Alkaptonuria

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Alkaptonuria
Classification and external resources

ICD-10
ICD-9
OMIM
DiseasesDB
eMedicine
MeSH
GeneReviews

Homogentisic acid
E70.2 (ILDS E70.210)
270.2
203500
409
ped/64
D000474
Alkaptonuria

Alkaptonuria (black urine disease or alcaptonuria) is a rare inherited genetic disorder

of phenylalanine and tyrosine metabolism. This is an autosomal recessive condition that
is due to a defect in the enzyme homogentisate 1,2-dioxygenase (EC 1.13.11.5), which
participates in the degradation of tyrosine. As a result, a toxic tyrosine byproduct called
homogentisic acid (or alkapton) accumulates in the blood and is excreted in urine in large
amounts(hence -uria). Excessive homogentisic acid causes damage to cartilage
(ochronosis, leading to osteoarthritis) and heart valves as well as precipitating as kidney
stones. Treatment with nitisinone, which suppresses homogentisic acid production, is
being studied.[1] Alkaptonuria is more common in Slovakia and the Dominican Republic
than in other countries.[2][3]

Contents
[hide]

1 Signs and symptoms

2 Diagnosis
3 Pathophysiology
4 Treatment
5 Epidemiology
6 History
7 See also

8 References

9 External links

[edit] Signs and symptoms

Alkaptonuria is often asymptomatic, but the sclera of the eyes may be pigmented (often
only at a later age),[1] and the skin may be darkened in sun-exposed areas and around
sweat glands; sweat may be coloured brown. Urine may turn brown if collected and left
exposed to open air, especially when left standing for a period of time. Kidney stones and
stone formation in the prostate (in men) are common and may occur in more than a
quarter of cases.[1]
The main symptoms of alkaptonuria are due to the accumulation of homogentisic acid in
tissues. In the joints this leads to cartilage damage, specifically in the spine, leading to
low back pain at a young age in most cases. Cartilage damage may also occur in the hip
and shoulder. Joint replacement surgery (hip and shoulder) is often necessary at a
relatively young age.[1]
Valvular heart disease, mainly calcification and regurgitation of the aortic and mitral
valves, may occur, and in severe and progressive cases valve replacement may be
necessary. Coronary artery disease may be accelerated in alkaptonuria.[1]
A distinctive characteristic of alkaptonuria is that ear wax exposed to air turns red or
black (depending on diet) after several hours because of the accumulation of
homogentisic acid.[4]

[edit] Diagnosis
The diagnosis of alkaptonuria needs to be suspected before diagnostic testing can be
performed using paper chromatography and thin layer chromatography. Both blood
plasma and urine can be used for diagnosis. In healthy subjects, homogentisic acid is
absent in both blood plasma and urine. In alkaptonuria, plasma levels are 6.6
micrograms/ml on average, and urine levels are on average 3.12 mmol/mmol of
creatinine.[1]

[edit] Pathophysiology
Homogentisic acid is a natural intermediary of the metabolism of tyrosine, an amino acid.
Hepatic homogentisate 1,2-dioxygenase (coded by the HGD gene) metabolises
homogentisic acid into 4-maleylacetoacetate. Alkaptonuria arises in people who have
inherited two abnormal HGD genes: one from each parent. Numerous different HGD
mutations have been identified.[1]

In a patient who underwent a liver transplant for an unrelated problem, alkaptonuria

resolved and joint disease stabilised after the transplant, confirming that the liver is the
main site of homogentisic acid production in alkaptonuria.[5]

[edit] Treatment
No treatment modality has been unequivocally demonstrated to reduce the complications
of alkaptonuria. Commonly recommended treatments include dietary restriction of
phenylalanine and tyrosine and large doses of ascorbic acid (vitamin C). Dietary
restriction may be effective in children, but benefits in adults have not been
demonstrated.[6]
The insecticide nitisinone inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme
that generates homogentisic acid from 4-hydroxyphenylpyruvic acid. This reduces
homogentisic acid. The main side-effect is irritation of the cornea, and there is a concern
that it will cause the symptoms of hereditary tyrosinaemia type III because of the possible
accumulation of tyrosine or other intermediaries.[7] Further studies are being conducted.[8]

[edit] Epidemiology
In Slovakia the disease occurs in 1:19,000 people. In other ethnic groups, the normal
prevalence is between 1:100,000 and 1:250,000.[2] It is reported frequently in the
Dominican Republic, but exact prevalence there is not known.[3]

[edit] History
Alkaptonuria was one of the four diseases described by Sir Archibald Edward Garrod, as
being the result of the accumulation of intermediates due to metabolic deficiencies. He
linked ochronosis with the accumulation of alkaptans in 1902,[9] and his views on the
subject, including its mode of heritance, were summarised in a 1908 Croonian lecture at
the Royal College of Physicians.[10] The defect was narrowed down to homogentisic acid
oxidase deficiency in a study published in 1958.[11] The genetic basis was elucidated in
1996, when HGO mutations were demonstrated.[12]
A 1977 study showed that an ochronotic Egyptian mummy had probably suffered from
alkaptonuria.[13]

[edit] See also

Ochronosis
List of cutaneous conditions

[edit] References

^ a b c d e f g Phornphutkul C, Introne WJ, Perry MB, et al. (2002). "Natural

history of alkaptonuria". New England Journal Medicine 347 (26): 211121.
doi:10.1056/NEJMoa021736. PMID 12501223.
http://content.nejm.org/cgi/content/full/347/26/2111.
2.
^ a b Zatkov A, de Bernab DB, Polkov H, et al. (2000). "High
frequency of alkaptonuria in Slovakia: evidence for the appearance of multiple
mutations in HGO involving different mutational hot spots". American Journal of
Human Genetics 67 (5): 13339. doi:10.1016/S0002-9297(07)62964-4.
PMC 1288576. PMID 11017803.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?
tool=pmcentrez&artid=1288576.
3.
^ a b Milch RA (1960). "Studies of Alcaptonuria: Inheritance of 47 Cases
in Eight Highly Inter-related Dominican Kindreds". Am. J. Hum. Genet. 12 (1):
7685. PMC 1932065. PMID 17948450.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?
tool=pmcentrez&artid=1932065. Full text at PMC: 1932065
4.
^ Srsen S (1978). "Dark pigmentation of ear cerumen in alkaptonuria".
Lancet 2 (8089): 577. doi:10.1016/S0140-6736(78)92912-4. PMID 79943.
5.
^ Kobak AC, Oder G, Kobak S, Argin M, Inal V (2005). "Ochronotic
arthropathy: disappearance of alkaptonuria after liver transplantation for hepatitis
B-related cirrhosis". Journal of Clinical Rheumatology 11 (6): 3235.
doi:10.1097/01.rhu.0000191157.25894.55. PMID 16371803.
6.
^ de Haas V, Carbasius Weber EC, de Klerk JB, et al. (1998). "The
success of dietary protein restriction in alkaptonuria patients is age-dependent".
Journal of Inherited Metabolic Disease 21 (8): 7918.
doi:10.1023/A:1005410416482. PMID 9870204.
7.
^ Suwannarat P, O'Brien K, Perry MB, et al. (2005). "Use of nitisinone in
patients with alkaptonuria". Metabolism: Clinical and Experimental 54 (6): 719
28. doi:10.1016/j.metabol.2004.12.017. PMID 15931605.
8.
^ ClinicalTrials.gov NCT00107783
9.
^ Garrod AE (1902). "The incidence of alkaptonuria: a study in clinical
individuality". Lancet 2: 16161620. doi:10.1016/S0140-6736(01)41972-6.
Reproduced in Garrod AE (2002). "The incidence of alkaptonuria: a study in
clinical individuality". Yale Journal of Biology and Medicine 75 (4): 22131.
PMC 2588790. PMID 12784973.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?
tool=pmcentrez&artid=2588790.
10.
^ Garrod AE (1908). "The Croonian lectures on inborn errors of
metabolism: lecture II: alkaptonuria". Lancet 2 (3): 7379. PMID 20992918.
11.
^ La Du BN, Zannoni VG, Laster L, Seegmiller JE (1 January 1958). "The
nature of the defect in tyrosine metabolism in alcaptonuria" (PDF). Journal of
Biological Chemistry 230 (1): 25160. PMID 13502394.
http://www.jbc.org/cgi/reprint/230/1/251.
12.
^ Fernndez-Can JM, Granadino B, Beltrn-Valero de Bernab D, et al.
(1996). "The molecular basis of alkaptonuria". Nature Genetics 14 (1): 1924.
doi:10.1038/ng0996-19. PMID 8782815.
1.

13.

^ Stenn FF, Milgram JW, Lee SL, Weigand RJ, Veis A (1977).
"Biochemical identification of homogentisic acid pigment in an ochronotic
egyptian mummy". Science 197 (4303): 5668. doi:10.1126/science.327549.
PMID 327549.

[edit] External links

Alkaptonuria Society (UK)

[hide]v d eInborn error of amino acid metabolism (E70E72, 270)
Lysine/straight Glutaric acidemia type 1 type 2 Hyperlysinemia Pipecolic
chain
acidemia Saccharopinuria

Kacet
yl-CoA Leucine

Tryptophan

Maple syrup urine disease Isovaleric acidemia 3Methylcrotonyl-CoA carboxylase deficiency 3-hydroxy-3methylglutaryl-CoA lyase deficiency 3-Methylglutaconic
aciduria 1
Hypertryptophanemia

Sarcosinemia D-Glyceric acidemia Glutathione

Gpyruvatec
synthetase deficiency
Glycine
itrate
GlycineCreatine: GAMT deficiency Glycine
encephalopathy
Histidine
Gglutamate
-ketoglutarate Proline

Carnosinemia Histidinemia Urocanic

aciduria
Hyperprolinemia Prolidase deficiency

Glutamate/glutamineSSADHD
G
Valine

GpropionylCoA
succinyl-CoA

Maple syrup urine disease Hypervalinemia

Isobutyryl-CoA dehydrogenase deficiency

Maple syrup urine disease Beta-ketothiolase

Isoleucine deficiency 2-Methylbutyryl-CoA dehydrogenase
deficiency
Methionine

Hypermethioninemia Homocystinuria
Cystathioninuria

General

Propionic acidemia Methylmalonic acidemia

BC/OA

Gfumarate

Methylmalonyl-CoA mutase deficiency

Phenylalanine/tyr
osine

Phenylketonuria

Tetrahydrobiopterin
deficiency 6Pyruvoyltetrahydropte
rin synthase
deficiency

Tyrosinemia

Type II tyrosinemia
Type III
tyrosinemia/Hawkinsi
nuria
Alkaptonuria/Ochron
osis Type I
tyrosinemia

Albinism: Ocular
albinism (1)
Oculocutaneous
albinism
TyrosineMelanin
(HermanskyPudlak
syndrome)
Waardenburg
syndrome
Dopamine beta
TyrosineNorepine hydroxylase
phrine
deficiency reverse:
Brunner syndrome

N-Acetylglutamate synthase
deficiency Carbamoyl phosphate
Urea
synthetase I deficiency Ornithine
Goxaloacetate
cycle/Hyperammonemiatranscarbamylase
(arginine, aspartate)
deficiency/translocase deficiency
Citrullinemia Argininosuccinic
aciduria Argininemia
Transpo
Solute carrier family: Cystinuria Hartnup disease Lysinuric protein
rt/
intolerance Iminoglycinuria
IE of
Fanconi syndrome: Oculocerebrorenal syndrome Cystinosis
RTT

Other

Trimethylaminuria 2-Hydroxyglutaric aciduria Fumarase deficiency

M: MET

mt, k, c/g/r/p/y/i,
f/h/s/l/o/e, a/u, n, h

k, cgrp/y/i, f/h/s/l/o,
au, n, h, epon

m(A16, C10),i(k,
c/g/r/p/y/i, f/h/s/o/e,
a/u, n, h)

Retrieved from "http://en.wikipedia.org/wiki/Alkaptonuria"

Categories: Amino acid metabolism disorders | Autosomal recessive disorders | Skin
conditions resulting from errors in metabolism
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