycoproteins, formation of galactosides, iprds, and glycosaminoglycans. Galactosemiadenotes rhe elevated level of galactose the blood and is found in 3 distinct rn in metabolismdefecrive 1 of rhe folinborn errors of salactose galacgalacrose-1-phosphate uridyl transferase, lowing enzyrnes: The tokinase, and uridine diphosphategalacrose-4-epimerase. in for althoughadequate the deficiencies any terrngalactosemia, defrciency. generallydesignares transferase the of thesedisorders, DEIICIENCY UBIDYT TBANSFERASE GAIACTOSE-1-PHOSPHATE exisr: Infants with Two GAIACT0SEMIA, forms of the deficiency galacdeficiency the enzyme(classic of or complete nearcomplete deficiency Classic tosemia) and those with partial transferase galactosemia a seriousdisease with onserof symptomstypiis callv bv the 2nd half of rhe 1st wk of !fe, The incidenceis high amountsof lactose 1i50,0d0.The newborn infant receives (up to 40% in breastmilk and certain formulas),which consists

sible in is population. of Six Clinic Manile$tations, features rype VII are distrncrive: (1) Exerciseintolerance,usually evidenr in childhood, is more with nausea, and severe than in type V disease may be associated causes sevele musclepain; vigorousexercise vomiting, and severe hemolym.,scleitamps and myoglobinurra (2) A compensated level of serum bilirubin by sis occurs as evidenced an rncreased

610 | PABT r Metabolic X Diseases of eqLralparrs of glucose and galactose. lfirhout the transferase enzyme, the infant is unable ro metabolize galacrose-1-phosphate, the accumulation of which results in injury ro krdne_v,liver, and brain. This injurv may begin prenatally in the affecred fetus by transplacental galactose derived from the diet of the herefozygous mother or bv endogenous producrion of galactose rn ffre lerus. Clinical Manilsslations. The diagnosrs of uridyl transferase de6ciency should be considered in newborn or young infants wirh any of the following fearures: jaundrce, hepatomegaly, vomrting, hypoglycemia, convulsions, lethargn irritabilirl, feeding dif6cultres, poor weight gain or failure to regain birth weight, aminoacidurla, nuclear cataracts, vitreous hemorrbage, hepatic faiLure, liver cirrhosis, ascites, splenomegaly',or mental retardarion. Symptoms are milder and improve when milk is temporarily withdrar,r.n and replaced by intravenous or lactose-free nutrition, Patients wirh galacrosemia are at increased risk for Escberichia coli neonatal iepsis; the onset of sepsisoften precedes the diagnosis of galactosemia. Death from liver and kidney failure and sepsis may follow within days. \X/hen che diagnosis is nor made at hitth, damage ro the liver (cirrhosis) and brain (mental retardatron) becomcs increasingly severe and irreversible. Partial translerase deficiency is generally asympromatic. ft is more frequen! than classic gaLacrosemia and rs diagnosed in nervborn screening because of moderatell' elevated blood galactose and./or low rransferaseactivit-v'. Clalactosemiashould be considered for the newborn or young infant who is not rhriving or who has any of the preceding 6ndings, Light and electron microscopy of hepatic tissue reveals farty rnfiltrarion, che formation of pseudoacini, and eventual macronodular cirrhosis. These changes are consistent with a metabolic disease but do noc indi, cate the Dreciseenzvmatrc defect. Diagnosis. The prehminary diagnosisof galactosemiais made bv demonstrating a reducing subsrancein several urirte specimens collected while the patien! is receiving human mrlk, cow's milk, or any other formula containing lactose, The reducing substance found rn urine by Clinitest (glucose, galactose, others) can be identilied by chromarography or bv an enzymatic test specific for galactose. Galacrosuria is present, provided che lasr milk feed does nor dare back more chan a fer,,'hours and rhe cbild is nor vomiting excessively. Chnistix urine test results are negarive becausethe rest matenals rely on the action of glucose oxidase, t'hich is specific for glucose afld is nonreactive with galactose. O$.ing to a proximal renal tubular syndrome, however, the acurely rll babv may also excrere glucose together with amino acids. Because galacrose is injurious to persons with galactosemra, diagnostic challenge tests dependent on administering galacrose orally or intravenously should noc be used. Direct enzvme assay using erythroc,vtes establishes the diagnosis. One needs to confirm that the Danent did not receive a blood transIusron before the collection of the blood sample, as a diagnosis could be mrssed. Deficient activit,' of galactose-l-phosphare uridyl cransferaseis demonstrable in hemolysates of eryrhrocytes, which also exhibit increased concentratrons of salactose-1 phlsphate. Genetics. Transferase deiciency galacrosemla rs an autosomal recessivedisorder. There are several enzymatrc variants of galactosemia. Tbe f)uarte variant, a single amino acid substitution (N314D), has drminishedred cell enzyme actrviry but usually no clinical significance. Some Afrrcan-American pacienrs have milder symptoms despicethe abselce of measurable rransferase activity in erythrocytes; these parienrs retain 107o enzyme activity in Jiver and inrestinal mLrcosa,.,vhereas most white parients have no detectable activity in any of rhese tissues. In African-Americans, 62% of allelesare represenred che S135L mutation, a muraby tion tha! is responsible for a milder diseasecourse. In the white population, 70% of alleles are represenred b,v the Ql88R and K285N missense mutations and are associated wich severe disease. Carrier tescing and prenatal diagnosis can be pertbrmed by drrect enzyme analysis of amniocytes or chorionic villi; resting cirn a[5o be DNA basrd. Trealrnent and Prognosis. Because of newborn screening for galacrosemia.parienrr are berng identrfied and rreared iarlr'. Variuus milk suhlirur(\ are arailable (ca.ein hydrolysarei, so,vbean-based formula). Elimination of galactose from the diet reverses growrh failure and renal and hepatrc dysfunction. Cataracts regress, and most parients have no impairment of eye srght. Early diagnosis and treatment have improved the prognosis of galactosemia; howeve! on long-term follor-up, patients still manifest ovarlan failure wich primary or secondarv arnenorrhea, decreased bone mineral densit,v,deveJopmenral delali and learning disabilities that increase in severit,vrvirh age. Most manilest speech disorders, whereas a smaller number demonsrrare poor growth and impaired moror function and balance (r,r,'ith or wrthout overt araxia). The relative control of galactose-:lphosphate levels does not alwa,vs correlate with long term outcome, leading co the belief that orher faccors, such as clevated galactitol, decreased uridine diphosphate galactose (UDP-galactose, a donor for galactolipids and proteins), and endogenous galactose production may be responsible. GALACT0KINASE DEfICIENCYThe deficient enzvme is 'g.rlacro.e, ealactokinase.vrhrch normallv caralyzes phosphorvlaiion of the The principal metabolites accumulated are galactose and galacri tol. Tu'o genes have been reported to encode galactokinase: GK1 chromosome 1r-q24 arrd. GK2 on chromosome 15. Cataracrs are usually the sole manifestation of galactokinase deficiency; pseudotumor cerebri is a rare complicarion. The affected infanr is othenvise asymptomacic. Heterozygore carriers may be at risk for presenile cataraccs. Affected patienrs have an increased concentration of blood galaccoselevels, provided they have been fed a lactose-containing formula. The diagnosis is made by demon straung an absence of galactokinase activiry in erylhrocytes ot fbroblasrs. Transferase acrivrty is normal. Treatment is dietary rescriccion of galactose. URIDINE DIPH0SPHATE GAtACT0SE-4-EPIMERASE DEtICIENCY. The abnormalJy accumulated merabolites are simrlar ro those in trans ferase deficrency; ho.w'ever,there is also an increase in cellular UDP-galactose. There are 2 drstinct forms of epimerase de6ciency. The 1st is benign form discovered incidentally through neonatal screening programs. Affected persons are healthy and r.ithout problems; the enzvme deficiency is limlted to leukocytes and eryrhrocytes- No rreatmenr is required. The 2nd form of epimerase deficrency is severe, and climcal manifestations resemble transferase deficiencl r.r'ith the additional symptoms of h;rpo conia and nerve deafness. The enzyme defciency is generalized, and clnical symptoms respond ro restdction of dietary galactose, Although thrs form of galacrosemia is rare, it rnust be considered in a symptomatic patient wirh measurable galatose-1-phosphate who has normal transferase activity. Diagnosis is conlirmed by the assayof epimerasein erythrocytes. Patients wrth rhe severe form of eDimerase deficiencv cannot synthesize galactosefrom glucoseand are galactosedependenr. Becausegalactoseis an essentralcomponent of manv nervous system structural proteins, patienrs are placed on a galactoserestricted diet rather rhan a ealactose free diet. Infants with the mild {orm of epimerase deficrency have not r e q u r r e d f e a t m e n t i. t j * a d v i s a b l e , ' f o l l o w u r i n e ' p e c i m e n s o r t r f reducing substances and exclude aminoaciduria within a fevv weeks of diagnosis while the infant is still on lactose-containing formuia. The gene for UDP-galactose-4-epimerase is located on chromosome I at 1p36. Carrier detecrion is possible by measurement of eprmerase activity in the er)'throcyles. Prenatal diagnosis for rhe severeform ui eprmerase de6.iencl. using an enzyme assar of cultured amniotic fluid cells. is oossrble.

r of 87 Chapler . D.lects in Metaholism Calbohydiates 611

. . METAEOLISM INFBUCTOSE 87.3 DEFECTS Chen and Priya Kishnani Yuan-Tsong S.

TBUCTO(ESSENTIAT BENIGN OR OT DIFICIENCY TRUCTOKINASE with is cy of fruccokinasenot associated anyclinSURI finding usuallymade ons. ft is an accidental rcal suba patient's urinecontains reducing the because asvmptomatic
stance. No treatment is neiessaty and the prognosis is excellent Inheritance is autosomal recessive with an incidence of 1/120,000. The gene encoding fructokinase is locared on chromosome 2p23.3. Fructokinase catalyzes the 1st step of metabolism of dietary fructose: conversion of frucrose to fructose 1-phosphate (see Fig 87-1). Without this enzyme, ingested fructose is not metabolized. Its level is increased in the blood, and it is excreted in urine becausethere is practically no renal threshold for fructose. CIinitesr resLrltsreveil the urinary-reducing substance, which can be identilied as fructose by chromatography. DEFICIENCY OF

An intravenous fructose tolerance tesc, admrniscered with great caution! is 1 step in facilitating diagnosis. The fructose challenge will cause a rapid fall, lst of serum phosphate and then of blood glucose,and a subsequentincreasein uric acid and magnesium. -An ,rral rolerancete*i should not be perfurmed becau:epatienrs can become acutely ill. Definitive diagnosis is made by assay of fruccaldolase B activiry in the liver' Gene-based diagnosis is available for most patients with thrs disease;a common mutation (substicution of Pro for Ala ar position 149) accounts for 537. of HFI alleles worldwide. Treament Treatment consists of the complete elimination of all sources of sucrose, frucrose, and sorbirol from the diet. Ic may be difficult because these sugars are widely used additives, found even in most medicinal preparations Wirh tleatment, liver and kidney dysfuncrion inproves, and catch-up in grorwh is common. Intellectual development is usually unimpaired. As the patient matures, symptoms becom milder evell after fluctose of ingesrion;rhe long-term prognosis1 good. Because volunrarv diilary avoidance of suciose,affec d patients have lew denral canes.

CARB0HYDRATE 87.4. DEFEcrs INTERi|EDIARY lN . w|TH Acto0sts Ass0ctATED LAcrlc METABoUsM Chen Priya Kishnani Yuan-Tsong S. and
Lactic acrdosrs occurswirh defectsof carbohydratemetabolism chac inrerferewith the conversionof pyruvate to glucosevia the

ATDOTASE FRUCTOSE.I,6.8ISPHOSPHATE

5 f

uctute' The true incidence of hereditarY unknown but maY be as high as

are de6ciency chain defeccs, pyruvatecarboxylase and respirarory drsorders the pathway of pyruvaremetabolismcausinglactic in can also occur in defectsof fatty acid acidosis,Lactic acrdosis oxrdacion, organic acrdurias(seeChapters856, 85.10, and Thesedisorders easily are 86.1),or biotin utilizadondiseases. distinguishable by the presence of abnormal acylcarnicine profiles and amino acids in the blood and unusual organic acids in the urine, Blood laccate,pyruvate, and acvlcarnitne profiles and lhe presence these unusual urine organic acrds of ihould be determinedin infants and children with unexplained acidosis, especiallyif there is an increaseof aoion gap (see 55). Chapter Lactic acidosisunrelated ro an enzYmaticdefect occurs in

dosisis shownin Figure87-5

DISORDERS OF GLUCONEOGENESIS
(WPE I DEFICIENCY GTUCOSE-G.PHOSPHATASE GTYCOGEN OF associGSD is the only glycogenosis acidosis.The chronic metabolic aciafter prolonged lien!s to osteoPenia; is ted wirh hypoglycemia a life-threatChapter87.1). eningcondition(see

612 r PABT r Metabolic X Disass

dehydrogeMse'

El active

Acetyl-coA \-> Cilic acidcycle \______:"_r,

H:U

I'igurc 87-1. Enzvmatic reachons of carbohydrate metabolsn, delicienciesof u'hich can gjve rise ro lactic acidosrs,pvruvate elevarions,or hypoglycemia The pvruvare dehydrogenase conplex comprises,in addition to Er, Fr, and E:, an exfia lipoate containing prorein (nor shown), called protein X, and p_vruvare dehyorogenaspnospnarase. e

PYBUVATE DEHYDR0GENASE After entenns C0MPLXDEFICIENCY the mitochondria. pyruvafe is converted into acetyl coenz\me A (acetyl CoA) by the pyruvate dehydrogenase complex (PDHC), *'hich catalyzes the oxrdation of pyruvate to acetl'l CoA, .rvhich then enters the tricarboxylic acid cycle for ATP production. The complex comprlses 5 components: E1, an cr-keto acid decarboxylase; E2, a dihydrolipoyl transacylase; E1, a dihydrolipoyl dehydrogenase; protein X, an extra lipoate-conraining protein; and pyruvate dehydrogenase phosphatase. The most common is a defect in the Er (see FiE- 87-4). (PEPCK} PHOSPHOENOTPY8UVATE DEFIGIENCY Deficiencv of the pvruvate dehydrogenase complex is the most CARBOXYKINASE PEPCKis a key enzymein gluconeogenesis. catalyzes conIt rhe common of the disorders leadine ro lacric acidemia and central versionof oxaloacetate phosphoenolpyruvate Frg. 87-4). (see ro nerrr'ous system dysfunction. Tlie cettttrl nervous syscem dysPEPCKdefrciency both a mitochondrialenzl'medeficiency is and funccion is becausethe brain obtains irs energy primarill,from a cytosolicenzymedeficiency, eflcodedby 2 distinct genes. oxrdation of glucose. Brarn acetyl CoA is synthesrzed nearlv The disease beenreportedJn only a few cases. has The clinical exclusively from pyruvatefeatutesare heterogeneous, laccicacidemia, with hypoglycmia, The E, defects are caused by mutations in the gene coding for hepatomegaly, hypotonra, der.elopmental deJay,and farlure co E1 a subunit, which is XJinked. Although X-Lnked, its deficiency thrive as the major manifestations. There may be multisyscem is a problem in both males and females, even thor.rgh only 1 E1 invoLvemenc, wlth neuromuscular deficrts, hepatocellular o allele in femalescarriesa mutatiorr. damage,renal dysfunction,and cardiomyopathy. The dragnosis ClinicalManilestations. disease The has a r,r.ide soectrumof oreis basedon the reducedacrivity of PEPCKin liver,6broblasrs, or \entations from the most severeneonatal oresenrarion a mild to

fBt CTOSE-1,5-DIPHOSPHATASE DEFICIENCY Fruccose-.6-diphos1 pharasedefieiencl impairs rhe formarion ol glucoseirom all glucooeogenic precursors, including dietary fructose. Hypoglycemia occurs when glycogen reservesare limited or exhausted. The clinical manifestations are characterzed by life-rhreatening episodes of acidosis, hypoglycemia, hyperventilation, convulsions, and coma. ln about 7. of che cases, the deficiency presents in the 1st wk of life. In infants and srnall children, episodes are triggered b1' febflle inlections and gastroenterrtis if oral ibod inrake decreases.The frequency of the attacks decreaseswith age. Laborarory lindings include low blood glucose, bigh lactate and uric acid lerrls. and metabolic acidosrs. In contrast to bereditary frucrose intolerance, rhere is r-rsually no averslon to s\{'eers; renal rubular and liver functions are normal. The dragnosisis established demonstratingan enzyme defiby ciency in erther liver or intestrnal biopsl', The enzyme defect can also be demonsrrated in leukocytes in some cases. The gene eodrng for frucro.e-1.6 dipho'phata'e rs locatedon chromosom. 9q22; mutarions are characteriz-edmaking carrier detection and prenatal diagnosis possible. Treatment of acute attacks consists of correction of hypoglycemia and acidosis bv inrravenous glucose infusion; the response is usually rapid. Avoidance of fasting, aggressive managemenr of infections and reslriclion of fructose and sucrose from the diet can Dreve[r further eDisodes. For l,'ng-1er6 preventionof hyp'glycemia. a slowll rele.:iedcarbohydrate such as cornslarch is useful. Panents who survive childhood develop normallv.

lymphocytes.Fibroblastsand lymphocytesare not suirablefor diagnosing cl,tosolicform of PEPCKdeficiency the because these tissues possessorly mirochondrial PEPCK. To avoid hypoglycemia,patientsshould be treatedrvirh slow-release carbohydratessuch as cornstarchand fascing should be avoided.

DISORDEBS OF PYRUVATE METABOTISM

Pyruvate is formed from glucose and other monosaccharides, from lacrate, and from alanine. It rs metabolized through 4 main enzyme sysrems: lactate dehydrogenase, alanine aminouansferase, pyruvate carboxylase, and pyruvare dchydrogenase complex. De6crency of the N{ subunit of lactate dehydrogenase causes exercise intolerance and myoglobinuria (see Chaprer 87.1). Genetic deliciency of alanine aminotransferase has not been reported in humans.

. Chapter I Dof.crsio ilo|lholilm ol Carbohydrates 613 S,

Acids UrineOrganic plEsmaacylcamitineprofi19

FanyAcld OxidationOetects

l Propbnic acidemh acidomb i MEthylmalonic Other organic ac*furia i

Metabolic Acidosis

Biotinidass Holocarborylase Eynlhetasedslicbncy

Skinrash/Alopecia

Decraador normalpyruvaie increasedlaclale/pyruvaloralio

Normal02saturation MultisysleminvohEment Red Fibei "Ragged in musde biopsy to Normal low 3 Hydroxy Butyratel Acetoacoiale

lncreased 3 Hydroxy Butyraie: Acetoacetale

mellitus Diabetes

Hyprglycemia

NormalGlycemia No Ketosis
FiBure 87-5. Algorithm of the drflerentiaj diagnosjsof lactic acidosis.

late-onset form. The neonatal onset is associatedwith lethal lactic acidosis, white matter cystic lesions, agenesisof the corpus callosum, and the most severeenzyme deficiency. Infantile onset can be lethal or associatedwith psychomotor retardation and chronic

glutarateand brancheddrogenase complex,but alsoin the cr-keto complexes. Pyruvatedehydrogenchain keto acid dehydrogenase has also beenreported.Theseother asephosphatase deficiency within the variable PDHC defectshave clinical manifestations with PDHC deficiency due to E' deficiency. spectrumassociated in prognosisis poor exceptin rare cases TrestnentThe general with altered affinity for thiamine which mutation is associated pyrophosphate, which may respond to thiamine supplementalactic acidosis, ketoa tion. Because carbohydrates agglavate can The eenicdiet is recommended. diet has beenfound to lower the A 6lood lactatelevel,but limited or no long-termbenefitis seen. potentialtreatmentstrategyis to maintain any residualPDHC in an its activeform by dichloroacetate, inhibitor of Er kinase.Ben-

614| PABT r Mebbolic X Diso.so6 eficial effectsrn controlling postprandiallactic acidosisin some patientshave beenshom, DEFICIENCY PYBUVAIE CABBOXYTASE0F Pvruvatecarboxylase is a mirochondrial.biotin-conraining etuyme essentialin the processof gluconeogenesis; catalyzes conversionof pyruit the vate to oxaloacetate. The enzyme also essential Krebscycle is for function as a provider of oxaloacetate and rs involved in lipogeneslsand formation of nonessential amino acids.Clinical rnanifestationsof this deficielcy have varied from neonatal severe citrulhnemia, lactic acidosisaccompanied hyperammonemia, by (typeB) to late-onset and hyperlysinemia mild to moderatelactic acidosis and developmental delay(typeA).In both types,patients psychomotorretardation with who survivedusually had severe seizures, spasticicy, microcephal,v. and Somepatientshavepathoin Iogic changes the brainstemand basal ganglia that resemble The clnical severityappearsto correlatewrth the Leigh disease. levelof the residualenzymeactivity.A "benign" form of PC defrby ciency charactenzed recurrent attacks of lacric acidosisand mild neurologicdeficitshas also beendescribed. Laboratoryfindings are characterized elevatedlevelsof blood lactate,pyruby vate, alanine, and ketonuria. In the case of type B, blood ammonia, citrulline, and lysine levels are also elevated,which a might suggest primary defectof the urea cycle.The mechanism is likely causedby depletron of oxaloacetate,which leads to reduced levelsof aspartate, substrate argininosuccinate a for synrhetase the urea cycle (seeChapter 85.11).Trearmentconsists in of avoidanceof fasring, and eating a carbohydratemeal before patrents of should bedtime,During acuteepisodes lactic acidosis, receivecontrnuous intravenousglucose.Aspartate and citrate supplements restore the metabolic abnormalities;whether this fieatmentcan preventthe neurologicdeficitsis not known. Liver has transplantation beenattempted; benefitremainsunknown, its Diagnosis pyruvatecarboxylase of deficiency madeby the meais surementof enzymeactivity in liver or cultured skin frbroblasts synthetase or and musr be differentiatedfrom holocarboxylase biotinidasede6ciency. TO DCFICIEI'ICY PYRUVATE OF CARBOXYI.ASE SECOIIOARY DEFICIENCY HOTOCARBOXYIASE OF SYNIfiETASE BIOTIT{IDASE. OR (HCS) or bioDeficiencyof either holocarboxylase synthecase tinidase,whrch are enzymes biotin metabolism,result in mulof ciple carboxylasedefrciency(pyruvate carboxylaseand other brotin-requiringcarboxylasesand metabolic reactions)and in deficiencies. clinical manifestations associated with the resDective and alopeciJ as well as ra'h, iacricacrdosis. iseealso Chaprer can be pro85.6). The courseof HCS or biotinidasedeficiency tracted,with intermitten!exacerbation chronic lactic acidosis, of failure to thrive, seizules,and hypotonia leading to spasticity! lethargy,coma, and death. Late-onsetmilder forms have also been reported, Laboratory findings include metabolic acidosis biotin and abnormalorganicacidsin the urine.In HCS deficiency, in concentrations plasmaand urine are normal. Diagnosiscan be madein skin libroblastsor lymphocytes assayfor HCS activby ity, and in the caseof biotnidase, in the serum by a screening 5blood spot. Treatment consistsof biotin supplementation, if 20 mg/day,and rs generally effective treatmentis startedbefore the developmentof brain damage.Parientsidentifredthrough and wrth biotin haveremained asympnewbornscreening treared tomatic. traits. HCS Both enzymedefciencies are autosomalrecessive and biorinidaseare located on chromosome2'1q22 and 3p25, mutationsin the HCS genehave been respectively. Ethnic-specific identified.Two commonmutations(del7lrns3 and R538C) in the biotinidase geneaccount for 52lo ol all mutant allelesin sympwirh biorinidase tomaucparen15 deficiency. (oX|DATTVE MrTocHoNoRtAr RESPTRAToRY oEFECTS PHoSCHATN PHORYIAflON DISEASE). mitochondrialresoiratorychaincatThe the alyzescheoxidation of fuel molecules and transfers electrons to molecularoxygenwith concomitantenergytransductioninto ATP (oxidativephosphorylation). The respiracory chain produces (NADH) or FADH2 AT? fiom nicotnamide-adenine dinucleoride (l: complexes NADH-coenzymeQ reducand includes5 specific tase; II: succinate-<oenzyme reductase;III: coenzymeQH2 Q V: cytochromeQ reductase; cltochrome C oxidase; ATP synIV rhase).Each compJexis composedof 4-35 individual proteins a[d, wrth the exceptionof complex II (which is encodedsolely is by nucleargenes), encodedby nuclearor mitochondrial DNA (inheritedonly from the mother by mitochondrial inhertance). produce Defectsin any of thesecomplexes assembly or systems presumably chroniclactic acidosis due to a changeof redox state concentrations NADH. In contrast ro PDHC of wrth increased de6ciency', or pyruvatecarboxylase skeletalmuscleand heart are usuallyinvolvedin rherespiratorychain disorders; and in muscle biopsy, "ragged red fibers" (rndicatingmitochondrial proliferation) are often see[ (seeFig.87-5). Because rhe ubiquitous of nature of oxidative phosphorylation,a defect of the mitochondrial respiratorychain accounts a vast array of clinical man for ifestations in and should be considered patientsin all agegroups presenting with multisystem involvement. Some denciencies resemble whereas Leigh disease, otherscause infantile myopathies Iactic suchasMELAS (mitochondrialmyopathy,encephalopathy, MERRF (myoclonusepilepsn acidosis, and strokelikeepisodes), with ragged red frbers), and Kearns-Sa1re s;rrdrome (external ophthalmoplegia,acidosis, retinal degeneration,heart block, myopathy,and high cerebrospinal flr.ridprorein) [Table87-2; see Diagnosis measuremenr alsoChapters 598.2and 610.4]. requires of enzymeactivitiesin tissues analysis mitochondrialDNA or of (mtDNA) mutation, or both (Fig. 87-5). Analysis of oxidatrve phosphorylationcomplexesI-IV from inraccmitochondria isolated from fresh skeletalmuscleis the most sensitiveassayfor mitochondrialdisorders.Specific criteria may assistin making a diagnosis(Table 87-3). Treatmentremainslargely symptomatic and does not significantly aller the outcome of disease. Some patients,however,appear to respondto cofactor supplements, doses. typicallycoenzyme Q10 plus L-carnitineat pharmacologic (SUBAGUTE TEIGH OISEASE NEGROTIZTNG EIICEPHALOMYETOPAis THY).Leigh disease a heterogenous ner:rologicdiseasethat descriptioncharacterized demyeliby remainsa neuropathologic relativeneuronalsparing,and capillary nation, gliosis,necrosis, proliferation in specific brain regrons.In decreasing order of cereseverity, affectedareasare the basalganglia,brainsrem rhe bellum, and celebral cortex (seeChapter 598). The classicprese ation is of an infant who presentswith central hyporoma, developmental regressionor arrest, and signs of brainstem or basal ganglia involvement.The clinical presentationis highly variable.Diagnosisis usuallyconfrrmedby radiologic or pathologic evidence symmetriclesionsaffectingthe basal ganglia, of brainstem,and subthalamicnuclei. Patientswith Leigh disease have defects in several enzyme complexes. Dysfunction in cl.tochrome C oxidase (complex IV) is the mogt commonly reported defect, followed by NADH--coenzvmeQ reductase (complexI), PDHC, and pyruvatecarboxylase. Mutations in the a nuclearSURF1gene,which encodes factor involvedin the biogenesrs clrochrome C oxidaseand mitochondrialDNA mutaof tions in the ATPase6 coding region, are common molecular findings in patientswith Leigh disease.

. IN PENTOSE METABOTTSM 87.5. DEFEGTS

and Priya Kishnani Yuan-Tsong S. Chen

Abour 90% of glucosemetabolismin the body is via the glv colytic pathway, with the remaining 10% via the hexose

I 515 in ol 87 Chapter . Delecls Metabolism Carbohydrates

(IAIIT DITETIONS IN mtDlia S16N5, rl sYltlPTol$5, AND G0ll{Gs ITTRVOUs 5Y5T[M GNTRAL 5e rLrre!

(5S

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MUTATION IN TNA SFER RNA MTRRI ]I4ELA5

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r 616. PARTX Metabolic DisEosos

Figure 87-6. Murations jn the human mitochondial genomethat are known to causedisease. Disorders thar are {requently or prominenlty associated with butadue to murations in a parricular gene are shown in 6old. Diseases due Eo mutations $at imparr mitochondrial prorein synthesis,re sholvn h rl&e. Diseases tions in protin-coding genesare shown in raL ECM, encephalomyopathyiFBSN, familial brlateral stnatal necrosisiLHON, l,eber hereditary optic neuropathyi LS, LeiSh syndJonq MELAS, rnirochondrial encephalomyopathr lacrc acidosis, and srrokelike episodes;MERR4 myoclonic pilepsy with ragged-redlibers; tvlll-S, maternally inherited Leigh syndrome; NARB neuropathy, ataxia, and retinrtis pigmentosa;PEO, progssive external ophthalmoplgiai PPK, palmoplantar keratoderma; and SIDS, sudden infant dearh syndrome. (From DiMauro S, Schon EA: Mirochondrial respirarory-chain disesses.N Engl J Med 2003;348:2656-2668. Copyright @ 2003 Massachusetts Medical Societt All flghts reserved.)

monophosphatepathway. The hexose monophosphateshunr leadsto formation of pentoses, well as providing NADH. One as of the metabolitesis ribose-5-phosphate, which is used in the bioslnthesis of ribonucleotides and deoxTribonucleotides. Through the transketolaseand cransaldolase reactions, the pentose phosphates can be converted back ro fructose-6phosphateand Blucose-6-phosphate. Essential pentosuriais a benigndisorder ESSEIIflAL PEIIITOSUBIA. principally in AshkenaziJews and is an autosomal encountered

trair, The urine contains L-xylulose, which is excreted in increased of amounts because a block in the conversionof Lxylulose to xylitol due to rylitol dehydrogenase deficiency, The condition is usually discoveredaccidentallyin a urine test for no reduci[g substances; treatmentis required. IWt SAIO0|ASE DERGIEXCY. date, only 2 patints are To reported; 1 presented with liver cirrhosisand hepatosplenomegneonatal aly in early infancy and rhe other presented with severe hepatopathy and cardiomyopathy,Biochemical abnormalities

Chapte.07 r Dol.cls ir Mdabolisn ol Carbohydrates r 6lt

revealedelevatedlevelsof arabitol, ribitol, and eythrirol in the demonurine. Enzyme assay in the lymphoblasts/fibroblasts activity,which was confirmedby mutastraredlow transaldolase gene. trons in the transaldolase Only I case has IS0MEBASE DFlClEt{CY RIBOSE-5-PHOSPHATE been reported.The affectedmale had psychomotorretardation epilepsyar 4 yr of age.Therefrom early in life and developed developed,with prominent after, a slow neurologic regression optic atropht and a mild senataxia, somespasricity, cerebellar MRI of the brain at ages11yt and 74 yr sorimotor neuropathy. showed extensiveabnormalitiesof the cerebral white rnatter Proton magnetic resonancespecffoscopy(MRS) of the brain levelsof ribitol and D-arabitol. Thesepentitols revealed elevated in were also increased urine and plasma similar ro the patient found in transaldolasedeficiency.Enzyme assaysin cultured isomerase activfibroblastsshoweddeficientribose-5-phosphate iry which was confirmedby a molecularstudy.

Amatnrano A, Bengur AR, Morse RP, t al: Recombinant human acid alpha glucosidaseenzyne cherapy Ior infanrile glycogen storage diseaserype Il: Resulrsof a phase VII clinical vial. Genet Med 2001;3:132-138. Arad M, Maron BJ, Gorham JM, er al: Glycogen storage disasepresentlng as hypertrophic cardiomyop thy. N Ensl J Me.l 20O5352:362-372 BachrachBE, \gehstein DA, Otbo Melander M, et al: Glycogensynrhasedefirype O) presentingwrth hyperglycemiaand ciency (glycogenstoragedisase glucosuria: Report of rhree new mutarions..l Pedatr Z0n2;1401781-783 Bosch AM, Groorenhuis MA, Bakker HD, er al: Living wrh classicalgalacqualiry of life consequences. Pel,dtli.s rosemiai Heal${elrtd 2 0 0 4 ; 1 I 3 : e 4 2 3 4 2 8 . type II: Chamoles NA, Niizawa G, Blanco M, et a| Glycogen storage disease Enzymat,c screeninsin dried blood spors on fiher paper, CIn Arn Acta 20A347:97-s1tJ2. In Chn YT: Glycogenstorasediseases. krjver CR, BeaudetAL, Sly WS' Valle D leds). The Metabolic and Molecular Bases of lnherited Disease, 8rh ed. New York, Mccraw-Hill, 2001, pp 1521 1551. Cnmi M, Papadlnitrious A, Galbiati S, er al: A new mitochondrial DNA muracion ir ND3 gene caustng severeLeis.h syndrornewjth early lerhality Pediatl Res 2004;5 S:842-846. D Menleir L: DIecrs of pyruvate merabolisrnand the Rrebs cycle.J Child Ne/rol 2002j1 7(Suppl 3):l526-iS34. Den Boer MEJ, Dronisi-Mci C, Chakrapani A, et al: Mitochondrial trifunc' lional protein dficincy:A xvere fany acid oxidation disorder wrth cardiac and neurologic involvement.I Pediatr 2003.742:68a489. N DiMauro S, Schon EA: Mitochondrial respirarory-chain diseases. Engi / Med 2003;3 48:265 6:2668 Res Elpeleg O: Inherited mitochondrial DNA depletion. Pedia, 2003;54:153-159. Franco LM, Krishnamurrhy V, Bali D, t al, Heparocellujar carcinoma in glycogen storage disease rype la: A case series. I lftheit Metab Dis 200Ji28:153-162. carcoa-Cazorla A, De Lonlay ! NassogneMC, er J: l]]n8-tetm follow-up of neonaral rnirochondrial cytaparhies: A study of 57 parients. Pedhttics 2O05t116:1170-1777 . second wind in muscle phosphofrucHaller RG, Vissing J: No spotrraneous tokinase deficiency.Neurclogy 2004\52:82-85. In Holton JB, Waher JH, Tyfield IA, a al: Galacrosemia. ScriverCM, Beauder AL, Sly wS, Valle D (eds):The Metabolic and Molecular Basesof lnherited Diiersd, 8rh ed. New York, Mccrrw-Hill, 2001, pp 1551-1J87 isomerase de6Huck lH, VerhoevenNM, StruysEA, er al: Ribose-s-phosphate with ciency:New inborn error in rhe pentost phosphateparhway associard Genet a slowly progressive leukoencephalopathy: Am J Huft 2004'74:745-751. Hunrsman RJ, Sinclair DB, Bhargava R, Chan A: Atypical presentatioflsof Leigh syndrome:A caseseriesand re"rew, PedratrNeroi 2005;32:33+-340. K,shnani PS, HowelL RR: Pornpe disasein irfants and children. I Pediarl 2004;144:Sl5-S43Livingstone C,.\l Riyalri S, Wilkins P, FernsGA: McArdle's dneasediagnosed followrns statin induced myositis. Affi Clin Biocben 20O4i41tJ38-340. Scaslia R Toqbin JA, Craieehr0q, ec al: Clinical spectrum, morbidity, and Pediattics mortality in 113 pediatnc patients with mitochondrial dtsease. 2004;114:925-931.

I, Scheers Bachy V Stephenne Sokal EM: Risk of hepatocellularcarcinorna X, rn liver rnicochondrial resprratory chain disorders. ,f Pediatr 200511461 4t4417. ShenJJ,Chen YT: Molecular characrerizationofglycogen storagedisease type IIL CUn Mol Med 2002t2:r67-175. ShoffnrJM: Oxidarive phosphorylation diseases. ScDverCR, BeaudetAL, In Sly wS, Valle D (edt: Metabolic and Molecutu Bases of tnherited "r Diseds?,8rh ed, New York, Mcc.aw-H'll, 2001, pp 2367 2423. Strcpoole Pw, Keff DS, BarnesC, et al: Controlled Clinical trial of dichloro atate for rratment oI congenital lacric acidosis in children. Pediatrics 2006i117:1519-1531. Uusimaa J, Finnila S, RemesAM, et al: Molecular epiderniologvof ch:ldhood mitochondrial encephatomyopathres a Finnish population: Sequence in analysisof entire mtDNA of 17 children revealsheteroplasmicmurations in rRNA Arg, tRNAGIU, and IRNA l-eu(UUR) Eenes.Ped.iafti.s 2004;1141 443-450. Van den Hout JMP, KamphovenJHJ, Winkel LPF,et a| Long-term intravenous rratmencoI pompe diseasr with recombinant human cr-glucosidase {tom mtlk. Pediarlrcs2O04;113:e448-<457. VerhoevenNM, Wallor M, H''ckJH, etal:A newborn wrth severe liver failure, cardromyoparhy and transalodase deficrency, / Inhelit Metab Dis 2005128:169-179 . VissingJ, Haller RG: The effectoforal sucrose exercisetolerance,n pariencs on with McArdle's disease. Ensl I Med 2OO3i349:2503-2J09. N Webb AL, Singh RH, Kenndy MJ, Elsas LJ: Verbal dyspraxia and gajacrosemi^. Pediatr Res Z00J;53:396-402. Wber P, Scholl S, Baunganner ER: Ourcome in parientswith profound bioiinidas deficiency:Relevanceofnewborn screening. Deu Med.Child Neurol 2004\46r''81484. Winkel LP, Van den Hout JM, Kamphoven JH, et al: Enzyme replacernent rhrapy in late-onsetPompt disase: three-year Iollow-rp. Ann Neutol A 2004r55:495-502. Zeviad M, Di Donaro S: Ifrcochondridl disorders. Brain 2004;127:

21s31172.

87.6. DISORDERSGTYGOPROTEIN OF DEGRAOATION . MargaretM. McGovern AND STRUCTURE and Robert Oesnick J.
The disordersof glycoproteindegradation and structureinclude several lysosomal in storagediseases result from defects glythat coproteindegradation, and the congenitaldisordersof glycoprotein (CDGs), which are pathophysiologically unrelated. Glycoproteins macromolecules arecomposed oligosacare of that charide chains linked to a peptide backbone.They are synthesized by 2 pathways: the glycosyltransferase path\ray, which s''nthesizes oligosacchandes linked O-glycosidicallyto serrne or lhreonine rsidues;and the dolchol, lipid-linked pathway, which synthesizes oligosaccharides linked N-glycosidically to aspafaSrne. The glycoprotein lysosomalstoragediseases result from the deficiency of the enzymes that normally participare in rhe degradationof oligosaccharides include sialidosis,galactoand sialidosis, aspartylglucosaminuria,and c-mannosidosis. In someinstances! underlyingabnormality that leadsto glycothe protein accumulationalso results in abnormal degradacion of ofher c)asses macromolecules of that cortain similar oligosaccharide linkages,such as certain glycolipidsand proteoglycans. In theseinstances, underlyingenz)'matic rhe deficiency resultsin the accumulationof borh glycoproteinsand glycolipids. The classiEcation theserypes of disordersas liprdosesor glycoof proteinosesis dependenton the nature of the predominantly storedsubstance. general, glycoproteindlsordersare charIn the acterizedby autosomalrecessive inheritanceand a progressive disease those seenin coursewith clinical featuresthat resemble the mucooolvsaccharidoses.

618 r PARTX. MelabolicDiseEse$ SlALlD0SlS AND GAIACTOS|AI|D0SlS. Sialidosisis an aurosomal recessivedisorder that resuks from the orimarv deficiencv of neura m inidasedue ro murarionsin the genethar encodes rhis prorein. which is locared on chromosome 10. In conrrast. salacrosialido' i s i s d u e r o t h e d e f i c i e n co l 2 t y s o s , ' m a l e n z y m e . e u r a m r n i d a r e ) n. and p-galactosidase.The loss of these enz_ymaoc acrivities results from mutations in a gene located on chromosome 20 tbat encodes protective protein/cathepsin A (PPCA), which funcrions to stabilize rhese eozymatic activiries. Neuraminidase normally cleaves terminal sialyl linkages of several oligosaccharides and glycopro teins. Its deficiency results in rhe accumularion of oligosaccharide(, .lnd rhe urinart e\cr.tion of sialic acid rerminal oligosaccharides and sialylglycopeptrdes. Examrnation of tissues from affected individuals reveals pachologic srorage of substrate in many rissuesincluding liver, bone marrow, and brain. The clinical phenotype associated with neuraminidase deficiency is vanable and includes type I sialidosis which usually presents in the 2nd decade of life with mvoclonus and the oresence . , f a e h e r r y r c d s p , , r .T h e s ep a r i e n r rq p i r a l l y e o m e r o j t t e n l o n secondaryto gait disturbances, myoclonus,or visual complaints. In contrast, type II sialidosis occurs as congenital, infanr e, and ;uvenile forms, The congenital and infantile forms result from isolated neuraminidase de6ciencn t'hereas the juvenile form results from boch neuraminidase and B-galactosidase deliciency. The congenital type II disease is characterized bv hydrops fetalis, neonatal ascites, hepacosplenomegaln stippling oi the epiphyses, periosteal cloaking, and srillbirth or death in infancy. The type II infantile form presents in the lst,vr of life with dysosrosis mulriplex, moderate mental recardation, visceromegall, corneal cloud ing, cherr;r red spot, and seizures. The juvenile type II form of sialidosis, which is somerimes designatedgalactosialidosrs, has a variable age of onsec ranging from infancy to adulthood. In infanc;i tbe phenotvpe is similar co thar of GMr gangliosidosis, u.ich edema, ascites, skeleral dysplasia, and cherrv red spot. Parienrsrvirh laler-onsetdiseasehave dvsostosismulriolex. visi e r o m e g a l l .m e n r , r r e r a r d . l i o n .d yr m o r p h i s m .c o r n e a l l o u d i n g , l i progressive neurologic dererioranon, and bilateral cherry red spots. No specific therapv exists ior any form of rhe disease, although studies in animal models have demonstrated improvement in the phenotype after bone marrow rransplantacion. The diagnosis of sialidosis and galactosralidosis achieved by the is demonstration of che specific enzymatic deficiency. Prenacal diagnosis using cultured amnioric cells is also possible. ASPARTYLGIUC0SAMI|'IUR|A {AGU). This is a rare autosomal recessivelysosomal storage disorder, except in Finland, where the carrier frequency is estimaced at l/36. The drsorder results from the deficient activity of aspartylglucosaminidase and rhe subse quent accumulation of aspartylglucosamine, particuLarly in the liver, spleen, and rhyroid. The gene for the enzyme has been localized to tbe Long arm of chromosome 4 and the cDNA has been cloned and sequenced. In the Finnish population, a single mutaoon in the gene (C153S) accounts for most mutaor alleles, rvhereas outside of Finland, a large number of privare mulations have been described- Affected individuals with AGU typicallv present in the 1sc 1r of life w-ith recurrenr infecrions, drarrhea, and hernras.Coarseoingof the facies and short stature usually develop later, Other features include jornt laxity, macroglossia, hoarse voice, crystal-like Lensopacities, hypotonia, and spasciciry. Psychomocor der.elopmenr is usually near normal untrl the age of 5 when a decline rs noted. Behavioral abnormalities are typical and lQ values in affected adults are usually <40. Survival to aduLthoodis common, with most earlv deathsarcributablero p n e u m o n i J o r o t h e r p u l m o n a r v c a u . e s . D e E n i r r v ed i a g n n s i s requires measuremenc of the enzyme in peripheral blood leuko cytes. Molecular diagnosrsby analysis of DNA for the C163S mutation is possiblefor Finnish patien!s. Severalparients have undergone allogeneic bone marrotr,' cransplants, but rhis approach has not been proven effective and no specific treatment rs available. PrenataLdiagnosrs by the determinatron of the level of asparcylglucosaminidase in cultured amniocyres or chorionic villi has been reported. This autosomal recessivedisorder resulcs aS-MANNOSIDOSIS. from the delicient acnvity of q-mannosidase and rhe accr.rmula tion of mannose-rich compounds. The gene encoding the enzyme has been localized to chromosome 19p13.2-q12, although the cDNA has not been cloned. Affected patjents wich rhis drsorder drsplay clinical heterogeneicy.There rs a severe infantile form, or type I disease, and a milder juvenile varianr, type II disease. All parients have psychomotor retardation, facial coarsening, and dysosrosismultiplex. The infantile iorm of the disorder, hou'ever, is characterized by more rapid mental deteriorarion, with death occurring betrl,'een ages of 3 and 10 yr. Parienrs.rvichthe infan the tile form also have more severe skelecal involvement and hepatosplenomegaly. The juvenile drsorder is characterized b;' onser of symptoms rn earll' childhood or adolescencewirh milder somanc features and survival to adulthood. Hearins loss. destruc , r i v e , , y n o v i t i sp a n i \ r o p e n r a .a n d . p a . r i . p a r r p l e g i ah a v e b c e n reported in type II patients, No specific therapv exists for the disorder The diagnosis is made b1' the dernonstrarion of the de6 cieocy of q-mannosidase actrvity in white blood cells or cultured fibroblasts, and prenaral diagnosis has also been achieved. CONGENITAL DISORDEBS GLYG0SYLATI0N 0f These are a {CDGS). heterogenous group of aurosomal recessivedisorders tbac result from defects rn tbe processing and svnthesis of the carbohydrace moiety of glycoprotetns. There are at least 22 jdentiliable disorders; rype Ia is the most common (Table 87-4). One main group includes those rvith defects in biosynthesis or transfer of sugar chains from a lipid hnked oligosaccharide precursor to a nerv protein in rhe endopLasmic reticulum (group Ia to IL). Group II (Ila ro IIf) is characcerjzed by defects in N linked sugar chain Golgi processing. Undefined disorders are cemporarily assigned to group X. A distinctive brochemrcal marker of che disorder rs the pres ence of carbohydrare deficient transferrin in serum and cerebrospinal fluid. The most consisrent clinical t-eatures of the disorder include psychomocor retardarion, which varies in severity, and facial d1'smorphic fearures that rnclude a prominent )a$' and ears and inverted nipples. l'requenc neurologic Endings in infancy include cerebellar atrophy lFiS. 87-7), hypotonia, weakness, hyperreflexia, and strokelike episodes, In chrldhood, ataxia, muscle atrophl, decreased deep cendon reflexes, toe r',alking, and continued strokelike episodes are observed. The latcer events may be related to coagulopathjes characterized by reduced factor XI, protein C, and ancithrombrn III. Strabismus is a consistenr finding and retinitis pigmenrosa rs common. Growth failure, liver dyslunction, retinal degenerationJ and skeletal abnormalities have also been described. The skeletal features can include contractures, kyphoscoliosis, and peccuscar inatun, all of which may be secondaryto rhe neurologic eifeccs of the disorder Pericardral effusion in older patienrs and hvoert r o p h i co b s r r u c L r vcra r d r o m y u p a r hitn r h e i n l a n r a l " o o c c u i Transferrin studies ha.'e also revealed rhar infantile olivooontinecerebellar atrophy is e revcre form ol LDC. Lrpudv'rrophv u'ith prominent fat pads on the buttocks is a dishnchve feature. The disorder should be considered in patients u.ith mental retardation, cerebellar hypoplasia, heparic dysfunction, and episodic scrokelike episodes, and in parienrswith various combrnationsof rhe features detailed in the previous paragraph. The diagnosis can be confirmed by analysis of the transferrin patrern by rsoelecrric focusing. Although prenatal diagnosis by analysis of transferrin has been attempted, rt has not proven reliable. Trcatment of these disorders rs symptomaric, except for CDGIb. whrch responds tcr oral mannose (100-150 mgikgiday ever,v 4 6 hr), and possible CDGIIc, whrch may respond to oral fucose (25 mg/kg/day nd).

ir of 87 chapter r Defects l{otEholism carbohydrdesr 619

622 " PARTX, Metabolic Diseases

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r Chapler | Mucopolysaccharidoses6Ul 88 proThis fbrm of MPS I (lvlPs l-H) rs a severe, HurlerDisease. The clinrcal phenotype of NIPS I IVS is Hurlerscheie Disease. and is characbecweenHurLer and Scheiediseases incermediace rerized by progressive somalic in\.olvemenr, including d,vsostosis multiplex with litrle or no intellectuaIdysfunction.The onset o1 3 sympromsis usuallv observedbetrveen and 8 vr of age;survival ro adulrhood is common. Cardiac involvemeotand upper airu'a,v obstrucrion contribute ro clinical morbidicy. Some pariencshave rvhich nay causecord comptession. spondylolischesis, N{PSI-S is a comparativelymild disorder charScheie0isease. corneal clouding, aortic vah'e disease, accerized jornr stiffness, bv multiplex. Onset of signiGcantsymptoms is and mrld dysostosis usually after the age of 5 vr, rvith diagnosis made betu'een 10 and 20 vr of age. Patients with Scherediseasehave normal rntelligence and srature but har.e significant joint and ocular involvement. A carpal runnel syndrome ofren develops. Ophthalmic features include corneal clouding, glaucoma, and retinal degenerarion. Obstruccive airway disease,causing sleep apnea) develops rn some patients, necessrtating tracheotomy. Aortic valfe disease is ( L , m m o na n d h a r r e q u i r e dv a l v er e p l a c e m e ni t s o m e p a t i e n t i . n

arrery narrowing. Obstructive airway isease, nocably during sleep, may necessicaterracheotomy Ob ructive air',vav disease, respiratory infection. and cardrac compl atiols are the common causesof death. Most chrldren $'tth Hurler s)'rdrome acquire onlv limited lan-

'r.r'irhdentigerous cysts,

ll. Hunter disase(MPS II) is an XMUCOPOLYSACCHARIDOSIS linked disorder caused by che de6cienc,vof iduronate 2-sulfatase (tDS). The gene encoding IDS is mapped to Xq2ll. Point mutain tions of rhe IDS genehave beenderecred abouc807o of patients wirh \4PS IL Major delerions or reatrangements of the IDS gene have been found in the resr; these are usuallv associared wlth a more severeclinical phenotype (see Fig. 88-2). Hunter disease manifestsalmoscexclusrvelyin males; it has been observedin a ferv fernales and this is explained by skeu'ed rnactivarion of che X chromosomecarrying the normal gene. \.larked molecular hecerogeneiw explains the rvrde clinical t'rth severeMPS II have feaspectrum oi Hunrer disease.Paciencs

Irist'c88.]'D-v5ostosismuhiplex.A,sanlilippodiseasc,4lr:T a i o , C , H u r l e r d i s c a s e1 8 m o : . n t e r i o r s u p e t x ) rh y p o p t a s i a f l - - 1 r e s u l t r n gn h o o L - s h a p e d p p e a r a n c e

624 r PABTXr MetabolicDiseases

Figurc 88-4. Dysosrosismu[iplex. A, Mucopolysaccharidos,s(MPS) I'H, 10 yr. The inferior porrions of the jlia are hypoplastic with resufting iliac flare and shatlo{' ace|abular fossae.The femorat necks ar in valgus position. B, MPS I-H, 4 yr. Metacarpals and phalangesare abnormally shorr, wide, and deformed uith proxlmal pointing of the rnetacarpalsand bullet shapd phalanges.Bone trabeculation is coarse and the cortices are thin. C, MPS l-S, 13 yr. The carpal bones are smalJleading to a V-shapedconfguration of rhe digits. The short tubular bones are well rnodeled.Flexion of the middte and dLstalphalangesII-V is causedbv ioint concractures.

tures simllar to those of Hurler disease except for rhe lack of corneal clouding and t}le somewhat slower progression of somatlc and CNS deterioration, Coarse facial features,short multiplex, )oint sriffness, staturerdysostosis and menralretardation manifestbetween2 and 4 yr of age. Grouped skin papules are presentin some patients.ExtensiveMongolian spots have in beenobserved African and Asian patientssincebirth and may storagemay be an early marker oI the disease. Gastrointestinal produce chronic diarrhea. Communicatilg hydrocephalusand In spasticparaplegiamay developdue to thickened meninges. neuroseverelyaffectedpatienls, exrensive!slowly progressive logic involvementprecedes death,which usually occursbetween 10 and 15 yr of age, Patients with the mild form havea prolongedlife span,minimal and slow progression somaticdererioration CNS involvement, of wirh preservationof intelligencein adult life. Survival to ages 65 ar'd 87 yr has been reported; some palients had children, Somatic features are Hurler-like but milder with a greatly reducedrate of progression. Adult height may exceed150cm, Airway involvemen!,valvular cardiac disease, heating impairment, carpal tunnel syndrorne,and joint stiffnessare common and can result in significantlossof function in both the mild and seveleforms. (MPSIII) makes MUCOPOLYSACCHARID0SIS lll. Sanfilippodisease up a generically heterogeneous clinically sirnilar group of 4 but recognized types.Eachtype is causedby a differentenzymede6ciencyinvolvedin the degradation heparansulfate(see of Fig. 881), Mutatlons have beenfound in all the MPS III disordersfor whrch the seneshave beenrsolated.

Phenotypicvariation existsin MPS III patientsbut to a lesser degreethan m other MPS disorders.Patrenrswith Sanfilippo drseaseare characterizedby slowly progressive,severe CNS involvementwith mild somatic disease. Such disoroportionate rnvolvemenr the CNS is uniquero MPS Ill, Onsettf clinical of featuresusuallyoccursbetrveen ar'd, yr in a child who previ2 6 ouslyappeared normal.Presenting features includedelayed development, hyperactivity with aggressivebehavior, coarse hair, hirsutism,sleepdisorders, and mild hepatosplenomegaly Fig. {see 88-2),Delaysin diagnosis MPS III are commondue ro the mild of physical features,hyperactivity,and slowly progressive neurologic disease. neurologjc Severe dereriorarion occurs in most patientsby 5-10 yr of age, accompanied rapid deterioration by of social and adaptiveskills. Severe behavior problemssuch as sleepdisturbance,uncontrolledhyperactivity,temper tantrums, destructivebehavior,and physicalaggression common. Proare found mental retardationand behaviorproblemsoften occur in patientswith normal physicalstrength, parmaking management ticularlv difficult.

lV Morquio disease (MPS IV) is MUCOPOIYSACCHABID0SIS (MPS caused a deficiency N-acetylgalactosamine-5-sulfatase of by (MPS IV-B). Both resuftin the defecIV-A) or of p-galactosidase tive degradarion keratansulfate.The geneencodingN-acerylof galactosamine-5-sulfatase on chromosome 16q24.3 and the is geneencodingp-galactosidase, GlBl, on chromosome 3p2:1.33. p-galactosidase GNoganglioside addition to keratan in catalyzes gansulfare,and mos! mutarionsof GlBl result in generalized

| r ChspterSS Mucopolysaccharidoses625

OIAGl{OSIS DIAGI{OSIS DIFFERE]IITIAT AND

Radiographs chesr, of spine,pelvis,and handsar usefulcodetect Semimultiplex Figs. 88-3 nd 88-4). earlvsigns dysostosrs of {see urrnary GAG excretionare quantitativespot tescs increased for MPS IV-A is usually more severethan MPS lV B, intelligence. *ith idult heightsof <125 cm in the former and >150 cm in the in variability of expression both sublatter.There is considerable grorvth kyphosis. ofgenuavalga. The however. appearance rypes, gartwnh a with shorrrrunk and neck,and waddling riiardaLion tendencyto fall are early symptomsof MPS IV (seeFig. 88-2) includemild cornealclouding,small manifestations Extra skeletal

Vl Maroteaux-Lamy drsease(N{PS MUCOPOTYSACCHARIDOSIS of VI) is caused mutations rhe,4RSBgeneon chromosome by sulfatase(arylsulfa5q11-13 encodingN-acetylgalactosamine-4 by to taseB). It is characterized severe mild somatrcinvolvemenr, as seen in MPS I, but with preservationof intelligence The Vl form of IVIPS is charactersomaticinvolvemenrof the severe ized by corneal clouding, coarsefaci features,lornt stiffness, and cornmunicating drocephalus, dysosvalvular heartdisease, f.,rm.growthcan be In Frg.88-21. the severe rosismultiplex{see t s o b n o r m a lf o r r h e l s t f e w y e a r s l ' l i F e u t s e e m v i r t u a l l y o s r o p forms of Nlaroteaux after aee5-8 yr The mrld to intermediate Spinal wirh Scheie syndrome, irn Lamy Jisease be easilyconfused of from chickening the dura in the upper cercord compression in vical canalwith resultantmyelopathvis a flequent occutrence Vl. palienrswirh IVIPS

ably be diagnosedin serum using monoclonal antibodies to of keratansulfate.Any indivrdualwho is suspected an MPS dis radiographicresults,or urinary order basedon clinical features, established GAG screening testsshouldhavea definitivediagnosis by enzyme assay,Serum, leukocytes,or cultured fibroblasts are used as the tissuesourcefor measuringlysosomalenzymes (see Table 88-2). Prenatal diagnosisis available for all and mucopolysaccharidoses is carriedout on culturedcells from of amniotic fluid or chorionic villus biopsy.Measurement GAGs in amniotic fluid is unreliable.Carrier testing in Hunter syndrome, an X{inked disordeqrequiresanalysisof 1DSgeneonce at.angementin the family the specificmutation or chromosome under considerationis known. Molecular analysisin Patients with other mucopolysaccharidoses rn known carriersrequirs or rationale.Attemptsare beingmadeto developmethods a specrfic tor routrnenewDornscreenlngmanifesrwith the same Mucolipidoses and oligosaccharidoses (see as clinical and radiographicfeatures mucopolysaccharidoses conditions, urinaryexcrethe Chapters 86,4 and 86.5).In these Hurler-hkefacial feais tion of glycosaminoglycans not elevated. mulriplex, and elevated rures, joint contracture!. dysostosis urinary GAG excretiondilferentate the mucopolysaccharidoses from other neurodegenerative dwarfing conditions. and

TBEATMEI{T
Bone marrow transDlantarion from related or unrelated donors or cord blood transplantation results in significant clinical improvement of somatic drsease in MPS I, II, and Vl, Clinical effects include increased life expecta[cy, resolution or improvement of growth failure, heparosplenomegaln joint stiffness, facial appearance, pebbly skin changes in MPS II, obstructive sleep apnea, heart disease,communicaring hydrocephalus, and hearing loss. Enzyme activity in serum and urinary GAG excretion normalize. Transplantation does not significantly improve the neuropsychologic ouccome of MPS patients if there is irnpaired mentation at the time of transplaoration. This is true for MPS IH, II, and III. Patients with MPS I who have undergone transplantation befbre 24mo of age and with a baseline menral derrelopment index >70 have improved long-rerm or:rcome, Early transplantation in MPS Il may have the same effect. Transplantarion in MPS VI stabilizes or improves cardiac manifestations, poslure, and joinr mobility, Stem cell transplantalion does not correct skeletal and ocular anomabes; they have to be treated with appropriare orthopedic and ophthalmologic procedures, Cord blood lransplantalion is the therapy of choice in chrldren with MPS I-H, and possibly MPS lI, before the age of 2 yr, but transplantation-related dearh or primary graft failure, which occurs in =307o of the patients, must be weighed against other therapeutlc optlons. Enzyme replacement uslng recomblnant enzymes is approved for patrents with MPS I, MPS II, and MPS VI. It reduces organomegaln ameliorates rate of grouth and joint mobiliry and reduces rhe number of episodes of sleep apnea and urinary GAG

Vll Sly MUC0P0LYSACCHABID0SIS syndrome(MPSVll) is caused 7q21.11. locaced chromosome on of by mutatrons the GUSBgene intracellular of Mutationsresukin a deficiency p-glucuronidase, fragmentsand a very wide range srorageof glycosaminoglycan as fotm Presenls lelhal The most severe of clinical inr.olvement. in nonimmuneferal hydropsand may be detected utero by ultra

and usual cleal dysostosismultiplex but normal incelligence They may be found incidentallyon the bastsof blood corneae. smearthat showscoarsegranulocvticinclusrons.

b;r is lX.The MUC0P0LYSACCHABIDOSIS disorder caused a muca'

were rhe only radiographicfindings. acetabulae

X 626r PABT r Metrbolic Diseos.s excretion.The nzymes not crossthe blood-brain barrier and do do not prevent deterioration of neurocognitiveinvolvemeot. Consequently, rhis therapy is the domain for patients with mild central nervousinvolvement.To stabilizextlaneuralmanifestations, is also recommended young patientsbeforestem it in cell transplantation.The combination ol enzyrnereplacement therapy and stem cell transplantationmay oIfr the best treatmf,t. Recombinart iduroflate-2-sulfatase amelioratesthe nonnewologic manifestations Hunter disease, of and recombinant N-Ac-gal4-suUatase beensuccessfully has testedin patientswith MPS VI. Prirnary prevention through Beneticcourseling and tertiafy preyentionto avoid or treat complications remainsthe mainstay of supportivepediaric care,Multidisciplinary attentionto respiratory and cardioyascularcomplicatiofls,hearing loss, carpal tunnel syndrome,spinal cord compression, and hydrocephalus, other problemscan greatlyimprovethe qualiry of life for patients nature of cliniand theL families (Tabte88-3). The progressive cal involvementin MPS patientsdictatesthe needfor spcialized and coordinatedevaluation.

Allen JL: Treatmenr of respiratory systm (not just lung) abnormaljties in mucopofysaccharidosis I. J Ped.iatr 20n4;144:561-562. Beesley CE" Meaney CA, Greenland G, et al: Mucational aralysis of 85 mucopolysaccharidosisrype I families: Frequncy of known mu[arjons, identincation of 17 norel mulacions and in viro expression of missense muratioff, Hrrtt Genzt 2O0(;1O9:5Q3-511. BroadheadDM, Kirk JM, Burt d er al: Full expressionof Hunrer's disease in a female with an X-chromomme deletion leading to non-random rnactivati,on. CIin Gerret 19 86i30:392-39 8. Cheng Y, Vrp MS, (nuil I Hibbard JU: Mucopolysaccharidosis ry?e \all as a cause of recu-trena non-immune hydrops fetalis. J Pettwt Med 2003i31:535-537, Fuller M, Rozaklis T, Ramsay SI. et al: Disease-specinc markers for the mucopolysaccharidoces. PeAafi Res 2004\5617 33-738. Grewal SS, Wnn R, Abdenur JE, et al: Safery and effrcacy of enzyme replacemenr rherapy in combitration with hematopoietic stem cell transplantation in Hr:rlet syndrome. Genet Med 2005;7t1,43-146. Harmatz P, Ging[ani R, Schwartz I, et al: Enzyme replacemenr therapy for mucopolysaccharidosis M: A phase 3, randomized, double-blind, placebo-concrolled, multinational study of recombrnant human Nacetylgalactosamin+sulfatase (recombrnant human arylsulfatase Bor RHASB) and fofLow-on, openlabel extension study, J Pediafi 2006;1481 533-539. Harmarz 4 Whitley CV, Waber L, et aJ: Enzyme replecemeot rherapy in mucopolysaccharidosis VI (Maroteaux-lffy syr.&ome). I Pediatr 2004;144574-580, Hershkovitz E, Young Er Cmper A, et al: Bone marrow transpLantatior fo! Maroteaux-Lei$y syndrome.J b herit Metab Dis 1,999t22r5}4z Ito K, Ochiai T, Suzuki H, et al: The effect of haematopoieticsrem cell transplant on papuleswith 'pebbly' apprence in Hunter's syndrome. BrJ Dermatot 2004;15 1:207-271, Meilde PJ, Ranien E, SkLmonsen et al: Newbom screeningfor lysosomal H, srorage disordersr Clinical evaluetion of a two-trer stategy. Ped.iat i.s 2004i714:9O9-914. group of disorders Muenzer J: The rnucopolysaccharidoses: heterogeneous A with variable pediatric prcse$tations. Pedidt 200444:527-533. / on J, Crowhursr J, Carey B, Greed L: Incidence of rhe mucopolysaccharidoses in Vsrern Australia, An J Med Genet A 2003;123A:31G-

313.

Ochiai I lto K Okada T, et aL Significancof extnsiveMonBolian spors in Hunter's syndrome. 8r / Defltutol 2003t148t1173-1178. Robeftson SB Idug GL, Roge6 JG: Cerebrospinal fluid shunts in the management of behavioural problems in Sanflippo syndrome (MPS I ). J Pediatr 1998\157 953-65 5. SouillecG, Guffon N, Maire I, et al: Ourcome of 27 patienrs with Hurler! syndrometransplantedfrom eirher relatedor unrelatdhaemaropoieticstem cell sources.Bonc Marrolr Traflsplant 2003;37:1105-1117. Saba SL, Escolar MI. Po lvt er al: Cord-bJood transplanrs ftom unrelated dono$ in pati$ts with Hurler's syndrome. Nea, Engl I Med 20041350: 1960-1969. Tomatsu S, Okamura K, Takrani T, et al: Development and testrng of new screening method for kelatan sulJate in mucopolysaccharidosis IVA. Pel,dtl Res 2004;55 :592-597 . Triggs-RaineB, Salo TJ, Zh^nE 4 et ^L Mutations in HYAU, a member of a taademly distibured mubigene femily ncoding disparate hyaluronidase activities, cause a newly describd lysosomal disorder, mucopolysacchari dosis IX. Pnc Ndt Acad Sei U S A 199996:62964300 . VeJlodi A, Young E, Cooper A" et a| lrcng-term follow-up following bone marrow transpfantatiotr for Hunler dtsease. J Inheit Dis Meab 1999i221638-548. Vihox \(R: Lysoeomal storage disc,rders: The need for beBer pedianic recognrtion and comprehursive czre. J Pediav 20041,144: S3-S14. WrairlJE, Clarke LA, Beck M: EnzymerepLacment thrapy for mucoFolysaccharidosis I: A randomized, double-blinded, placebo-controlled rnLrltinational study of recombiaant human o-jduronidase \LaronidaseJ. J Ped.iatr 2004j144:581-588.

ilelabolism . 627 89 Chaptoi r Diso.doFof Puiine.nd Pyrimidino nus of rhe proximal tubule, and (4) limited reabsorption near these secretory sites. Thus, renal loss of uric acid is result of renal rube excretion and ls a function of serum ull acid concentration and a homeostatic mechanism to avoid hyperuricemia' Because renal rubule excretion is greater in chrldren than in adults, serum uric acid leve.lsare a less reliable indicator of uric acid production in children than in adults, and consequently, measurement of the level in urine may be required to determlne excessiveproduction. Clearance of a smaller portion of uric acid is via the gastrointestinal tract (biliary and intestinal secretion). Owing to poor solubrlrty of uric acid under rrormal circumstances, uric acid is near the maximal tolerable limrts, and small alteratrons in production or solubility or changes in secretion may result in high serum levels. In renal nsufficiency, urate excretion is increased by residual nephrons an by the gastrointestinal tract lncreased production of uric acid is found in malignancv; Reye syndrome; Down syndrome; psoriasis; sickle cell anemia; cyanotic congenital hearr disease; pancreatic enzyme rePlacement; glycogen storage disease types I, I[, IV, and V1 hereditary fruclose ifltolerance; acyl coenzyme A dehydrogenase deficrency; and eout. The metabolism of both purines and pyrirnidines can be drvided into two biosynthetic parhways and a catabolic pathway. The 1sr, the de novo parhway, involves a multrstep biosynthesis of phosphorylated ring structures from precursors such as CO2, glycine, an glutamne. Pr-rrine and pyrimidine nucleolides are produced om nbose-S-phosphate or carbamyl phosphate, respectively.The second, a single-step salvage pathwav, recovers purine and pyrimidine basesderived from eicher dietary intake or the cataboLc pathway {seeFigs. 89-1, 89-2, and 89-3). In rhe de novo pathway, the nucleosides guaoosrner adenosifle, cylidine, uridine, and thymidine are formed by' che addition of nose 1phosphate to the purine bases guanine or adenine' and to the pyrimrdine bases cytosine, uracil, and thymine. The phosphoryIation of these nucleosides produces monophosphale, diphosphate, and triphosphate nucleotides. Under usual crrcumstances, the salvagepathway predomrnates over the biosynthetic pathway Synthesis is most active in trssues with high rates of cellular turnover, such as gut epithelium, skin, and bone marrow. The

The inherited disorders of purine and pyrimidrne metabolism

Purines are involved rn all biologic processes;all cells require a balanced supply of purines for growrh and survival. They orovide the ptimary source of cellular energy through adenosine irrphosphate (ATI-) and. Logetherwirh pyrimidines' proride rhe source ior the RNA and DNA that stores, tlanscribes, and translates qenetic information. Purines provide the basic coenzymes (NAD-, NADH) for metabolic regulation and play a ma,or role in sisnal transduction (GTl cAMP, cGMP) Metabolically active nucliotides are formed from heterocyclic nitrogen-contarning

Urlc acid is not a specific drseasemarkeq so the cause of its elevation mus! be determined- The level of uric acid present at any time depeflds or the size of the purine nucleotide pool, which rs derived from de novo purine synthesis, catabolisrn of tissue nuclerc acids, and increased rurnover of preformed purines. Uric acid is poorly solubl and must be excteted continuously to avoid ro{ic accumulations in the body. Its renal excretion involves lhe following components: (1) glomerular filtration, (2) reabsorption in rhe proximal coavoluted cubule, (3) secretion near the lermF

Phosphoribosylpyrophosphate (PRPP) synthetase

o o l l l l
OH 1Phosphoribosylpyrophosphate (PRPP)

P-O-P-OH OH

phosphate D-ribose

l ' ' t s u r c 1 )l . E a rl v x e p s r n r h e b i o s ln t h e ' r so f 8 rhe purine ring.

c\
N/

OH I

c c

nr

cH <reactions Numrous 5-Phosphoribosylamine

Inosin-5rphosphate (lnosinic IMP) acid,

628r PART I Motabolic X Diseases DNA <synthesis

RNA

dGTP

+
I

Feedback inhibition -----

De novo ---> synthesis

Feedback inhibition

DNA dATP -----t- synthesis

I

<synthesis

GTP

ATP ---------> synthesis

I I

RNA

-----+ --_-rInosinic acid -+ (rMP) Adenosine deaminase

Adenylicacic phosphoribosyl Adenine transterase iciency def

I Y

deficiency
FAdenosine

Guanosine

I I
{ o

Hypoxanthineguanrne PRPP lransferase

q Hypoxanlhine riboside (lnosine)

NH,

t + Phosphoribosyllpyrophosphate (PRPP)

+ PRPP + PRPP Hypoxanthine oxidase _lXanthine

Adenine

t I

Ribose-s-phosphate + ATP

o I

T I

H Xanthine Figurc89-2. Parhways purinemerabolism saLvaBe. in and

H Uric acid

third pathway is catabolism.The end product of the catabolc pathway of the purinesis uric acid,whereas of catabolism pyrimidinesproducescitric acid cycleintermediates. Only a small fraction of the purines turned over each day are degradedand excreted. lnborn errorsin the synthesis purine nucleotides of include:(1) phosphoribosylpyrophosphatesynthetase superactivi!y, (2) adenylosuccinase defrciencnand (3) 5-amino-4-imizolecarbox(AICA-ribosiduria).Disorders amide (AICA) riboside deficiency resulting from abnormalitiesrn purine catabolismincluder (4) (AMP) deaminase muscleadenosine monophosphate deficiencn (5) adenosine (6) phosdeaminase deficrency, purine nucleoside phorylasedeficiency, and (7) xanthineoxidoreductase deficiency. Disordersresultingfrom the purine salvage pathway includer(8) (HPRT) deliphosphoribosyltransferase hypoxanthine-guanine (APRT) ciency, and (9) adenine phosphoribosyltransferase Genclency, Inborn errors of pyrimidine metabolisminclude disordersof p1'rimidinesynthesis and of pyrimidine nucleotidedegradation. Disorders nclude: (1) hereditary orotic aciduria {uridine monophosphacesynrhase deficiency), (2) dihydropyrimidine (DPD) defrciencl', dihydropyrimidinase (3) (DPH) dehydrogenase (5) deficiencS(4) p-ureidopropionase deficiency, UMPH-1 deficiency (previously pyrimidine S'-nucleoridase deficiency), (5) pyrimidine nucleosidedeplerion and overactive cytosolic 5r (7) nucleotidase, thymidinekinase2 defrciency, (8) thymidine and phosphorylase ciency. defi

GOUT
Gout presentswith hyperuricemia,uric acid nephrolithiasis, and acute inflammatory arthritis. Gouty arthritis is due to monosodiumuracecrystaldeposits that result in nflammation in joints and surrounding tissues.The presentationis most comjoint monly monoarticulai,typically in the metatarsophalangeal of the big toe.Tophi, deposrts monosodium of urate cryscals, may occur over poirits of insertion of tendonsar the elbows, knees, and feet or over the helix of the ears.Primary gout, ordinarily occurring in middle-agedmen, resultsfrom overproductionof uric acid,decreased renalexcretionof uric acid,or both. The brochernical etiology of gout is unknown for most of thoseaffected, and it is considered be a polygenictrait. When hyperuricemia to and gout occur in childhood,rt is most often secondary gout, che result of another drsorderin which there is raprd tissue break dort'n or cellularturnoverleadingro increased producrionof decreased excretion of uric acid. Gout occurs in any condirion that leadsto reducedclearance unc acid: during therapy for of malignancy or wrth dehydration, Iactic acidosis,ketoacidosis, starvation, diuretic therapy, and renal shutdown. Excessive purine, alcohol,or carbohydrate ingestionmay increase uric acid tevels, with hereditarydisordersin rhreedifferent Gout is associated enzymedisordersthar result in hyperuricemia. Theseinclude the severe form of HPRT deficiency (Lesch-Nyhandisease)and

Met.bolisn r 629 Chapter r oisoidersol Purin. and Pydmidine 89

cooH I NH, CH, t - t c-:o-Hc-cooH

N H

OH
--------->

Nz"'cH. | |

O:C.rr.,C$!O"
Dihydroorotic acid

/*Carbamyl-L-aspartaie
Feedback inhibiiion or rcpress|on

.,

\nu

co2+

I I

-vn

ll

UMPSynthase (Orotidylic acid , . decarboxylase) +1f-

I *zc-c" t t l O:C\N,,-C-cooH
ribossphosphate

OH

phosphate ribose (UlvlP) 5'-monophosPhate uridine

Y

orotidine-5honophosphale (OMP)

Orotic acid

I
RNA

CTP l--------+and DNA dCTP I synthesis dTTPI

Figure 89-3. Pathways in pyrimidine biosynthesrs.

UTPI

diminished renal excretion of urate. Glycogen storage disease types III, Y nd VII are associated with exercise-induced hyperuricemia, th consequenceof rapid ATP urilization and failure to regenerate it effectively during exercise (see Chapter 87 1). Autosomal dominant iuvenile hyperuricemia, goury arthritis,

Treatmentof hypenricemia involvesthe combinarionof allopuric acid prourinal (a xanthine oxidaseinhibitor) to decrease in duction. probenecid increase to uric acid clearance thosewrth the normal rinal function, alkalinizationof the urine to increase fluid intake to reducethe solubiliw of uric acid. and increased concentrationof uric acid. A low-purine diet, weight reduction, and reducedalcohol inrake are recommended.

IN PURII{E SATVAGE ABiIOBMALIIIES

LESCH-NYHAN DISEASE llJ{D}.This is a rare Xiinked disorderof purine metabolism that results from HPRT deficiency.This in enzyme normally present eachcell in the bodn but its highesr is in concentration in the brain, especially the basalganglia.Clinis include hyperuricemia, intellectualdisabiliry ical manifestations dystonic movement disorder that may be accompanied by and dysarthricspeech, cornpulsive and choreoathetosis spasticiry, self-biting,usually beginningwith the eruption of teeth, of There are severalclinical presentations HPRT delicienry. HPRT levelsare relatedto the extent of motor symptoms,to the presence absence self-injury, or of and possiblyto the levelof cognitive function. The majority of individuals with classicLND Partial defilevelsof the HPRT enzyme. havelow or undetectable syndrome)with >1.5-2.0Y' ciency in HPRT (Kelley-Seegmiller with hyperuricemia and variableneurologic enzymeis associated with HPRT deliciency). HPRT defrciency dysfuncrion(neurologic >87oleadsto a severe form o{ gout, with apparentlynormal levels althoughcogcerebral functioning(HPRl-relaredhyperuricemia) nidve deficits may occur. Qualitarively similar cognitive deficit Variorofileshave beenreportedin both LND and variant cases. ints produced sco.is that are intermediateberweenthose of

ulin-associated kidney disease(IJAKD) has been proposed. Unlike the three inhented purine disorders that are X-linked and the recessively inherited glycogen storage disease, these are autosomal dominant conditions. Familial iuvenile gout or familial juve-

nephropa thy.

630 r PARTXr Mdabolic Diseases patients u'lth LND and normal controls oo nearly everv neuropsychologic measure tested. Genetics. The H?RT gene has been localized ro the long arm of the X chromosome (q26-q27). The complete amino acrd sequence for HPRT is known (=a4 kb; 9 exons). The drsorder appears in males; occurrence rn lemales is excremelv rare and ascribed to nonrandom lnactivation of the normal X chromosome. Absence r.:f HPRT prevents che normal merabolism of hl.poxanthine resulting in excessive uric acid producrion and rnanifestations of gout, necessltating specilic drug treatmenr (allopurinol). Because of the enzyme deficiency, hypoxanthine accumulates in the cerebrospinal fluid, but uric acid does not; uric acid rs not produced in the brain and does nol cross the bloodbrain barrier, The behavior drsorder is no! caused by hyperuricemia or excess hypoxanthine because patients with partial HPRT deliciencl rhe variant$ with hyperuricemia, do not selfiinjure and infants having isolared hyperuricemia from birth do not develop self-iniurious behaviorThe prevalence of the classic Lesch-Nyhan disease has been estimated ar 1/100,000 co 1/380,000. The rncidenceof partial variants ls no! known. Those with classic LND rarely surwive the trd decadebecau"eof renal or respirator) compromise.The liie span rnay be normal for patiertts with partial HPRT deficiency without severe renal involvement. Parhology.No specific brain abnormality rs documented after detailed histopathology and elecrron mrcroscopy of affected brain regrons. Magnetic resonance imaging has docunenred reductions in the volume of basal ganglia nuclei. Abnormalities in neurotransmitter metabolism have been idenri6ed in three autopsied cases.All three patients had very low HPRT levels (<1ol" rn striatal tjssue and 1-2Y" of control n thalamus and cortex). There was a functional loss of 65-90% of che nigrostriatal and mesolimbic dopamine terminals, although the cells of origin rn rhe substantia nigra did not show dopamine reduccion. The brain regions primarily involved were the caudare ntrcleus, putamen, and nucleus accumbens. It is proposed chat the neurochemical changes ma,v be linked to functional abnormalities, possrbly resulting from a djminution of arborization or branching of dendrites rarher than cell loss. A neurotransmitter abnormalrty is demonsrrared by changes in cerebral spinal flurd neurotransmitters and their metabolites, and confrrmed bv posrtron emission tomography scans o[ dopamine {unction. Reductions in vrvo in the presynapric dopamine transporrer have been documented in rhe caudate and putamen of six individuals. The mechanism whereby HPRT leads to the neurologic and behavroral symptoms is unknown. Borh hypoxanthine and guanine metabolism is affected; guanosine triphosphate {GTP) and adenosine have substantial effects on neural tissues. There is a functional link betra'eenpurine nucleotrdes and the dopamine system that involves guanine, the precursor of GTP Dopamine brnding to its receptor results in either an activatron (Dr receptor) or an inhrbition (D2 receptor) of adenylcyclase. Both receptor effects are medrated by G proreins (CTP-binding proteins) dependenc on guanosine diphosphate (GDP) in the GDP/GTP exchange for cellular activation. Dopamrne and adenosine s,vstemsare also linked through the role of adenosine as a neuroprotective agent ln preventi[g neurotoxiciry Adenosrne asonists mimic the biochemical and behavioral actions of d6pamine antagonrsts, whereas adenosine receptor antagonists act as funcrional dopamine agonists. Dopamine reduction in brain is documented in HPRT deficienr strains of mutant mice. Clinical Mani{estati0ns. At birrh, infants wirh LND have no apparent neurologic dysfunction. After several months, develop mental delan intellectual disabilicy, and neurologic signs become apparenl. Beforerhe age of 4 mo. hyporonia. recurrent vomiting. and difficulty r,'ith secretions may be nored. By =8-12 mo, extrapyramidal signs appear, prirnarily dystonic movemenrs. In some cases! spastrcity may become apparent at this time or, in some instalcest later in life. Cognirive function is usually reported to be in che nild-comoderate range of rntellectual disability, alchough some indrviduals test ln che low normal range. Because test scores may be influenced by drfficultv m tesdng rhe sub,ects owing to their movement disorder and dysarthric speech, overall inrelligence may be underestimated. The age of onset of self-injury may be as early as 1 vr and, occasionally, as late as rhe teens. Self-injury occurs, although all sensory modalities, including pain, are intact- The self inlurious behar.ior usually begins with sel{-biring, although other patterns of self-injunous [rehavior emerge wrth time. Most characteristrcalln the fingers, mourh, and buccal mucosa are mutilated. Self biting is intense and causes tissue damage and may result ln rhe amputation of fingers and substanrial loss of rissue around the lips (Frg. 89-4). Extraction ol primary reerh may be required. The biting parrern can be asymmetric, with preferentral mutilation of the left or righr side of rhe bodl'. The cype of behavior is different from rhar seen in other intellecrual disability slrndromes involving self-rnjury; self-hitting and head banging are the most common initial presenrationsin other s)'ndromes.The inrensiry of the self-injurious behavior generally requires chat the parient be restrained. When restrajnts are removed, the individual rvitl LNI) may appear terfified, and stereot)?icalll' place a 6nger in chemouth. The patient may ask for restraints to prevent elbow movement; when the resrraints are placed or replaced, the patrent may appear telaxed and better humored. Dysarthlc speech may cause rnlerpe$onal commumcation problems; chehigher-functioning children can express themselvesfully and participate in verbal rherap1.. The self-mutilation presenrs as a compulsive behavior that the child tries to conrrol bur frequently is unable to resist. Older rndividuals may enlist the help of others and notify them when they are comfortable enough ro have restuaints removed. In some instances, the behavior may lead to deliberate self-harm. Indr viduals with LND may also show compulsive aggressron and inflict injur,v to others through pinching, grabbing, or hitting or by using verbal fotms of aggressron.Afterwards thev may apologize, stating that rheir behavior was out of their concrol. Orher maladaptive behaviors include head or lrrnb banging, eye poking, and psvchogeoic vomiting. Diagflosis.The presenceof dystonia along wirh self-mutilation of the mouth and frngers suggests Lesch-Nyhan disease. With partial HPRT deficiency', recognition is linked to either hyperuricemia alone or hyperuricemia and a dystofllc movemenr disorder. Serum levels of uric acid >4-5 ms uric acid/dl- and a urine uric acrdrcreatininrratro oi 3:4 or more are highly sugge'tive of HPRT deficrenc%particularl)' when associated wirh neurologic symptoms. The defininve diagnosis requires an analysis of che HPRT enzyme. This is assayed in an erythrocyte lysare, Individuals wrth classic LND have near 07o enzvme activity and r r h o s ew i L hp . r r l i J lv a r i a n r s h u w v a l u e s e t w e e nl . i q . a n d 6 0 o b . b The intact cell HPRT assal' rn skin fibroblasts offers a good correlation benveen enzyme acrivity and the severity of the disease. are M-olecular rcchniqr-res used tbr gene sequencrng and rhe identrfrcatton ot catflers, Di{ferential diagnosis includes other causes of infanhle hypotonra and dystonia. Children with LND are often initially incorrectly diagnosed as having athetoid cerebral palsy. !' hen a diagnosis of cerebral palsy is suspectedin an infanr with a normal prenatal, perinatal, and postnatal course, LND should be considered. Patial HPRT deliciency may be associated u.ith acute renal failure in infancy; therefore, clinical awareness of partial HPRT deficiency i5 of parricular importance. An understanding of che molecular disorder has led to effective drug treatrnent for uric acrd accumulation and anhritic tophr, renal srones, and neuroparhy. Reduction rn uric acid alone does not rnfluence the neurologic and behavioral aspects of LND, Despire rreatment from birth for uric acid elevation, behavroral and neurologic sydptoms are unaffected. The most srgmficanr complications of LND are renal farlure and self-mutilatxrn-

Motabolismr 631 S9 ChoDter . Diso.dFofPuiine end Pyrimidino

Figurc 89-4. SelI-iniurv in LeschTissue damaBero the Nyhan disease. lip 1Al and fineers fBl was self inflicrd. Managernent o{ rhis problem requires covering any dangerous porcions of rhe wheelchair in with combinarion Protectrve resuaints fcl. (From Visser JL Bar PR, Jinah HA: Lesch-Nyhan disease and the basal ganglia. BlaillRes Rer

5.) 2000;32:449a7

Medical management of this disorder focuses on the Treabnent.

ble. Self-mutilation is reduced through behavior management and the use of restraints, removal of reeth, or boch. Injection of bor ulism toxin into the masseter muscles was useful in one patient. Pharmacologic approacbes to dectease anxiety and spasticity rvith medication have mixed results. Drug cherapy focuses on svmptomaric managementof antrcrpatoryanxiery, mood srabilirarion, and reduction of self-iniuriousbehavior.Diazepam may be helpful for anxiety symptoms' and calbamazePine ol gabapentin for mood srabilization. Each of these medications may ieduce self-injuriousbehavior by helprng ro reduce anriery and srabilize mood.

have nor proved alone, using operalt conditioning approaches, ro be an adequategeneraltratment.Altl,ough behavioralprosuccess reducingself-injury, in cedureshave had some selecti*'e generalization outside the experimental setting limits this may revert to their previous approachand palients under stress may also focus on behavior. Behavioral approaches self-injunous reducing the self-injuriousbehavior rhrough the treatment of phobic anxiety associated with berng unrestrained,The rnost extinction, common techniquesare systematicdesensitization, and differentral rernforcementof other (competing)behavior. to has beenrecommended assistpatieDtsto Stressmanagement Individualswith LND copingmechanisms. developrnoreeffecrive do not respondto contingentelectric shock or sirnilar aversive An in behavioralmeasures. increase self-injurynay be observed mechods utilized. are when aversive ate Restrainr(day and night) and dental procedures common meansto prevent self-injury.The time in restraintsis linked to Childrenwith LND can participate the ageof onsetof self-injury. restrairtsand the typeof restrainrs. in makingdecisions regarding wrth systematic The time in resrraints may potentiallybe reduced programs.Many patientshaveteethextracted behaviortreatment ro prevent self-injury. Others use a protective mouth guard reduclion that stress designed a dennst.Most parentssuggest by and awareness the patient's nedsare the mosc effectivein of of reducingself-injury.Positrve behavioraltechniques rernforcing behavior are rated effectiveby almost half of the lppropriate
taml11es,

the birth of an unaffected male infant. Both the motivation for self-injury and its biologic basis must be addressed in creatment programs. Yet behavioral techniques

ADENINEPHOSPHORIBOSYTTRANSFERASE {APRTI DCFICIEI{CY. the of enzyme, catalyzes synthesis AMP APRI a purinesalvage (PP-nbosefromadenine 5-phosphoribosyl-1-pyrophosphate and of results the inabihtyto utilize in P),The absence this enzyme
adenine and accumulated adenine being oxidized by xanthine dehydrogenase co 2,8-dihydroxyadenine, which is extremely

GP I PABT r Metabolic X Diseases rnsoluble. APRT deficrencyis presenr from birth, becoming apparentas early as 5 mo and as late as the 7rh decade.Genetics:The disorderis an autosomalrecessive with considerable ior have been described.Heterozygousfemale rriers may trait clinical heterogeneicy. AIDRTgeneis locatedon chromosome also developgout and hearing impairment.The la juvenileto The 16q (16q24.3) and encompasses kb of genomrc 2.8 DNA, There earlv adult onset type is found in maleswho show gour or uric is an APRT knockout mouse model that replicares the disease a c i d u r o l i r h i a r r s r n o n e u r o l o g i c : i g nA . m e c h a n i . m r r h e bu s fo process. Clinical manifestations include urinary calculusformaneurologic symptomsis unknown. Laboratory findings: Blood tion rvich crystalluria,urinary tract infecrions,hemaruria,renal uric acid may be two to three times normal values, and the coLic, dysuria,and acuterenal failLrte. The presence brownish of urinary excretion of uric acid is increased.The diagnosis spors on the infant's diaper or of yellorv-browncrystalsin the requires enzyme analysis erythrocytes of and cultured6broblasts. urine is suggestive the diagnosis, of Laboratory findings:Urinary This disorder must be drfferentiatedfrom partial HPRT defrlevels adenine, hydroxyadenine, 2,8-dihydroxyadenine ciencyinvolving the salvage of 8 and parhwan which also resulrsin neuare elevated, plasmauric acid rs normal. The deficiency r:ologicHPRT deficiencyor hyperuricemiawithout neurologic rvhereas mav be complete(typeI) or pardal (typeII); rhe partial deficiency leatures, is reportedin Japan.The diagnosis madebasedon chelevelof is Treatmentis wirh allopurinol,which inhrbitsxanthineoxidase, residualenzymein erythrocytelysates.The renal calcuJi,comthe last enzymeof the purine catabolicpathwav.Uric acrd pro posedof 2,8-dihydroxyadenine, radiolucent,soft, and easily are duction is reducedand is replacedby hypoxanthine,which is crushed. These stones are not distineuishablefrom uric acid more soluble, than xanthine. The initial dose of allopurinol is \tone\ hv routinetesrsbur requirehigh-pressure liquid chro 10-20 mg/kgl24hr in children and is adjusted ro maintain matographv(HPLC), ultravroletor infrared radiation detection, normal unc acid levelsin plasma.Occasionallnxanthinecalculi (MS), x-ray crysrallography, capillaryelecmassspectroscopy or may form. Consequently, low-purine diet (one free of organ a particularlyto distinguishfrom stones meats,dried beans,and sardines), trophoresis diagnosis, for high llurd intake, and alkalinin HPRT defrciency. rzahon of the urine ro establisha urinary pH of 6.0-6.5 rs necTreatmentincludes high fluid intake, dietarvpurine resrnction, es.ar). These mea'urt's.onrrol rhe hypiruricemiaand ur.rre and allopunnol, which inhibits the conversionof adenineto irs neuropathybut do not affect the neurologicsymptomsThere is metaboltes, further2,8-dihydroxyadenine excrerion, fufther and no known treatmenrfor the neurologiccomplications. stone formation. Alkahnization of tbe urine is ro be avoided, because, unJike that of uric acid,the solubiJity 2,8-dihydroxof does not increase up to a pH of 9. Shock-wave ,vadenrne lithotnpsy has been reported to be successful. The prognosis ADENYT0SUCCINATE (ADSt) TYASE DEFICIENCY. is an inherThis dependson renal function at the rime of diagnosis. Early treat ired deficiency de novo purine synthesis humans.Adenyloof in ment is critical rn the preventionof stonesbecause severe renal succlnase lyaseis an enzymethat catalyzes two pathwaysin de insuffrciency may accompanv late recognrtron. rovo synthesis purinenucleotide and recycling. Thesearethe conversion of succinvlaminoimidazole carboxamide ribotide (SAICAR) rnto aminormidazole carboxamrdenbotide (AICAR) in the de novo synthesis purine nucleotides, of and the conver(S-AMP) inro adenosinemonophossion of adenylosuccinare phare (AMP); the latter is the 2nd step in the conversionof DISORDEBS TINKED PURINEUCTEOTIDE TO (llvlP) rnto AMP in the purinenucleotrde inosinemonophosphate SYNTHESIS cycle.ADSL deEciency resultsin rhe accumulation urine,cerein brospinalfluid, and, ro a smaller extent, in plasma,of SAICA PHOSPHORIBOSYTPYBOPHOSPHATE (SAICAT) succrnyladenosine (S-Ado), SYNTHSTASE SUPEB- riboside and {PBPPI dephosphoryAGTIVITY. is a substrate PRPP involved the synlhesis essen- lated derivativesof SAICAR and S-AMP,respectivel)'. in of Genefics: trallyall nucleotides irnportant rhe regulation rhe de and rn of Thrs is an autosomal recessive disorder; the gene has been novo parh!{'ays purineand pyrirnidine of nucleotide svnthesis. mapped chromosome to 22q13.1-q13.2 =20 genemutations and produces This enzyme PRPP from rjbose-S-phosphate ATI and havebeenidentified.Laboratoryinvestigations shor,r,. presence the asshown Figures in 89-1and89-2-PRPP the 1sc is intermediary in urine and cerebrospinal fluid of succinylpurines, which are norcompound in the de novo synchesis purine nucleotides rhat lead of mally undetectable. !o the formatron of inosine monophosphace. Superactivrty of the Clinical manifestarions include varying degrees psychomo of enzyme results in an increased generation of PRPP BecausePRPP ror retardation, generally accompaniedby a seizure disorder amidotransferase, the 1st enz;.me of the de novo pathwan rs not and/or aulistic like behaviors(poor eye contacr and repetitive phvsiologically saturated by PRPP, the synrhesis of purine behaviors).Neonaral seizuresand a severeinfantile eoileoric nucleorides increases, and, consequently, the production of uric encephalopathy oftenrhe lsLmanifestarions thi. disorder. are of acid is increased. PRPP s;rnthetasesuperactlvity is one of the few Others demonstratemoderate to severeintellectual drsabilicv hereditar;,''djsorders in which there is enhancement of the acrrvwirh growth rerardarion mu,elehypr. 50metimes as.ociared and rty oi an enzyme. ronia. One reportedcase,a girl, testedin rhe mild rangeof incel Genetics: Phosphoribosylpyrophosphare synthetase (PRS) lectual disability.The form with prolound inrellectualdisabiliry superactivity is inherited as an X-linked rrait and presencswith hasbeendesignated rype I, the variant casewirh mild intellectual two clinical phenotypes with varying degrees of severicl'. Three disabrliryas type II. Other patientshave an intermediate clinical drstinct PRS cDNAs have been cloned and sequenced.Two forrns symptom pattern with moderatelydelayedpsychomotordevelare X lrnked to Xq22-924 ar'd,Xp22.2-p,22.3 (escapesX inacriopment,seizures, stereorypies, agiration,Pathology:CT and and vation), respectively, and are widely expressed; rhe third maps to MRI of the brain may show hypocrophyor hypoplasiaof the human chromosome 7 and appears to be transcribed only in rhe particularlythe vermis,It is proposed cerebellum, rhat rarherthan testes.Even though the defect is X linked rt should be considered being causedby purine nucleotidedeficiency, symptomsare the in a child or voung adult of either sex with hyperuricemra and/or due co the neurotoxic effectsof accumulatingsuccinylpurines. hyperuricosuria and normal HPRT acrivrty in lysed red cells. The ratio of S-Ado/SAICAT beenlinked ro phenotypeseverhas Clinical manifestatioos in the more severe tvDe in affected hemity suggesting that SAICATjs the more toxic compoundand that izygousmales rncludr signsof uric acid overproductronrhar are S-Ado might be neuroprorective, The laboratory diagnosisis apparent n infancy or early childhood, neurodevelopmental basedon the presence urine and cerebrospinal rn fluid of SAICAT

! MetEbolisrn633 ol and 89 Chapter r Disorders Purinr Pyrinidine exercrse for mav be screened by performingrhe forearmischemic test.The normal elevationof venousplasmaammoniaafter exeris in rn ciserhat is seen normalsubjects absent AMP deaminase or rs The 6nal diagnosrs made by histochemical biodeliciency. The primary fotm is distinof chemrcalassays a musclebiops,v. guishedby the linding of enzymelevels<2% $,'ith little or no immunoprecipirable enzyme.Affe ed individualsare advisedto and myoglo(AICA) DEFICIENCY exercisewith caution to prevenr habdomyolysts RIB0SIDE cARB0xAMIDE 5-AMlt{0-4-lMl0Az0tf binuria- Although rhereare no documelted fully effectiveueatments, ir has been proposed thac enhancing the rate of replenishment the ATP pool might be beneficial.Using this of rationale, treatmentwirh ribose (2-60 gl24 hr orall,v,in divided to or doses) xylirol, whrch is converred nbose,has beenreported bur is and musclestrengthin somecases cycLohv- to improve endurance by chebifunctionalenzymeAICAR transformylase/llvlP ma-vbe leasiblein the ineffeccive others, Geneticapproaches in (ATIC). The transformylase deficienrin fibroblastsin is diolase whereastreatmentof the Lrnderlving future for inherited cases, Thts is an inborn error of purine biosynthis disorder.Genetics: ln cascs. conditionis essential secondatv by a muration of ATIC geneeffectingAICAR transthesiscaused was AICAR rran'formyla'e case, form'la'e actrvitl.ln a reported ev l p r o f o u n d l d e 6 c i e n w h e r e at.h e I M P c y c l o h y d r o l als e e w a t y r, in The disorderis described a 407" of no.-"I. Clinical features: See DEFICIENCY Chapter125.1 A0EN0SINE DEAMINASE
and S-Ado; both are usually undetectable. No successtul tfeatment has been demonstrared for this disorder Prenatal diagnosis has been reporced, Systematic screening lvrth the Brarcon-Marshall test isiuggested in infancs and children with unexplarned psychomotor retardation and/or seizure disorders

See DEFICIENCY Chapter PURllttE NUCtEoSIDE PH0SPHoRYIASE t25-2. treatmentis described. der No successful

IN FROM RESUTTING ABiIORMATITIES OISOROERS CATAEOTISM PURIiIE

(MUSCtE AOENOSINE DEAMII{ASE OEFICIENCY MYOADENYTATE Myoadenvlare deam0EAMlf{ASE DFlClEf{GY). MOItI0PH0SPHATE inase rs a muscle-specific isoenzyme of AMP deaminase that is active in skeletal muscle. Dunng exercise! lhe deamination of AMP leads to increased levels of IMP and ammonia in propor-

ical manifestarions are, most commonly, isolated muscle weakness, fatrgue, m,valgrasafter moderate to-vtgorous exerclse' with an increasedserum or cramps. Myalgias may be assocrared abnorelecrromyelographic creatine kinase level and derecrabLe

tion durrns muscle contraction. lt is unclear how individuals mal' carry the Jencit and be asymptomatic.In addition to muscledysfunction, a mutation of liver AMP deaminase has been proposed as a cause of pflmarv gout, leading to overproductron of uric acid. The inherited form of rhe disorder is an autosomal recessrve vart. AMP-DI, the gene responsible for encoding muscle AMP deaminase, is located on the short arm of chromosome 1 (1p13 2l). Population rudres reveal that chis mutanc allele is found at high frequenc in Caucasian popLrlations. The disorder

DEFICIEiICY HEREOITARY XANTHINXANTHII{EOXIDOREDUCTASE Xanthine oxrdoreDEFICIENCY C0FACTOB UBIAAI0tYBDEt{UM ductase(XOR) is the catalyLc enzymein che frnal step of the purrne catabolicpathway and oxideshypoxanthineto xanthrne XOR exisrsrn rwo forms,xanand xanthrnero uric acid.Because thine dehydrogenase and xanthine oxidase, the deficiency rs oxidase also referred to as xanchine debydrogenase/xanrhrne (XDHD(O) deficiency. precursorof uric Xanthrne,rhe rmmediate of acid, rs lesssolublethan uric acid in urine and de6ciency rhe enzyme results rn xanthinuria. Xanrhine oxidoreductasedefimay occur in ao isolatedform {xanrhinuriatype l), rn a cienc-v and deficiency combinedform involving xanthineoxidoreductase aldehydeoxidasedeficiency(xanthinuria rype Il), or in a comaldehyde of binedform with deficrency xanthineoxidoreduccase, oxidase,and sulfite oxidase (molybdenumcofacror defrciency). of The isolatedform resultsin an alrnost total reDlacement uric c . e a c i db v h l p o x a n r h i na n d \ a n t h r n el.a t i e n r s a n o x i d i z e r l l u p with the isourinol ro oxypr:rinalvia aldehyde oxidase.Parients or lared form are usuallyasymptomaric have mild symploms; are often nor visibleon radiography, a risk howe,.er, renal stones, xanfor renal damage and may appearat any age.Crystalline rn thine deposrts musclemay resut in musclepain following exertion. Rarely, xanthine sloneshar.ebeen reported as a result of is allopurinol administrarion.In rype II, the clinical presentation similar to rype I. Type ll patienrsare deficientin borh oxidases and cannot metabolizeallopurinol. Molybdenum cofactor de6ciency (failure to s)'nthesize molybdenumcofacror)rnvolves the oxidasedefi all three molybdoenzymes and, like isolatedsr.rlfite ciency,resultsin neonatal feediogproblems,neonatal seizures, severe muscle tone,ocular lensdislocation, increased decreased or intellecrual disabilicy, deathin earlychildhood. and the The inheriranceof types I and II is autosomalrecessive; 2p22. In both forms humanXOR geneis locatedon chromosome plasmaconis of the deEciency, diagnosis madeby measuring the cenrrations uric acid; plasmauric acid is lorv (<1 rng/dl-)and of xanthineis elevated plasmaand urine.Urinary uric acid is in reduced, being replaced bv xanthrne and hypoxanthine. In moLybdenum cofacrordeliciency, there is, rn addrtion,an xcesmetabolites. sive excretionof sulfiteand other sulfur-containing jeyunal liver bropsy or measuremen! requires Enzyme diagnostic that contain appreciabecause chese the only human tissues are Sulfiteoxidaseand the ble amountsof xanthine oxidoreducrase.

63{ r PARTXr MelabolicDise8ses mol,vbdenum cofactor can be measured in liver and libroblasrs. Although rhe isolated deficiency is generally benign! treatment with a low purine dret and increased fluid intake are recommended. Allopurinol has been recommended for chosewith resid ual xanthine oxidoreductase activiry It completell blocks the conversion of hypoxanthine into the far less soluble xanrhrne. The prognosis for molybdenum cofactor deficiency rs very poor, rhis disorder can lead to developmencal drsabilirl', intellectual dis ability, failure to chrive, cardiac disease,strabismus, crysralluria, and occasional urereric obstruction. Renal unction is eenerallv normal. Heterozygoles mar' have mild orotr aciduria buf ar. noi

DISORDERS OF PYRIMIDINE METABOTISM

The pyrimidines afe the burlding blocks of DNA and RNA and involved n the formarion of coenz,vmes,as active inlermediares in carbohydrareand phospholipid metabolism, glucuronidation in decoxification processes, and glycocylation of proreins and lipids. Pvrimidine synrhesis drffers from thac of purines in that the single pynmrdine ring is 1st assembled and then linked to ribose phosphate to form uridine 5rmonophosphate (UN{P), The pyrimrdines uracil and thymine are degraded in four steps, as shown in Figure 89-3. Eight disorders of pyrimidine metabolism are revrewed-Purine metabolsm has an easily measurableend pomt in uric acid; however, there is no equrvalen! compound in pvrimidine metabolism. The 1st defect, heredrtary orotic aciduria, is in the de novo synthetic pathwal whereas the other disorders involve overacrivitl' (in one syndrome) or defects in rhe pvrimldine degradation pathway. Degradation disorders may presenr as anemra, neurologic disorders, or rnultisystem mitochondrial drsorders. The 1st three steps of the degradacion parhways for thymine and uracil make use of the same enzymes (DPD, DPH, and UP). These three steps result in the corversion inco p alanine from uracil. There rs increasing evidence chat pyrimidrnes play an important role in the regulation of the nervous system. Reduced production of the neurottansmitter function of p-alanine is hypothesized to produce clinical symptoms. Clinicalll., these rare disorders may be overlooked because symptoms are nor hrghly specrfic; however, chey should be considered as possible causesof anemia and neurologic disease and are a conrraindication for treatment of cancer patients with certain pyrimidine analogs.

pharmacologic agents (5-azauridine,allopurinol) produce secondary ororic aciduria and orotidrnuria by specilically inhibicing ODC. Orotic aciduria rnay also occur in association with parenteral nutritionr essenrial amino acid deficrency, and R e synd r o m e , T h e e n z \ m a t r cd e f e . t m a y b e d e m o n s t r a r e d l r " e r , lvmphoblasrs, erythrocytes, leukoc,r'tes,and cultured skin fibroblasts. A carrier detection test is available, as s prenaral diagno'is. ln OD( deficiencl rUVP synrhaseryp 2 deficiencyl, rhc clinical symptoms show neurologic abnormaliti u'ithout megaloblastic anemia, In reported cases, both orotid una and orocic aciduria were found.

impror.ement and reduction in orotic acid excrerion. Lifelong t f e a r m e n it \ r e q u i r e dU r a c i l i sr n e f f e r r i vb e i a u s eu nl i k e p u r i n e s , . e , p y r i m i d i n es a l v a g e c c u r sa r r h e n u c l e o s i d eu r i d i n e l l . v e l . l h e o l long-cerm prognosis in uncomplicated cases is good; however,

(DPD) DIHYDIOPYRIMIOII{E DEHYDROGINASE DETICIENCY, DPD

catalyzes the initial and rate-hmiting step in the degradation of the pyrimidine bases uracil and thiamine. DPD has been identi fied in most tissues, rvith the highest acrrvrty being in lymphoq'tes. Genetics: DPD deficiency is an autosomal recessivedisorder mapping to chromosome 1p22 wirh ac leasr 32 pol,vmorphisms detected. It is estimated tbat the frequency of the heterozygote may be as high as 3%. The clinical manifestations in children may rncLude seizure disorder, inrellectual disabilit_v.and motor delay. Lrs. frequenr are grourh rerardation, microcephalv.and autisrrc-like behavior and ocular anomalies. Others do noc show developmental abnormalities but may have milder neurologic symptoms and language disorder. In most cases,rhere is an initial perrod of normal psychornotor developmenr, followed b_v subsequent developmental delays. Sympcoms may be linked to altered uracil, chymine, and p-alanine homeostasis. DPD is the initial and rateimiting enzyme in the catabolism of the neoplastic drug S-fluorouracil (5 FU), being responsible for u07o of its catabolism. Patients wrrh a partial deliciency of this enzyme are at risk for developing a severe s-Fu-associared toxici In adult paciencs,neurotoxlclty (headache. somnolence, visua lLr sions, and memory impairment) linked ro pyrimidinemia after 5FU treacmenr for cancer is reported in prevrously healthy rndividuals. Prenatal diagnosis has been reported. Laboratory findings: DPD deficiency is characterized by a varrable phenocype and diagnosed by che accumulation of thramine and uracil in urine, plasma, and cerebrospinal fluid and no activit], in fibroblasts. Diagnostic tests use high-pressure liquid chromatography (HPLC) or gas chromatography-mass spectroscopv (GC-MS). Alternarively, DPD defciency mav be conlirmed by measuring the enzyme in cultured fibroblasrs and leukoblasts. Uric acid levels have been reporred to be normal. Because B-alanine is a struc tural analog of y amioobutl.ric acid (GABA) and glycine, it has been proposed rhat it na1' affect inhibirorl.neurotransmission. There is no established treatment for this disorder: Datienrs rvirh seizures rerpond to annconvulsanL do medirations.iarienrs rr irh DPD deliciency should not be given 5-FU, and thrs deficiency should be suspected when neurologrc symptoms emerge after cancer rreatment wlth 5-FU,

(URIOII\IE HEBEDITARY OROTIC ACIDURIA MONOPHOSPHATE SYN. THASETYPE1 DEFIGIENCY). Thrs is a disorder of pyrimidine synthesis assocrated v,ith deficient acrivity of the last two enzymes of the de novo pyrimidine synrhetic pathway, ororare phosphor! bosyluansferase (OPRT) and orotidine--5!monophosphate decarboxylase (ODC). The activities of rhese two enzvmes reside rn separate domains to a single polypepride coded by a single gene. This bifuncrional protein, r.rridine5'-monophosphate (UMP) synlhase, catalyzes the two step conversion of orocrc acid co UMP, via orotidine monophosphate (OMP). Hereditary orotic aciduna results in the excessiveaccumulation of orotic acid. Genetics: This disorder is autosomal recessive. Two functional domains are encoded on a single gene. The gene for UMP synthase is located on the long arm of chromosome 3 (3q13). Genecic metabolic defects that nvolve four of rhe six enzymes associared with the urea cycle mav result in orotic acrduria secondary ro PP-ribose-P depletion resulring from a substantial increased flux rhrough the de novo pathwal', Clinically, patients with hereditary orotic aciduria (UMP synthas type 1 defciency) have a macrocytic hypochromic megablastic anemia lhat ls unresponsive to the usual forms ol rherapy (iron, folic acid, and B1r) and may have leukopenia. Onset is usually rn the 1st months of life. Untreated,

r of Chapter r Disorders Plrin. .nd PyrinidineMetoboliEm fi15 89 pvrimidine S'-nucleocidase and assessmentof lead levels should (DIHYDROPYRIMIDIN(DPH} DIHYDBOPYBIMIDINASE DEFICIENCY

8q22 ln one studn therewas no signifto maDDed chromosome in icani differetrce residualactivirv betweenmutations observed individuals.Populationprevaand asympromatic in symptomaric in sample is 0.1% Clinical manifestations lenie in a Japanese with dysmorphrc three unrelatadaffectedcasesinclude setzures

te included whenever rhe hemolltic anemia, p,vrirnidrne 5' nucleotidase deficiencn and basophilic strpplng are found rogerher. Diagnosrs requires demonstration of a complete de6ciencv of the major isoenzyme uridrne monophosphate hydrolase1. The enzyme defect should be suspected in parients with nonspherocytic hemolytic anemia with basophilic stipplng The anemia is usually moderate, and transfusions are rarely necessary There is no specific treatment. Splenecromv has not proved to be an effective treatment. Lead-induced acquired pyrimidine S'-nucleotidase delicienc;; is treatable, unlike che congenital deficiency.

CYTOSOTIC DEPTETION OVERACTIVE AND PYfl IMTDINE I{UCTEOSIDE nucleoside depletion overactive and 5,-NUCLE0TIDASE. Pyrimidine
tests with uracil, dihydrouracil, thymine, and drhydrothymine this havebeenusedto differentiace disorderfrorn DPD deliciencyIo symptomatic casesi teatment with p-alanine has been attemDt;d with equivocal results. Although ir has not been because to sensitiviry fluorouracilis expected reported,inc.eased of its role in pyrimidine mecabolism.
tion in the activiry of pyrimidine S'-nucleoridase in fibroblascs with both purine and yrimidine substrates. Investigarion in cultured fibroblasts der ed from these patients showed normal incorporation of purine bases into nucleorides but decreased incorDoration of uridine and orotrc acid. Clinical manifestations delay. serzures.ataxia. recurrent iniec include developmenLal tions, severe language deficit, hyperactivity! short atcention span' and agg ssive behavior appearing in the 1st feu' yr of life. Affected atients show electroencephalogram (EEG) abnormaliN-CABBAMYt-g-AMlN0AclDuRlA(DEHCIE -URElD0Pfio" ties. Metabolic testing is normal except for persisrent hypouricoare degraded suria. It is proposed that increased catabolic activiry and uracil and PIONASE). pyrimrdinebases The anine and p decreased pyrimrdrne salvage cause a deficiency of pyrimidine action of three enzym via rhe consecutive nucleotides. Treatment is with oral uridine, based on its effects The chird enzyme in the aminoisobutyric acid, respectively. (UP) and its deficiencyleads co on reversing rncreased nucleotide catabolism. AII reporred patiway is p-ureidopropionase patients rreated wich uridrne show improved speech and behavin aciduria.Urinary analysis a reportedcase N carbamyl-p-amino and ior. decreased seizure activitv with disconrinuation of seizure levelsof N-carbamyl-p-alanine N-carbamyl showedelevated onlf in the liver medications, and decreased frequeocy of infections. p-aminoisoburyric is acid, The enzyme expressed

in is and no activrtyof p-ureidopropionase derected a liver biopsy. rn Fluorescence situ hybridizationlocalizedthe human Genetics:
DCFICIENCY Thymidine phosphory THYMIDtNEPH0SPHORYLASE lase catalyzes the conversion of thymidine to thymine. This enzyme is also known as platelet-derived endothelial cell growth factor due to its angiogenic or "gliostatin" properties, indicatin8 its inhibitory effects on glial cell proliferarion. Ic has been implicated in mitochondlal nucleoside metabolism. Plasma thvmidine level is increased >20-fold in paciencscompared to controls. l-oss of funcnon of thymidine phosphorylase causes mirochondrial treatmentfor UP deficiency. neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive disorder rvith mitochondrial DNA alteratrons. Geoeticsr It rs an aulosomal recessive disorder, and che gene (PYRlMlDll'lE encoding thymidine phosphorylase has been identified as the 1 DEFICIENCY HYDR0LASE M0N0PH0SPHATE URlDlt{E rs maturation accom- MNGIE gene and mapped to chromosome 22q13,32-qrer. Erythrocvte DEFICIENCY). 5'-l{UCtE0TIDASE of paniedby RNA degradation and the release mononucleotides, Clinical manifestations of MNGIE rnclude prosis, progressive enzymeof the external ophthalmoparesis, gastrointestrnal dysmotility and Pyrimidine Slnucleotidaseis tbe 1st degradative malabsorption, cachexia, peripheral neuropathv, skeletal muscle the pyrimidine salvage cycle and catalyzes hydrolysisof pyrimiEnzyme myoparhy, and leukoencephalopathy. Laboratory findings: dine Srnucleotidesto the correspondingnucleosides. Muscle biopsies typically reveal mitochondrial abnormalities. resultsin the accumulationof high levelsof cytidine deficiencv and urid'ine nucleotidesin the erythroc;tes of those affected, The diagnosis is made by assay of thvmidine phosphorylase accivIncreased thymidine may cause mito ity in penpheral ler-lkocytes. Defi ency of pyrimidine 5: which results,in turn, in hemolysis. chondrial nucleotide pool imbalance resulting in mitochondrial is atleastin par! compensate in vivo by other nuclenucleotidase DNA alterations through a mitochondria-specific rhymidioe osidases or perhaps other nucleotide metabohc pathways. salvage pathu'ay. Supportive treament is indicated. recessive disorderinvolvrnga gene This is an aurosomal Genetics:

KINASE (IK2) DEFICIENGY 2 Thymidrne kinase2 (TK2) THYMIDINE is a key enzyme rn micochondrial DNA (mtDNA) precursor synrhesis. TK deficiencies cause tissue-specificdepletion oi mcDNA.

636r PARTX.Metabolic Diseas6s TK2 normally phosphorylatesdeoxlthymidine, deoxycytidine, and deoxyundine.Genetics: The geneis locatedon chromosome 16q22- Clinically, in TK2 delicienry,affectedindividuals have myopathy and depletionof muscularmitochondrialDNA severe in infancy. No specifictreatmentis available,Supportivetreatment is indicated. syndromes rhat have overlappingfeatures. Mutations in IMNA, the geneencodinglamin A-/C,are the only mutationsknown co be associated with HGPS. Approximately 90% of individuals with HGPS have had an identifable lMN/ mutation, C NICAI MANIFESTATIONS. Children with progeria usually appearnormal in early infancy, but manifestarions such as midfacial cyanosis,"sculptednose," and "sclerodema"mav suggest the existnce the syndromeat birth. Profound growrh {ailure of occursin the 1styr of life. The characterisric facies,alopecia, loss of subcutaneous abnormal posture, stiffnessof joints, and fat, bone and skin changes usually become apparenrin the 2nd yr of life (Fig, 90-1). Moror and mental development normal. The is dominant clinrcal manifestations rnclude short stature; weight distinctly low for heighr;diminishedsubculaneous head disfar; proportionately large for face; micrognathia; prominenr scalp alopecia;prominent eyes;delayedand abnorveins;generalized mal deDtition; pyriform thorax; short, dystrophic clavicles; wide-based "horse-riding"stance; shufflinggait; coxa valga,thin limbs, and prominent,stiff joints; and failure to complece sexual maturation. Features frequentlypresenr skin that is thin, taut, dry, wrinare kled, and brown-spotredin various areas;sclerodermatous skin over the lower abdomen,proximal thighs, and buttocks;prominerrtsuperficial veins;lossof eyebrows and eyelashes; persistently patent anterior fonranel; sculpted, beaked nasal tip; fainr nasolabialcyanosis;thin lips; protruding ears; absenceof ear lobules; thin, high-pirchedvoice; dystrophicnails; and progressive radiolucencyof the rerminal phalanges and distal clavicles (acro-osteolysis). Differentialdiagnosis includes mandibularacral dysplasia,Cockayne syndromerHallermann-Streiffsyndrome, and neonatalprogeroidsyndrome(\(riedemann-Rautenstrauch). Wernersyndromeis anotherdisease premarureagingdue preof gene{Table90-1). dominantly to murationsin the DNA helicase

Augoustids-SavvopoulouP, Papachrisrou 4 Farrbanks LD, er al: Parrial hypoxanthine guanine phosphoribosyluansferasedefciency as the unsus, peded causeof rena) disease spannrngthree generations:A cauhonary tale. Pediafiics 2O02ilO9E17 Caneron J5, Moro R Simmonds HA: Gour, uric acid and purine metabolisrD in paediarric nephrology, Pediatr Nepbrcl 1993;7:'105-118. Cameron JS, Simmonds HA, Hereditary hyperuricemia and rnal disase. Setnin Nefihrol 2005 25:9-78. Dabrowski E. SmathersSA. Ralstrom CS. et al: Botulinum toxin as a novel rreatment for self-mutilation in Lesch-Nyman Syndrome. Det Med Child N eutol 2005 i47 :63 6-639. Jinnah HA, De Gregorio L, Harrrs JC, et al: The spectrum of inherited mutations causing HPRT deficiency: 7i new casesand a review of 195 prevr ously reported cases. Mutat Res 2000t463:309-326. Loffler M, Fairbanks LD, Zameitat E, et al: Pyrimidine pathways in health ^nd diselse,Mol Med 2005t1,1,:430437. Marinaki AM, EscuredoE, DuleyJA, ecaI Genetic basrsof hemolytic anemia cau*d by pyrimidine 5'nucleorjdasedefrciencr I lood 2O01;97:3327-3332. Nrshino I, Spinszzola A, Hirano M: MNGIE: From nuclear DNA to mitochondrial DNA. Nearorfluscul Disotd 2001l'1117-10. Nyhan Ii/L: Disorders of purin and pyrimidine metabolisn. Mol Genet Metab 2O05;86:2s-33. Nyhan Vl, Vuong LU, Broock R: Prenataldiagnosisof Lesch'Nyhan disease. -809. PI etrdt Diag" 2003,23 1807 RaceV, Marie S, Vincent MB et al: Clinical, biochemicaland molecular generic correlations in adenylosuccinate lvase deficiency. Hum Mol Cenet 20O0;9:2159-2165. SchredenDJ, Harris JC, Park K, er al: Neurocognitive furctioning in Leschand partial hypoxanrhrne-guanine phosphoribosyltransferase Nyhan disease deiciency. I Int Neu/opsychol Soc 2001i7:8O5-812. SchretlenDJ, Vard J, Myer SN{, er al: Behavjoral aspectsof ksch-Nyhan diseaseand its varianrs. DeLj Med Child Newol 2O05t47:673-677. Scriver CR, BeandetAL, Sly WS, et al ledsl The Metdholic ad Molecular Bask of Inbe ted Diseasa Vol. 2, 8th ed. Nell York, Mccraw-Hill, 2001, pp 2513J7O2. Sinmonds HA, Duley JA, Fairbanks LD, et al: When to invstigarefor purine and pyrimidine disorders: Inrroduction and review of cLinicaland labora' rcty ,ndlc tions. I lftherit Metab Dis 19972O:214-226. van Gennip AH, van Kuilenburg AB: Defectsofpyrimidine degradarion,Clinical, nolecular, and diagnostic aspeccs.Adz Ex.p Med Biol 2000t486: 233 241. Wons DR Hafiis JC, Naidu S, et al: Dopamine transponers are markedly reducedin l*sch-Nyhan disease vivo. Pror Natl Acad Sci U S A 1996193: in 5539-5543.

Progeria's most striking featureresembles accelerated aging,This rare syndrome,also referredto as the Hutchinson-Gilfordprogeria syndrome (HGPS), has an incidence of -118,000,000. Affected children do not becomesexuallymature or reDroduce of parenr-ro-child asa result \fverefaiJure rhrive; ro transmission has not beenobserved. The clinical diagnosisof HGPS is based on recognitionof commonclinicalfeatures and exclusionof other

Figure 90-1. A 4.5yr old Bnl with height of 1.75yr and bone age of 4yr" (From Wilkins L: Diaposrs and Treatmmt of Endocine Disordets in Child. hood and Adolescetce,3rd ed. Springfield,IL, Charles C Thomas, 1965.)

r 9l Porphyrias 63t Chapler i The disease281, muscular dyscrophy1B, Charcot-Marie-Tooth mandibuloacraldysplasia,and atypical Werner svndrome {see Table90 1). HUTCHItI$lt{ltFoBDSYl{)mMt
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athero PR0GN0SIS. Childrenwith progeriausuallvhavese"ere as of sclerosis, deathoccurs a resultof complications cardiac and generallybet*'een age 5 and 20 yr, disease, or cerebrovascular and tumorshave wirb a medranlife span of =13 yr Cataracls infrequenclv been noted, but many changes associatedrvith presbyopia, arcus normal agingin adults,such as presbycusis, senile personalitychanges,or Alzheimer senils, osteoarthricis, disease, not found, are TREATMENI specific No treatmentior this conditronexists.There which is a progena foundarion (u.wrv.progeriaresearch.org), mainrains ProgeriaRegisrry help with diagnosis to define ro and a rnoreclearlv the incidence and molecularbasrsof chedisorder

+ hypoplasia ll4andibular + + ,{heDsderc5i5 + osteopeoia/o(mporcsis + + + atopi'y wa) L!rySed oiSh + Ilymi( arcphy lbrdble D + + Itpogonadhm + Grcersur(ep'btt) lderitanc MlM,Mendelian inMro+,pnltinj-,absn r sy li,lodifted ftDir1 RA: dle inpngii omsion 2001J62r416*417 HegekD'rwirq line

\hriable degrees of insulin resistance FINDINGS. LAB0RAT0RY insulin dependenrdiabetesmellirus),abnormalines ioccasionallv,

Bro$'n VT, Gordon LB, Collis l-S: Hutch,nson-G,lford progeria syndronte.In a;cnc Rev,ewsat Ccnc Tesrs:N.ledlcalCenericsInformarion Rescurceldatabaseonlinel AvallabLeac hrrp://r'w$'senerestsors/(updared Ansust 2006). CapeUBC, Erdos VR, Madigan ll', er al: lnbrbinng farnsylation of proserin prerents the characteristicnuclear blebbing of HLLrchinson Gilford progeria syndrone ProzNari Acad S./ U S A 200i;102:1287912884 Chen I, t-ee t., KudLow A, et al, lMr\H mutarions in atypical Werner\ syn' drome. I-!,r.el 2003j-163r44(H45. Eriksson.1v1, Brol.n V! Cordon LB. ct al: Rccurrenr de novo point muta lions in lamin A cause Hurchnrson Cilford progeria syndrome. Nar,/e 2001;423,293-298. HegeleRA: DrawjnB rhe line rn progena svndromcs Larcer 2003;362: 416417.

are no demonstrableabnormaliriesof chyroid,parathyroid, pituitar-v,or adrcnal ltunccron.

The nuclear lamrna, a proceinM0IECULAB PAIH0GEi{ES|S. containing layer arcachedto the inner nuclear membtane, is com-

by alternative spl ing of rhe LMNA gene transcript. SeParale genesencodelami Bl and 82. Lamin A is normally svnthesized as a precursormo cuJe(prelamin A). Alternative splicing wichrn exon l0 gives rise to tu'o different mRNAs that code for prelamin A and lamin C. PrelaminA, rvith 564 amino acids,has 98 uniqLre carboxy-termrnalamino acids. Lamin C has six unique carboxv prelamin A containsa CAAX (cvstermrnaLaminoacids.Because teine-alipharic alipharic-anv amino acid) box ar its carboxyl terminus,ir is modilied by farnesylation,whereaslamin C is noc. After farnesylation, cleavage of the last three amino acids, and methvlahon of che C-terminus, an internal proteolytic cleavage occurs, removing the last 15 coding amino acids, to Senerate mature lamrn A with 646 amino acids. The most common HGPS mutation is a G608G (GGC > GGT) muration in exon 11. This mutalion results in an activation of a crvptic splice site within exon 11, resulting in production of a rranscript that deletes50 amino acids near the C-terminus. The HGPS G508G mucation and consequent abnormal splicing produces a prelamin A that relains the C,{AX box but is missing the site for endoproteolytic cleavage. This HGPS mLrtation acts as a dominant negatlve mutatron. A grorving lisc of other diseases is associated with differenr mutations in IMNA, which have come !o be knoE n as laminoparhies. These include Emery Dreifuss muscular d,vstrophy tvpe 2, familial dilated cardiomyopatby and conduction s,vstem defects, Dunnigan t,vpe familial partial lipodysrrophy; limb girdle

Porphyrias are metabolic diseasesresufting from deficiencies of specific enzymes of the heme biosynchetic pathu.a-r These elzymes are most active in bone marrou'and [ver. !?hen these diseasesare manifesr, accumularion of 1 or more intermediates porphyrias, in occursinitially in I ofthese tissues. Er,vthropoietic rvhich overproduction of heme path*ay intermediates occurs pri marily in bone marrorv erythroid cells, usually present at birth or in early childhood u.ith cutaneous photosensitiviry, or in the case of congeniraler\throporetic porphyria. even in utero a\ nunimmune h,vdrops..Nlostporphyrias are hepatic, with overproduccion aod initial accumulatiorr of porphyrin precursors or porphvrins occurring 1st in the liver. Regulacor,v mechanisms for heme biosvnthesisin liver are drstinct from those in che bone marrow and appear !o account lor activation of hepatic por ph,vriasduring aduLt liie rather than childhood. Homozygous forms of che hepatic porph,vrias may manifest clinically prior to pubertl and asymptomatic heteroz-vgouschildren rnay present u'ith nonspecilic and unrelated symptoms. Parents often reques! advice about Long-termprognosis and intormation abou! man-

638r PABTXr MetabolicDiseases agementoi thesedisordersand drugs rhat can be taken safelyto lrcat other common conditions. The D\A sequences and chromosomal locatxrns arc escab lished for the hrLman genes of rhe enzvmes in this pathwan and :nultiple diseascrclated mutations have been iound fol each porph,vna.All but 3 oi the inherited porphyrias displav autoso nraL dominant jnheritance. Although iniriaL diagnosis of porph,rria by biochemicalmerhods remains esscntial, is especrally ir irrportanr in chilclrcnco conlirm the dragnosisb,vdemonsrracing a speciEc gene lnu tation(s). pool {seeFig. 91-li, rvhich can be augmenrcd b,v ner;r'ly svnthesized heme or bv exisring hcme released from hernoproreins and destrnedfor brcakdown to biliverdjn by heme oxygenase. In the cryrhron, no\el regulatory nrechanisrns allorv fbr the production of drc ver,vlarge amounts of heme needecl for hemoglobin synrhesis. The responseto stimuli for hemoglobin synrhesis occursdLrringcell differenriation,leadingto an increase cell il number- Also, unlikc the liver, heme has a shmulatory role rn hemoglobin formation, and the stimularion of hemc s,vnthesis rn erythroid cells is accompaniedby incrcasesnot onl,v ill ALAS2, but also b,v sequenrial induction of other hcme biosyntheric enzymes. Separate ertthroid specilic and noner;-throid or "housekeeping" rran\cripts are known ior the 1sc4 enzvmesin the pathu'ay, The separarc iorms of ALAS are encoded by genes on different chrooosomcs, bur for each of the othcr 3, erythroid ald nooervthroid trdnscripts are rranscribedb,v altcrnative pro moters in the samegene. Heme also regulatesthe rate of its syn rhesisin erythroid cells bv controlling thc transporr of iron intri retrculocyles. Intermediares of the heme biostntheric pathway are efficienrly convercedro hene irnd, Lrormally,otly small amounrs of che inrermediates are excreted. Some may undergo chemical modi6cations bcfore excretion.Whereasrhe porphyril precursors ALA and I'BG are colorless, nonfluorescenr,and largeL-v ercrered unchangedin urine, PB(i ma1'degradero colored producrs such as rhe L)rolv11ish pigrnent calLedporphobilit or spontaneousl,v polymerize to ur<>porpb,vrLls. Porphvrins are red in color and when cxposedto long wavelength displav bright red fluorescence ulrravioler light. l'orphlnnogens, rvhich arc colorlessand tron fluorescent, are the reducecl iorrr of porpbyrins, and lr'hen they accumulatc, arc readily aucoxidizedto the correspondingporphyrins outside the cell. OnLl' the c1'peIII isomers of uroporphynnogen and coproporphvrinogenare cor'rverted herne (see to Fig.91 1). ALA and IrB(] are excretedin urinc- Excrcrion of porphvrins and porphvrinogensin urinc or bile is determinedby the number of carboxll groups. those rvirh many carboxvl groups. such as uroporphvrin (ocrac;rrboxll porphyrin) and heptacarboxyl porphyrin), are rvater soLuhleand readiJ,v excrctcd in urinc. Thosc rvith ferver carl.oxll grorrps. such as protoporphvrin (dicarbox,vl porphvrio), are not warcr solr.rble and are excreted in bile ard feces. Coproporph,vrin (terracarboxyl porphyrin) is excreced

THE HEME BIOSYNTHETIC PATHWAY

Heme is required for a variery of hemoprotcins such as hemoglobin, m,voglobin, respiraror,v c_vtochromes, and c,vrochrome P450 enzyrnes (CiYPs). k rs believed rhat the ll enzyrnes in the pathway for heme bursynthesis are acrive in all rissues.Hemoglobin s,r'nrhesis erythroid precursor cells accounts for =85-nzo in r f . l ; i l y h c m r r u n r h c . r 'r r rh u m a n . .H e p a t o . r t c .a . c o r r r ri o r r n u r t of the resr.primarily ior s,vnrhesis CYls, u.hich are especially of abrndant in the liver endoplasmicrcriculLLrn iER), and turn over nrore rapidly than many other hemoproteins,such as the mitochondnal respiratory cltochromes. As shorl,l in Figure 9l l, pnth\.ay inrcrmediatesare the porphvrin precursorsli-aminoleacid) and por vulinic acid (l\Lr\, also knorvn as -l-aminoler.uLinic phobilinogen (l']BG), and porphyrins (mostly in rheir reduced forras, knou'Lr as porphvnnogens). Ar least in humans, these intermediatesJo not accumulale in significanr amounts under normal conditions or have irnportant physiologic fr.rnccions. A deficierrcy oi each enzyme in rhe pathrvay, *'irh rhe exception of che1st, is associated w-ith a different porphvria lTable 911). The 1sr enzyme, AI-A synthase(AIAS), occurs in 2 fonns. Al erythroid specilic form, fermed ALAS2, is deficienr in X linked sideroblastic anemia, due fo mutations of rhe AI-A52 gene ol chromosorneXp1l.2. The ubiquitorLslbrm of rhis enzyme, rermedALASI, is found in all rissues inclnding liver, and ils gene is locatcd on chromosomc 3p21.1. Discascrelated mutations of AI,AS L have rot been described. Regulation of heme svnthesisdiffers rn the 2 m:rlor hemeis tbrming tissucs I-ivcr henc biosynthesis primary conrrolled by of ALASl . S,vnchcsis ALASl in liver is reg acedby a "free" heme

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r Diseases 64llI PABTX ilerabolic partly in urine and pardy in bile. Because coproporphyrin I is in more readilyxcreted bile than is coproporphyrrn impaired III, hepatobiliaryfunction may increase total coproporphyrinexcretion and the ratio of theseisomers. detect patients with ALA dehydratase porphyria. Urinary porphyrins may remain increased longer than porphvrin preculsors in HCP and VP. Therefore,it is useful to measure total urinary porphyrinsin the samesample, keepingin mind rhat urinary porphyrin increases often nonspecific, are Measurement urinary of porphyrinsalone should be avoidedfor screening, because these are often increased many disorders in other than porphyrias,such aschronic liver disease, misdiagnoses porphyria can resuh and of from minimal increases urinary porphyrinsthat haveno diagin nostlc slgnlncance. PBG is a colorlesspyrrole rhat forms a violet pigment with Ehrlich reagent (p-dimethylamrnobenzaldehyde). Other subprincipally urobilinogen, also react with Ehrlich aldestances, hyde, The Vacson Schwartzand Hoesch tests, which involved rnitial addition of Ehrlich reagentto urine, are considered obsolere. A reliable quantitative method for both ALA and PBG, which uses small amon and cation exchange columnsto separate interfering substances before adding Ehrlich reagent,has been availablefor many years. ALA ls reacted form a p1'rrole, to whrch is then also measured using Ehrlich reagent.The TracePBG kit is basedon this method. Measurement of erythrocyte porphobilinogen deaminase (PBGD)is not usefulasa firstline testin rhe acutesettingbecause ir does not differentiatelatent from acrive AIR Moreover, the enzymeactivity is not decreased all AIP patientsand is never in deficientin other acuteporphyrias. BlisteringCutsneous Porphyrias, Blisteringskin lesionsdue to porphyna are virtually alwavsaccompanied increases total in by plasmapotphyrins. A fluorometricmethod is preferred,because the porphyrins in plasmain VP are mostly covalendylinked to plasma proreins and may be less readily derected by highpressure liquid chromatography(HPLC), The normal range for plasmaporphyrins is somewhatincreased Fatientswith endin staserenal disease, lionhlistering Porphyria. Cutaneous Ahhough a total plasmapor phyrin determinacion usuallydetectEPI an erythrocyteprowill toporphyrin determination is more sensirive. lncreases rn erythrocyte protoporphyrin occur in many other conditions. Therefore,the diagnosis EPPmust be conflrmedby showinga of predominant increasein free protoporphyrin rarher than zinc protoporphyrin. Interpretationof laboratory repons can be dif6cult, because term "free erlthrocyte protoporphyrin" somethe zinc protoporphyrin. times actuallyrepresents SEC0ND-I|I{E TESTlilG, More extensivetesting is v.ell justified when a firstline test rs positive. A substantialincreasein PBG may be due to AIB HCP, or VP. Theseacute porphyriascan be distinguishedby measuring erythrocyte PBGD, urinary porphyrins (usingthe samespot urine sample), fecalporphyrins,and plasmaporphyrins,The variousporphyriasthat causeblistering porphyrins in urine, skin lesionsare differentiatedby measuring feces,and plasma.Confirmation at the DNA level is important once the dragnosis established biochemicaltesring.Further is by details are provided in the follou'ing sectionson each type of porphyfia. TESTING SUBCLlillGAt P0flPHYBIA. rs ofien diffrcult to diagFOB ft nose or "rule out" porphyria in patients who had suggestive

A1'ID DIAGNOSISPOBPHYRIAS CTASSIFICATION OF

Two classificationschemes reflect either the underlying pathophysiologyor clinical Ieatures, and both are usefulfor diagnosis Table91-1).In hepaticand erythropoietic porand treatment(see phyrias,the sourceof excess production of porphyrin precursors and porphynns is the liver and bonemarrow, respectively. Acute porphyriascauseneurologicsymptomsthat are associated with increases 1 or both of the porphyrin precursors ALA and PBG. of porphyrias,photosensitivity In the cutaneous resultsfrom transport of porphyrinsin blood frorn the liver or bonemarrow to the of skin. Dua[ porphyria refers to the very rare occurrence deficiencies 2 differenrhemepathway enzymes, of It is notablethat acuteintermittentporphyria (AIP), porphyria cutaneatarda (PCT), and erythropoieticprotoporphyria (EPP), the 3 most commonporphyrias,are very differentin clinical preand effecse[tation, precipitatingfactors,methodsof diagnosis, tive therapy (Table 91-2). EPP is probably rhe porphyria rhat manifesc Two of the 4 most commonly becomes beforepubercy. acute porphyrias, hereditary coproporphyria (HCP) and variegateporphyria (VP),can alsocause lesions indistinguishable from porphyria (CEP) PCT (see Table91-1). Congenitalerythropoietic blisteringlesions,often with secondary infeccauses more severe portion and mutilation. EPPis distinctfrom the other cutaneous photosensiti\'rty phvrias in causingnonblirrering that occurs acutetyatter sun exposure. |AB0BAT0SY DlAGilO$lC TESTING. few sensitive FISSI-I-INE A and soecificfirstline laboratorv tesn should be reled on whenthe ever symptomsor signssuggest diagnosisof porphyna. If a test is significantlyabnormal, more comfrrst-lineor screening prehensivetesting should follovv to establishthe type of por phyria, Overuseof laboratory tests for screeningcan lead to and In unnecessary expense evendelayin diagnosis. patientswho presentwith a past diagnosisof porphyria, laboratory reports that were the basisfor the original diagnosismust be reviewed, further testingconsidered. and if thesewere inadequate, in Acute porphyria should be suspected patientswith neurovisceralsymptomssuch as abdominalpain after puberty,when initial clinical evalualion does not suggestanother cause,and uritaty porphytix ptec&rcors(ALA and PBG.)should be meaduring acute sured, Urinary PBG is virtually always rncreased artacksof AIP, HCP, and VP, and is not substantiallyincreased is in any other medicalconditions.Therefore,this measurement and specilic.A method for rapid, in-housecesting both sensrtive for urinary PBG,suchas the TracePBG kit (TraceAmerica/Trace Dragnoscics, Louisville,CO), should be availablein houseat all malor medical facilities. Results from spot (single void) urine specimensare highly informative because very substantial during acuteattacksof porphvria.A 24 hr increases expected are delaydiagnosis, The samespot urine colleccion unnecessarily can specimen should be savedfor quantirativedeterminationof ALA and PBG,in order coconfirm the qualitativePBGresult,and also

r Chtpterglr ThaPo4lryrias 641 rhrive. A 63 yr old man in Belgiumdevelopedan acute motol drsorder polyneuropathyconcurrenrlywith a myeloproliferative tAB0BAT0RY FINDINGS. Urinary ALA, coproporphyrin IlI, and er],throcyte zinc procoporphyrin are substantially increased ErythrocyteALAD Urinary PBG is normal or slighrly rncreased. activity is markedly reduced, and both parents should have approximatelyhalf-normal activity of this enzymeand normal urinary ALA. por0|AGN0SlS. 3 otheracute The DIAGN0SIS DIFFEREI{TIAL AND in by phyrias are characterized substantialincreases both ALA increased and PBG.In contrast,ALA but Dot PBGis substancially in ADP A marked deficiencyof erythrocyte ALAD and halfOther causes normal activity in the parentssuppor!the diagnosis. of ALAD deficiencnsuch as lead poisoning,must be excluded. tyrosinemia type 1 and in Succinylacetone accumulates hereditary is structurally similar to ALA, inhibits ALAD, and car cause increased urinary excretion of ALA and clinical manifestations that resemble acute porphyria, Idiopathic acquiredALAD deficiency has been reported. Unlike lead poisoning, rhe delicient ALAD activity is nor restored by the in vitro addition of sulfhydryl reagents suchas dithiothreitol. Even if no other cause ro is of ALAD deficiency found, it is essential confrm the diagnosisof ADP by molecularstudies. TREATMENT Treatment experienceis Lnited but is similar to not other acuteporphyrias.Glucoseseems very effeclivebut may Hemin therapywas apparentlyeffecbe tried for mild symptoms, and weekly infumale cases, tive for acute attacksrn adolescenr sions orevenced actacksin I of these cases.Hemin wa not effectiveeither biochemicallyor clinically in the Swedrsh hild response no but with severe drsease, produceda biochemical and form, clinical improvementin the Belgianman wirh a late-onset Hemrn rs who had a peripheralneuropathybut no acuteacracks. rvith associated alsoeffective treatingporphyrialrke symptoms in reduceurinary ALA hereditarytyrosinemia, and can significanrly and coproporphyrinin lead poisoning.Avoidanceof drugs that porphyrias advisable, is Ljver transare harmful in other acuce plantation was not effectrve the child with severe in disease. PROGN0SIS. The outlook is generally good ir typical cases, although recurrentattacksmay occur The coutsewas unlavorand able in cheSwedish child with more severe disease, rs uncer associated with myeloprotain in adults with late-onsetdisease Iiferative disorders. parents PREVENTI0N GENETIC AN0 C0UNSEtING. Heterozygous should be aware that subsequent children are at risk for the disorder. Diagnosis urero in disease, in any autosomalrecessive as is possible, has not beenreported, but

to euid rhe choiceof tests for rhe family members.The index casi or nother farnily memberwith conlirmedporphyria should mutaIdentilicationof a disease-causing if be retested necessary. tion rn an index casegreatly facilitatesdetecrionof additional Senecarrlers.

ACID 6-AMINOTEVUTINICDEHYOBATASE POBPHYRIA IADPI

humanporphyria and is someThis is the most recendydescribed who described investigator timestermedDossporphylio aket th,e 'fhe the tern pluttboporpDyriaemphasizes simthe 1st 2 cases. ilarity of this condition to leadpoisoning,but rncorrectlylmplies to that it is dr-re lead exposure.

the AND PATH0GENESIS. ALAD catalyzes condensaPATH0t0GY of tion of two molecules ALA to form the pyrrole PBG (seeFig. 91-1).The enzymeis subjectto rnhibition by a numberof exogechemicals.ALAD is rhe pnncipal leadnous and endogenous and lead can displacethe zinc binding protein m erl/throcytes, atoms of the enzyme.ErythrocyteALAD acrivity is also a sensirive index of lead exposure, inheriteda differentALAD mutatronfrom each A1l ADP cases parent. ElevenALAD mutations,mostl point mutations, hav parrial ctivirv, such that heme beeoidentified,someexpressing The amount of residualenzyme is synthesis partially preserved. activity may predict the phenorypic severicyof this disease. nonfunctional demonstraced studiesin 3 cases Immunochemical enzymeprorein that cross reactedwith anti-ALAD antibodies. with a myeloproliferativedrsolder Late-onsetcasesassociated or may be heterozygous have a somatic mutatron, with expan sion of an affectedclone of erythroid cells as ADP is often classified a hepaticporphyria,althoughthe sice A of overproductionof ALA is not established. patient with severe, early-onset disease underwent liver transplantation, rvirhout significantclinical or biochemicalimprovement,whrch did inrermediates not originatein that the excess might suggest urinary coproporphyrinIII in ADP might origithe liver Excess in a other ofALA to porphyrinr.:gens tissue natefrom metabolism rhan the site of ALA overproduction Adminisrration of large coproto also of doses ALA to normalsubjecrs leads substantial ma), as in proloporphyrin porphyrinuria. Increased eryrhrocyte porphyrias, explained accumularion be by ill orherhomozygous in of earlierpathway intermediates bone marrow erythroid cells followed by their transformationto during hemoglobinsynrhesis, protoporphyrin after hemoglobin synthestsis complete.As in of other acuteporphyrias,the pathogenesis the neurologicsympon toms is poorly understood(seeseccion AIP). In CtlNlCAt MANIFESTATI0NS. most cases,symptomsresemble of other acuteporphyrias,includingacuteartacks abdominalpain and neuropathy. Precipitating facrors, such as exposure to Four of the harmful drugs,have not beenevidentin most cases. males.A Swedishinfant had 6 reported caseswere adolescent wrth neurologicimpairment and failure ro disease, more severe

(AIP} ACUTE INTERMITTENT PORPHYRIA

This disorder has also been tenned pyrroloporphyria, Sutedish porphyia, and ifltefttlittent acute porphyria and is the most commontypeof acutcporphyriain mostcuuntrie.. ETl0t0GYAIP resuhs from the deficient actrvrty of the house(PBGD).This erzymeis also keepingform of PBG deaminase (HMB) synthase; prior term known as hydroxymethylbilane the uroporphyrinogenI synthaseis obsolete.PBGD catalyzesthe deaminationand head-to-tarlcondensation 4 PBG molecules of to form the linear terrapyrrole,HMB (alsoknown as preuroporphyrinogen; Fig. 91 1). A uniquedipyrromethane cofactor see binds the pyrrole intermedratesar rhe catalytic sice r.rntil 5 pyrroles (including rhe dipyrrole cofactor) are assembled a in

642| PARTXr Mebbolic oiseases Iinear fashron, after rvhich rhe tetrap,vrrole H\.{B is reLeascd. The epo deamjnase generates dipyrrole cofactor to fornr fhe holo the dearninase. end fhis occurs more readrl,vfrom HMB thar irom l'BG. lnclecd,high concentrarions PBG mal inhibir formarion of of rhe holodeamilase. The product HMB can c1'clizcnonenzy malicall,vto form nonphysiological uroporphylinogen I, but rn the plesenceof the nexc enzyme in the pachrvavis more rapidlv clclized to iorm uroporphvrinogen Ill. Eryrhroid and housekeeping forms ol the enzvrneare cncoded by a singlc gene or hurnan clrromosome Il I I1t124.1->qZ4.2), r,r'hich contains 15 exors. fhe 2 isoenzlmesare both lnonomeric proteins and diifer or-rlyshghdv in molccurlrr weighr (=40 and 42 kd, respectrvelv), and rcsult frorn alternativesplicing of exons 1 and 2. The crvthroid specificisoenzyme,thcrcfore, is encoded b,vexons 2 through 15, and rhe eryfhrord promoter. rvhich lunc ti(xrs onlv in erychroid cells, is locarcd immediateLyupstream lron exon 2. Thc housekeeping is isoz_ynle cncodcclbl exons 1 ancl3 rhrough f-i, and irs promoter is inrnediateh upstreamfionr exor I (lis lcring sequences bind thc erlrhroid specific D\Abindrng factors NF E1 and NI,-1,i2, leading ro c\pressi(D of rhe cr,vthroidpromoter. The housekeepirgpronloter fllncoons in all cell types, ircluding erylhroid cclls. The pattern oi inhcritanceof AIP it autosornaL tlominanr, rvith r.eryrare homozygouscasesthat presentir childhood. \.{ore rhan 200 l:BCD rnutati()ns,inclLrdingmissense, nonscnse,and splic iog rnutations and insertions and dclctions have been rdenrilied in i\lP, ald in manv populatron groups, ilclucling l>lecks. l\'lost mlrtarions are lound in only 1 or a fcu families. But due ro founder eifecrs,somc arc rrore commoLr in cerrain geographic nrcas such ns northern Su.edeniV'19llX), Holland iR116\fl, Argentina ((ill6R), Nova Scotia (l(17iW), anrl Srviczeriald (If283X). De novo mutations may hc fbr.rncl =37u of cases. iu Ohester porphyna was initiallJ' describcd as a variant forrn of acutc porphyria in a large Lnglish famill-, brrr \ras iound ft) be ciuc ro a PBGD rnutation.'lhe naturc of rhc PBCD mutation does not account ior the severity of che clinical presentation, n'hich varics markedll r,ithin lamilies. \.lost murationslead ro approximately half-norrnalactivity of the housekeeping ard eryrhroid isozymes and half norrnal amounls of rheir respectivc of enzyme proteins iD alL rissues heteroz,vgotes. =5!16of unrelated AIP parlents,rhc housekeeping ln rsozymeis norrnal. isoz,vme deficicnt.but the erythroid specrfic is \4utarions caLrsing this variant are usuallv found rvjthin cxon 1 or irs -i' splice clonor sire or iniriation of rranslation codon. Lnrnunochemical methods can distinguish mLrfationsthat are CRlN4-posirrve(r.e., havJng cxcess cross reactive imnunoi()gic material lCRl,\.11 relative ft) the mutanI cnz! me activit,v)! whereas CRI\{ negative mutafions either do rot synfhesizc a mutanl aLldn()t immunolog enzlme protein. or the proteiD is not staL)le icall,v detectable using ann-PBC;D intibodres. A chiid rl,ith homoz-vgousAIP was founcl to have inheritcd a diftcrcnt CRIN'I p()sitrve nutarion from each parent. PATII0L0GY AN0 PATH0GENESIS. lnducrion of rhe rateJimiting hepariccnz,vneAl-AS1 is thought to underlieacureexacerbations of rhrs and rhe other acure porph,vrias.AIP remarns larent (or as)'mptomatic)in the great mxjority o{ rhosc rvho are heterozv [jous carriers of PBGD mutatiots, and rhis is aimosf a]rlays the casebefore puberty. ln rhose rvith no hisrorv of acute symproms, normal, suggeslingthat porphvrin precursorexcrccionis usuall,v half nornal hepatic PBCD acrivity is sui6cienc and hepatic ALAS1 accivity is not rncreased. Many nongenetic facrors chat lead to clinical expressiono[ AII', including cerrain drugs and steroidhormonesJ have !he capacltyto inducc hepaticAI AS1 and is CYPs. tJnder conditions in r.hich heme synchcsis increasedin the liver, hrif normal PBGD actrvity ma-v become limirrng and ALA, PBG, and othe. heme parhway intennediates malv accu impaired and heme muLate. addition, heme synthesrs In becomes mediatcd rcprcssionoi hepatic Al,ASl is lesseffecrive. Ir is not proven, horvc\jerthat hepaticPBGD renains constant ar =50-!'. oi normal dcriviry during exacerbarions and remission of AIP, as in er_vthroc-vrcs. earl,v rcport suggestedthat the An enzvmc activitl. is consrderaLrly than half-nornlal in rhe liver less during an acute atrack. Ilepatic PBGD activity night be redrrccd iurther once,{ll' becorncs activared if, as rccenrly suggesced. .,vlthassembl,v chedipyrromerhanecofacexcess PBC,interfcres of tor for dris cnzymc. It also seemslikely chat currentlv unknorvn geneti. fircors play a contriburing role in, for examplc! patierlts u.ho cortinue to hat,e artacks even rvhen l<rtou'n prccipitants are avoided, The fau thar,{lP is :rlmost alwa,vslatenr bcfore puberry suggesfsth:rt cndocrine factors,adult Icr,els sreroidhormones,are of imporrant ior clinical exprcssion.Symptoms arc more comm(rl in u'omcn, which sr.rggesrsrole for fcrrale hormones.Prcmen a strual attacks are probrbll due to endogenous progester()ne. Acutc porphvrias are sometirncs exacerbared bv cxogenous ' t e ro r J . . r r r . r r . l r n l I ' r . c o r r t r a c ! , p lrr r n r c l d r i l i o ' r ( \ r ' D l J t , ! i progesfins. pregnancyis usually u'ell tolcrated, sugSurprlsingll-, gc:cing rLrat beueficial rnetabolic changes ma,v arncliorate rhe cffuctsof high Jevels progesterone. oi l)rugs rhat are unsafc in acute porphvrias (Table 91 3) include those har.ing rhe capacit,vto induce hepatic ALAS1. r.vhrchis closcl,vdssociatedr,vith inducrion oi (lYPs. Griseofulvin is an exanple oi a .hcrnical thrt can iDcrease heme turnover by prom.rting the destruction of specihc (lYPs co form an inhibitor of (FE(il{. thc linal enzvmein rhe pathwa,v), ferrochelarase such as N-rncthyl pror6p6rphyrrr. Sulfonarnideandbiotics are harmfnl Lrut apparettll not inducers oi hepatic heme svnthesis.Ethanol and orhcr alcoholserc inclLrcers ALr\ synthasc of anclsome CYIs. reduced rntake of calorics and Nutritional factors, principalll-. carbohvclrates. nlay occur $.ith illncss or attempfs to losc as

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SlFt tarcctc irdl!P5 c A5prfn Arelirinophen f n e n citz f e 5 l Pel inalli dl1fi!atyP! r nfepto:nyc I i; Ji:riar-io d5 BDmCe! n5ut1 Aircp ne (rmetdrne llanitiirne Aietinimhm (friraaelart l Afctazclariie A opurf! l m o rd e Bethdnidre Bumetanide ainei ire d lcumirnr :luoxerre iaD;pPftn aentim rn q? ir(ra1.":hid CtuMl pr.iFLn..cl 5 u (f y i h on i Tetirqliins

Ihr pifiil innq not ?bod elely 0lh' rhoud oe dcr ndudealauilibh nfdnadon druq ir drule Frphlrlal rourc: ronlultei druq5 blEl] for not he{e 'PoqhIz irIned,r5i advefi? nU.5 ellerl abel]nq ttuedrugr Io trl|cqeniare rcirrEindicr0n.w?m 0n,,r nqpit(d!t inrplraH hirmful &uLe ,kol lted haflnfrl po0hym, h p&n br l! n 0r ar n U0]r!ftsriody[$d ony ${r prqterL cn Pll i5 evidrnft arc trrE iantu' erfe thenogn w r rcmbndio$ h errrsFnt exrrftare {rere | c:e Wh 'Po0hlm How$Elirisdilg r ra.!2rdi by 50!r.!s 5 BEd pRrarim U5 'abtllnqlfirdtuq 6a in tu a5qle 0tlfi

r ChaFergl r The Poiphyrias 643

can increaseporphyrin precursorexcretionand tnduce \,r'eight, intakemav ameliocarbohvdfate anail. of porphlrra.increased A t R e c e n f i n d i n g 'i n d i c a r eh a r h e p a t i c L A S I i s t .nre "rtr. r. receptory regulatediby the peroxisome Proliferator-activated an which may represenc imporrant link iu co"activator (PG'C-1cr), betweennurritional statusand acureporphyrias.

inal distention and decreased bowel sounds. Nausea, vomiting,

rologic manrfestations. and rs the mosl common in AIP EP|DEM|0L0GY occurs all races

by controls, Population screening erythrocyrePBGD activiry or per of DNA analysisrevealeda prevalence =200 hecerozygotes France. and in 100,000 FinLand, 1 in abour1,675(60/100,000)in

carecholamines, Ocher common manifestations include menral \!mptomsi pain in the extremities.head, neck. or chesti muscle weakness: and sensorv loss. Becauseall these manifestations are neurologic rather than rnflammacory there is little or no abdominal tenderness, fever, or leukocytosis. Porphyric neuropathy is primarily motor and appears to lesul! from axonal degeneration rather than demyelinization. Sensory involvement is indicated by parn in lhe extremities, which may be descnbed as muscle or bone pain, and by numbness, patesParesismay occur early in an attack, thesias,and dysesthesias. bur is more often a late manifestation in an attack that is not recognrzed and adequately treared, Rarely, sevete neuropalhy develops when there is lrtrle or no abdominal pain. Motor weakness most commonly begins rn the proximal muscles of the upper exlremities and then progresses to the lower exrremities and the periphery. It is usually symmetric, but occasionally asvmmetric or focal. lnitrall,v, tefldon reflexes may be little affected or hyperactive and become decreasedor absent. Cranial nerves, most com rnonly the 10th and 7th, may be affected, and blindness from involvement of the optic nerves or occiprtal lobes has been reporced. More common central nervous system manifestations include seizr.rres, anxiecy, insomnia, depression, disorientation, hallucinations, and paranoia. Seizures ma1'result from hypona tremia, porphyria itself, or an unrelated cause. Chronic depression and other mental symptoms occur in some pacients, but attriburion to porphyria is often diffrcult. Hyponatremia is common duflng acute attacks. Inappropriate antidiuretic hormone (ADH) secretion is ofren the mosc likely mechanism, but ir is diffrcuk to document and other mechanisms musf be considered in rndrvidual cases.Salt depletion from excess renal sodium loss, gastroinrestinal loss, and poor intake have been suggested as causes of hypooatremia in AIP In sorne pa[ients, unexplained reductions in total blood and red blood cell volumes were found and increased ADH secretion might then be an appropriate physiologic response- Other electrolyte abnormalities may include hypomagnesemra and hypercalcemia. The atcack usually resolves qurte rapidly, unless trearmen! is delayed. Abdomrnal pain may resolve within a few hours and paresis wichin a few days, Even severe motor neuroparhy can rmprove over months or several years, buc may leave some re srdual weakness. Progressron of neuropathy to respiratory and bulbar paralysis and death is uncommon with approprjate tfeatmenr and removal of harmful drugs. Sudden death may result from cardiac arrhythmia.

nosnc crlterla,

Neurovisceral manifestations of CLlNlCAt MANIFESTATIONS. acure porphvrias may appear any time after pubeny; but rarel,v before. Verv .are cases of bomozygous AIP develop severe neurologic manifestations early in chrldhood, and acu!e attacks do not occur. In affected heterozygotes, acute attacks are characterized by a constellation of nonspecrfic s,vmptoms,which may become severe and life-threarening. Abdominal pain occurs in 85-957o of cases, rs usually severe, steadn and poorly localzed, but somenmes cramping, and accompanied by srgns of ileus, including abdom-

tAB0RAT0BYFINDINGS. Levels of ALA and PBG are substantially increased during acute aftacks and these may decrease after an attack but usually remain increased unless the disease becomes as,vmptomatic for a prolonged period. A populatton based study in Sweden indicated that symptoms suggestive of porphyria mav occur in heterozygotes during childhood, in contrast to adults, even when urinary porphyria ptcursors are nor elevated. This study lacked, however, a comparison with the frequency of such nonspecrfic symptoms in a control group of children. Porphvrins are also markedly increased, whrch accounts for reddish r.rrine in AIP These are predominantly uroporph;rrins, which can form noneozymatically from PBG. But because the increased urinary porphyrins in AIP are predorninantlv rsomer IlI, rheir formation is likely to be largely enzymatic, whrch might occur if excessALA produced in liver enters cells in other tlssues and is tben converted to porphyrins via the heme biosynthetic

r 644r PABTX Motdbolic Diseasos pathway. Porphobilin, a degradation product of PBG, and dipyrrylmethenes appearto accountfor brownish urinary discoloration, Total fecal porphyrins and plasma porphyrins are normal or slightly increased AIP Eryrhroclte protoporphyrin in may be somewhatincreased patientswith manrfestAIP in Erythroc;te PBGD activiry is approximarely half-normal in mos! patients l7U8O%) with AIP, The norrnal range is wide, however,and overlapswith the rangefor AIP heterozygotes. As noted, somePBGD genemutationscausethe enzymeto be deficient only in nonerythroid tissues. Also, PBGD is highly dependent on erychrocyte age,and an increase erythropoiesis ro in dr-re concurrentillnessin an AIP patientmay raisethe activity into the Irormal range. with hemin for a severe attack be srarted onlv after an unsucgiucose several cessful rrialof inrravenous for dayr.MiJdatracks, without severe manifestations suchasparesisand hyponatremia, may be treared initially with intravenousglucose.After intravenousadministration,hemin binds to hemopexinand albumin in plasma and is rakenup primarilyin heparocyte.. Heminthen entersand augmentsthe regulatory heme pool in hepatocytes, represses the synthesisof hepatic ALAS1, and dramatically reduces porphyrin precursoroverproduction. Hemin+ is available for intravenous adminisrration in the United Stares a lyophilizedhematinpreparation(Panhernatin, as Ovation). Degradationproducts begin to form as soon as rhe lyophilizedproduct is reconsrituted with srerilewater, and these are responsible phlebitisat chesite of infusronand a transrent for ancicoagulanteffect. Loss of venous accessdue to phlebitis is common after repeated administrarion. Stabrlizatron of Iyophilizedhematinby reconstiturion with 307o human albumin carrpreventthese effects,and is recommended, adverse especially if a peripheral vein is used for the infusion. Uncommon side effectsof hemin include fever,aching, malaise,hemolysis,anaphylaxis,and circulatory collapse. Heme arginate,a more stable henin preparation,is availablein Europeand SouthAfrica. Hemin reatment should be institutedonlv after a diagnosis of acute porphyrra been inirially has conErmed'by marked"increase a in urinary PBG (determined most rapidly r.rsiog kit, asdesctibed a earlier),When prior documentationof the diagnosis available is for review,it is not essential confrrm an increase PBG wich to in every recurrent artack, if other causesof the symptoms are excluded The clinically. standard regimen heminfoi rrearment of of acuteporphyric attacksis 3-4 mg,4<g daily for 4 days. Lower doses havelesseffecron porphyrin precursorexcretionaod probably less clinical benefit. An investigationalapproach is to combine heme therapy with an inhibitor of heme breakdown, suchas tin proroporphyrinor tin mesoporphyrin, prolong the to efficacyof the administered heme. Measures. Genetaland Supportive Drugs that may exacerbate porphyrias (seeTable 9l-3) should be discontinuedwhenever possible,and other precipitaringfactors identified.Hospitalization is warranted,exceptfor mild attacks,for treatmentof severe pain, nausea,and vomiting; for administration of hemin and fluids; and for monitoring vitaLcapaciry, nutritional status,neurologic function,and electrolytes. Pain usuallyrequiresa narcotic analgesic; there is low risk for addiction after recoveryfrom the acuteattack. A phenothiazine such as chlorpromazine needed is for nausea,vomiting, anxietn and restlessness. Chloral hydrate or low dosesof short-acringbenzodiazepines be given for can restlessness nsomnia. p-Adrenergicblocking agentsmay be or usefulduring acu!eattacksto control tachycardra and hyperteflsion, but may be hazardous in patients with hypovolemia and incipient cardiac failure. because increasedcatecholamine secrerio;may in this srtuationbe an imporrantcompensarorr mecnanlsm, Carbohydrate l-oading. The effectsof carbohydrares reptess on ing hepatic ALAS1 and reducingporphyrin precursorexcretion are weak compared to those of hemin. Therefore, only mild attacks(nild pain, no paresisor hyponatremia) trearedwith are carbohydrateloading. Glucosepolymer solucionsby mouth are somerimestolerated. At least 300 g of intravenous glucose, usually given as a 1Oo/"solution, has been recommendedfor adults hospitalizedwith attacks of porphyria. Amounts up to 500 g daily may be more effective,but large volumesmay favor development hyponatremia. of

porphyrias(see Table91-2),MeasuringPBG in serumrspreferred when there is coexistent severe renal disease, is lesssensitive buc when renal function is normal, Measuremenr urinary ALA is of lesssensitive than PBG and alsolessspecific, will detectADP, but the fourth type of acuteporphyria. ErythrocyrePBGD activity is decreased most AIP patients,and helpsconfirm the diagnosis in in a patreflt with high PBG. A normal enzymeacdvity in erythrocytesdoes not excludeAIP, however,for reasonsdiscussed earlier.Measuringerythrocyre PBGD is quite usefulfor screening family members a patientwirh AIP known ro havelow enzyme of activiry in erythrocytes. However,5-1570 of individualscan be usrng the eflzymatic assay.This is not useful in misclassified infants <4 mo of age, when rhe enzymecan be physiologically increasedin erythrocyles.Erythrocyte PBGD activity may be falsely low if processing, storage,or transport of the sampleis compromised. Simultaneousmeasurementof multiple heme biosyntheticpalhway enzymes, offered by some commercial as laborarories, lessreliable than assays is that urilize specilicsubA srrates. report of low activitres both erythrocyre ALAD and of PBGD suggests unreliableresult, an Knowledgeof the PBGD mutation in a family enables reliable identificationof other genecarriers,PBGD deficiency be doccan in umented a ferusby measuring enzyme rhe activityin amnioric fluid cells,or more reliably by frndinga PBGD mutadon in thes
cells.

C0MPtlCAT|0NS. and other acuteporphyriasare commonly AIP with mild abnormaliries liver function. The risk of associated in liver disease carcinomais also more advanced and hepatocellular during adult life, perhaps50- to 7O-fold, evenrn asympincreased porphyrinsor porphyrin tomatic individualswho haveincreased precursors. Few patients who developedthis neoplasm had in Therefore,cufrent recommenincreases serumo,-fetoprotein, porphyrias,especially >50 yr dationsare that patientswith acr-rce at old, be screened least yearly by ultrasoundor an alternative imaging method. The risk of chronic hypenensionand impaired renal funcrion appears to be increasedin AIP Hypertension or a possible nephrotoxic effect of ALA may explain impaired renal funcrion in AIP, which may progressto severerenal failure and require renal transplantation. Increasedserum thyroxin levels due to increasedthyroxinbinding globulin occur in some AIP parients. Hypercholesterolemiaand elevated low-densitylipoproteincholesterol appear co be lesscommon in this disorderthan previouslythought. TREATMET'lT Hemin.Intravenoushemin, combined with symptomaticand is supportivemeasures, the treatmentof choice for most acute attacksof porphl,ria. There is a favorablebiochemicaland clinical response early treatmentwith hemin, and lessresponse co if that therapy treatmefltis delayed.It is no longer recommended

*Hemin is rhe gennc name for alt heme prepararions used for inEa"enous administradon- Henin is also a chemical term thac refers to the oxidrzed (ferric) form of beme /iron proroporphrrin IX), and is usualty isolated as hernrn chloride. In alkalin solution, the hloride is replacd by $e hydroxyl or ion, forming hydroxyhen].e, bendtin.

r I Chaptelgl ThcPorPhYlias645 recurrentatlacks, chronic parn, and orher symptomseven after factor:. avoidrng known exacerbating

before this can be.ecommended. Cimeridine' a well-known

high in carbohydrace 160-7Oy'of total calories)and sufficientto There is little evidencerhat maintain weisht is recommended. additional dietary carbohydrare helps further in preventing who wish to lose attacks,and it may lead coweight gain. Patients werght should do so gradually and rvhen cheyare cliniexcess by which can bedetected a low serum cally stable. Iron deliciency, ferritin, should be corrected. ovulation, can be GnRH analogs,which reversiblysuppress dramaticallyeffectivefor prevenlrngfrequentlv recurring lureal phaseattacks, but baselineand continuing gynecologicev uaare tron and bone densirymeasurements lmportan!, and t nsdermal estrogenor a biphosphonatemav be added to prevent onceor cwiceweeklycan prevent boneloss.Hemrn adrninisrered frequent,noncyclicattacksof porphyria in somepahents. GEI{ETIC COUNSEL|i{G. Children with a family history of porand counphyria are often seenby pediatnciansfor evaluacion seling,Inforrnation and laborarory'resultsfrom a relative with proven porphyria must be reviewedin order to guide testing of on rhe child, which is differentdepending the type of acuteporphvna. A muration identiliedin the index casecan be soughtin the child. If the child is found to have inherited the mutation, counselingco avoid porentially harmful drugs is appropriate, that Counseling shouldalsoemphasize the greatmajority of those who rnherit a PBGD mutation neverdevelopsymptoms,and the prognosrsof those who do is favorable. Therefore,a normal, healrhy life is expected,especiallywith avoidanceof harmful drugsand other factorsand prompt recognitionand treatmentof symploms should they occur Given the favorable outlook for mosr mutation carriers,even during pregnancnhavrngchildren is not precluded,and prenatal diagnosisof acute porphyrias is Inherlessimportant than it is for many other rnheriteddiseases. rtanceof a PBGD muratron should be resardedas confidential or inlormacionand not inlerlerewirh emplovmenr insurance eligibiliry.

ltransplantation. 'D r o Padentl often do well with avoidance s drugs known or strongly suspected o[ t the acute porphynas are listed in ,o Table 91-6. Updared and more xtensivelistingsare availableon an i eractive website of th European Porphyria Initiative

probably be avoided rn patients with acute porphyria. Danazol can be carried out safely in specrallY iI barbiturates are ommended as an inhalation agenr and propofol and midazolam as intravenous induction

(CEP} POBPHYRIA CONGET{IIAI ERYTHBOPOIET|C

this rare disease usually presents Also termed Gtinther disease, with photosensirjviry shortly after birth, or io urero as nooimmunenyorops. disease to a marked ETI0L0GY due CEPis an autosomalrecessive deficiency of uroporphyrinogen III synthase (UROS). Many UROSmutatrons havebeenidentifiedamoneCEPfamilies.Laterwirh myeloproonsetdisease adulrsis likely ro be a'sociared in liferativedisorders of and expansion a cloneof erlthroblaststhat carry a UROS mutation. PATH0t0cY ANDPATH0cENESIS. UROS, which is markedly deficrent in CEP,caralyzes inversionof pyrrole ring D of HMB (rhe pyrrole ring shown on the righr end of the moleculein Frgure911) and raprd cychzationof the linear tetrapyrrole!o form uroporphyrinogen This enzymeis also rermeduroporphyrinogen IIL cosynrhase. The human enzymeis a monomei The genefor the 10q25.3->q25.3, contains and enzyme found on chromosome is ranscripts are generated 10 exons.Eryrhroid and housekeeping The housebv alternative oromotersbut encoderhesameenzvme. splicedto exons keepingtransciipt containsexon 1 (untranslated)

a contraindicaced dmg sometimes used to treat hyperemesis gravldarum. Diabetes mellirus and other endocrine condirions are not known to precrpitace attacks of porphyria ln fact, the onset of diabetes mellitus and resulting high circulating glucose levels may decreasethe frequency of attacks and lower porphyrin Precursor levels in AIP PBOGN0SIS.The outlook for patients with acute porphyrias has improved markedly in the past several decades. In Finland, for exanple,74lo of pacients with AIP or VP reported that they led normal lives, and less than % had recurrent attacks during several years of follow-up. In those presentrng with acute symptoms, recurrent aftacks were mosr Lkely within the nexr 1-3 yr Moreover, only 57o of gene carriers who had never had atracks developed symptoms. The improved outlook may resuh from earlier detectlon, belter treatment of acute attacks, and replacement of harmful drugs such as barbiturates and sulfonamides with safer drugs. A smaller number of patients, however, continue to har,e

645 | PARTXr MetabolicDiseases 28 through 10, while the erythroid rranscript contains exor 2A (untranslated) also spiiced to exons 28 through 10. The housekeeping promoter is upstream of exon 1, whereas the eryrhroidspecrfic proximal promoter is upstream of exon 2A and contains erychrord transcription factor binding sires including GATA1 and NF-E2. Thus, there is erythroid-specifc regularion, but the enzyrne product is the same in all tissues. In CEq large amounts of HMB accumulate in erythroid cells during hemoglobin synthesis and cychze nonenzymatically to form uroporphyrinogen I, which is auro-oxidized ro uroporphyrin L Some of rhe uropurphyrinogen I rhar accrmuLres is merabolized to coproporphvrinogen I, wbich accumulares because it is not a substrate for coproporphyrinogen oxidase. Thus, both uroporphyrin I and coproporph,vrin I accumulate in tbe bone marrow and are then found in circulating erythrocytes, plasma, urine, aod feces. A variery of UROS mutatrons have been rdenrified in CEP, including missenseand nonse[se mutations, large and small dele tions and insertions, splicing defects, and nfionic branch poinr mutarions. At least 4 mutations have been identified in rhe erythroid-specific promoter. Many pacienrs inherited a different mutatron from each parent, and most mutations have been detected in o y 1 or a few families. An exception is a common mutation, C73R, whrch is at a mutatronal hotspor aod was found in =33 % of alleles. Genotvpe phenotype correla ons have been based on rhe in vitro expression of various CEP mutanons and the severity of associated phenorypic mamfesrations. The C73R allele, which is associatedlv'ich a severephenotype in homozygotes or rn patients heceroallelic for C73R and another mu[arion expressing little residual actrvitg resulted in < 17o of normal enzyme activity. Patients wirh the C73R allele and heteroallelic for other mutations expressing more residual activrty have mrlder drsease. Hemolysis is a common feature of CEP Excess porphyrins in circulating erythrocytes cause cell damage, perhaps bv a phototoxic mechanism, leading to both intravascular hemolysis and increased splenic clearance of ert/lhrocvtes. Also important is ineffective erythropoiesis, wich intramedullarydesrruction of porphyrinJaden erythroid cells and breakdou,'n of heme. Expansion of the bone marrow due to ervthroid hyperplasia mav contribute to bone loss. Nutrrent de6ciencies sometimes cause ervthroid hypoplasia. Despite the marked deficiency of UROS, heme pro dr-rctionin the bone marrow is increased, due to hemolysis and a compensatory increase in hemoglobin production. This occurs, however, at the expense of marked accumulation of HMB, which is converted to porphyrinogens and porphyrins. CtlNlCAt MANIFES l0NS. In severe cases, CEP can cause fetal loss, or be recognized in utero as intrauterine hemolytic anemia and nonimmune hydrops fetalis. CEP may be associated with neonacal hyperbilirubinemia, and phototherapy may unintentionally induce severephorosensitivity. The most characteristic presentation is reddish urrne or pink stainrng of diapers by urine or meconium shordy aFter birth (Fig. 91 2). Wifi sun exposure, severe blistering lesions appear on exposed areas of skin on the face and hands, and have been termed ltydroa aestiuale becausethey are more severewrth greater sunlighr exposure during summer (Fig. 91 3). Vesiclesand bullae, as well as flabrlry, hypertrichosis, scarring, thickenirg, and areas of hvpo- and hvperpigmentation are very similar to those seen in PCT, but usually much more severe.Infeclion aod scar.ing somrimes cause loss of facial feacuresand fingers and damage ro the cornea, ears, and narls. Porphylns are deposrted in dentine and bone in utero- Reddish-brown teeth in normal light, an appearance termed erythrodontia, displa;,'' reddish fluorescence under long wave ultraviolet liglt {Fig, 91 4), Hemolysis and splenomegalv are features of many cases.Bone marrow compensation may be adequate, especially in milder cases.Pacients with severe phenotypes, however, are often transfusion-dependent.

ligure 91-2. Congenital er_]'thropoietic porphyria. The diaperoI an affected bab1. demonstrares redco1o. urine.l}'ron PaUef MaciniAJ:H,]r,/,tu rhe o{ AS, Clinical Pedidttic Detnarologl .lrd ed.Philadelphia, Elsevier Saunderc, 2005,

Splenomegaly may contribure ro the anemia and cause leukope nia and thrombocytopenia, which may be complicated by significant bleeding. Neuropathic sl.mproms are absenc, and there is no sensitiviry to drr:gs, hormones, and carbohydrate restriction. The liver may be damaged by iron overload or hepatitis acquired from blood lransfusions. Milder casesof CEP with onset of svmocoms in adult life and wirhour eryrhrodontia mav more rlosell mimic PCT. These laLeonser casesare likely to be associatedwith m-veloproliferative diso o r d e r . .a n d e x p a n s i o n f a c l o n eo r c e l l sc a r r y i n g U R O S s o m a r c I i mutation. tAB0BAT0RY FINDINGS,Urinary porphyrin excrelion and circu lating porphyrin levels in CEP are much higher than in almost all other porphyrias. Urinary porphyrin excretion can be as high as 50-100 mg dail-v, and consisrs mosdy of uroporphyrin I and coproporphyrin I. ALA and PBG are normal. Fecal porphynns are ma_rkedly increased, with a predominance of coproporPnyrln r. Marked rncreases in eryrhrocyte porphvrins rn CEP consist mostly of uroporphyrin I and coproporphyrin L These porphyrins are also increased in bone marrow, spleen, plasma, and, to a lesser excent) liver. The porph;rrin partern in erythrocytes is influenced by racesof erythropoiesis and erythroid maturation. A pledominance of procoporphyrin has been noted rn some CEP

Figurc 9l l. Congenital eryrhropoietic porphyria. Vesicles,bullae, and crusts on sun exposedareas (From PaLler AS, Macni Al: Hureitz Clinical Pediatri. Dermatologl,3rd ed. PhiJadelphia, Ilsevier Saunders,2006, p 517,)

r $ Ghaptei r The PorpftYrias 647 UROS cDNA has been subcloned into retrovital vectors, which hare been used to lransduce Fbroblast* and lrmphobla'rs from padents u'ith CEI resulrrng in significant levels of enzvme ex esiion. Transducuon of hematopoietic progenitor cells arrd rly erythroid cells was also achieved. PB0G 0SlS. The outlook is favorable in milder cases and in patienm wlth more severe disease treated by transfusions suffiii"nt to .upp.... erlthropoiesis and bone rnarrow porphvrin production at least partiallv. Successfulbone marrow or stem cell transplantation has proven effective.

is CoUltlSEtlNG. counseling PBEVtilTlo$ AtlD GENETIC Genetic

imoorcant for affected families, becauseCEP can be recogJriled before birch and a severe phenotype can often be predicted by idenrifying rhe nature of the UROS mutation\.

Figurc 91-4. Congeniral erlthropoieric porphyria. Brownish teeth that fluo-

TABDA PORPHYRIA CUTAIIIEA {PCTI

p s17.) humanporphyria Thrs is rhe mosrcommonand readilyIreated (see Table 91-2). lt occursin mid or late adult life, and is rare in children, Prevrousterms include symptorfiaticporphlri', PC'f The underlyingcause dnd symptomatica, ldiosyncrrlti.porpDyrr,r. decaracquireddeficiencv uroporphyrinogen of is a iiver-specific, types of geretic boxylase(UROD) with contributionsby several factors, UROD mutations are found in famihal PCT. The homozygousform of familial PCT is HEB which has a more presentation, usuallyin childhooO. severe ET|OI0GY. of PCT is due to a marked deficiency hepaticUROD must be substantial t'20'lo of normal This enzymedefrciency manifest,and its developrnent activity or less)for PCT to become in of is atribured to generation a UROD inhibrtor specilically the is liver This inhrbiror,which has noc beencharacterized, derived from a heme pathway intermediatesuch as uroporphyrinogen, and CYPs such as CYP1A2, as well as iron, are involved in its inhrbition of hepatic formation (Fig. 91-5J.Evenwith substantial UROD activity, the amoun! of enzvme protein measured determined level. remainsat its genetically immunochemically rhe of UROD catalyzes decarboxylation the 4 acetrcacid side to chainsof uroporphyrinogen(an octacarboxylporphyrinogen) (a form coproporphyrtnogen tefi acarboxyl porphyrinogen)(see

patients,and in 1 suchpatient!uroporphyrinand coproporphyrin was srimulatedby blood removal when erythropoiesis increased of The ANDDlfFEltl{Tl,AtDIAGI{OSIS. diagnosrs CEP DIAGN0SIS of by should be documented full characterization porphyrin parof ternsand idenrification the underlyingmutations ln later onset cases,an underlying myeloprohferativedisorder and a UROS and somaticmutation should be suspected studiedin detail'

porPhyrins in amnioric red-brown discoloration and increased and plasmaand porphyrinsin fetal erythrocytes Iluid, measuring UROS acuvitv in culrured amnioric fluid cells, or identiffing UROS genemutationsin chorionicvtlli or culturedamnioriccells minimizing skin sunlight exposure, n! of anY cutaneousinfectionsare g CEP (see Table91-4) Sunscreen Transfusions beneficial. sometimes !o to achievea level of hemoglobrnsufficienc supplesselythrocan be qurte effectivein reducingporphyrin poiesissignrficantly ro ievelsand photosensitiviryConcurtenr defetoxamrne reduce iron overload, and hydroxyurea to suppresservthropoiesis further may provide addidonal benefit. Splenectomyteduces in hemolysisand transfusionrequirements some patients.Oral charcoal may increasefecal loss of porphyrins, bur may con cribute little irr more severecases.Inrravenoushemin may be but has not been exlensivelystudied and somewhat effeccive, unlikely to provide long-termbenefit.Chloroquinehasnot seems beenbeneficial. whrch hasmarkedly Bonemarrow or stemcell transplantation, longand porphyrin levelsand photosensltiviry increased reduced for drsease especially severe rerm survival,shouldbe consrdered, in Genetherapymay be accomplished the future. To date,human

Glycine + SuccinylCoA I acid 6-Aminolevulinic

ALASI

I I
I

CYPIA2

CoproporPhyrinogen

I I
I Heme
lE^2+

t'igurc 91-5. Formation of a specinc inhibrror of uroporphvrinogen decar boxylasein rhe liver in porphtria cutanea rarda. AL.\S, &aminolevutinic acid synthase; CYPlA2, c-vtochrome P450 1A2r UROD, uroporphyrinogen

648 I PARTXr MetabolicDiseass Fig. 91 1). The enzyme reaction occurs rn a sequertjal, clockwise l:ashion,wirh lhe inrermediareformarion oi hepra-. hexa-. and n r o p o r p h y r r ad , ' c s n o ' 6 . u " , o p i n C Y P I A 2 k n o e k l u r m i c e . S t u d i e sw i r h C Y P 2 E l I n o c k u u r r r u g g e ' r r h a t l h i \ e n T v m em a t also contriblrte. Mrce wrth disruption of one UROD allele and either 1 or 2 disrupred HFE alleles provide an important model for PCT wichouc adminrsrration of halogenated cliemicals.

strate. Human UROD is a dimer with rhe 2 acrive sire clefts juxtaposed. The UROD gene is on chromosome 1p-j4 and cont a i n s l 0 e x o n s . ' " r ' i r h o n l v p r u m o l e r . l h e r e f o r e r h i g e n ei s r r a n l . scribed as a sinele mRNA in all trssucs. The majoritv of PCT parrenrs(=80%) have no UROD murarions and are said to have sporadrc (rype 1) disease.Some are heterozygous for UROD mutarrols and are said to have farnilial

patlelrt. lron. A normal or increased amounr of iron in the liver is essen-

cause PCT unless a UROD inhibitor is also generated. Because penetrance of the genetic ait rs loq many parienrs with famil ial PCT have no famrlv hi orv of the disease. lnduction of hepaticALAS1 rs nor a promin t featureinPCT, although alcohol may increase this enzyme ightLy..Iron and estrogens are also not potent inducers of ALAS1 and drugs that are potelt inducersof ALASl and CYPs are much lesscommonly rmplicatedin PCT rhan in acurepurphyrias. Blistering skin lesions resulc from porphyrins tlar are released from the liver Sunlight exposure leads to generation of reactive oxy_genspecies in the skin, complement activation, and lysosomar oamage. E es probably relate to geog ctors such as hepatitjsC and e he United Kinsdom was estim a r e da r 2 - 5 1 1 , 0 0 0 . 0 0 0a n d t h e p f e r a l e n c en c h eU n i r e d\ r a l e s . i and Czechoslovakia!.i'asestimaled ac =1/25,000 and 1/5.000. respectivel). The disease *.as reported to be prevalent in the Banrusof South Africa in association wirh iron overload.PCT is more common in males, possible due to greater alcohol intake, and m wornen it is commonly associated with estrogen use. A massive outbreak of PCT occurred in easrern Turkev in the l q 5 0 \ . ! V h e a r i n r e n d e df o r p l a n r i n g a n d r r e . r r e dw i t h h e x a chlorohenzene as a fungicide was consumed bv man,v at a time of {ood shortage. Cases and small outbreaks of PCT after expo, sure to other chemicals including dr- and rrichlorophenols and 2,3,7,8-cetrachlorodibenzo-p-dioxin (TCDD, dioxin) have been reported. The manlfestatlons rmproved in most cases when lhe exposure rvas stopped. There are, however, reported cases of delayedonsecmany years after chemicalexposure. PATH0[0GY AND PATH0GENESIS. is currentlv classifiedinto PCT t c l i n i c a l l y i m r l a rt 1 p e r ,G e n e r a t i o n f a U R O D i n h r b i r o ri n r h e s o liver plays an important role rn all 3 qvpes.The -80% of parients rvrth type I (sporadic) PCT have no UROD mutationsr and UROD activity is normal in nonhepatic tissues. familial (type In 2) PCT, a UROD mutation is associated wirh a partial (=50%) deficrency UROD in nonhepaticri*'ue.. fhe genericalll derer. oi mined level of rhe enzl.me is also 50% in rhe lir.er, bur rs much lower when a UROD inhrbiror is generated and the disease becumes.linrcallr acrive.Type t is rare. and deocrrbe,lC f rvrrh normal erytbrocyte UROD activity occurring in more than 1 family member UROD muradons or another seneric basis have nor been idenrilied in rype 1. and tamilial occurrencei5 the ont] feature that distinguishes it from tvpe 1. CYPs, especially CYPY1A2, can catalyze the oxidation of uroporphyrinogen to uroporphyrin. This uroporphyrinogen oxidase (URO-OX) activit]' is enhanced by iron, and leads ro formahon of a UROD inhibitor (seeFig. 91-5). CYP1A2 seemsessentral for developmenr of uroporphyria in rodents, because experimental

major cause of hemochromatosis i *.hire people, is increased in both tvpe 1 and cype 2 PCI and 10% of pacienrsare C282Y homozygotes. In sourhern Europe, where rhe C282Y is lessprevalent, rhe H63D mutatjoo is mote commonly associated.PCT may occur with secondary iron overload. Hepatitis C. This viral infecdon is highly prevalent in PCT rn most geographic locations; in the United States, for example, it rs present in 56-747o of cases,which is simrlar to tbe (ate cired

oxjd ve stress Jn hepaticis C may favor rron mediated generation reactive oxygen species and a UROD inhibitor HIV Many reporcs suggest HIV rnfection can contribute to the developmenc of PC! hoLrgh less commonl,v than does hepatitis C. The mechanism not known. Ethanol.The long-recognized assocjation between alcohol and PCT may be expJained chegeneracion acriveoxygen species, by of

increased production of endotoxm, and activation of Kupfler cells. Smoking and CytochromeP450Enzymes.Smoking has not been

CYPs and oxidative srress, Hepatic CYPs are thought to be

CYP1A2 and 1A1 have been imphcated rn human PCT. The fre quency of an inducible genotype was more common rn PCT palenls rhan in controls rn 2 studies Antioxidant Status.Ascorbic acid de6cienc,vhas been rmphcared in conrriburing to uroporphyla rn laborarorv models and human PCT. In 1 series, plasma ascorbate levels were substanciall,r' reduced in 847" of patients \\,rth PCT. Lorl'' levels of serum carotenoids were also described, furcher suggesting thac oxidaoc stress irl heparocytes is importanr in PCT. Esttogens. Use of escrogencontaining oral contraceptives or postmenopausal estrogenreplacemen!is very commonlv associated wich PCT (type 1 or 2) in women. PCT sometimes occurs during pregnancy, afthough it is noc clear whether the nsk is lncreased. CU'CAI. MAI{IFESTATIONS CutafleousManitestations. PCT is read ,v recognized by blisrering and crusted skin lesions on rhe backs oI rhe hands, rvhich are rhe most sun-exposed areas of the body',and somewhat less com monly on rhe forearms, face, ears, neck, legs, and feet. The fluidfilled vesicles commonlv rupture and become crusced or denuded areas, heal slowln and are subject to infecion. The skin on rhe backs of the hands is characteristically friable, and minor trauma may cause blisters or denudation of skin. Small white plaques, tetmed tui\fu, ma1' precede or follow vesicle formation. Facial hypertnchosis and hyperpigmentation are also common. Severe scarring and rhickening of sun-exposedskjn mav resemblescle-

I Chaptelgl r ThePorDhyrias 649 are porph,vrins DlAGN0SlSPLasma DIAGN0SIS AND DIFFERENTIAI aLways increased in clinically manifest PCI and a total plasma porplvrin determination rs most useful for screening. A normal value rules out PCT and other porphvrias rhat produce bltstering skin lesions. If increased, it is useful to determine the plasma fluorescen.. emission maxrmum at neutral pH, because a maximum near 519 nm is characteristic of PCT (as well as CEP and HCP) and, most important, excludes VP, which has a distinctlv different fluorescence maximum lncreased urinarv

occurin VP for chanses nol soecilic PCT.The samefindings are thoseof ( tl and HEP but are usually and FCP, and reiemble in Onsetof the drsease childhood is rare' and is more lessserrere,

normal,

PC! but with an additional marked tncrease in erythrocyte zinc

stage renal disease. Cutaneous blisters may ruptute and become C0MPLICATI0NS, infecred, sometimes leading to cellulitis. In more severedrseasein patients with end-scagerenal disease, repeated infections can be mutilating, as in CEP, Pseudoscleroderma, with scarring, contracrion, and calcification of skin and subcutaneous trssue, is a rare complication. Other complications, such as advanced liver diseaseand hepatocellular carcinoma, were alreadv discussed. TFEATMENI Management of PCT includes choice of 2 specific aod effective forms of treatment, phlebotomv or low-dose hydroxvchloroquine, and removal of susceptibility factors when possible. The diagnosis of PCT mLrst be 6rmly established, and iondirions thar produce identical cutaneous lesions excluded, becausethese do not respond to treatments used in PCT. Treac

in Porphyrinaccumulates the liver mostly FlN0lNGS. tAB0RAT0RY

and III.

and tested for hepatitrs C, HIV, and HFE mutations. Some susceprrbility factors influence the choice of treatment. Phlebotomy is considered standard therapn and is effective both in children and adults with PCT because tt reduces hepatic rron contenr. Treatment is guided bv plasma (or serum) ferritin and porphyrin levels, Hemoglobin or hematocrit levels shoul be follou.ed to prevent symptomattc anemia. For adults, a un of blood 1=456 -1; is temoved at =2 wk intervals urtil a larger serum ferritin near the lower lmit of normal (=15 ndml-) is achieved. A rotal of 6 to 8 phlebotomies is often sufficienr. After this, plasma porphynn concentrations continue to fall from pretreatment levels (gnerally 10-25 pgldl-) to below the upper limic of normal \=1pg/dL), usually after severalmore weeks. This rs followed by gradual clearing of skin lesions, sometimes including pseudoscleroderrna. Lrver function abnormalities may improve, and hepanc siderosrs,needleJike inclusions, and red fluorescence of liver tissue will drsappear Although remission usually pelsrsts even rf ferritin levels later return to normal, it is advlsable to follow porphyrin levels and reinstitute phleboromies if these begin to rise. lnfusions of deferoxamine, an tron chelator, may be used when phlebotomy is contraindicated.

Diseases 650r PABTXr Metabolic An alternarive *'hen phlebotomy is concraindicared or poorly tolerared is a low-dose regimen of chloroquine or hvdroxychloroquine. Normal doses of these 4-aminoquinoline antimalarials increase plasma and urinarv porphvrin levels and increase photosensitivicf in PCI reflecring an outpouring of porphvrrns from the liver This is accompanied by acure hepatocellular damage, with fever. malaise, nausea, and increased serum traflsaminases, but is followed by complete remission of the porphyria. These adverse consequencesof normal doses are largely avoided by a low-dose regimen (chloroquine 125 mg or hvdroxychloroquine 100 mg, Y. of a normal tablet, twice weekly), which can be continued undl plasma or urine porpbyrins are normal ized. There is ar least some risk of rerrnopathy, which may be lower with hydroxychloroquine. Prospective treatment trials comparing chis treacment with phlebotomy are lacking. Low-dose chloroqurne ma)' not be effective in patrents homozygous for the C282Y mutation in the HFE gene, Therefore, the degree of excess heparic iron may influence response to chis creatment. The mechanism of action of 4-aminoquinolines in PCT is not known, but is quice specific, since these drugs are not useful in other porphyrias. In patients with PCT afld hepatitis C, PCT should be treared 1st because this condition rs more svmgtomatic and can be rreatedmore quicLly and eflectrvell.lreatmenc of PCT hr phlebotorny may not be possible once rnterferon-ribavirin treatment is complicared by anemia. Moreover, treatment of hepatiris C may be more effecrive after iron reduction. Resrstanceof hepatitis C to treatment with rnterferon-d or pegylated interferon and ribavirin has been reporred in patiencspreviousl,v treated for PC! but prospective studies are lacking (see Chapter 355). PCT rn patients with end-stage renal disease is often more sel'ere and difficult to rreaf. Although phlebotom,v is ofren contraindicated initiall,v, er1'thropoietrn admrnistratron can correct anemia, mobilize iron, and support phlebotomy in manv cases. Response may also occur after renal transplantacion, due in part ro resumption of endogenous erythropoieric production. Liver imaging and a serum o-fetoprorein determination may be advisable in all PCT patients, perhaps at 6-12 mo intervals for early detection of hepatocellular carcinoma. Finding low er,vthrocyte UROD activity or a UROD mutation identifies those with an underll,ing genetic predrsposition, whrch does not alter treatment but is useful for genetic counseling (see later). PR0GN0SIS.PCT is the most readily treated form of porphyria, and complete renissron rs expected wlth treacment either by phlebocomy or low dose hydroxychloroquine. There is iittle infor mation on rates of recurrence and long-term ourlook. Risk for hepatocellular carcinoma is increased, and some suscepribilitv factors such as hepatitis C can lead to complications even afcer PCT rs in remission, porphyrins originate mostl,v from liver, wlth a paltern consrsrent !.i'ith severe UROD deficiency. This rare disorder has no patticular racial predominance. ETl0L0GY HEP is an aucosomal recessivedisorder, altbough mosr patients have inherited a diflerent mutacion liom unrelated parenrs.In contrast !o most mutalions in familial (tvpe 2) PC! most causing HEP are associated with expressiot of some residual enzyme activiry. At least 1 genotype is associated with the predominanr excretion of pentacarboxyl porphyrin. PATH0L0GY AND PATH0GENESIS. Excessporphyrins originate primarily from the liver io HEP, although che substanrial increase in eryrhrocyte zinc procoporphyrin indicares rhat the heme biosyntheuc pathway is also impaired rn bone marrorv erythroid cells. Apparently, porph,vrinogens accumulate in the marrow while hemoglobin svnthesis is mosc active, and are merabolized ro proroporphvrin alter hemoglobin synthesis rs complece. The cutaneous lesions are due to photoactivation of porphyrins in skin, as in other cutaneousporphyrias. CUNICALMANIFESTATI0NS.Like CEP. rhis disease usuallv oresenrswirh blisrering,,kin lesions.hl perrrichosis. 'carrrng. and red urine in infancy or childhood. Sclerodermoid skin changes are sometimes orominent. Unusuallv mild caseshave been described. Concurreni condrtions rhat affect liver funcrion can alter disease severity. For example, hepatirs A caused the disease ro become manifest in a 2 year old child, and then improved with recoverv of liver function. LASORATORY Flt{DlNGS. Brochemical frndings resemble those in PCT with accumularion and excretjon of uroporphyln, heptacarboxyl porphyrin and isocoproporphvrin. But in additron, erythroclte zinc procoporphyrin rs substantially increased. DIAGN0SISAND DIFFERENTIAL 0IACN0S|S. HEP is drstineuished lrom CEP hv Increa5.sIn borh uroporphyrin and hepra.irhowl porphyln, and rsocoproporphyrins. In CEP the excss erythrocyce porphyrins are predormnantly uroporphyrin and coproporphyrin racher than proroporphl'rin, Blistering skin lesions are unusual in EPI the excess erlthroc,vte protoporphyrin in that disease is free and_noc complexed with zinc, and urinary porpnylrns are normal. IREATMEI'IT AND PR0GN0SIS.Avording sunJight exposure is mosr important in managing chis disease,as rn CEP. Oral charcoal was helpful in a severe case associacedwith dyserythropoiesis. Phlebotomy has sholr'n litcle or no beneft. The outlook depends on the severity of the enzvme deliciency and may be favorable rf sunlight can be avoided, Retrovirus-mediaced gene transfer corrected porphyria in transduced lvmphoblastoid cells from HEP patients, suggescingthat gene therapv may eventually be developed. PnEVENTI0N AND GENETIC C0UNSEUNG, part of geneticcounAs seling in affecred families, it is feasible to diagnose HEP in utero, either by analysis of porphyrins in amntottc fluid or DNA studies.

PREVEI'|T|0N GENETIC AllD Patients with PCTmay e0UNSEtlNG.

have concerns about risk ro other family members, A hericable L,'ROD nutauon can usually be detected or excluded by measuring erythrocvte IIROD acrivity, although DNA studies are more sensitive. Relarives of Datients with UROD mucations have an rncreased risk for developing PC! and may'have increased motivation ro avoid adverse behaviors such as ethanol and tobacco use and exposures to hepatitis C and HI\'. Such counseling would be given to an,vone, however. The linding of HFE muratrons, and especially C282Y, should prompt screening of rel ativesr some of r.r.hommay be C282Y homozygotes and &'arrant I i i e l o n gm u n i r o r r n g f r e r u m f e r r t t t n . u

(HCP} HEREDITARY COPROPORPHYRIA

This autosomaldomrnanthepaticporphvria is dueto a deficiency (CPO). The disease presenrs of coproporph,vrinogen oxidase with acute atlacks, as in AIP Cutaneousphotosensitivitymay occur, but much less commonly than in VP Rare homozvgouscases presentin childhood. ETI0LOGY partial (=50%) defrciency CPO activitv has been in A found rn all cells srudiedfrom patients\{'ith HCP A much more

HEPATOERYTHROPOIETIC PORPHYRIA
(HEP),rvhichis the homoz),gous Hepatoervthropoietic porph,vria form of famrlial (type 2) PCT, resembles CEP clinically. Excess

r ' Chaptelg'l ThrPorphYrias661 coproporphyrrn.Plasmaporphyrins are usually normal or only slightly increased. of DIAG[{0SlS. diagnosrs HCP The DIAGNOSIS DlttERCNT|AL AND

in mostly coproporphyrin(isomerIII) in HCP,whereas VP,coproaPProriiporphyrin lll and protoporphytin are often rncleased marely equally.Plasmaporphyrins are usually normal in HCP in and increased \?.

of ture release harderoporphyrinogen. family members. HCP is lesscommon than AIP and VP, but its EPIDEMI0LOGY Acute attacks of HCP are treated At{D TREATMENT PR0GNOSIS.

Increased ALA and PBG dunng AND PATHOTOGY PATH0GENESIS.

erally berterthan in AIP C0UNSEI-lNG. Theseare the sameas in PREVENTI0N GENETIC AND other acute porPhYrias.

(VP} PORPHYRIA VARIEGATE

This hepatic porphyria is due ro a deficiency of protoporphyrinogenoxidase (PPO),which is inherited as an autosomal rt because can dominant trait. The disorderis terrneduariegate Other terms mamfestions. presentwirh neurologicor cutaneous have iocluded porPhyria eariegata,proto.opropotphJtw, a d VP of South Aftican geneticporphyria. Rare cases homozygous in are symptomatrc childhood. half normal in all cells studied EflOIOGYPPO is approximacely in patientswith VP The enzymeis more markedly deficientin rare casesof homozygousVP, with approxrmatelyhalf-normal enzymeactivity in arents. Human PPO is homodimer that containsFAD and is localized to the cytosohcside of the inner mitochondrial membrane. domainsmay be dockedonto hurnanFECH, Membrane-brnding in the next enzymein the pathway,whrch is embedded the oppothe srte side oI the memb.ane.PPO catalyzes oxidation ot Pro-

rn HCP Symptomsare identical to those of GtlNtCAtMAI{|FESTATI0NS AIP except that attacks are generally milder, and c.utaneous lesionsthit resemblethose in PCT developoccasionallySevere

acute orphyrias. Th cLnical features of homozygousHCP, whrch begin in early childhood, may include ,aundice, hemolytic anemia, Thesesymptoms and hepatosplenomegalv, skin photosensitivity. distrnctfrom thoseseenin heterozygotes ari getre.allyqr-:ite ALA and PBG S The porphyrinprecursor\ morerapidlt culeattacks, maydecrease bul ncreases coproporphyrinIII in urine and in that causeprocoporphyrinto accumuand by certain herbicides late and induce phototoxicity in plants. Inhibrtion bv bihrubin PPO activity rn Gilbert disease. may accountfor decreased of 1q22-q23 consists L The hr-rman PPOgeneon chromosome noncodingand 12 coding exons,A singlePPO transcriptis probut ducedin a varieryof tissues, putative ftansclrptionalelement ma allow for erythroid specificexPression. binding sequences Many PPO mutadons ave beenreportedin VP farnilies A missensemulation, R59W, is prevalent in South Africa. No con-

. 652r PABTX Metabolic Diseoses vincing genotype-phenotype correlations have been rdentified. Mutations in homozygous cases VP are more likely to encode of enzymeproteinswith residualactivity. EP|DEM|0L0GY. is lesscommon than AIP in most countries. VP The R59\V mutation is highly prevalentin SouthAfrican whites (=3/1,000).This exampleof geneticdrift or "founder effect" has beentraced to a mafl or his wife who emieraredfrom Holland ro Sourh Airica in 1o88. In linland. rhe orevalence is ' L l / 1 0 0 , 0 0 0 n d i s a b o u ra sc o m m o n s A I P a a PATH0LOGY ANO PATHOGENESIS. Acute attacks develop in a minority (=25%) of hererozygotes PPO deficiencnand are for often aftributableto drugs,steroids,and nutritional factorsthar play a role in other acute porphyrias. Protoporphylnogen IX accumulates and undergoesauto-oxidation to protoporphyrin IX. Coproporphyrinogen may accumulate III due to a closefunctronal association PPO in the inner mitochondrialmembetween brane and CPO in the intermembranespace.Liver porphyrin contenr is nor ilcreased. The increasedporphyrin contenr in plasmaconsrsts porphyrin-peptide of conjugates, which may be formed from protoporphyrinogen. IncreasedALA and PBG during acuteattacksmay be explained,as in HCP, by induction of ALASl by exacerbating factors,and by the normally relatively lorv activity of PBGD in liver Furthermore, PBGD is inhibited by proroporphyrinogen, substratefor PPO. the CUNICAL MANIFESTATI0NS. Symptoms develop in some het, erozygotes tter puberty.Neurovisceralsymptomsoccurring as a acute atracksare idenrical ro AII but are generallymilder and lessoften fatal. Drugs, steroids,and nutritional alterationssuch as fasting,which are harmful in AII can also induce attacksof VP.Attacks occur equally in malesand females, leastin South at AJrica. Cutaneousfragility, vesicles, bullae, hyperpigmentation, and hypertrichosis sun-exposed areasare much more common of than in HCP They are likely to occur aparr from and be more Iong lasting than rhe neurovisceral symptoms.Oral contraceptivescan DreciDitate manrfestatiols. Acute aftackshave cutaneous become iess iommon, and skin manifestationsare more frequently rhe nihal presentation; this may be due co earlier diagnosis and counseling.The risk of hepatocellularcarcinomais increased Vl as in other acuteporphyrias. rn Symptomsof homozygous begin in infancy or childhood. VP photosensitivitS Thesechildren generallyhave severe neurologic developmental symptoms,convulsions, disturbances, and sometimes growth rerardation,but do not have acuteattacks. IAB0RATOSY F|N0|NGS. Urinary ALA, PBG, and uroporphyrin are increased durilg acute artacksbut often lessso than irl AIP, and these may be normal or only slightlyincreased dttlng rernission, Plasmaporphyrins, urinary and fecal coproporphyrin III, and fecal coproporphyrinIII and protoporphyrin are more persistentlyincreasedbetweenattacks. Erythrocytezinc protoporphvrin levelsare markedlyincreased homozygous and may in Vl be modestlyincreased heterozygous in cases. DIAGN0SIS DIFFERENTIAL DIAGN0SIS. is readilydistinAND VP guishedfrom AIP and HCI which alsopresent with acuteactacks and increases PBG. Plasmaporphyrin analysisis especially in useful, because plasmaporphyrins in VP are tightly protern the bound, resulting in a characteristic fluorescence emissionspecffum at neutral pH. Fecal porphyrins are increased, wirh approximately equal amounts of coproporpbyrin III and protoporphyrin. Fluorometricdetectionof plasmaporphyrins is more sensitive in than stool porphyrin analysis asymptomatic VP PPO assays using cells that contain mitochondria, such as lymphocytes,are sensitive identifying asymptomatic for carriersbut arenot widelyavailable. TREATMENI Acute atracksare treatedas in AIP. Hemin is beneficial for acute attacks but not for cutaneoussymptoms,Light protectionis important in padentswith in manifestations, using long-sleeved clothing, gloves,a broad- mrred hat, and opaque preparations.Exposureto shorr-wavelengrh sunscreen ultravio let light, whrch doesnot exci!eporphyrins,may increase skin pigmentation and provide some protection. Phlebotomy and chloroquine are not effective.Surprisingll., oral activatedcharcoal.was reported to increase porphyrin levelsand worsen skin manrlestallons. PROGN0SIS PREVENTION. outlook of padenrswith VP AND The has improved, which may be attributed to improved tteatmenr, earlier diagnosis,and detection of latnt cases.Cyclic acure attacksin women can be prevented with a GnRH analog, as in AIP. A diagnosisof VP or any other acuteporphyria should not lead to difficulry obtaining insurance,because the prognosisis good once the diagnosis established. usr.rally is GENETIC COUNSEIING. Theseare the sameas in other acute oorphyrias.

(EPP} EBYTHROPOIETIC PBOTOPORPHYRIA

In this autosomal dominanr disorder, protoporphyrin accumulates due co a partial deficiency of FECH, the last enzyme in rhe heme biosynthetic patbway. EPP is sometimes @tmed protoporphyria ot etythrohepdtic protoporphyria, although the liver does not concribute sr.rbstantially to production of excess protoporphyrin in uncomplicated cases. ETl0t0GY. FECH, the enzyme that is defcienr rn EPP, catalyzes the final step in heme synthesis, which is lnsertion of ferrous iron (Fe'?*) into protoporphyrin IX (seeFig.91-1), The enzymeis also termed heme sykthetase or protohetue fettolyase. The human enzyme is a dimer, and each homodimer contains a [2Fe-2S] cluster, whrch nay have a role in bridging homodimers. FECH is found in the mitochondrial inner membrane where its active sire faces the mirochondrial matrix. It mav be associated with complex I of the mitochondrial electron transporr chain, and rhe ferrous iron substrate may be produced upon nicotinamideadenine dinucleotide (NADH) oxidarion. FECH is specilic for the reduced form of iron, but can utilize other metals such as Znr* and Co'* and other dicarboxyl porphyrins. Accumulation of free protoporphyrin rather than zinc protoporphyrin in EPP indicates that formation of the latter is dependent on FECH activrty in The human FECH gene is locared on chromosome 18q21.3, has a single promoter sequence, and contains 11 exons. Two mRNAs of =1.5 and =2.5kb were described,which may be explained by the use of 2 alternarive polyadenylation signals. The larger cranscripcis more abundant in murine er;.throid cells, suggesring erythroid-specilic regulation of FECH. A vanety of FECH mutarions have been reported in EPP, including missense, non sense,and splicing murations, small and large deletions, and an rnsertio[. The inheritance of 2 alleles associated with reduced FECH activity is required for diseaseexpression. This is consistent with FECH activities as low as 15-25% of normal in EPP patrents. In most patients, a disabling mutation on one FECH allele is combined with a common polymorphism affecting the other allele, whrch produces less than normal amounts of enzyme. This intronic single nucleotide polymorphism, [VS3-4ST/C, results in the expression of an aberrantly spliced mRNA that is degraded by a nonsense-mediatedRNA decay rnechanism, which decreases the steady-sratelevel of FECH mRNA. Inheritance of EPP in mosr affecred families is correctly rermed autosomal dominant because the IVS3-48Ti C polymorphism by irself does not cause disease,

r 9l Chaptcr . ThePorphyrias 65:l

with ln

normal subunits would have enzyme activlty' rianc casesof EPP,FECH activrty is normal, and both free

EPP rs the 3rd most comrnon porphyria' although EPIDEMI0[0GY. irs orevalence is nor precisel' known (see Table 9l-2l lt is describedmostly in whrte people. hut occurs in other race' a' well, including blacks. ihe IVS3'48T/C polv-morphism is common in rvhlicesand East Asians buc rare in Africans, thtch would be predictive of a lower diseaseprevalence in populations of African origin.

triglyceridemraand somewhat lower levelsol erlthrucYte pfotopoiphyrin and increased sunhght rolerance dr-rringpreBnanc) have been described.

porphyrins and porphyrin precursols are normal in uncomplicated EPP A DIAGNOSIS. diagnosisof EPP is AND DIFFERENTIAL DIAGNOSIS conlirmed primarilv by 6nding a substantially elevated concentralron of eryth.ocyre protoporphyrin, which is predominantlv

FECH is deficient in these cissues

blasts has been noted in the bone malrow of some patients' however, suggesringthar FECH deficiency sometimes imPairs eryrhroid heme synthesrs. Liver damage that develops in a small proportion of EPP is D.rtienrs atrribured ro excessprotoporphvrtn. which rs insolu61. ,n *ut.. and is excreredonly by hepari( uptake and biliary excretion, Some mav be reabsorbed by the intestine and undergo enteroheDatic circulation. Excess protoporphyrin can decrease hepadc 6ile formation and flow, form crystalline structures in hepatocvtes, and impair mitochondrial function. Symptoms of cutaneous photosensiCtlNlCAt MAiIIFESTATIONStivitv beein in childhood, and consist of Pain, redness,and itching occurrin-g within minutes of sr-:nlight exposure. Swelhng may resemblJ angioneurottc edema, These are referred to as solar urticaria and are usually worse in the spring and summer

must be interpreted with care The increase in plasma total porphyrin concenrratjon ln EPP is often less than in ocher cutaneous porphvrias. Great care must be taken to avoid light exposure during sample processing, becauseplasma porphyrins in EPP are partrcularly subiect ro Phorodegradation. Other findings rnclude normal levels of urinary porphyrrn precursors and porphyrrns. Measurement of FECH activity requires cells containing mitochondria and is not widely available. Demonstration of nolmal FECH activity and a greater than expected proportjon of zinc protopoporphyrin in erythrocytes is importalt in idenrifying variant EPP Dr..r..A studies are increasingly important {or confirming the mode of inheritance and for genetic counseling. The development of life-thratening hepatic complications of EPP is accompanied by abnormal liver function tests, increasing erythrocyte and plasma protoporphyrrn levels, and increased photosensicivity, Increases in urinary porphyrins, especrally coproporphyrin, are attributable to hver dysfunction. COMPtlGATl0NS. Biliary stones conraining protoporphyrin are sometimes symptomatic and require cholecysrectomy. Liver diseaseoccurs i; 1-2% of EPP patienrs, including children, and

viral hepaticis, alcohol rntake, iron deficrency'fasting, or oral contraceptive steroids, may contribute. Liver histology shorvs markid deposirion of protoporphyrio in liver cells and bile canaliculi. Pattents with procoporphyric liver failure, which rep-

654 r PART . MetEbolic X Diseases resentsa severephenotype, most often have "null mutations" and the IVS3-48T/C polymorphism in the nonmutant allele, bur some nay have 2 mutant alleles and autosomal recessiveinheritance. The bone marror;r. is probably the major source of protoporphyrin, even in EPP patients wrrh heparrc failure. TBEATMENT. Exposure ro sunlight should be avoided whenever possibLe,which is aided by wearing closely woven cloching, Oral beta-carotene leads !o clinical improvement and greater tolerance to light in some patients, usually 1 to 3 mo after srarling treatment. In mosr adulrs, doses of 120-180 mg daily will maintain serum carotene levels in the recommended ranee of 600800 mg/dl . bur do.e, up ro J00 mg daily mav he nieded. Mild skin discoloracion due to carorenemia is expeced. The recommended producc is Solatene (Tishcon), lvhich u,.asdeveloped as a drug specrficallv ior treating rhis direase,rarher rhan nuiritional products that are less standardized. Beta-carotene may quench singlet oxvgen or {ree radicals, but does not substantially alcer circulating porphyrin levels. Be er rolerance of sunlight nay result in tanning, which provides ddirional protection. Oral cysteine may also quench excited oxygen species and was found mole recently to increase rolerance to sunlight in EPP Other measures ro darken lhe skrn may also be helpful. This ma1 be accomplished by n.rrrow band UV-B photorherapr or wrth topical products such as dihydroxyacetone and lawsone { n d p h t h o q u i n o n e )C a l o r i c r e s r r i c r i o n n d d r u g s o r h o r m o n e . a preparadons that imparr hepatic excretory fr-rncdon shor.rld be avoided, and iron deficrencv should be corrected rf present. Treatment of protoporphlric lir.er disease must be individual GENETIC C0UNSEIING. DNA studies are i reasingly imporrant for genetic counseling, especialll'rn famili in which a child or adult has developed protoporphyric hepatopachy. This u.ill usually identify a disabling FECH mrrtarion and the IVS3-48T/C polymorphism. In some EPP families, however, 2 diseaseassociated mulations are foLrnd, with a pattern of aucosomal recessrveinhericance. EPP may in-rprove during pregnancy.

DUAtPORPHYRIA
Dual pctrpbyria relers ro patients \.ith porphyria who have de6crenciesof more than 1 enzyme of the heme biosynthetic pathway, Molecular documentation is Lmportant in such cases. For

UROD mutarrons. An infant with severe potphyria was found, based on enzyme measurements,to have rnherited CPO deficiency from 1 parent and UROS deficiency from borh parencs. Coexis tence of UROS and UROD deficiencies *'ere described in a pa ent wilh an erythropoietic porphyla. A iamily u.ith deliciencies of both PBGD and CPO has also been descnbed.

PORPHYRIA TOTUMORS DUE

coal may rnterrupt the enterohepatic circulation of protoporphyrin, promote its fecal excretion, and reduce liver protoporph;'rin conlent. Spleflectomy may be benelicial when EPP is complicated by hemolysis and splenomegaly. Spontaneous resolution may occur, especially if another reversible cause of liver dysfunction, such as viral hepatitis or alcohol abuse, is con tributing. Otheru,ise! exchange transfusioo, plasma exchange, and intravenous hemin to suppress erythroid and hepatic protoporphyrin production may be beneficral. Motor neuropathy resembling rhat seen in acute porphyrias sometimes develops in EPP patients with livet diseaseafter transfusion or liver transplantation and is sometrmes reversible. Artificial lighcs, such as operating room lights during liver transplantation or other surgery, may cause severe photosensitivily, w.irh extensive burns of the skin and petironeum and photodamage of circulating erlthrocytes in parients with protoporphvric liver drsease. NVirh continued progression of liver disease,liver ransplanta tion ma) be considered. But because livel dlssar. may recur in the transplanted liyer due to continued bone marrow produccion of excess protoporphyrin, bone marrow transplantation (BMT) should also be consideredif a suitable donor is available.BMT did ameliorate hver diseasein a murine model of protoporphyria, and led to remissionof protoporphyria in a patient who underwenr BMT for acute myelogenous leukemia. Gene therapy srrategies are undr study in murne models. For example, a dual gene therapy approach allowed selection of hemaropoietic srem cells with erythroid-speci6c expression of the cherapeutic FECH gene, leading to a progressive increase of normal erythrocyres and correction of photosensirivity, PR0GN0SIS-Typlcal EPP patients have lifelong photosensitivity, b can othenvise expect rormal longeviry Protoporphyric liver d ase is often life-threatenrng; however, the incidence is low. PBEVENTI0I{.Symptoms can be prevented by avording sunlight. Avoiding agents that may cause liver damage may help prevent liver complicahons.

carefully. Hepatocellular carcinomas complicaring PCT and acute hepatrc porphyrias usuallv are nor described as containing large amounts of porphyrins. Eryrhropoietic porphyrias can develop lace in life due ro clonal expansion of erythroid cells containing a specrfic enzyme deliciency in parients who have developed myelodysplastic or myeloproliferative syndromes.

General Anderson KE, SassaS, Bishop DF, Desnick RI: Discrders of heme biosynrhesis: X linked sideroblastic anernias and the porphyrias. In Scriver CR, Beaudet AL, Sly \i/S, et at leds): The Metabah. and Molealat Basis of Inherited Disease, vol II, 8rh ed. \es York, Mc(]ra\'! Hill, 20{ll, pp 2991-3062. Hjft RJ, Mejssner PN, An analvsis of 112 acure porphyric arracks iD Cape Town, Sourh Africa. rvednne 2005;8+48-60. Kauppinen Rl Potphyllas. La ..et 2005;365:241-252. Congenital Erythropoietic Porphyria l)upuis-cirod S, Akkan V, Ged C, et al: Successful match-unrelared donor bone maro.* transplantation for congenital ervthropoicric porphyria (Gunthr diseasel.E,rr / Pedidtr 2005;164:101-107. Pjomelli S, Poh-FLapatlick N{B, SeamanC, er al: Complete suppressionof the symptoms of congenrtal erychropoietic porphyria by long term treatment with highlcveltranstusions. Erg1.l M?d 1985;314:1029-r031. N Soljs C, Aizencans CI,.{strin KH, et al: Uroporphyrinogen III synrhaseery throid promoter mutarioRsin adjacenrGAIA1 and CP2 elementscausecongeniral eryrhropoietic po.phyti^. J Clin Inuest 2001;107:753-762. VerstraetenL, Van RgemorterN, Pardou A, et at: BiochenicaL diagnosjs of a faral case of Gunrher's diseasein a newborn with hydropsJeralis Ear.f C l i n C h e m C l i n B i o c h e m1 9 9 3 ; 3 1 : 1 2 1 - 1 2 8 . Acutc lnrermittent Porphyria Andant C, Puy H, Bogard C, et al: Hepatoceltular carcinoma in parientswirh acure hepacic porphyria: Frequency of occurrence and related facton. -/ H etatol 2000;32.9 3 3-9 39.

t
r I ChaPtelg2 HyPoglycemia 655 cipitously to levelstbar impair brain funccion, an elaborateleg ulatory systemhas evolved. The defense against hypoglycemia is integrared by the auto-

2005;142:439-450 Ve1.er UA, Schuur-"ns MNl, Lindbers RLI': Acute porPhvrias: Patho8enesis oi newological rianlfest..dons semin Liuet Dis 1998;18:43 52 Solis C, N{ariinez-Bermejo,\, Naidich TB cr aL:Acute intermirrent porPhvria: provide insigh$ inro rhe homozygousdomtnant diseasc Srudiesofthe severe

i z a t i o no f a m y t h l ' e n p e . t B / o l M e d 1 9 9 0 i 1 3 : 5 9 8 - 6 1 1 ' Hereditary Coproporphyria and Variegare Porphyria Hifr RJ, Meissne. PN, An analysx of 112 ac e po'ph,vric attacks iD Cape Tor,n, South AfDca: Evtdencerhat acute rnr mittcnt porphvia and varre gare iorphv.ia djfie. in suscepribilir) and rerio Medi'ine (Babimofe)

DEFIt{lTl0trl
Porphyria Cumnea Tarda Egger NG, Coeger DE, Payne DA, et aL:Porphvria cutanea tarda: N{ulriplicity of risk facion lncluding HFE mutations, heparitis C. and inherked uroD d oorohvrinosen r.arborrla'e defirrenev rs DA 5,r 2002'4-:4le4Z6' l l t t e r ' r , i l , P o r p h r r i : c u t r n e . rt a r J a : n d r e l a r e dd r ' o r d e n l n K r d r ' h K \ l Snirh K, Guilard R (eds):Porphyrin Hanclbook, pa't II! vol l4 San Drego, Academic P.css,2003, PP 67-92 Erythropoietic ProtoPorphyria Cox TNL Protoporphyria ln Kadish KV, Smith K' Guilard R (eds)'Porpbviz Halldbook, pa-tll, vol14. San Dicgo, Academic Press'2003, pp 121 149 Goodivin RG, Kell V{, Laidler B et al, Photosensirivitvand acute liver iniDrv in myeloproliferative disorder secondarv to late onset Protoporphjrra ca"r.i trv d.t.tion o{ a ferrrxhelatasc gene rn hematopoietic cells Blood

There is evrdence rhat hypoxemra and ischemia may Potentiate

concentralion of <50 mg/dl (10-15% higher fot serum ot h,vpogll'cemia. plasma) represents
11:1i90-1596.

A1{O SIGI{IFICAI{CE SEOUELAE

Merabolism bv the adult brain accountsfor chemajortry of roral

Glucose has a central role in fuel economy and rs a source of

and chrldren can retard brain development and function. Transient isolatedhypoglycemiaof short duration does not appear ro be associated wrth rhese severe sequelae. In the rapidly grorvrng brain, glucose may also be a source of membrane liprds and, together \^'ith protein synrhesis, it can provide structural ploteins and myelinatronchat are important for normal brain maturation. Under conditions of severe and sustained hypoglvcemra, these cerebral strucrural subslrates ma,v become degraded to energy such as lacta!e,pytuvale, amino acids, and usable lntermediates ketoacids,which can support brain metabolismat the expenseot brarn growch. The capaci!)' of rhe newborn brain to take uP and oxidizl ketone bodies is abour livefold greater than thar of the

656. PART r MetabolicDiseasos X mtabolize ketones, rhese alternate fuels cannor completely replace glucose as an essential central nervous syscem(CNS) fuel. The deprrvation of the brain's major energy source during hypoglycemia and the limiced availability of alternare fuel sources dr-rring hyperinsulinemia have predicrable advetse corseqLrences on brain metabolism and growth: decreased brain oxygeri consumption and increased breakdown of endogenous strucru.al componenrs with destruction of functional membrane integrit,v. Hypoglycemia may thus lead ro permanenr impairment of brain growch and funcrion. The potenriating effects of hypoxia may exacerbare brain darnage or indeed be responsible for rr when blood glucose values are not in the classic hypoglycemic range, The major long-term sequelae of severe, prolonged hypoglvcemia are mental rerardation, recurrent seizure activlty, or both. Subtle effects on personalrty are also possible but have not been clearll' defined. Permanent neurologic sequelae are present in 25-50% of patients with severe recurrent sympromatic hypogl1'cemiawho are younger than 6 mo of age. These sequelaemay be reflecred in pathologic changes characterized by atrophic gyri, reduced myelination in cerebral whrte matter, and atrophy in the cerebral cortex. Infarcrs are absent if hvooxia-ischemia drd not conrrrburero cerehral manifeslarions; rhe-cerebellum spared if is hypoglvcemrars rhe sole insulr. These srquelae Jre more Iikely when alternative fuel sources are limited. as occurs with hvoerinsulinemia.when Lheepisodes hypoglycemiaare reperirive of or prolonged, or when rhey are compounded b1' hypoxia, There is no precise knowledge relaring the duration or severrry of hypoglycemra to subsequent neurologic development of children in a predictable manner Although less common, hypoglycemia in older chrldren may also produce long-term ner-rrologic defecrs through neuronal death medrated, in part, by cerebral excitotoxins released during hypoglycemia. non while FFAs and ketones provide alternative fuel sources for muscle as well as essential gluconeogenic factors such as acetyl coenzyme A (CoA) and the reduced forn of nicotinamide-adenine dinucleocide (NADH) from hepatic fattv acrd oxidation, which is required to drive gluconeogenesis. In the early postnatal period, responsesof the endocrine pancreas favor glucagon secrerionso thar blood glucoseconcentration can be maincained. These adaptrve changes in hormone secretion are paralleled b1' similarly striking adaptive changes in hormone receptors. Key enzl'mes involved in glucose production also change dramatically in the perinatal period. Thus, there is a rapid fall in glycogeo synthase actrvitv and a sharp rise in phosphorylase after delivery. Similarly, the amounr of rate limiring enzyme for gluconeogenesis, phosphoenolpyruvate carboxykinase, rrses dramatically after birth, activaced in part by the surge in glucagon and the fall in insulin. This framework can explain severalcausesol neonaralhypoglvcemiaba'ed on inappropriare changes In hormone secrerion and unavailability of adequate reserves of subs[rates in the form of hepatic glycogen, muscle as a source of amino acids for gluconeogenesis,and lipid stores for the releaseof fatty acids. ln addition, appropriate activities of ke_v enzymes governirrg glucose homeostasis are required (see Fig. 87-1). Ittl 0IDEB INFANTSAND CHlLDfiEN. Hypoglycemia in older infants and children is analogous to that of adults, in whom glucose homeostasis is maintarned by glycogenolysis n the jmmediate postfeedin8 penod and by gluconeogenesrs ser.eral hours afcer meals. The Lver of a 10 kg child contarns =20-25 g o{ gllrcogen, which is suffcient to meet normal glucose requirements of 46 mg&g/min for only 6-12 hr. Beyond this period, heparic gluconeogenesis must be activated. Both glycogenolysis and gluco neogenesis depend on rhe metabolic pachway' summanzed in Figure 87-1. Delects in glycogenolysis or gluconeogenesis may not be manifested in infanrs until the frequent feeding ac 3-4 hr intervals ceasesand infants sleep through the night, a situarion usually present by 3-6 mo of age. The source of gluconeogenic precursors is derived primarilv from muscle protein, The muscle bulk of infants and small children is substantially smaller relative to body mass chan thac of adults, whereas glucose reqr-riremenrs/unit of body mass are greater in chrldren, so the ability to compeflsate for glucose deprir.ation by gluconeogenesis is more limited in infants and young chiLdren, as is the abiliry ro wrthstand fasting for prolonged periods. The ability of muscle ro generate alanrne, the principal gluconeogenic amino acrd, may also be kmited, Thr-rs, in normal yotrng children, the blood glucose level falls afrer 24 hr of fasrrng, insulin concentrations fall appropriately to levels of <5-10 pU/mL, Iipolysis and kecogenesisare activated, and ketones may appear in the urine, The switch from glycogen synthesis dunng and immediately after meals to glycogen breakdown and later gluconeogenesis is governed by hormones, of which insulin is of central rmportance. Plasma insulin concenlrations increase to peak levels of 50100 pU/mL after meals, which serve to lower rhe blood glucose concentration through the activation of glycogen synthesis, enhancement of peripheral glucose uptake, and inhibition of glucose production. In addition, lipogenesis is stimulated, whereas lipolysis and ketogenesrs are curtailed. During fastrng, plasma insulin concentratlons fall to <5-10 pU/mL, and together wirh other hormonal changes, rhis fall results in acrivation of gluconeogenic paihways (see Frg, 87-1). Fasting glucose concerffations are mainrained through the activation of glycogenolysis and gluconeogenesis,inhrbitioo of glycogen synthesrs,and activadon of Lpolysis and ketogenesis. It should be emphasrzed thar a plasma insulin concentration of >5 pU/mL, in association wirh a blood glucose concentratron of <40 mg/dl (2.2 mM), is abnor mal, indicating a hyperinsulinemic state and failure of the nechanisms that normally result il suppressioo of insulin secretioo during fasting or hypogl;rcemia.

E]'IZYME, HORMONAT SUBSTRATE, AND I'{TEGRATION OF GTUCOSE HOMEOSTASIS

lN THE NEWB0BN ISEE CHAPIER107). Uoder nonstressed conditions, fetal glucose is derived enrirely from che mother through placental transfer. Therefore, fetal glucose concentration usually reflects but is slJghtly lower than marernal glucose levels. Catecholamine release,which occurs wirh fetal stresssuch as hypoxia, mobilizes fetal glucose and free fatty acids (FFAs) through padrenergic mechanisms, reflecting p-adrenergic activity in {etal liver and adipose tissue. Catecholamines mal also inhibit fetal insulin and srimulate glucagon release. The acute incerruption of macernal glucose transfer ro lhe fetus at delivery imposes an immediare need to mobilize endogenous glucose. Three related events facilitate this transition: changes in hormones, changes in their receptors, and changes in key' enzyme activitl'. There is a three- to fivefold abrupt increase in glucagon concenuation within minutes to hours of binh. The level of rnsulin usuallv falls initially and remains in the basal range for several days without demonstrating rhe usual brisk response to physiologic stimuli such as glucose, A dramatic surge in spontaneous catecholamrne secretion rs also characteristic. Eoineohrine can also rugment growth hormone secrerion bv o-idrenergic mechanisms; grouth hormone levels are elevated at brrth. Acting in unison, these hormonal changes at birth mobrlze glucose via glycogenolysis and gluconeogenesrs, activate Lpolysis, and promote kerogenesis, As a result of these processes, plasma glucose concentradon stabilizes after a transient decreaseimmediatel;' after birth, liver glycogen stores become rapidly depteted wirhin hours of binh, and gluconeogenesrsfrom alanine, a major gluconeogenic amino acid, can account lot =10ok of glucose tumover ln the human newborn infant by several hours of age. FFA concentrations also increase sharply in concert with the surges in glucagon and epinephrine and are followed by rises in ketone bodies. Glucose is thus partially spared for brarn utiliza-

. r Chaptergz Hypoglycemia657 G1\,1S 4500

3500 10% (12t126) 2504 5% \2/40)

,;e' ,iii;^,
10% '
I t

500
in infancv and childhood rtilect rnapproPnatc a(lapt'f()n to iastlng.

67./. 10/1

26

30

34

38

42

46

(wk) Gestation

107) MANIFESTATIONS CHAPIER {SEE CtINICAt

i8 i1,/rnlft-.1971i47:8I1-8 l

.rre missed.Occasrolallv.hvpogl,vceniamaY be asymptomaticin the immedlaccnewborn period. Nervbornswirh h,vperinsulirremia

tPltltPHnlNt At{o SYSTEM NtRlro,s oF ffTlvAlloll AuloiloMl( WnH ttaTuRtg ASSoqATED

RITEASE* PeApiralion' a) PaipLtal on(ra(hy.ard hor Tremu ousmss luryer NauSea Em6 s coronary aneri6) normdl Anq (with ni 61U(OP[IIIA WITH FTATURTS ASSO(ITTD (EREBMT Headarhe' Mentalonfuscn' a) Vi5uald nurbances ly,diplop lJ aru peBonallyahange5 0rqani( it[ conrentrate lnJbi 10 U)5art|lru 5hring Pale51he5,r5 Dizine5i Ahxia,in(oordinauon somnolence,lelhaqy Seizues [oma a Strcke, d, hemidqaphas |]r decort po5ture Decerubmte cate
$i 5ome0f ftele le,nu|6 I beatsMFd 'f e pat$i I tie Yn9EadRmBi.b o3:ngaqenl5

jitterinessor tremors, apachl, episodesof c,van()sis. con LncLuclc or or rulsions. intermirrent apnerc spelJs tachypnca,r,r''eak high

sugar to rormal Jcvcls;if rhe," do not. orher dtagnoscstnusf be considered.

r 658r PARTX Metabolic Diseases

CTASSIFICATION HYPOGTYCEMIA INTANTS OF IN A N DC H I T D R E N

snrall br' r'rrtue of prernaturirl or rrrrpairecl placental rransfer of

NEONAIAT, TRANSIENISMATLFORGESTATIONAI- AND PRE. AGE, (SEE INFANTS CHAPTEB Thc csrirlated MATUBT 107). inciclence of hypoglycernia neu,borns I j/1.(l0tl hvebirths. symptornaric in is 'lhis incidence increased is sevcralfbld certain high-risk rn neonagroufs (see t.LL Tablc 92 2 and Fig. 91.1j. Thc prenarurcand srnrll for gcsrlrionalagc (SGA)infants are vulneraLrle rhe tt> devcloprrenr h,vpogl,vcernia. factorsrcsponsiblc rhe of The for high frcqoenc,v hvpogllcerria thisgroll.l,rs well as in other of in groLrps olrt|led lrr Tablc92 1, arerclaretl the inddequate &) sl(]fes of liver gl!cogen, musclc protein, lnd bod,v rcededro susfilin fat the subsrrirres requircdto rreet cnerg)DeeLls. These infaursare

In confritst ro dcficiencv oa substratcsor etrzvntes!fhc hor

significantnse in glucose.During rhe inirial 24 hr of lrfi:, plasnra coLrcenrratrons acetorcefateand Jl hVdroxybutyrateirrc lou.er of irr SGA iniarrcs rhan in frdl temr irhncs, implving dinLnishcdlipid fat.v acid mobilization, impaired ketogencsis. scores, dLminished or a combination of dresecondiri<>ns. Dimilishcd lipicl storcsare mosr likely bccausefat itrighceride) tcccling<>f novbons rcsulrs

Asrociared inadequate with substnle ififiature oa entyme fln(lion otherwise in nonralneonatet +enrturitl 5rr qe5tdt allfor (]nalaE, Tranrient hype neonatal nrulinhm prcsent aho in: lnkntofdabetir notfer aq sna :orqenathna ll (crdant twn B(h alchyx i l:motlr,or ifdf l]ftoxem i OR i]EONATAt, INIANTILE, GII.DI{OO|) PTRSISTENT HYPOGTYGMIAS HornonaldirodeB H,rper n5m nr, Hl llereisK{rrh?'rne !e F taailGr rhanne DaflinantKrpcnannelN fl Danrnanrqu(okne5e qhtafiiale fthydroger liD,pelin5ul |minarl a5r Hl lism/hyperamn5I1dftrme) onem a A(qJred ietadelorna r,(eceranrtndrome Be|k$rti pnrry) n5.tln niiratrl]n adlr syndror,re i[lunl:']aLrfn by oral 5ulton/ dtuqt Lrria {ongeIit,] on i lol15ofqlycojybr (ounterrcgulatory def hormone dlnry PrnftpcpltJ i:fis,n dei(i?niy hcared hmrnone tironh homcre AdnocoftrdrcFt de hxr!
Lld lcf d 5ea5e

lerondary crnitne defraieni e5 very 04 .nreiium onq a.y denc Enq ,rhoflchain icAdehydrc_oenase oTHIR tTtotoclEs Subrtrate-limihd (totrhypo!ty(ginii Poisoninldrlgj 5arqare5 Ord ypocy(em(aqen6 h tn5ut1 Prlrprunolol P randne lisopfamiCe A.kee ftri nrpe)-hypcg n ){ /aor lratepolslrn) (!r/ Tr meih0prm sulhmetl.omzoh rcnal;iluE) rh Livrditaase levesyrdome flepitr 5 I rhos5 fleFtonr Amino andorga0i(add add disorders lVap syrLrp d 5ta5e e Lrn.. Pnpon(acdFmid [lathyharff caridemia 1'rosinc55 Glutirr( addurn I'ilydrcry melh/lo acidLrrid 3 uhrl,: lyttemic disodeE 5P!5s 'nrior (a( nnmaAarcfi'a (secieiing-'-rniuln IiieEroflt ) Hearlfailue MalnLrl ion lVa ibiorpton Ani nsu ietepto n an[bodies irr in5LrJnli$dies r Neonda iyperuisoiily Rerral ,'re [a DErrhea Burn5 Shork Fcneur!cal F5e,Jdahipo! a lhrrcrytoli5,tqthenrai po Kem L(e55r in5uin thezpy n!uin cependentd rnelt,. 0f abeies ! taitt:oLi fl55en fundo0{at,oFrping slrCome) ldL fu( parum mdl,.ia

Ep nephr.ne oeni:enq Glycogenolysi! 9lu(oneogenelir and disorde6 (GSD defuienry lal !aucc5e 6 phoiphataie (iLrco5e'5-phospf (G5D ,rte ar'oca5e .i,.n(r f il]fr 1b) Arnyl0 glur05ida5e 1,5 enzyme) deli(ierry i) iGSD ldebranrflnq (CSD ph0rph0lla!e Lir'ef dehden(y 6) deii Pfo5phorykrase ency 9l a5e iGii (G5D def(enq l]) Gy.oqen 5tnihetai? Fru.to5 d fihospiat;ie 1,6 defide1(y Ffuvatil rarboxy defrenq aie 6alattose a flaeditrry irurnlentoehne Lipolysis diioderu oxidaondirnrdeB Fattyadd Gl| t ne'ransporGr eqq(!inrarycirnitine errc, 0enc de6a [an t]ne to!tranlleD!e l Cefriienij/ falm [amitrr:e 'cie denflenr/ teri pa [a.nitce nrtcyrrandeTdse 2 den(e].cy ,e9( FGJ5 ihdre ClD,q irifaterealer|], d hyFinrrlnrni,r,la,arcc um roqci

r I ChaPlolg2 Hypoglycenia 559

are allv it is 1st evidentin older children.Insulin concentrations elevatedat the time of documenredhypoinaooropriarelv elviimii; *ith non-hyperinsulinernichyroglycemia. plasma shouldbe <5 puiml and no higherrhan insulinconcentrations

should be treatedwith diazoxide. UoTHERS {SEf CHAFIEI1o}. of the l]{fAl{TSEOBI{T0 DIABEfIC transient hyperinsulinemic states, infants born to diabetic affectssome diabetes mothersare tfuemost common.Gestadonal

administrationof insulin as a {orm of child abuse(Munchausen by prory syndrome),[SeeChapter 36'2.] Provocativetestswith in ar rolbutamideor leucine not necessary infants;hypoglycemia

ins them to hvposlvcemia. "trloth..r t"hosJiiabetes has beenwell controlledduring preg-

92.7). The measurement serum IGFBP-1concentrationmay help of The secretionof IGFBP-I is acutely diagnosehyperinsulinemia. inhibited by insulin; IGFBP-1 concentrationsare low during In hypoglycernia. patientswith spontahyperinsulinism-induced hypoglycemia with a low insulin level neousor fasting-induced (ketotic hypoglycemia, normal fastilg), IGFBP-1coflcntrations are significantly higher The differential diagnosis of endogenoushyperinsulinism includes di{fuse p-cell hyperptasia or focal p-cell microadenoma' The distinction betweenthese two major eotities is imPortant to the because former, if unresponsive medicaltherapy,requires

listed in Table 92-2. Infants born with crytbroblastosis fetalis may also have hypersuchas largebody insulinemiaand sharemany physicalfeatures, size, with infants born to diabetic mothers. The causeof the is hypirinsulinemiain in{antswith erythroblastosis not clear'

Iil HYPOGTYCEMIA OR PERSISTEilTRECURRET{T AttlD CHItDREt{ ll{fANTS

HYPERI SUUiIISI|, Most children with hyperinsulinism that causes hypoglycemiapresntirl the neonatal period or later in

X 660I PABT I Metabolic Diseases

ASS0OATID ftllllftL, TYPE tpcrad(

ntJm $I0

R[(0t1tr,ltttDtD

IflPOGTY(ETIIA/ FAMILY 8t0(Hti{Gt, 0R t rDtcfl. SuRGt(At MA(flIXOMIA IIYPERITISUIINITIIA MOLT(UIAR HIsTORY DtfI(TS MOITOTAI FIATURTsMI}IAGTMEI.IT APfNOA(H P,esrntb(h at ltrlodec telewrc I 5t in Ca)5 weeb I fe io oi Ne_oatve ItURl/KN6) MLrtalions n0talways iCentiRed ndifu5e hyperpla5ia

Pn(XNoSrS

retes5 ve domrnart Autc5omil

Presen, albrrth sel/ere inl5tdays to Po5live tUlJKa6) r'rceki oflitu tome Npuiat0n5 LlnurLl2 [lcdera(e lsually Po5:1ve 6fu(0k hcvariig) None onlet ndie prtn an0 5 0tage \ome ra5e5qene 'Jnu5Lral ll0dpr,ttc usualy oniet pcll m0 o 0laqe Mcderate,sNmaneous y Neqalve posi rcJoivrs E 6 mo cFage

Los5 lraero4go5ity oF 6enerallypooI l:rld pai(reiteatl]rJl in I [rrelenr micrc,rdenom,Iouj niy resp0nd l!5Ue bener lo l - a 3 l t r o dn 9i r r 5 r n i c nlde miirljdderomi man l0 iulr.rtd >!t% abetes Gu3ded;d 0ldZoXrCe nelitu5 15ll% derelcpt ofFatieit5; nvpo!1ae'llE peAh[ ]3% in panrraled0mJ riTmftn 5eflcn shohsqant nui iin le ! e F - d lruse n/perptasa (o[sa guinity panarealedo.l))' lil]irded aleature Poor ]n 5uLto:3

qmd Very 10 ex(elent

Pre5eil Be.l( th albirt[ wecemann 5ln0i0tne

q0rd Gluiamale Modesi hypeBfitrnoftmiiVeq t0 'lehydrcgena'e e)((elent (activalnq) Dupiratinll/mpdntnq lva(mgloi5a,onphalorele, 6ood n(hromo5ome hemlhypeffiophy llcl5l

!urqery r5LrlinotreqIed h r t d p a n ( r e i r e drc nl!f ni nreotG manrllme E 5 )uqel uju3y flolre(jL rco

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Fr(e lentlol fyp0qr/rema; \!1tf ai50iat0 enbr)o'al tumo15 i!!1ln,s hepitobartomaJ Nolrerommend,.d

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Nol u5ua

po5i l\,loderare/onset I moofage

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Phosphomanro5e Hepatomeliltvomitng, 6oodrh w i50meE5e defr:enc! intractable tTtann0!e Canhed

tun

suppernenr locrl fomr (iocal uprakc <rf l8lluoro I- clopa and localizcd lluo rescence) .3.]. [Scc lrig. :,12 ILrsulil-sccrcf macroailenomls are rare in chilclhooclancl ing rnay be diaenoscd prcoperafii'elyvia CT or MRL The piasma lcr'cis o1 insulin alrrc, holvever, cannoc disringuish the lforementi(ncd cntitics. The diffuse or nricroaclelomarous forltts of islet cell hypcfplasiarepresert a vnrietv of eeleric defectsrespronsible ior abnorrralitics in the erdocrine pancreas characterized by aLronomous lls lin secrctiol fhat is nor appropnarelv rccluced u'hen blood glucose decliles sponfarreousl]' in resporse ro or provocafi\.emaneuversslrch as fasfins (scc labies 92,r- a||d.92 8). Cllinical,Lriochcmical, and moleculer geneticapplo:rchesnou' permit classilic.rtion oI congeniral h,vpcrinsulinisnr.fornrcrl,r into disrincr cnrities.I'ersisrcnrhvperinterrnednesidioblasrosis, sulincmic hypoglycemia oI infancy (PHHI) nray lre nherircd or sporadic, is sclcre, ancl is causedby lrrutirfionsiLrthc rcgulation of rhe porassiumchannel intimately involved ir Lrsulin sccrcriorl by che pancrearicB ccll (Fig. 92 2). Nororally, glucoseentrv into the p cell is enahledb-vthc non insulin-rcsponsive glucosetrrns porter GLL-l'l-2.On enfry, glucoseis phosphorylatecl lilucosc ro 5 phosph.ate by rhr cnz,-rne glucr>kinase, enabling glucosc

llear totrrl pilncreelectom\i dcspite which hypoglycellra tnav pcrsistor rLabetes mcllitus mav ensueat somc lirtcf frme. Bv corr i r r r t . t . r . : l , t . l r r r , ' r n r . d i a q n o ' e J p r r , , l ' . r r r r r e l r 'r ' i n r r , r , l ' e r . r nvch pcnnif loc:rlrzed curarivc resectionwith subscqLrent normdl ghLcoscnrctaLroLisrn. ALrour 509/oof rhe au<rsomal recessi\r ()r spordclicforms of neonatal/inlhltile h1'perinsulinisnr dre ro lre iocal n-icroaclenonas,\rhich ma,v be tlistingLrished lrorn rhc forn by thr lirttcrn of insulin responscto sclective cliffuse insulin secretirgoguesLniusctl into irn arrery suppl,ving fhc pirncreas \'!.ith srmpling viu rhe heparic vein. Positror enission tomographv (Pt-l scannnlfl)usinq 18 fluoro L <1opa can disringLrish diffuse rhe form (ulifornr lluorrscencethroughorLtrhc pl crcas) fion fhc

5U85TMTIS 6lurosP ireeiacytirdr l(eloft5 L3atalt u l c a0 ( HoRMollt5 lnrutn tortl5ol lromone .lrohft rhyrod-stimu ating lFrmone ihl.crine, l r3F3P
'6 urdgdr 5,lrrqlkq rhm mum I mqlV0r M a if 'M!:r!rc0fte0n bebreoi i|1erq u(iqon idmiii{,m0n m9l!(seol>40mg/d: g u{dgongMndther'me Rie rlifl ! nrnqy 5uqq6tia hypernlulmrirftre wt zdeqeare g['(o,;en rf hy".0911{em, hepdtk rores ind r,t( s4mei I dnm0nli eel'alrd 100-100 $i3'der nh(r glirdEe.o is t 0g arrivar mlbr m ot gidamal r,M, porerrl 6igPI, n5!ln rloroMh'?r1r bndinq

(pasma >2 I ilypedn!u[[emia insu,n /lJ/mL]r (paifid htly <1 2 |]ypofaftyacidemia lree a(ids 5 flmo,/l) l] mmo/i) I Hypoketonem Flrydrcxybutyrdte:<2 a (pldgma ,lly{emri 4 lnappropflaie re5p0n5p toqlucagon,: iV(decq ucoie m_q,/dll n! >40 *Cependr ri!iry nrdn on 5en5 of i5s?l fmn5hnlqLdIlomron filE0 d DN, al: er hypqtFrma nfdn15 [Le0niIEl5ref ]VA r0,): P5. i. ,rid | iiq kd Pel/rF. pprl5 ladwn\hry ed,P\i phn,\\8 )td dt)e 5aunder.?002 l59

I r Chaplergz HyPoglycemia661

PRESIIIT A(UT[SYMPTott'lS suspetf ( hcnnone ketot 0n if orfalty oxida de{KL pre*nt, hyFllniulinemia add su5pe{t

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syn0lome,e( l

rLlarions.nofabl,v Arabic and Ashkenazi Jervish communiries, <rI u,hereir nay reachan incidence about 1/2,500,compared u'ith These the sporadic rates in rhe generalpopulation of =1/-50,000. auroiomal recelsive forms of PHHI t,vpicaliv Presenf in rhc

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(0 DfloN N0[na inernia Hypern!r K:tolir yre|r l'yprg a futly a(d.rd;. lisol:r lllrD0pilurdr5m ddrcna r5Jfliren.y tzime cetcent ei ilur:D5e 5 tiorpiatale rher iebi rroiploryla$ hucos? drphc5pl'alaje 1,6
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Reautrc4l5ewTe severe m[5ed 5 w{h mea l,ith 5everc miJsed 5 mea l,4oderdte mi55ec with meals j te\,e,e thm$edmea w Severe ton5lanl Modetule fastng l! lh [lild moderire !everewith nq h5i Aiier lkormlkpadurt5 r After ftuctose

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irnrnediete neu-Lrornperiocl irs nracros()rlic reu,horns r,r'irh a ()r weighr >,1.0kg and scvererecLrrreltf persisreLrt hvpoglycernia manifesting, lhc initiLrlhours or days of lifi. (,lucosc infusions in as hJgh rs 1.5-20n/k/min and frerluent fcec[ngstail ro rnain Diazoxide, rvhich:rcrsbv opening, rail cuglvccmra. Kr'" channels (see!ig. 92-2). fajls to concrol hy|.Tog)vcernia rclequarelv. Somato stlrrirr.\\,hich nlso opels K111and inhibrts c;rlciunrf1ux, mav be p a r t i a l l ye i i c c f i v ci n = 5 0 i ' , o f L r a f i e n t ls e eF r g . 9 2 - 2 ) . ( - a l c i L r n r s agents have had rncorsistcnr cticcts. \\iheLr channcl hLocLin.e allecrerlparicnrsarc Lrnrcsporrsive thesemelsures. pancrcatcc to ft) tonry is stronglv rec()rnrrended avoid thc long rcrrr neurolt>gic prcopcrarire secluclac hr poglvccrria.Ii surgerl is Llnderfaken. oi (il or N{RI firclv rcvcalsat isoiafedaden()[r.r, \\,LrLch rvould rhcn pcrmit locrl fcsccrior). IlrttaoperativeuLtrasonogr aphv mav rden tif,va small irrpllplble acienona,pernirung local rcscction.Ade lomls ofren present in lare inlancv or earlr chilclhood. Disringuishrng Lrcnvccn focal and diffusc cascs oi persistent hvperinsulinism has bccn artcnrprcd in sevcrai rvars. Preoperarivcll., transhcpirticp(rrtnl vcin cathctcri?irtionand selecrirepancrearic veDousSaLIplirlgt() neasure ilsulin rnav localizc a focal lcsion from the stcp up in insulin colcelfration rt a speciiicsite. Selective cathcrerizariol of arterial branchessupplying the pan sLrch crlciunr and es creas,follo\cd br infusion of a sccrct:rgoglrc for insulrn concenlriloon iertenal srimuLa porral veill srrrrplrrrg localizca lcsion. Both eppfoachesar'e fi()n-venous sarnplrlgl rna,v highlr- invasr"e. restricted to speclalizedcenfers. .rnd not Lrriin iorrrly sr.rccessful clistinguishingthe loca fronr the diffrLsc iorms. l8F llbc)cd I clopa cornbined wirh Pt.T scuniLrg is :r pornisirg, rncani t() disrin[juishthc iocal frorn rhc c]iffuselesions ()f hrferinsulinrsrnLrnresponsivc mcdicdl mlrnaecrrcnt(Fig. 92 to .1). I-hc 'gold sranciard" rcmarns irltraopcr.tiyc histologic char ilcrcri7.lcio11. Diffusc h,rperilsulinisll is chdrrcferireclbv lrr14ep cclls \.\,ithirbrrornally large rtuclei, whereas focrl ddenomat()Lls l c s i o n sd l s p l r r y m i l l i r n d n o n n . l B c e l l n L r c l c iA l r h o L r g h U R I s S in rhc focal lcsio s alisc bv a nrutilfl()ns.rc prcscLrf both 11pes, rnrrcll)irr lr)sr{rI i rrritterrallyrlnprinredgrou'rh inhrbrtory gelreoll nrtefnal chronlos()rnel1p il associ:rfiorlwith pafcrlrxl rr:rlrs 7 I orissionof a nruritcd .S{-iR or K|1 6-2 prrcrnrl chr'onr':rsomeI pr. ThLrs thc rrrcrl iofm representsa cloLrble hrt ()ss oi nrarenlal [-ocalercision rcpress()r dnd trrnsrlrission a pitcrnel nrrrrrrtion. of isler celLhyperpl:rsiir rcsulfs Lr1 cr.Lrc :1 lvirh of focal .ldenonraftrus lrrtlc or no rccurrcrrccFor rhe clifiuselofnr, rrcrr tofrl resection Thc rcer rotal panoi 8.5-90'11, thc p.rrcrc.s is rcconrrncrrrled. oi crcilfccrorrr\ reqrrired k)r rhe diffuse hi'perplasric lcsions is, ,"vithpcrsistcnfhvpoglr'ccrrirrrvirh rhe hor,r'ever, oifel rss()ciatcd later dcr.clopmcnrof hypelglvcenril or frank. irsLrLiu rcquirurg diabctcsrncllitus.

Further resecrionoi thc rcm:riningpancrcirsnril)_ occisiona[]-v be necessar,v hypogli.ccmil recurs alld cannot be cortt()lled Lry ii medrcai mcaslrrcs, such rs the Llsroi somdtostafinor diazoxiclc. Lxpcricnccd pcdiatric sLrrgeors rnedicalccntersequipped f{) in provide dre ncccssnrv and posropcrltire care, diagl)rL1)pcrafive rrostic ev.rlLrafxxr! ancl rnanagernent pcrform srrgerv. In shoLrlcl sonrepaticnrs who hlve beeu managcd rrcdically, hyperillsrLlincmia and ht po.qLvcemLa regrcssover nonths. This is siurilar to rvhat oc.Lrrsrn childlcn wirh rhe h,vperlnsulincrnic hyL.og[1cs11ix sccn in Beckuith-Wiedenann syndronc. It hvpoglrccrrrialsr rrrrrrifests bern'ccn3 ancl 5 rno oI age or later a rherapeuticrrlal rLsingnredicelapproachesrvirh diezox ic1e. sonatosratin, :lnd freqnent fccdingscau be rtteDfted for Lrf to 2-4 wk. l'arlurc to marntain cllllllcerriit with()ut undcsirablc side effecrs from the drugs miy pronrpt the leecL firr surgcry, Sone success suppressrng in insulirrrclcasealld c()rrecnngh,vpo gJlcerniain pirtients\iiith PHHI has been reporrcd lvith thc use ol rhc long-rcting som:lt(rstafirr Most cascsof analog octreofLde. neolaral PHHI ,rrc sporaciic; famllial fornts pennit !,cncti':colur selingon rhe L.asis anncrparedautosonralrecessive of inheritance. ,\ 2nd iorm oi farrilill PHHI suggestsdutosomal dominant inhcritancc, lLrechnical ieaturestenrl t() bc lcssscr,efe, anclonsel oi hypog,lvceLlJa nosr likcJ1',brrr rrot exclusLvell-, occur is tr> bcvond thc rnrrnediatcncrvborn period errclusuall]. bclond the per'iod()i \t'eanilrgat aLr averagcaec rr onset of dbouf I rr. l\t birth, rnlcnrsornia is rlr'clv obsen'ed..urd responscto cliir?o\idc is alnrosr rLnifbnn.Thc lrritial presenretionLral be dclal'cd .nd rarely occLrris ldte as l0,vr, ulrlcss provokecl bi 1:rsting,. The geneoc bisjs ior rhis .rurosornaldonrinant f':rrrn has ror been clelilearedr is nor alu,rlr linked ro Kl1 6-2l-ltiR 1. Howcver-, it the activrting nutati(r1 in ,5lucokrrrase transrnitced ln eutosors irt r n , r l J , , r ' r 'r l r r ' r nr . r r rl. , r l J n r r l \ r i r r u r \ \ l r e \ ( r ) t . F e n r r - ( , r ' r . l i '' sellngfor-a j0']l rceurrence rarc can bc given ior iuture of|spring. A .lrcl iornr of per-srstenr lllHI i\ .rssociared vith mild and asymptonaric hypcrammonemia, usualLr as a sporadic occr.rr rcnce. althotlgh dominarrr inhcrirancc occurs, Itresentafronis rrrorc likc rhe ilLrtosonrirl donrinant for-nr than the aut()s()lnal recessi\.e iofrn Dier ancl Ji:rzoxide corlrrol symptonls. l)Lrtpiul crcatcctonrl nrrlv be ncccssir\rin sor'ne of cases.lhc associarron hl.perrnsuLiLrLsrr lrvperammolemia is calLscd err rnhcritcd and hy or dc novo girirrof funcfion fiLrfation rrl the enz)ine gLutarrate ()xid:lfi(ni irr dehvdrrrgellasc. The resulting incrcrsc ill glutarrrirte p the p,rncrcntic ccll rrrsesthe ATP conccntrrrior ancl,hcnce.thc r ario of ATP:,{Dl \\'hich closesK.r-rr, lelcling to membranedepol a r i z a t i o nc a l c i r L n r f l u x .a n d i n s u l i ns c c r c r i o ns c cf i g - 9 2 2 ) . I n , rn l rhc livcr, thc cxccssrvc oxidation oi itlutarndfcto [] kcrogltitirrirtc nriry gcnerare lnrnronir alrd divelt glLrtnmdte Ionr lreing

; !| Chapter92 Hypoglycemia 663

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c o disorders i thc K11p hetrtrc

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usLrilllvprcscnr with neLllo L)irorilers of proccin .e,lvc()svletion occurs il ntluv oi thcsc infirnrs- I)iffuse rslcr ccll hvp.cr-plasia ind dlcrri!l occLrrs ini.rrltswirh hvpoglrcenli,r' lhe dr.tgrrosrrc

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664r PABT r ilelabolic Disoases X and hypoglycemia(seeChapter 87,5). Thesedisordersare often underdiagnosed, One entity associated with hyperinsuLnemic hypoglycemia is caused by phosphomannose isomerasedeficiency,and clinical improvementfollowed supplementaltreatment wrth oral mannoseat a doseof 0.17 g/kg six timesper day. After the 1st 12 mo of life, hyperinsulinemic states uncomare mon unril isletcell adenomas as reappear a cause after the patient yearsof age.Hyperinsulinemia to isletcell adenoma is several due should be considered any child 5 yr or older presenring in with hlpoglycemia.The diagnosticapproachis outlined in Tables927 alnd92-8. Fastingfor tp to 24-36 hr usually provokeshypoglycemia; coexisting hyperinsulinemiaconErms the diagnosis, provided that factitiousadminislrationof insuhn by the parenrs, a form of Munchausensyndromeby proxy, is excluded.Occasionally,provocacive testsmay be requrred.Exogenously administeredinsulin can be distinguished from endogenous insulin by simultaneousmeasurementof C-peptide concentration. If Cpeptide levels are elevated, endogenousinsulin secretion is responsible the hypoglycemia; C peptidelevelsare low but for if insulin valuesare high, exogenous insulin has beenadministered, perhapsas a form of child abuse.Islet cell adenomas this age ar are treatedby surgicalexcision;famrlial multiple endocnneadenomatosrs type I iVermer syndrome) shouldbe considered. Antibodiesto rnsulin or the insulin receptor(insulin mrmeticacrion) are also rarely associatedwith hypoglycemia,Some tumors produce rnsulinJike growth facors, thereby provoking hypoglycemiaby interactingwith the insulin receptorThe asruteclinician must alsoconsiderthe possibilrry deliberate accidental of or ingestionof drugs such as a sulfonylureaor relacedcompound that stimulales insulin secretion. such cases, In insulin and CpeDtide concentratio[sin blood will be elevated. Inadvertenr subiriiution of an insulin secretagogue a drspensrng by error should who suddenlydevelop be considered thosetaking medications in documented hypoglycemia. A rare form of hyperinsulinemic hypoglycemia has been reported after exercrse.\0hereas glucose and insulin remain unchangedln most people after moderate,short-term exercise, with hyperinsulinerare patients manifesrseverehvpoglycemra mia 15-50 min after rhe samestandardized exercise. This {orm by of exercise-induced hyperinsuhnism may be caused an abnorin mal responsiveness p-cell insulin release response pvruof to vate generated during exercise. Nesidioblascosis also rarely been reported after bariatric has surgeryfor obesiry END0CRINE DEFICIENGY associated wi!h endocrine Hypoglycemia deficiencyrs usually caused by adrenal insufficiencywith or (see growth hormonedeficiency wirhour assocrated Chapters558 and 576). In panhypopituitarism,isolated adrenocorticorropic hormone (ACTH) or growth hormone de6cienc,.', combined or ACTH deliciencyplus growth hormone deficiency, incidence the of hypoglycemia as high as20%. In the newbornperiod, hypois glycemiamay be the presentingfeature of hypopituitarism; in males,a rnicrophallusmav provide a clue to a coexistentdeficrencyof gonadotropin, Newborns with hypoprtuirarismoften have a form of "hepaticis"and the syndromeof septo-opticdysplasia.When adrenaldisease severe, in congenitaladrenal is as adrenal hyperplasia causedby cortisol syntheticenzymedefects, hemorrhage, congenitalabsence the adrenalglands,disturor of bances in serum electrolyteswith hyponatremia and hyperkalemia or ambiguous genitalsmay provide diagnostic clues(see Chapter577). ln older children,failure of growth should suggesr growth hormonedeficiencv. Hyperprgmentation may provide the ACTH levelsor adrenal clue to Addlson disease with increased Lrnresponsiveness ACTH owing to a defect in the adrenal to receptorfor ACTH. The frequentassociation Addison disease of (hypocalcernia), in childhood wich hypoparathyroidrsm chronic mucocutaneous candidiasis, and other endocrinopathies should be considered. Adrenoleukodystrophy should also be considered
in the differential diagnosis of primary Addison diseasein older children (see Chapter 86.2). Hypoglycemia in cortisol-growth hormone deficiency may be caused by decreased gluconeogenic enzymes with conisol deficiency, rncreased glucose utilzation due to a lack of the antagonistic effects of growth hormone on insulin action, or failure to strpply endogenous gluconeogenic substrate In the form of alanine and lactate with cornpensatory breakdown of fat and generatron of ketones. Deficiency of these hormones results in reduced gluconeogenic subsrrate, which resernbles the syndrorne of ketotic hypoglycemia. Investigaron of a child with hypoglycemia, therefore, requires exclusion of ACTH-cortisol or growrh hormone deficiency and, if diagnosed, its appropriate replacement with cortisol or growth hormone. Epinephrine deficiency could theoretically be responsible for hypoglycemia. Urinary exctetron of epinephrine has been diminished in some patients with spontaneous or insulin-induced hypoglycemia in whom absence of pallor and tachycardia was also noted, suggesting that failure of catecholamine release, due to a defect anywhere along the hvpothalamic-autonomicadrenomedullary axis, might be responsible for the hypoglycemia. This possibrlrty has been challenged, owing to the rarity of hypoglycemia m patients with bilaceral adrenalectomy, provided that they recei.'e adequate glucocorricoid replacernent, and because drminished epinephrine excretion is found in normal pa ents witb repeated insulin-rnduced hypogll'cemia. Many of the patients described as having hypoglycemia with failure of epinephrine excretion fit the criteria for ketoric hypoglycemia. Glucagon deficiency in infants or children may rarely be associated with hypoglycemra. SUBSTfiATE TIMITED Ketotic Hypoglycemia.This is the most commor form of childhood hypoglycemia, This conditron usually presents between the ages of 18 mo and 5 yr and remits spontaneously by the age of 8-9 yr Hypoglycemic episodes typically occur during periods of intercurrent illness when food intake is limited. The classic hisrory is of a child who eats poorly or completely avoids rhe evening meal, is diflicult to arouse from sleep the following morning, and may have a seizuaeor be cornatose by midmorning. Another common presentatio[ occurs when parents sleep late and the affected chrld is Lrnableto eat breakfast, thus prolonging the overnieht fasr. At the time of documenred hypoglycemra, rhere is associated ketonuria and keronemia; plasma insulin concentrations are appropriately low, <5-10 pU/mL, thus excluding hyperinsulinemia. A ketogenic provocative diet, formerly used as a diagnostic !est, is not essential to establish the dragnosis because lasting alone provokes a hypoglycemic episode with ketonemia and ketonuria within 12-18 hr in susceptible individuals. Normal chrldren of similar age can withstand fasting wirhout hvpoglycemia developing during the same period, although even normal children may acquire these features by 35 hr of fascing. Children with ketotic hypoglycemra have plasma alanine concenffatiols that are markedly reduced in the basal state after an overrught fast and dechne even further with prolonged fastrng. Alanine, produced in muscle, is a major gluconeogenlc precursor Alaoine is the only amino acid that is significantly lower in these children, and infusions of alanine (250 mg/kg) produce a rapid rise in plasma glucose wrthout causing significanr changes in blood lactate or pyruvate levels, indicating that the entire gluconeogenic pathway from the level of pyruvace is intact, but that there is a deficiency of substrate. Glycogenolytic pathways are also intact becauseglucagon induces a normal gly'cemic response in affected children in the fed state, The levels of hormones that counter hypoglycemia are appropriately elevated, and insulin is appropriately low. The etiology of kerotic hvpoglycemia may be a defect in any of the complex steps involved in protein catabolism, oxidative

r 92 Chapter I HYPoglycomia 665 deaminatron of amino acids, transamination, alanine synrhesis, or alanine efflux from muscle. Children with ketotic hypoturnal cornsrarch therapy is also beneficial. Transtenr nocturnal hypoglvcemia is not completely prevented, and renal glomerular dysfuncrion plus formation of hepatic adenoma lemain selious complications, Liver transplantacion offers promrse of long-term cufe,

defects have been described. Hepatomegaly, excessivedeposition of gLycogenin liver, growth retardation, and occasional svmptomaiic hypoglycemia occur A dret hrgh in Protin and reduced in

cholamines, are appropnately elevated or normal, and insulin levels are appropriarely low. The liver is nor enlarged. Proteinrich feedings at frequent rntervals result in dramatic cltnical improvement, rncluding growth velociry This condition mimics the syndrome of ketotic hvpoglvcemia aod should be considered in the differential diagnosis of that syndrome OF DISOBOEBS GTUCONEOGENESIS

Clrco8enol) crsremainr provoked bv inhibrtion ol glycogenolysis. a inracr,and glucagonelrerts normal glycemicre\ponseln the fed. but not rn rhe fasted, state. Accordingly, affected individuals have

hypoglycemJaSee DISEASE. Chapter 87.1. GLYCOGEN STOBAGE Clinical features simulare those of rype I glycogen scorage disease. Hepatomegaly in individuals with fructose-1,5-diphosphatase deficiency is due to hpid storage talhet than glycogen storage. Lactic acidosis, ketosis, hyperliprdemra, and hyper uricemia occur; their pathogenesis is related to the severiq' and durarion of hypoglycemia and lhe resultant lorv levels of insulin and high levels of counter-regulatory hormones. Therapy for these infants, consistrng of a diet high in carbohydtates 1567", excluding fructose, which cannot be utilzed), lorv in protein (12%), and normal in far composrtion (32%), has permitted normal growth and developmenr- Continuous nocturnal provi sion of calories rhrough rhe intragastric infusion svstem described earlier for tvpe I glycogen storage disease is also applicable to children with fructose 1,6-diphosphatase de6cienc,v. Dunng intercurrent illnesseswith vomiting, intravenous glucose inlusion ro is necessary prevent severehypoglycemia. Oelects in Fatty Acid Oxidalion (See Chapter 861.The important role of fattl acid oxidation in maintaining gluconeogenesrs ts underscored by examples oI congeniral or drug-induced defects with fasting rn fatry acid metabolism that may be assocrated hypoglycemiaVarious congenitaI enzymadc deficrenciescausrng defective carnitine or fatty acid merabolism occur. A severe and relarively common form of fasting hvpoglycemia with heparomegall', cardiomyopathv, and hvpotonia occurs with long and mediumchain faty acid coenzyme-A dehydrogenase deficrency (LCAD and IvICAD). Plasma carnitine leveLs are low, ketones ate not

Affected untreated children manifest growth {ailure' mental

continuous gastric feeding. The dayome feedings are given eve 34 hr: 60-70L of the calories as carbohydrate low in fructo and qalactose,12-15% of rhe calories as protein, and 15-25% of th*ecalories as fat. At night, a small nasogastric cube is passed

1.87o as safflower oll, and 9 2o/" as crystalline amino acids (\rivonex, Novartis Nutrition, St. Lours Park MN 55416). Noc-

666 r PARTX. Melabolicoise8ses present in urine, but dicarboxylic aciduria is present. Clinically, pacients rvith acyl CoA dehydrogenase deficiency present with a Reye-like syndrome (see Chapcer 358), recurrent episodes of severe fasting hypoglycemic coma, and cardiorespiratory arrest (sudden infant death syndrome-like events). Severehypoglvcemia and metabolic acrdosiswithout ketosis also occur in oatients with mulriple a.rl ( oA dehydrogenase disorder'. HypuroniaJseizures, and acrid odor are other chnical clues, Survival depends on whether rhe deiect, are 'evere or mildi diagnosrsis eirablished from scudies of enzvme activlty ln liver biopsy tissue or rn cultured fibroblasts from affected patients. Tandem mass spectrometry can be employed for blood samples, eyen those on frlter paper, tor screening of congenital inborn errors. The frequency of this disorder is ar leasr 1/10,000*15,000 birrhs. Avoidance of fasting and supplementation with carnitine mav be lifesaving in these patients lvho generally present in infancl'. Interference with {artv acrd metabolism also underlies the fasting hypoglycemia associated with Jamaican vomiting sickness,with atractyloside, and with rhe drug valproate. ln Jamaican vomiting sickness,the unripe ackee fruit contains a water-soluble toxin, hypoglycin, which produces vomiting, CNS depression, and severe hypoglycernia. The hvpoglvcemic acciviry of h1'poglycin denves from its inhibition of gluconeogenesissecondary to its interference vvith the acyl CoA and carnitine mecabolism essential for rhe oxidarion of long-chain fatty acids, The disease rs almosc torally confined to Jamaica, where ackee forms a staple of the diet for the poor. The ripe ackee fruit no longer contains this toxin. Atldctlloside rs a reagent that inhibits oxidative phosphorylation in mitochondria by preventing the rranslocation of adenine nucleotides, such as ATP, across the mitochondrral membrane. Atractyloside is a perhvdrophenanthrenic glycoside derrved from Atractyls gummrfera. This plant rs found in rhe Medicerranean basin; ingesrron of this "thistle" is associated with hvpoglycemia and a syndrome similar to Jamaican vomiting sickness, The anticonvulsalt drug valproate is associated with side effecrs, predominantly in young infants, which include a Rer.elike syndrome, low serum carnitlne levels, and the porential for fasting hypoglycemia. In all these conditions, hypoglvcemra is zol associated uith ketonu/u, Acute Alcohol Intoxication. The liver metabolizes alcohol as a preferred fuel, and generalion of reducrng equivalents during the oxidation of ethanol alters the NADH:NAD ratio, which is essential for cerrajn gluconeogenic steps. As a result, gluconeogenesis is impaired and hypoglycemia ma,v ensue if glycogen stores are depleted by starvation or by pre-existing abnormalities in gl1'cogen metabolism. In toddlers who have been unfed for some cime, even the consumptioo of small quantities of alcohol can precipilate rhese events. The hypoglycemia promptly responds !o intra venous glucose, which should ahr.ays be considered in a child rvho presencsinitiaLly rvith coma or seizure, after taking a blood sample to determine glucose concentration. The possrbilit,vof the child's ingesting alcoholic drinks must also be considered if there was a preceding adulr evening parq'. A careful history allows the diagnosis to be made and may avoid needlessand expensive hospitalizacionaod investigation. Salicylate Intoxication (See Chapter5Sl. Both hypergh'cemia and hypoglycemia occur rn children with salicylare intoxication. Accelerared urrlizarion of glucose, resulting from augmentarion of insulin secretion by salicylares, and possible interference with gluconeogenesis may contribute ro hypoglycemia. Infants are more susceprible chan are older children. Momtoring of blood glucose levels with appropriate glucose infusion in the event of hypoglycemia should form part of the therapeutic approach co salicylate inroxrcatron ln chlldhood. Ketosrs may occur. Phosphoenol Pyruvate Caftorykinase Deliciency. Deficiency of this rateJimicing gluconeogenic enzyme is associated vr.rthsevere fascing h1'poglycemia and variable onset after birth. Hypoglvcemia may' occur within 24 hr aher birth. and defecrive gluconeogenesis from alanine calt be documenled rn vrvo. Liver,

kidnel and myocardium demonsrratefatqv infiltration, and atrophy of th optic nerve and vrsual cortex may occur. Hypoglycemiamay e profound. Lacrateand pvruvarelevelsin plasma havebeennormal, but a mild metaboli acidosrs may be present. The fatty rnfiltrationof variousorgans caused increased b,v formation ol acetylCoA, u.hich becomes for available fattv acid synthesis.Diagnosisof this rare enrity can be made,"l.rthcerrainty onlr through appropriareenzymaricderermrnarionr liver in biopsymaterial.Avoidance periodsof fasringthrough frequenr of feedings rich in carbohydrare shouldbe helpful because glycogen synthesis and breakdownare intact. (SeeGhapter Pyruvate Calboxylase Deficiency 87). This is pre dominanclya drsease the CNS characterized a subacute of by necrotizingencephalomvelopathy high levelsof blood lactare and and pyruvate.Hypoglycemiais not a prominent featureof this syndrome,presumablybecause gluconeogenesis from precursors other than alanine remainsintact, and theseprecursorsbypass the p)'ruvatecarboxylase step.The utilization of alamneas well as lactate through pyruvate cannot proceed,however,so tbese substrates accumulatein blood, and modest hypoglycemia may result during fastrng.AffectedpatieotsLrsually of progressrve die CNS disease. OTHER E]IIZYME DEfECTS Galactosenia(Galactose-1-Phosphate Uridyl Transferase Deficiencyl. Chapter87. See (tructose-l-Phosphate Fructose Intolerance AldolaseDeficiency) 871, rs [SeeChapter Acute h,vpoglycemia due to the inhibicion by fructose-1-phosphate glycogenolysis of via the phosphorylase syscem of gluconeogenesis rhe levelof fructose-1,5-diphosand at phate aldolase. Affected indivrdualsusually learn spontaneously to eliminatefructosefrom their diet. DEFECTS GTUCOSE IN TRAI{SPOBTERS GLIJT-I Deficiencv. Two infancswith a seizuredisorder were found to have low cerebrospinal fluid (CSF)glucoseconcentrations despilenormal plasma glucose.Lactate concentrations in glycolvsisrather than CSF were also lolri suggesting decreased bacterial infection, whjch causeslow CSF glucose with hrgh lactare.The erythroq/te glucoseuanspofter was defective,suggescing simrlardefectin the brain glucose a transporterresponsible for the clinical features. ketogenicdiet reducedthe severiry A of seizures supplying an allernate sourceof brain fuel rhat by bypassed defectin glucose rhe transport. galactose GLUT-2 Deficiency. Childrenrvichheparomegal,v, intol erance, and renaltubular dysfuncrion(Fanconi-Bickel syndrome) have been shown to have a deficienc,v the GLUT-2 glucose of cransponer plasmamembranes, addition to Lver and kidney of In tubules, GLUT2 is also expressed pancreaticp cells.Hence, rn the chnical manifesradons reflect impaired glucoserelease frorn liver and defectivetubular reabsorptionof glucoseplus phospharuriaand aminoaciduria. SYSTEMIC DISOBDERS. Severalsystemicdisordersare associated wirh hypoglycemiain inlants and children. Neonaral sepsisis often associated with hypoglycemia, possiblyas a result of diminished caloric intake wirh rmpaired gluconeogenesis. Similar nechanismsmay apply to the hypoglvcemiafound in severely malnourished infantsor thosewich severe malabsorption, Hyperviscositywith a central hematocritol >65"/ojs associated with hvpoglycemia at least10-157" of affecred rnfancs. Falciparum in malaria has been associated wirh hyperinsulinemiaand hypoglycemia.Hean and renal failure have also beenassociated with hypoglycemia,but the mechanismis obscure.Infants and chif dren with Nisseofundoplication,a relativelycommon procedure used to ameliorate gastroesophageal reflux, frequently have an associated "dumping" syndromer.ith hypoglvcemia,Characteristic features include srgnificanthyperglycemraof up to

I Chapterg r Hypoglycemia 667 500 mg/dl 30 minutes postprandiallv and severe hypoglvcemia (aleraie 32 me./d in oni .eriesl 1.5-3-0 hr larer. I hc earlv hvperI elycem"iapha.e r\ associaredwirh brisk and excessivr insulin cau\e\ rhe rebound hypogllcemia 6lucagon i.i.rr" ,hl responseshave been inappropriatel]- low ir some. Although the o h i s i o l o e j c m e c h a n j \ m sa r e n o r l l w a y s c l e a r l y a p p a r e n t ,a n d an trearmenrsnor alwavs elfective'acarbose, inhibtlor anemore"d of glucose absorption, has been reported ro be successflrl in one small series. ' i o e l l c e m i a a n d r e s o l \ et h e q u e s t i o n f h yp e r r n u l i n e ma o r o t h e r Table q2 8). Such a fasr is conrraindicatedif a iondicion* L5ee fatty acid oxidatron defect is suspected;ocher approaches such as mass randem spectrometry or molecular diagnosis, or both, shor:ld be considered. Because adrenal insuffrciency may mimic

OIAGNOSIS AND DIAGiIOSIS DIFFEREI'ITIAL

Table 92 8 lists the pertinentclinical and iochemicalfindingsin rhe common childhood disordersassocia d with hypoglycemia
necessary, ln the presence of hepacomegaly and hvpoglycemia, a presumptil'e diagnosis o[ the enzyme defect can otten be made through the clinical manifestations, Presence of hyperlipidemia, acidoJis, hyperuricemia) resPonse to glucagon in the fed and

expertise available only in cerrain rnstirutions,

TREATMENT

5exes.

or suggescs hyperinsulinemia a defectin fatry acid oxidarion' In wrth the exceptionof galacmoit othet caos.t of hypoglycemia, tosemiaand fructoseintolerance,ketonemiaand kelonuria are h a a D r e s e n tt r h e r r m e , ' i f a s t i n g y p o g l y c e m iA t. t h e t i m e o f r h e oi serumshould be obrainedfor determinarion irvpog.lvcemia. measurement tollowed by repeated h,rrm"ones \ubslrares, anJ as rnjecnon glucaSon, of or after an intramuscular intravenous

somatostalln alogs. acute symptomatic neonatal ot infant hypoTreatment gl,vcemia inc des intravenous administtatron of 2 mUkg of D1n w, follo ed by a conrinuous rnfuslon of glucose at 58 mg/kg/min, djusting rhe rate to mainrain blood glucose levels In the normal range. If hvpoglycemic seizures are presenl' some recommend a 4 mUkg bolus of D16 !(/. The managemenr of persistent neonatal or infanrile h1'poglycemia rncludes rncreasing the rare of intrarcnolrs glucose infusion to 10-15 mg/kg/min or more, if needed. This may require a central venous or umbilical venous catheter to administer a h-vperromc 15-25% glucose solution. If hyperinsulinemia is present, it should be medically managed itiall,v with diazoxide and lhen somatostarin analogs or calciu channel blockers. If hvpoglvcemra is unresponsive to intravenous glucose plus diazoxide (maximal doses up to 25 mg/kg/day) and somastostadn analogs, surgery via partial or near-total pancreatectom; should be considered. Oral diazoxrde, 10-25 mg,&gi24hr given in divided doses every 5 hr, may reverse hyperrnsulinemtc hypoglycemra but mav hyperuricemia,electrolyre also produce hirsutism,edema,nausea, disrurbances, advanced bone age, IgG deliciencl', and, rareJ,v,

rapidlv by the histo lnadvertentor deliberatedrug ingestion shouldalsobe considered. and ertorsrn dispen g medrcines but acure symptoms re not When the history is suggestive, fast can usually provok hypopresent,a 24-36 hr supervised

tive in controlling hyperinsuhnemrc hvpoglycemia in patients mutations in KAir v'ith islet cell disordersnot causedby genecic channel and rslet cell adenoma. Octreotrde is adrninistered subcutaneouslyevery 6-12ht in dosesof 20-50 pg in neonatesand young infanrs. Potencial bur unusual cornphcations include poor growth due ro inhibition of growth hormone release, pain at the injection site, vomrtrng, drarrhea, and hepatic dysfunction (hepatitis, cholelithiasis).Octreocide is usually employed as a temporizing agent for various periods before subtotal pancreatec-

668r PABTXr Metabolicoiseases tomy for KArpchannel disorders. ft mav be parricularly useful for the rreatment of refracrory hvpoglycemia despite subtotal pancreatectomy. Tcrtal pancreacectomy is not oprimal therapy, owing to the risks of surgery, permanent diabetes mellitus, and exocrine pancreatic insufliciencl'. Conrinued prolonged medical therapy wjrhour pancreatic resection if hypoglycemia rs controllable is worthu'hile becausesome children have a soontaneous resolution , , i t h e h y p e r r n s u l r n e mhcp o g l ' c e m i a .T h i s ' h o u l d b e b a l a n c e d il against the risk of hypoglycemia-induced CNS rnjury and rhe tox lcll,v or orugs,
Hardy OT, Hrnandez'PampaloniM, SafferJR, er al, Diagnosis and localizanon of Iocal congenital h;,perinsullnism by l8f-fluorodopa PET scan. / Pedidtt 2007:15 0:'140-14 5. Huopio H, Reimann F, Ashfeld R, er al: Domjnanrlv inhcrrted hyperinsulin ism causedbv a muration in che sulfonylurea receprot typc 7. J Clin lfllest 2000;106,897-906. Katz LE, Ferry RJ Jr, Stanley CA, et al: Suppressn,nof insulin over secretun by subcutaneousrecombinant human insLrlintike growth iacror 1 jn chil dren v'nh congeniml hyperinsulinxm due ro defecrivebera-ccJl sulfcnylurea rccepror l Cln Endo.rinol Metab t999\84:3117 3124. Kelly A, Ng D, Ferrv RJ Jr, ei al: Acure insulin responsesto leucine in chil dren with the hyperinsulinism/hvperammonemia svndrome. / Clir Endod inol Metab 2001;86:3724 3728. Kinnala A, Rikalainen H, LapinLeimuH, et al: Cerebral magnedc resonance imaging and ultrasonography findings after neonataLhypogtycemia. Ped?dtrics 1999 ,101:724:29 . Lucas A, Morley R, Cole TJ: Adverse neDrodevelopmenrel outcome of mod erate neonaraL hypoglyceml^. b Med J 1988;297:1304 1308. Magge SN, Shvng SL, MacMullen C, et al: Fanrlial leucine sensitivehypoglvcemia of infancy due to a dominanr muradon of the beta cell sulfonv rurea recepror / Clik Endo.tinol Metab 2004;89:4450-4456. Mayefskv JH, Sarnaik AP, PosrellonDC: FactLtioushrcoglycemla Pedlrti.s 1982j69:804-805. NleissnerT, Wesdet U, Burgard P, et al: Long rerm tbLlow-up of I14 patients with consenital hype.insulinism. Eur J Erutoomol 2003l.'149.43-51 . Melis D, Parenri G, Della CR, er al: Brain damage in glycogen srofasedisease -642. qpeI. J Pediatu2004\144:637 Menni F, delonlay P, Sevin C, ec at: Neurologic outcomes of 90 neonatesand infancs w'irh persistenr hyperinsulinemic hypogll'cemia. Pedratzrrs 2001.,107:47 6479 Molven A, Rishaung U, Nlarre CE, er at: Hundng for a hlpo$ycer a gene: Severe neonaralhypoglycemiain a consangu ineous familv. Am I Med Genet 2002;113:4046 . Ng DD, Feny RJ Jr, Kellv A, et al: Acarbose rrearmenr of posrprandial hypo glycemia in children after Nissen tuDdoplicarion J Pediatr 2001;139: 877-879. Njuguna P, Newton C: Management of severefalcjparum malaria. / ?osrsTad M e d 2 0 0 4 ; 5 0 : 4 55 0 . concentrations Osier FH, Berkley JA, Ross A, et al: Abnormal blood gLucose and ouccome. on adnissron to a rural Kenyan dist.ict hospital: Prevalence Arch Dis Child 2003;88i2r-625 . Otonkoskr T, Nanro-SalonenK, SeppanenM, et a1:NoniDvasivediagrosis of {ocal hyperinsulinrsm of infancy u.ith Ir8F]-DOPA posirron emission tomographl. D iabetes2006;55:13-1 8. Otonkoski I Kaminen N, Usnnov J, et al: Physical exerciseinduced hyperinsulinemic h,vpoglycemiais an autosonafdominant uait characterized by abnormal pyruvate induced insulin release Dlabetes 2003.52.199204. Rrizen DM, Brooks Kayal ,\, Sreinkauss L, er a| CentraL nervous system gain of function hyperexcitabitity associated wirh gluramate deh-vdrogenasc mut^ti,ons. Pediatr 2005i146:388-394. I tubeiro MJ, de Lonlay P, DeLzescaux et al: Characterization of hyperiD ! suLinism infancy assessed in wirh PET and 18F-Flucrro-L-DOPA. NazlMed / 200ii46:550-.r66. Spar JA, Lewine.fD, Orrison vW Jr: Neonatal hypoglycenra: CT and MR lindings.,a,u / Nerrolrdiol L994;15 :1477-147 8. Sperling MA, Menon RK: Differenrial diagnosis and managernentof neonatal hypoglycemia.Psdia* Cli11North Am 2004t5L:703 723. StanleyCAr Advancesin diagnosisand treannent of hwerinsulinrsm in infanrs and children. ./ Clin Etulo.tlnol Metab 2002;87,4857-4859. StanleyCA, Thornron PS. Gangulv A, et al: Preoperativeevaluation oi inranN wirh local or diffuse congenitalhyperlnsulinismb-vintravnousacureinsulin rsponserests and selecriveFancreatic afterial calciuln stirnulation. / C/i, F,ndocrinol Meab 2004;89:288-29 6, SteinkraussL, Lrpman TH, Hendell CD, er al: Eflecrs of h,vpoglycemiaon de"eLopmental oDtcome in children wirh congenital hvperinsuli*m / Pediatr N /s 2005\2U109 118. Sun I-, Eklund EA, Chung \vK, et ai: Congenrraldisorder of glycosvlation is presentinsrvith hypcrinsulinemichypoglycemia and isLetcell hyperplasia / Clin Endocnnol Metab 2005r90:4371 437J. Taylor SI, Barbetri F, Accili D, er al: Sl.ndromesof autoimrnuniw and hypoglvcemia: Auroantibodies directed against jnsuLin and Lts rcccptor Endo.rinolMetab Chn Noth Am r989;r8:123-143 $ith Thornton PS, Satin-Snith li'ts, Herold K, er al: Famjlial h,vperinsulinism apparent aurosomal dcminart inhcritancc: Clinical anrl genetic diflerences f r o m t h e a u r o s o m ar e c e s s i vv a r j a n t . , /P r l i d t l 1 9 9 8 r 1 3 2 : 9 - 1 4 . l e

PROGNOSIS
The prognosis is good in aslmptomatic neonaces with hypoglycemia of shorr duration. Hypoglycemia recurs rn 10-15o% of infants afcer adeoLraLe treatment. Recurrence is more common if lntravenous fluids are extravasared or discontinued too raoidlv before oral teedine. are well t.rlerated.Children in whom keL.rric hypoglvcemia latir develops have an rncreased rncidence of neonatal hypoglvcemia. The prognosis for normal inrellectual function must be guarded because prolonged, recurrent, and severe symptomatic hypo gl_v-cemia associaled u'rrh neuroLogic sequelae. Sympcomatic is infants wrrh hvpoglycemra, particularl). low-birthweighc infants, those with persistent hyperinsulinemic hvpoglycemia, and infants of draberic mothers, have a poorer prognosis for subsequent normal intellectual development than asympromatic infants do.

A h m a d A , K a h l e r S C , K i s h n a n iP S .e t a l : T r e a t m e n r f p y r u v a r ec a r b o x y J a s e o deficiency uith high doses oI ci[ate and aspartate An I Med Geftet 1 9 9 9 ; 8 7 : 3 33 3 8 . 1 Bachrach BE. Weinstein DA, Orbo-MeLander M, et al: Glvcogen synthase dcficiency (gl1(ogen storage diseasetype 0t presentingurrh hypergtycemia and gtucosuria: Rcporr of three new mulatrons. I L'ediatr 2002\\40: 781-i83. hyperinsu Dacou-Vouterakis C, Psrchou I Maniatr-Chrisridrs Mr Persrstent of linemic hl.pogJ-vcemia infancy: l,ong term rcs:ults. Pedidtr Endoctinol J Metub 1998;1|:137-L4l. Dalgic N, lirgenekon E, Soysal S, et al: Transienr neonatal hypoglycemirl-ong term eflects on neurodevelopmenralo:utcome. Pediatr Lndacriftol J Metab 2002;l5 319-324. in DeBaun MR, King AA. White N: H-vpoglycemja Belkwtrh-wiedemann syndrome. Se-iri Pelinutol 2000\2+1t44-l /-1 de Lonlar P, Benelh C, Fouque 4 et al: Hyperinsulinism and hIprammonmja svndrome: Report of 12 unrelared parJena. Pediatu Res 2 0 0 1 i 5 0 : - ] 5 1j 5 7 . de Lonlay ( (lDer Nl, Vuillaumier-Barrot S, ef al, Hyperinsulinenic hypo glycemia as a presenringsign in phosphomannoseisomerasedeiciency: A nelv rnanifesrarionof carbohydracedeficient glvcoprorein syndrome rrear able $'irh mannose J Pedidtr 1999;1351379-383. Aetiolosies. de Lonley R ciurgea l, Touari G, et al: Neonatal h-vposlycaemia, Semi Neonatol 2004\9'49 58 dc Lonla,v-Debency Poggi-Traven 4 Fournet J-C, er at: Clinical fearures 4 of 52 neonares g.ith hyperinsulinism. N Engl I Med 1999340:11691 175 l)evivLr DC, IrifiLciti RR, Jacobson RI, er al: Defective glucose transport across dre bLood-brain barrier as a cause of persisrenthypoBlycorrhachia, delay. N ,Engl/ Med 1991;325:703 709. seLzures, and deveLopmcntal Dunne N{J, Kane C. ShepherdRM, et al, Familial perststenrhvperlnsulinenic hypoglycemiaof inlancy and mutarions in rhe suifonylurea receptor.N Ettgl J Med L997:336 703-706. Frckmann Ml-, Thorburn llR, Kirby DM, et at: Mirochondrial eteccron transporr charn defecr presendng as hyposlycemia. I Pedidtr 1997\1301

.+31-436.

ra Giurge. I,I-aborde K, Touati G, et al: Acute insuln responses calciun and colbutanrde dc not differentiate focal fron difluse congenrrathyperinsuLini\n I CIin Lndo.nnol Metdb 2004;89:925-929. et caDsedby an Glaser B, Kesavanl', Heynan N'1. aL:Familial hyperinsulinLsm acnvating glucokinasernttation. N F,nslJ Med 1998;338:226-230.