Malignant Hyperthermia Susceptibility - GeneReviews® - NCBI Bookshelf

1/8/2017 MalignantHyperthermiaSusceptibilityGeneReviewsNCBIBookshelf
NCBIBookshelf.AserviceoftheNationalLibraryofMedicine,NationalInstitutesofHealth.
PagonRA,AdamMP,ArdingerHH,etal.,editors.GeneReviews[Internet].Seattle(WA):Universityof
Washington,Seattle19932016.
MalignantHyperthermiaSusceptibility
Synonym:MalignantHyperpyrexia
HenryRosenberg,MD,NyamkhishigSambuughin,PhD,SheilaRiazi,MD,andRobertDirksen,PhD.
AuthorInformation
InitialPosting:December19,2003LastUpdate:January31,2013.
Summary
Clinicalcharacteristics. Malignanthyperthermiasusceptibility(MHS)isapharmacogenetic
disorderofskeletalmusclecalciumregulationassociatedwithuncontrolledskeletalmuscle
hypermetabolism.Manifestationsofmalignanthyperthermia(MH)areprecipitatedbycertain
volatileanesthetics(i.e.,halothane,isoflurane,sevoflurane,desflurane,enflurane),eitheraloneor
inconjunctionwithadepolarizingmusclerelaxant(specifically,succinylcholine).Thetriggering
substancesreleasecalciumstoresfromthesarcoplasmicreticulumandmaypromoteentryof
calciumfromthemyoplasm,causingcontractureofskeletalmuscles,glycogenolysis,andincreased
cellularmetabolism,resultinginproductionofheatandexcesslactate.Affectedindividuals
experience:acidosis,hypercapnia,tachycardia,hyperthermia,musclerigidity,compartment
syndrome,rhabdomyolysiswithsubsequentincreaseinserumcreatinekinase(CK)concentration,
hyperkalemiawithariskforcardiacarrhythmiaorevenarrest,andmyoglobinuriawithariskfor
renalfailure.Innearlyallcases,thefirstmanifestationsofMH(tachycardiaandtachypnea)occur
intheoperatingroomhowever,MHmayalsooccurintheearlypostoperativeperiod.Thereis
mountingevidencethatsomeaffectedindividualswillalsodevelopMHwithexerciseand/oron
exposuretohotenvironments.Withoutproperandprompttreatmentwithdantrolenesodium,
mortalityisextremelyhigh.
Diagnosis/testing. Aclinicalgradingscalehelpsdetermineifamalignanthyperthermia(MH)
episodehasoccurred.Contracturetesting,thestandarddiagnostictestforMHsincethemid1970s,
reliesontheinvitromeasurementofcontractureresponseofbiopsiedmuscletograded
concentrationsofcaffeine,theanesthetichalothane,andothercalciumreleasingagents.Todate,
twogenespredisposingtoMHShavebeenidentifiedfouradditionallocihavebeenmapped,but
thegeneshavenotbeenidentified.MHS1isassociatedwithmutationofRYR1,encoding
ryanodinereceptortype1MHS5isassociatedwithmutationofCACNA1S,encodingaskeletal
musclecalciumchannel.Upto70%ofMHSiscausedbymutationofRYR1andabout1%results
frommutationofCACNA1S.
Management. Treatmentofmanifestations:EarlydiagnosisofMHSisessential.Successful
treatmentofanacuteepisodeofMHincludes:
Discontinuationofpotentinhalationagentsandsuccinylcholine
Administrationofdantrolenesodiumintravenously
Surface,intravenousandbodycavitycoolingwithcoldsolutionsforhyperthermic
individualsand
Treatmentofmetabolicabnormalities.
Affectedindividualswhodisplayextremehyperthermiaareatriskfordisseminatedintravascular
coagulationtherefore,acoagulationprofileshouldbeobtainedonallindividualsexperiencing
fulminantMH.Thepresenceofmyoglobinuriamandatesreferraltoaneurologistforfurther
investigation.
Preventionofprimarymanifestations:Avoidanceofpotentvolatileanestheticagentsand
succinylcholine.Individualsundergoinggeneralanestheticsthatexceed30minutesinduration
https://www.ncbi.nlm.nih.gov/books/NBK1146/ 1/33
shouldhavetheirtemperaturemonitoredusinganelectronictemperatureprobe.
Agents/circumstancestoavoid:Avoidextremesofheat,butdonotrestrictathleticactivityunless
thereisahistoryofovertrhabdomyolysisand/orheatstroke.Calciumchannelblockersshouldnot
begiventogetherwithdantrolenebecauselifethreateninghyperkalemiamayresult.Inindividuals
withMHundergoingcardiacbypasssurgery,aggressiverewarmingshouldbeavoided,asitmay
beassociatedwithdevelopmentofclinicalsignsofMH.Serotoninantagonistantiemeticsshould
beusedcautiously.
Evaluationofrelativesatrisk:Ifthepathogenicvarianthasbeenidentifiedinthefamily,molecular
genetictestingofatriskrelativesiswarrantedtoidentifythosewhohavethepathogenicvariant
andwillbenefitfromavoidinganestheticagentsthatincreasetheriskforamalignanthyperthermia
episode.AbsenceofapathogenicvariantdoesnotimplythatanatriskindividualisnotMH
susceptible.
Pregnancymanagement:IfapregnantwomanwithMHSrequiresnonemergentsurgeryduring
thepregnancy,anontriggeringanesthetic(local,nerveblock,epidural,spinalanesthesiaoratotal
intravenousgeneralanesthetic)shouldbeadministered.Continuousepiduralanalgesiaishighly
recommendedforlaboranddelivery.IfaCesareandeliveryisindicatedinawomanwhodoesnot
haveanepiduralcatheterinplace,neuraxial(spinal,epidural,orcombinedspinalepidural)
anesthesiaisrecommended,ifnototherwisecontraindicated.Ifageneralanestheticisindicated,a
totalintravenousanesthetictechniqueshouldbeadministered,withananesthesiamachinethathas
beenpreparedforanMHsusceptibleindividual.
Geneticcounseling. Malignanthyperthermiasusceptibility(MHS)isinheritedinanautosomal
dominantmanner.MostindividualsdiagnosedwithMHShaveaparentwithMHShowever,the
parentmaynothaveexperiencedanepisodeofMH.TheproportionofindividualswithMHS
causedbyadenovopathogenicvariantisunknown.EachchildofanindividualwithMHShasa
50%chanceofinheritingthepathogenicvariant.Althoughprenataldiagnosisforpregnanciesat
increasedriskforMHSispossible,prenataltestingforpharmacogeneticconditions(likeMHS)that
haveeffectivetreatmentandpreventionisgenerallynotofferedoravailable.
Diagnosis
ClinicalDiagnosis
Consensusguidelinesforthediagnosisandmanagementofmalignanthyperthermiahavebeen
published[Robinson&Hopkins2001,Urwyleretal2001,Seietal2004,Litman&Rosenberg
2005,Carpenteretal2009,Glahnetal2010].Clinicaldiagnosticcriteriaformalignant
hyperthermiasusceptibility(MHS)aresummarizedinTable1.Thefindingsrelatetosigns
occurringduringorshortlyaftergeneralanesthesia.
Eachclinicalfindingisweightedastosignificanceinbeingassociatedwithmalignant
hyperthermiaasdeterminedthroughaDelphicstudyofexperts.Pointsareassignedaccordingto
weightandarethensummedtoproducearawscore,whichtranslatestoalikelihoodscore,range
from1(score0:almostnever/veryunlikely)to6(score50:almostcertain).Themorecriteria
anindividualfulfills,themorelikelythatamalignanthyperthermia(MH)episodehasoccurred.
Thus,withonlytemperatureelevationduringanesthesia,anindividualisnotlikelytobe
susceptibletomalignanthyperthermia.Ofcourse,alimitationofthescoringsystemisthatnot
everyclinicalfindingmaybemeasured,e.g.arterialbloodgas,orthesyndromeisrecognizedvery
quicklyandtreatedbeforeallsignsappear[Larachetal1994].
Table1.
CriteriaUsedintheClinicalGradingScaleforMalignantHyperthermia
ClinicalFinding
Manifestation2
(MaximumScore)1
Respiratoryacidosis
EndtidalCO2>55mmHg,PaCO2>60mmHg
(15)
Cardiacinvolvement Unexplainedsinustachycardia,ventriculartachycardia,orventricular
(3) fibrillation
Metabolicacidosis
Basedeficit>8mEq/L,pH<7.25
(10)
Musclerigidity(15) Generalizedrigidity,severemassetermusclerigidity
Musclebreakdown Serumcreatinekinaseconcentration>20,000/Lunits,colacoloredurine,
(15) excessmyoglobininurineorserum,plasma[K+]>6mEq/L
Temperatureincrease
Rapidlyincreasingtemperature,T>38.8C
(15)
RapidreversalofMHsignswithdantrolene(score=5),elevatedresting
Other
serumcreatinekinaseconcentration(score=10)
Familyhistory(15) Consistentwithautosomaldominantinheritance
FromLarachetal[1994],Rosenbergetal[2002]
1. Clinicalfindings(exceptfamilyhistory)areinorderofrelativeimportance.
2. Signsoccurringduringorshortlyaftergeneralanesthesiaintheuntreatedindividual
Testing
Contracturetest.Sincethemid1970s,thestandarddiagnostictestforMHhasbeentheinvitro
measurementofcontractureresponseofbiopsiedmuscletogradedconcentrationsofcaffeineand
theanesthetichalothane.Thetestisreferredtoasthecaffeine/halothanecontracturetest
(CHCT)inNorthAmericaandtheinvitrocontracturetest(IVCT)inEurope:
Note:Thecalciuminducedcalciumrelease(CICR)testisusedonlyinJapan,andnointernational
standardsexist.
Thetestmustbeperformedonabiopsyofapproximately2.0gofmusclefromthevastus
lateralisormedialis(somecentershaveusedbiopsiesfromothermusclegroups,butthetest
hasonlybeenstandardizedforthevastusmusclegroup)withinfivehoursofharvesting.
Usually,theindividualmustbeataMHdiagnosticcenter(seeTestingStrategy,*Note)in
ordertoundergotesting.
Theindividualisanesthetizedwithgeneralanesthesiaorwithafemoralnerveblockorone
ofitsvariants:
Directmuscleinfiltrationwithlocalanestheticiscontraindicatedbecauseitcould
affecttissueviability.
Inallcases,theanestheticdrugsusedmustbesafeforMHsusceptibleindividuals.
Thesurgeonmustnotuseelectrocauteryorstretchthemuscle.
Musclebundlesweighing100150mgaremountedinachambercontainingbuffersolutionand,
afteraperiodofstabilization,arecausedtocontractwithsupramaximalelectricalstimuli.The
isometriccontracturethatdevelopsfollowingexposuretovariouspharmacologicagentsthatcause
sarcoplasmicreticulum(SR)calciumrelease(e.g.,halothane,caffeine,andryanodine)ismeasured.
Thetwoversionsofthetestingprotocolwithinternationalstandardsoftestperformanceand
interpretationaretheNorthAmerican[Litman&Rosenberg2005]andtheEuropeanversions
[Urwyleretal2001].Theessentialdifferencesare:(1)theNorthAmericanprotocolutilizes
exposureto3%halothane,whiletheEuropeanversionutilizesincrementalexposuretohalothane
and(2)theNorthAmericanversionrequirestestingofthreemusclebundlesforeachdrug,
whereastheEuropeanversionrequirestestingoftwomusclebundlesforeachdrug(seeTable2).
Ofnote,inrecentyears,ryanodine(1.0mol/L)and4chloromcresolhavebeenusedtoelicit
contracturesaswell.
Table2.
TestingProtocolsforMalignantHyperthermia
Designation1 NorthAmericanProtocol EuropeanProtocol

Contractureof>0.7gto3%halothane Contractureof0.2gto2%halothane
OR AND
MHS
Contractureof>0.3gto2.0mmol/L Contractureof0.2gto2.0mmol/L
caffeine caffeine
Contractureof0.50.7gto3% Contracturetohalothaneonlyorcaffeine
MHE2
halothane only
Nocontracture
OR
Contractureof<0.5gtohalothane Nosignificantcontracturestoeither
MHN
OR agent
Contractureof<0.3gto2.0mmol/L
caffeine
Note:(1)Studiestodeterminethesensitivityandspecificityofthecontracturetestshowthatbothprotocolshave
asensitivityofabout100%.Specificityisgenerallybetween80%and97%,accordingtoseveralstudieswith
theseprotocols[Allenetal1998].(2)Somelaboratoriesemploy1.0or2.0mol/Lryanodineor4chlorom
chlorocresolinadditiontohalothaneandcaffeinetoclarifyequivocalresultshowever,theseagentshavenot
beenincorporatedintothestandardizedtest.
1. MHS=malignanthyperthermiasusceptibleMHE=malignanthyperthermiaequivocalMHN=malignant
hyperthermianegative
2. IntheNorthAmericanprotocol,theMHEdesignationisoptionalandmostcentersreportresultsaseither
MHNorMHSusingathresholdof0.5g.
SevofluranehasbeeninvestigatedasapotentialreplacementforhalothaneintheMHtesting
protocol.Preliminaryresultssuggesttherapidapplicationofsevoflurane(8%),andnotits
incrementalincrease,inducessignificantcontractureinMHS,andmaydifferentiateMHSfrom
MHN[Metterleinetal2011a].
MolecularGeneticTesting
Genes.Todate,onlytwogenesinwhichmutationcausesMHShavebeenidentified:
RYR1(MHS1locus)encodesthetype1ryanodinereceptorofskeletalmuscle.Molecular
genetictestingindicatesthatpathogenicvariantsinRYR1areidentifiedinupto70%80%of
individualswithconfirmedMHS[Sambuughinetal2005,Gallietal2006,Robinsonetal
2006,Kraevaetal2011].
CACNA1S(MHS5locus)encodesthe1subunitoftheskeletalmuscledihydropyridine
receptorLtypecalciumchannel.PathogenicvariantsinCACNA1Saccountfor1%ofall
MHS[Stewartetal2001].
Evidenceforfurtherlocusheterogeneity.Fouradditionallocihavebeenmappedthegenes
havenotbeenidentified:
MHS2(linkedtochromosomelocus17q11.2q24)
MHS4(3q13)
MHS6(5p)
MHS3(7q21q22)
Clinicaltesting
Table3.
SummaryofMolecularGeneticTestingUsedinMalignantHyperthermiaSusceptibility
ProportionofMHS
Gene1/ Variants
AttributedtoMutationof TestMethod
Locus Detected2
ThisGene
Targetedanalysisforpathogenic Mutation
variants panel3
Sequenceanalysis4/scanningofall Sequence
70%80% exonsandflankingintronicregions5,6 variants
RYR1/ Sequenceanalysis4/scanningof
Sequence
MHS1 selectexons&flankingintronic
variants
regions5,6
Unknown
Unknown Deletion/duplicationanalysis
nonereported
Unknown Linkageanalysis7 NA
Targetedanalysisforpathogenic
p.Arg1086His
variants
8 Sequenceanalysis4/variant Sequence
CACNA1S 1% scanning5 variants
/MHS5
Sequence
Sequenceanalysisofselectexons
variants9
Unknown
/MHS2
Unknown
/MHS3
Unknown
/MHS4
1. SeeTableA.GenesandDatabasesforchromosomelocusandprotein.
2. SeeMolecularGeneticsforinformationonallelicvariants.
3. Examplesofvariantsdetectedbysequenceanalysismayincludesmallintragenicdeletions/insertionsand
missense,nonsense,andsplicesitevariantstypically,exonorwholegenedeletions/duplicationsarenot
detected.
4. Apanelofthemostcommonpathogenicvariants(Table4)detectsapproximately25%30%ofindividuals
withmalignanthyperthermiasusceptibility(MHS)[Robinsonetal2002].Insomepopulations,(i.e.,in
Switzerland)amorelimitedpanelisacceptablebecauseofhomogeneityofthepopulation[Girardetal
2001].Mutationpanelisp.Cys35Arg,p.Arg163Cys,p.Arg163Leu,p.Gly248Arg,p.Gly341Argp.Ile403Met,
p.Tyr522Ser,p.Arg552Trp,p.Arg614Cys,p.Arg614Leu,p.Arg2163His,p.Arg2163Cys,p.Val2168Met,
p.Thr2206Met,p.Ala2350Thr,p.Ala2428Thr,p.Gly2434Arg,p.Arg2435His,p.Arg2454Cys,p.Arg2454His,
p.Arg2458His,p.Arg2458Cys,p.Gly341Arg,andp.Tyr522Ser(seeTable4).Mutationpanelsmayvaryby
laboratory.
5. Sequenceanalysisandvariantscanningoftheentiregenecanhavesimilarvariantdetectionfrequencies
however,variantdetectionratesforvariantscanningmayvaryconsiderablybetweenlaboratoriesdepending
onthespecificprotocolused.
6. AlthoughmanyRYR1pathogenicvariantsareclusteredinthreemutationalhotspots,rangingfromamino
acidresidues35to614(Nterminalregion),2117to2458(centralregion),and3916to4973(Cterminal
region)[JurkatRottetal2000,McCarthyetal2000,Robinsonetal2006],pathogenicvariantsarefound
throughouttheRYR1codingregion[Kraevaetal2011].Whenindividualswhohaveeitherapositive
contracturetestorstronglysuggestiveclinicalandfamilyhistoriesareselected,completesequenceanalysis
oftheentireRYR1codingregionincreasesthedetectionrateto70%80%[Sambuughinetal2005,Gallietal
2006].
7. LinkageanalysisforallMHSlocimaybeconsideredforgeneticcounselinginfamiliesinwhichatleastten
familymembersinmorethantwogenerationshavetheunequivocaldiagnosisofMHSbyIVCT.Linkage
studiesarealwaysbasedonaccurateclinicaldiagnosisofMHSintheaffectedfamilymembersandaccurate
understandingofthegeneticrelationshipsinthefamily.Inaddition,linkageanalysisdependsonthe
availabilityandwillingnessoffamilymemberstobetestedandonthepresenceofinformativepolymorphic
markers.
8. ExactfrequencyisunknownbecauseofthesmallnumberofindividualswithMHSattributedtomutationof
thisgene.
9. Exonssequencedmayvarybylaboratory.
Interpretationoftestresults
FailuretodetectapathogenicvariantonmoleculargenetictestingdoesnotruleoutMH
susceptibility.
Discordancebetweenthecontracturetestandmoleculargenetictestresultsisobservedinup
to10%ofindividuals.
Testcharacteristics.SeeClinicalUtilityGeneCard[Rosenberg&Rueffert2011]forinformation
ontestcharacteristicsincludingsensitivityandspecificity.
TestingStrategy
Indicationsformusclebiopsyandcontracturetestingtoconfirmthediagnosisinaproband
(see*Note)
Definiteindications
ProbandwithaclinicalhistoryofMH
FirstdegreerelativeofaprobandwithaclinicalhistoryofMH,iftheprobandcannotbe
tested(e.g.,tooyoung,tooold,MHdeath,notwillingtoundergothemusclebiopsy,notest
centeravailable)
AtriskfamilymemberswhentheMHcausingvariantisnotknown
SeveremassetermusclerigidityalongwithgeneralizedrigidityduringanesthesiawithMH
triggeringagents
Limitedmassetermusclerigidityalongwithrhabdomyolysisand/orelevatedplasmaCK
level(hyperCKemia)
Militaryservice.ThemilitaryrequiresdeterminationofMHsusceptibilitybycontracture
testinginpersonswithasuspicionofMHSbecauseindividualswithMHSarenoteligible
formilitaryservice.
Possibleindications.DebateexistsastootherindicationsfordiagnosticMHmusclebiopsy.Some
expertsbelievethatindividualswhoexperienceanyoneofthefollowingshouldundergobiopsy,
followingcarefuldiscussionoftheprosandconsofthetest:
Isolatedmassetermusclerigiditywithsuccinylcholine
PostoperativerhabdomyolysisandmarkedelevationofserumCKconcentrationwithout
othersignsofclassicMH
Exerciserelatedrhabdomyolysisintheabsenceofaknownmyopathy
SignssuggestiveofbutnotdefinitiveforMH
Notrecommended
Weightlessthanabout20kgorageyoungerthanfiveyears
Diagnosisofneurolepticmalignantsyndromeorserotoninsyndrome
*Note:(1)Becausethetestisavailableonalimitedbasis,somephysiciansconsiderallindividuals
withahistorysuspiciousforMHasMHsusceptibleandavoidanestheticagentsknowntotrigger
MH.Althoughthisstrategyisuseful,itdoesnotprovideguidanceandspecificanswerstofamily
membersandlimitstheanestheticoptionsfortheindividualandhis/herfamily.(2)Details
regardingMHmusclebiopsycenterscanbeobtainedfromtheMalignantHyperthermia
AssociationoftheUSWebsite(www.mhaus.org).
Indicationsformoleculargenetictesting(see**Note)
ConfirmedclinicalepisodeofMH
Positivehalothane/caffeinecontracturetest
HighlikelihoodofhavingexperiencedaMHepisode,asdeterminedbybiopsy
center/hotlineconsultants,and/orlikelyMHbasedontheClinicalGradingScale(seeTable
1)
RelativewithapositivecontracturetestoraknownMHcausingvariant
UnexplaineddeathwithsignsofMHduringorimmediatelyafteranesthesia
Exerciserelatedrhabdomyolysisintheabsenceofaknownmyopathy
**Note:RecommendationspertaintoNorthAmerica.TheEuropeanMHgroupdoesnotperform
moleculargenetictestingunlessanindividualorhis/herrelativehashadapositivecontracturetest.
Predictivetestingforatriskasymptomaticadultfamilymembersrequiresprioridentificationof
thepathogenicvariantinthefamily.
ClinicalCharacteristics
ClinicalDescription
Malignanthyperthermiasusceptibility.ThemanifestationsofMHresultfromexposureto
certainvolatileanestheticagents(i.e.,halothane,isoflurane,sevoflurane,desflurane,andenflurane)
thatactastriggerseitheraloneorinconjunctionwithsuccinylcholine,adepolarizingmuscle
relaxant.Atfirst,MHwasthought,inallcases,toconsistofanextremelyelevatedbody
temperature,skeletalmusclerigidity,andacidosisassociatedwithahighmortalityrate.However,it
isnowrecognizedthatMHisaninheritedpharmacogeneticdisorderofcalciumregulation
resultinginuncontrolledskeletalmusclehypermetabolism[Hopkins2000]withvaried
presentations,dependingonthetriggeringagentsandenvironmentalfactors,suchasmetabolic
stateandbodytemperature,atthebeginningofanesthesia.
Thetriggeringsubstancesreleasecalciumstoresfromthesarcoplasmicreticulumviathemuscle
ryanodinereceptor,thecalciumreleasechannelleadingtoanincreaseintheconcentrationoffree
myoplasmiccalcium.Thereisalsoevidencethatstoreoperatedcalcium(calciumcontainedinthe
extracellularfluid)entryalsoplaysaroleinthepathophysiologyofMH[Dukeetal2010].
Increasedmyoplasmiccalciumcausescontractureofskeletalmusclesandactivatesglycogenolysis
andcellmetabolism,resultinginproductionofheatandexcesslactate.Activationoftheoxidative
cycleleadstohighoxygenconsumptionandhighcarbondioxide.
Theclinicalmanifestationsaresomewhatvariabledependingontheclinician'sresponse.
Hypercapniaiscommon,asistachycardia.HyperthermiafollowsandmaybeanearlysignofMH.
However,failuretomonitorcoretemperaturemayleadtoadelayindetectinghyperthermia.Skin
temperatureisoftenmisleadinginMHcrises[Larachetal2010].Acidosismaybemildifthe
syndromeisrecognizedandtreatedpromptly.HyperCKemiaandrhabdomyolysisaremore
commonwhensuccinylcholinehasbeenusedbutmaybemildornotappearatallinsomecases,
forreasonsthatarenotclear.Insomecasesrhabdomyolysisdoesnotappearforseveralhours.
Hyperkalemia,leadingtocardiacarrhythmiaandevenarrest,isuncommonifthesyndromeis
detectedandtreatedpromptlybutmaydevelopwithremarkablerapidity.
Insurvivors,normalizationofedematousmuscleandserumCKconcentrationoccurswithintento
15days,butsymptomresolutionmaytakelonger(Figure1)[JurkatRottetal2000].
Figure1.
ClinicalfeaturesofmalignanthyperthermiasusceptibilityNote:
Earlydiagnosisandrapidtherapyarebothlifesavingandlead
toareductionoftheclinicalsymptoms.AdaptedfromJurkat
Rottetal[2000]
MHmayappearatanypointduringanesthetizationorwithinanhourorsooftheterminationof
anesthesia.Ifsuccinylcholineisusedduringinductionofanesthesia,anaccelerationofthe
manifestationsofMHmayoccurtachycardia,elevationofendtidalcarbondioxidelevels,
hypertension,markedtemperatureelevation,andarrhythmiasareseenoverthecourseoffivetoten
minutes.However,acompletelynormalresponsetosuccinylcholinemaybepresentinsome
individualssusceptibletoMHintheseindividuals,apotentinhalationagentisapparently
necessarytotriggerthesyndrome.
Inalmostallcases,thefirstmanifestationsofMHoccurintheoperatingroom.Inclassicmalignant
hyperthermia,theinitialsignsaretachycardia,rapidlyrisingendtidalC02,andtachypnea.
Tachypneaisusuallynotrecognizedbecausemostindividualsreceivinggeneralanesthesiaare
paralyzed.Shortlyaftertheheartrateincreases,thebloodpressuremayincrease,oftenassociated
withventriculararrhythmiasinducedbysympatheticnervoussystemstimulationfromhypercarbia,
hyperkalemia,andcatecholaminerelease.Thereafter,musclerigidityorincreasedmuscletonemay
becomeapparentandbodytemperatureincreasesatarateof12Ceveryfiveminutes.
Atthesametime,theCO2absorbentusedingeneralanesthesiabecomesactivatedandwarmtothe
touchfromtheexothermicreactionwiththeCO2exhaledbytheaffectedindividual.The
individualmaydisplayperipheralmottlingand,onoccasion,sweatingandrarelycyanosis.Blood
gasanalysisusuallyrevealshypercarbia(PCO2>60mmHg)andrespiratoryandmetabolicacidosis
withoutoxygendesaturation.ElevationofendtidalCO2greaterthan55mmHgisoneofthe
earliestsignsofMHhowever,vigorousmechanicalhyperventilationmaypreventhypercarbiaand
delaythediagnosis[Karanetal1994].Amixedvenousbloodsampleshowsevenmoreevidence
ofCO2retentionandmetabolicacidosis.Hyperkalemia,hypercalcemia,lactacidemia,and
myoglobinuriaarecharacteristicbutarenotpresentineverycase.IncreaseinserumCK
concentrationoftenexceeds20,000units/Linthefirst1224hours.
Deathresultsunlesstheindividualispromptlytreated(seeManagement).Evenwithtreatmentand
survival,theindividualisatriskforlifethreateningmyoglobinuricrenalfailure,disseminated
intravascularcoagulation(DIC),compartmentsyndrome,andrecrudescenceofthesyndrome
withinthefirst2436hoursfollowingtheepisode[Fortunatoetal2000].AstudyofMHusinga
NorthAmericanMHregistrycontaininginformationaboutaffectedindividualsreportedbetween
1987and2006showedthatnonfatalcomplicationsoccurredin35%oftheseindividuals.Twelve
ofthesecomplicationsincludedcardiac,renal,orhepaticdysfunctioncomaorchangein
consciousnesslevelpulmonaryedemaandDIC[Larachetal2010].
Earlydiagnosisandrapidtherapyarelifesavingandalsoleadtoareductionofclinicalsymptoms.
Itshouldbenotedthatmodernanestheticcareandmonitoringoftenallowearlydetectionof
malignanthyperthermia.Treatmentwithdantroleneresultsinmuchlowermorbidityandmortality
thanfirstreportedwhenMHwasrecognizedinthe1960s[Larachetal2008]butthemortality
maybeashighas11%[Roseroetal2009].Thelikelihoodofanycomplicationincreased2.9times
per2Cincreaseinmaximumtemperatureand1.6timesper30minutedelayindantrolene
administration[Larachetal2010].Themostfrequentcomplicationsassociatedwithdantrolene
administrationaremuscleweakness(14.6%),phlebitis(9.2%),andgastrointestinalupset(4.3%).
Thereisa25%increaseintheriskforanyoftheabovecomplicationswhenthetotaldoseof
dantroleneasrequiredbyclinicalindicationsistwicetherecommendedinitialtreatmentdoseof2.5
mg/kg[Brandometal2011].
ThepresentationofMHoutsideahospitalsettingmayposespecialproblems.Severaldeathsfrom
MHhaveoccurredwhentheepisodebeganinanambulatorysurgerysetting.Probablecauses
includeinadequatepreparationfortreatingMH,insufficientpersonnel,and/orproblemsin
stabilizinganaffectedindividualpriortotransfertoahospital.Itissuggestedthatallfacilitieshave
aplantodealwithMHandholdpracticedrillsatregularintervals(seeLarachetal[2012]for
transferofcareprotocols).
Malignanthyperthermiamayalsooccurintheearlypostoperativeperiod,usuallywithinthefirst
hourofrecoveryfromanesthesia.Characteristictachycardia,tachypnea,hypertension,and
arrhythmiaspresageanepisodeofMH.Isolatedmyoglobinuriawithoutanobviousincreasein
metabolisminthepostoperativeperiod(24hours)shouldalerttheanesthesiologisttothe
possibilityofMH.
Ofnote,anMHepisodemaynotoccurwitheveryexposureto"trigger"agents.Clinical
manifestationmaydependongeneticpredisposition,doseoftriggeragents,ordurationof
exposure.
SignsofMHhavealsobeenreportedwithoutexposuretoanestheticagents(seeDifferential
Diagnosis).InsomecasessignsfollowoverdoseofMDMAagonistsinothercasesMHmaybe
associatedwithheatandexercise.
Malignanthyperthermiasusceptibility(MHS)phenotypes.Severaldistinctclinical
presentationspredisposetoclassicMH:
Centralcorediseaseandmultiminicorediseasearemyopathiescausedbymutationof
RYR1(seeGeneticallyRelatedDisorders).
KingorKingDenboroughsyndromeischaracterizedby:distinctivefacies,ptosis,
downslantedpalpebralfissures,widelyspacedeyes,epicanthalfolds,lowsetears,malar
hypoplasia,micrognathia,higharchedpalate,clinodactyly,singlepalmarcrease,pectus
excavatum,wingingofthescapulae,lumbarlordosis,andmildthoracicscoliosis.Individuals
presentwithhypotoniaatbirth,slightlydelayedmotordevelopment,diffusejoint
hyperextensibility,andmildproximalmuscleweakness.Musclebiopsyrevealsminimalbut
identifiablechangesrepresentedbyfibersizevariability,typeIfiberpredominanceand
atrophy,perimysialfibrousinfiltration,andsomedisarrayoftheintermyofibrillarynetwork.
PathogenicvariantsinRYR1havebeenfoundinsomeindividualswithKingDenborough
syndrome[DArcyetal2008,Dowlingetal2011].
Massetermusclerigidity(MMR),orrigidityofthejawmusclesafteradministrationof
succinylcholine,presagesclinicalMHinupto30%ofcases.Evenintheabsenceofclinical
MH,myoglobinuriainindividualswithMMRiscommonpostoperatively.MMRprobably
occursinindividualsofallagesregardlessofMHSstatushowever,MMRismorecommon
inchildren,particularlyfollowinggasanesthesiainduction.
GenotypePhenotypeCorrelations
Alimitednumberofstudieshaveaddressedgenotypephenotypecorrelations.SeeRobinsonetal
[2002],Robinsonetal[2003],Carpenteretal[2009b].
GenotypephenotypecorrelationsinMHSaredifficulttostudy.Nocorrelationbetweengenotype
andclinicalphenotypeisapparentbecauseCHCT/IVCTtestresultsarevariableamongdiagnostic
laboratories,andclinicalepisodesofMHSthatfulfillallcriteriaarerarebecauseofsuccessful
interventionduringanestheticcomplications.
ArecentstudydemonstratedthattheRYR1pathogenicvariantsp.Arg163Cys,p.Arg2163His,
p.Arg2435His,andp.Thr4826IlewereassociatedwithhigherCKconcentrationsthanthe
pathogenicvariantp.Gly2434Arg.Strongercontracturesandshorterresponsetimesintheresponse
tocaffeinewerealsofeaturesofthesepathogenicvariants[Carpenteretal2009b].
Correlationsexistbetweengenotypeandhalothanecaffeineinducedcontractureresponse:
Analysisof15RYR1pathogenicvariantsshowedastrongcorrelation(r=0.95,p<0.001)
betweenthecaffeinesensitivityofdifferentRYR1mutantsandtheclinicalIVCT[Tongetal
1997].Agoodcorrelationwasalsoobservedbetweenthecaffeinethresholdandtension
valuesobservedfor11differentRYR1pathogenicvariants[Manningetal1998b].
FunctionalassaysofdifferentmutantRYR1proteinsexpressedinskeletalmusclemyotubes
derivedfromRyr1knockoutmiceshowedincreasedrestingmyoplasmiccalciumlevelsand
increasedsensitivityofchannelstoactivationbycaffeineandsubsequentdepolarization
[Yangetal2003,Dirksen&Avila2004,Yangetal2007].
TheRYR1pathogenicvariantsassociatedwithbothMHandCCD(p.Arg163Cys,
p.Arg2163His,andp.Arg2435His)exhibitmoreseverecaffeineandhalothaneresponses
thanthoseassociatedwithMHalone[Robinsonetal2002].
CHCT/IVCTresultsarestrongerinmalesthanfemalesandarealsoaffectedbymusclesize
andviability.
IndividualswiththeRYR1pathogenicvariantsp.Gly341Arg,p.Arg614Cys,and
p.Gly2434Argshowweakercontractionresults.Discordanceingenotypephenotype
correlationismorecommonamongthesepathogenicvariants[Robinsonetal2003].
SwissindividualswithMHSshowedstrongerIVCTresultsforRYR1variantsp.Arg614Cys
andp.Val2168Metthanforthevariantsp.Gly2434Argandp.Arg2458Cys[Girardetal
2001].
AsingleaminoaciddeletioninRYR1,p.Glu2348del,wasassociatedwithunusuallyhigh
contractiontensionintwounrelatedfamilieswithMHS[Sambuughinetal2001a].
Penetrance
ThepenetranceofMHsusceptibilityisunknown.Whatisknownisthatupto50%ofindividuals
withMHsusceptibilityhaveundergoneanesthesiauneventfullydespiteuseofoneoftheagents
knowntotriggerMH.
Anticipation
Anticipationisnotobserved.
Prevalence
TheincidenceofMHisbestdescribedbythereportedincidenceperanesthetic.Currently,the
estimatesoftheincidencerangefromonein3,000anestheticstoonein50,000anesthetics,with
mostestimatinganincidenceinchildrenofaboutonein10,000anestheticsandinadultsofonein
50,000anesthetics.TheprevalenceofMHinindividualsundergoingsurgeryinNewYorkstate
hospitalswasestimatedas1:100,000foradults[Bradyetal2009]and3:100,000inchildren[Liet
al2011].Becausemanyindividualsundergoingsurgerywhoexperiencemarkedhyperthermiamay
becodedasbeingMHsusceptible,theexactincidenceandprevalencehasbeendifficulttoclarify.
Itseemscertainthattherearemorethan1,000casesofMHintheUSeachyear[Brandom&
Muldoon2004].
Theincidencevariesdependingontheroutineuseoftriggeranesthetics,aswellastheprevalence
ofsusceptibilityvariantsinthepopulationMonnieretal[2002]estimatetheprevalenceofoneof
thecausativevariantsat1:2,000to1:3,000individualsintheFrenchpopulation.Ibarraetal[2006]
reportsimilarnumbersfortheJapanesepopulation.
GeneticallyRelated(Allelic)Disorders
RYR1.Severaldistinctcongenitalmyopathies,characterizedbyhypotoniaandslowlyprogressive
ornonprogressivemuscleweakness,areassociatedwithpathogenicvariantsinRYR1.Someare
inheritedinanautosomaldominantmanner,othersinanautosomalrecessivemanner[Kleinetal
2012].Thesemyopathiesincludecentralcoredisease(CCD),multiminicoredisease(MmD),
congenitalfibertypedisproportion,centronuclearmyopathy(CNM),KingDenboroughSyndrome
(KDS),andnemalinemyopathy(NM)[Robinsonetal2006,DArcyetal2008,Clarkeetal2010,
Wilmshurstetal2010,Dowlingetal2011,Kleinetal2012,Kondoetal2012].Pathogenic
variantsinRYR1havealsobeenlinkedtoexertional/environmentalheatstroke(EHS)[Hopkinset
al1991,Tobinetal2001,Capacchione&Muldoon2009,Nishioetal2009,Groometal2011]
andexerciseinducedrhabdomyolysis[Wappleretal2001,Davisetal2002].However,CCDand
MmDarethemostcommonlyassociateddisorderswithdominantandrecessivepathogenic
variantsinRYR1,respectively.
Centralcoredisease(CCD)ischaracterizedbymuscleweaknessrangingfrommildto
severe.Mostaffectedindividualshavemilddiseasewithsymmetricproximalmuscle
weaknessandvariableinvolvementoffacialandneckmuscles.Motordevelopmentis
usuallydelayed,butmostaffectedindividualsacquireindependentambulation.Lifespanis
usuallynormal.Severediseaseisearlyinonsetwithprofoundhypotoniaoftenaccompanied
bypoorfetalmovement,spinaldeformities,hipdislocation,jointcontractures,poorsuck,
andrespiratoryinsufficiencyrequiringassistedventilation.Theoutcomerangesfromdeath
ininfancytosurvivalbeyondagefiveyears.
ThediagnosisofCCDisbasedonclinicalfindingsofmuscleweakness,thehistopathologic
findingsofcharacteristiccoresonmusclebiopsy,andmoleculargenetictesting.About90%
ofCCDcasesareassociatedwithmutationofRYR1[Wuetal2006].
CCDisgenerallyinheritedinanautosomaldominantmanner,althoughfamilieswith
autosomalrecessiveinheritanceandmanysimplexcases(i.e.,asingleoccurrenceina
family)havebeenincreasinglyreported[McCarthyetal2000,Jungbluth2007,Zhouetal
2007,Monnieretal2008,Kleinetal2012].
Morethan100RYR1pathogenicvariantshavebeenassociatedwiththeautosomaldominant
orautosomalrecessiveformsofCCD,includingsmalldeletions,insertions,andsplicesite
variants.ThemajorityofallelicvariantsassociatedwithCCDaremissensevariantsclustered
intheCterminaldomainoftheprotein,whichcomprisesthetransmembrane/luminaland
poreformingregionofthechannel.
IndividualswithCCDareatincreasedriskforMHS.
Multiminicoredisease(MmD)isbroadlyclassifiedintofourgroups:classicform,moderate
formwithhandinvolvement,antenatalformwitharthrogryposismultiplexcongenita
(AMC),andophthalmoplegicform.About75%ofaffectedindividualshaveclassicMmD
characterizedbyneonatalhypotonia,delayedmotordevelopment,andaxialmuscle
weakness,whichleadstodevelopmentofscoliosisandsignificantrespiratoryinvolvement.
Varyingseverityofspinalrigidityispresent.Fewerthan10%ofindividualshaveeachofthe
otherthreeforms.
ThediagnosisofMmDisbasedonthepresenceofmultiple"minicores"visibleonmuscle
biopsyoxidativestains.Minicoresaresmallzonesofsarcomericdisorganizationand/or
diminishedoxidativeactivitythatcorrelatewithlackofmitochondriainmusclefibers.
BecauseminicoresarenotspecifictoMmD,thediagnosisofMmDisbasedonthepresence
ofminicoresinalargeproportionofmusclefibersassociatedwithstaticorslowly
progressiveweaknessandabsenceoffindingsdiagnosticofotherdisorders.
MmDisinheritedinanautosomalrecessivemanner.Pathogenicvariantsintwogenes,
SELENON(SEPN1)andRYR1,accountforabouthalfthecasesofMmD.ClassicMmD
withophthalmoplegiaandotherclinicalsubgroupshavebeenassociatedwithhomozygous
andcompoundheterozygouspathogenicvariantsinRYR1[Jungbluth2007,Monnieretal
2008,Jungbluthetal2011].
IndividualswithMmDmaybeatincreasedriskforMH,althoughtheevidenceissparseand
thereisnoconsensusastotherisk.
CACNA1S.PathogenicvariantsareidentifiedinCACNA1Sin70%ofindividualsmeetingclinical
diagnosticcriteriaforhypokalemicperiodicparalysis(HypoPP).TwodifferentformsofHypoPP
arerecognized:theparalyticform(75%ofindividuals)andthemyopathicformwithaslowly
progressivefixedmyopathy(25%ofindividuals).Theparalyticformischaracterizedbyattacksof
reversibleflaccidparalysiswithconcomitanthypokalemia,whichusuallyleadstoparaparesisor
tetraparesisbutsparestherespiratorymusclesandheart.Triggeringfactorsconsistmainlyof
carbohydraterichmealsandrestafterexercise.ThemyopathicformofHypoPPresultsina
progressivefixedmuscleweaknessthatbeginsasexerciseintolerancepredominantlyinthelower
limbsatextremelyvariableages.Itoccursindependentofparalysisandmaybethesole
manifestationofthedisease.
Thediagnosisofhypokalemicperiodicparalysisrestsonahistoryofepisodesofflaccidparalysis,
lowserumconcentrationofpotassium(<3.5mmol/L)duringattacks,theabsenceofmyotonia
clinicallyandonelectromyography(EMG),andafamilyhistoryconsistentwithautosomal
dominantinheritance.
Hypokalemicperiodicparalysisisinheritedinanautosomaldominantmanner.
ThetworeportssuggestingarelationshipbetweenHypoPPandmalignanthyperthermiaarenot
widelyacceptedbecausebothlackadequatedatatosupporttheassociation[Marchantetal2004,
Parnessetal2009].
DifferentialDiagnosis
Malignanthyperthermia.Thecombinationofhypercarbia,musclerigidity,tachycardia,
hyperthermia,metabolicacidosis,andrhabdomyolysisduringorshortlyafteranesthesiais
distinctiveforMH.SomesyndromessharesomeelementsofMH:
Sepsissharestheconstellationofhyperthermia,hypercarbia,andacidosis.However,rigidity
isuncommon,asismarkedelevationofserumCKconcentration.Leukocytosis,whichis
typicallypresentwithsepsis,isuncommoninMH.
Overheatingfromaggressiveheatingmeasuresutilizedduringanesthesia,(especiallyin
thepediatricpopulation)causeshyperthermia,tachycardia,andsometimesacidosis.
Pheochromocytomacrisismarkedbyhypertension,tachycardia,andsometimesfeverhas
beenmistakenforMH,particularlyinthepostoperativeperiod.Ifbetablockadeisusedto
treatthetachycardia,heartfailuremayresultfromunopposedalphaactivity.
Ischemicencephalopathyismanifestbyfailuretoawakenfromanesthesia,musclerigidity
sometimesprogressingtoopisthotonus,hyperthermia,andtachycardia.Seizuresarecommon
inthisconditionbutnotinMH.
Ascendingtonicclonicsyndromefollowsintrathecalinjectionofawatersoluble,high
ionicradiologiccontrastagent.Whentheagentascendsintothecerebralventricles,the
individualdisplaysascendingtonicclonicactivityleadingtofrankseizures,rigidity
accompaniedbyfever,andacidosisifrespirationiscompromised.
Thyrotoxicosisismarkedbyhyperthermia,hypercarbia,andtachycardiabutnotmuscle
rigidity.
Neurolepticmalignantsyndrome(NMS)hasallthefeaturesofMH,including:muscle
rigidity,rhabdomyolysis,acidosis,andfever,butismanifestafteradministrationof
neurolepticagentssuchasatypicalantipsychotics,haloperidol,anddrugsusedinthe
treatmentofschizophrenia.Postmortemhighresolutionmeltingfollowedbysequencingof
selectedexonsofRYR1in11individualswhodiedofNMSrevealedtwopathogenic
variant,oneofwhichhaspreviouslybeenreportedinindividualswithMH[Satoetal2010].
Serotoninsyndrome,whichisararereactionfromserotoninuptakeinhibitordrugs,
displayssimilarsigns.Thesesyndromesoccurinthenonanesthetizedindividual.
Dystrophinopathy(DuchenneorBeckermusculardystrophy).Affectedindividualsareat
increasedriskforrhabdomyolysisandlifethreateninghyperkalemiawithcardiacarrest
followingadministrationofsuccinylcholineorpotentvolatileanesthetics.Althoughthese
adverseeventswerefirstbelievedtorepresentaformofMH,itnowappearsthatthe
pathophysiologyofthehyperkalemicepisodesdiffersfromthatofMHinmanyrespects,
althoughelevationofintracellularcalciumconcentrationisprobablycommontoboth
syndromes[Hayesetal2008,Betzenhauser&Marks2010].
Myotonicsyndromes(myotonicdystrophytype1,myotonicdystrophytype2,myotonia
congenita)canbeassociatedwithmusclerigiditymimickingMHaftersuccinylcholine
administration.
Rhabdomyolysis
Succinylcholinemaycauserhabdomyolysisthatisnotobviousoncursoryphysical
examinationinindividualswhohaveanyofthemyotonicsyndromesordystrophinopathy.
Rhabdomyolysismayoccurintheperioperativeperiodinsomeindividualstakinginhibitors
ofcholesterolformation[Turanetal2011].
Environmental/exertionalheatstress(EHS).Recentclinical,genetic,andlaboratorystudies
usinganimalmodelsprovideevidenceforarelationshipbetweenenvironmentalorexertionalheat
stress(EHS)andMHsusceptibility[Cheluetal2006,Yangetal2006,Durhametal2008,Lanner
etal2012].Someindividualswhohaveexperiencedexertionalheatillnesshavebeenfoundtobe
MHsusceptiblebasedoncontracturetesting[Capacchione&Muldoon2009].Inonestudy,one
thirdofyoungmilitaryrecruitswhoexperiencedexerciseinducedheatillnesshadanabnormal
contractureresponse.
EvidenceofarelationbetweenEHSandMHSispresentedbyTobinetal[2001]inthecasereport
ofa12yearoldboywhodiedfromanMHlikeeventfollowingparticipationinafootballgame.
TheboyhadrecoveredfromapreviousclinicalMHepisodeduringgeneralanesthesiawith
sevofluranesequenceanalysisrevealedthatboththeboyandhisfatherhadacommonRYR1
pathogenicvariant(p.Arg163Cys).Amorerecentstudyfoundthattwounrelatedchildrenwho
experiencedfatalnonanestheticawakeepisodestriggeredbyeitheraviralprodromeorexposure
toenvironmentalheatstresspossessedanidenticalRYR1variant(p.Arg3983Cys),whileoneofthe
childrenalsohadasecondvariant(p.Asp4505His)[Groometal2011].
Inastudyof12youngmenwithexerciseinducedrhabdomyolysis(ER),tenweredeterminedto
beMHsusceptibleoncontracturetestingandthreehadknownMHSRYR1pathogenicvariants
[Wappleretal2001].Inaddition,thetwoRYR1pathogenicvariantsp.Arg401Cysand
p.Arg614CysareassociatedwithMHS,EHS,andexerciseinducedrhabdomyolysis[Davisetal
2002].
RYR1variantshavealsobeenfoundtounderlieERinAfricanAmericanmen[Sambuughinetal
2009].ThisstudyidentifiedthreenovelRYR1variants:p.Ala933Thr,p.Gly2160Ser,and
p.Thr4294Met,andtwopreviouslyMHassociatedvariants(p.Ala1352Glyanda9bpinsertionin
exon91)inindividualswithER.
RYR1andothermyopathies.UnderlyinggeneticchangesinRYR1maypredisposetoother
musculoskeletaldisorders.ArecentstudyidentifiedalargenumberofnovelRYR1allelicvariants
causingcongenitalmyopathieswithdominantorrecessiveinheritance[Kleinetal2012].Another
studybyLietal[2011]demonstratedanassociationbetweenMHandothermyopathies,especially
musculardystrophies.Vladutiuetal[2011]revealedthatvariantsinRYR1maycontributetothe
underlyinggeneticriskfornonanesthesiainducedmyopathies,suchasstatininducedmyopathy.
Management
EvaluationsFollowingInitialDiagnosis
Toestablishtheextentofdiseaseinanindividualdiagnosedwithmalignanthyperthermia
susceptibility(MHS),thefollowingevaluationsarerecommended:
Arterialbloodgasanalysisserumconcentrationofelectrolytes,lactate,andCKcoagulation
studiespresenceofmyoglobinintheurineandelevatedmyoglobinlevelsinserum.
Continuouscoretemperaturemonitoringuntilthesyndromehasresolved
MeasurementofserumCKconcentrationsuntilnormalized
Familyhistoryofanestheticcomplications
Oncethesyndromehasresolved,neurologicassessmentforevidenceofmuscledamage
Clinicalgeneticsconsultation
TreatmentofManifestations
Formanagementguidelines,seeGuidelines/ConsensusStatementsandFigure2.
Figure2.
MHAUStreatmentguideformalignanthyperthermia
Copyright,TheMalignantHyperthermiaAssociationofthe
UnitedStates(MHAUS)
EarlydiagnosisofMH,togetherwiththeadministrationofdantrolenesodium,isessentialinthe
successfultreatmentofanacuteepisodeofMH:
Discontinueuseofpotentinhalationagentsandsuccinylcholine.
IncreaseminuteventilationtolowerendtidalCO2.
Gethelp.OneresourceistheMalignantHyperthermiaAssociationoftheUS(MHAUS)
hotlineforacutecases:800MHHYPER(8006449737).Similarhotlinesexistinother
countries,specificallytheUK,Germany,andBrazil.
Prepareandadministerdantrolene:2.5mg/kginitialdose.Tachycardia,hypercarbia,and
musclerigidityrespondrapidlymultipledosesofdantrolenemaybeneeded.Thesuggested
upperlimitis10mg/kghowever,moremaybegivenasneeded.Continuedantroleneat1.0
mg/kgeveryfourtoeighthoursfor2448hours,titratingtothedesiredeffect(resolutionof
hyperthermia,acidosis,andmyoglobinemia).Dantrolenesodiumisahydantoinmolecule
thatbindstoaspecificregionoftheRYR1channel.Itdecreasestheuncontrolledreleaseof
intracellularcalcium[PaulPletzeretal2002].Thetoxicityprofileofdantrolene,when
administeredacutely,isextremelybenign.Calciumchannelblockingagentsshouldnotbe
administeredwithdantrolenebecauselifethreateninghyperkalemiamayresult.Dantrolene
mayaggravatepreviouslyexistingmuscleweakness.
Begincoolingmeasures.Ifpatientishyperthermic,administericedsolutions,icepacksto
groin,axilla,andneck,nasogastriclavagewithicedsolution,ormoreaggressivemeasures
asneeded.Stopcoolingmeasuresatcorebodytemperatureof38.5C.
Treatcardiacarrhythmiasasneeded.Donotusecalciumchannelblockers.
Obtainbloodgases,serumconcentrationofelectrolytesandCK,bloodandurinefor
myoglobin,andcoagulationprofile.Checkvalueseverysixto12hours.Theearliestsignof
rhabdomyolysisismyoglobinuria/myoglobinemia.SerumCKlevelsmaynotriseforseveral
hours.SerumCKconcentrationmayremainelevatedfordaysandshouldbemonitoreduntil
itreturnstonormal.
Treathyperkalemiawithhyperventilation,glucoseandinsulin,andcalciumasdictatedby
laboratoryandcardiovascularchanges.
Ensureurineoutputof2.0mL/kg/hrwithmannitol,furosemide,andfluidsasneeded.
Evaluateneedforinvasivemonitoringandcontinuedmechanicalventilation.
ObservetheindividualinanICUforatleast36hoursbecauseofthe25%chanceof
recrudescencefollowinginitialtreatment.Dantroleneshouldbecontinuedforatleast36
hoursfollowingsuccessfultreatmentinadoseofabout1.0mg/kgeverysixhoursormore
dependingonwhethersignsofMHarepresent.
Affectedindividualswhodisplayextremehyperthermiaareatriskfordisseminated
intravascularcoagulation.Acoagulationprofileshouldbeobtainedonallindividuals
experiencingfulminantMH.
RefertheaffectedindividualtotheMalignantHyperthermiaAssociationoftheUS
(MHAUS)forinformationandcounseling.CompletetheAdverseMetabolicReactionto
Anesthesia(AMRA)formforenrollmentintheNorthAmericanMHRegistry.
RefertheindividualtoaMHdiagnosticcenterformusclebiopsyandcontracturetesting
afterdiscussionwithMHconsultantsassociatedwithMHAUS.
Myoglobinuria.Thepresenceofmyoglobinuriamandatesreferraltoaneurologistforfurther
investigation.
PreventionofPrimaryManifestations
PreventivemeasuresforindividualsknowntobesusceptibletoMHorforanyindividualwithan
equivocalcontracturetestresponse(MHE)(treatedclinicallyasMHS):
Foranyindividualundergoinganesthesia,obtainathoroughanesthetichistorytodetermine
thepossibilityoftheindividualorafamilymemberhavingexperiencedanMHepisode.
WhensuspicionofMHSexists,familymembersshouldnotbegiventriggeranesthetic
agents,i.e.,potentvolatileanestheticagentssuchashalothane,sevoflurane,desflurane,
enflurane,andisofluraneorthedepolarizingagentsuccinylcholine.
Ingeneral,individualsundergoinggeneralanestheticsthatexceed30minutesinduration
shouldhavetheirtemperaturemonitoredusinganelectronictemperatureprobe.Skinliquid
crystaltemperaturesensorsarenotrecommendedastheyhavebeenfoundtobeunreliable
indicatorsofchangingtemperatureduringhumanmalignanthyperthermia(MH)events.
Individualswithanyformofmyotonia(seeDifferentialDiagnosis)shouldnotreceive
succinylcholine.
Individualswithcentralcoredisease,multiminicoredisease,nemalinemyopathy,congenital
fibertypedisproportion,orDuchenneorBeckermusculardystrophyshouldnotreceive
triggeranesthetics.
IndividualswithMHSshouldcarryproperidentificationastotheirsusceptibility
identificationbraceletsareavailablethroughtheMedicAlertFoundation,Turlock,
California(www.medicalert.org).
Agents/CircumstancestoAvoid
IndividualswhoareMHsusceptibleshouldavoidpotentinhalationanestheticsand
succinylcholine.
Calciumchannelblockersshouldnotbegiventogetherwithdantrolenebecauselifethreatening
hyperkalemiamayresult.
Serotoninantagonist(5HT3anatagonist)antiemeticsshouldbeusedcautiously,assuddendeath
hasbeenreportedinachildwithmultiminicorediseasecausedbyapathogenicvariantinRYR1
(p.Arg3983His)afterreceivingatherapeuticdoseofondansetron[Generetal2010].
IndividualswithMHaregenerallyadvisedtoavoidextremesofheatbutnottorestrictathletic
activityorlifestyleunlesstheyhaveexperiencedovertrhabdomyolysisorheatstroke.
InindividualswithMHundergoingcardiacbypasssurgery,aggressiverewarmingshouldbe
avoided,asitmaybeassociatedwithdevelopmentofclinicalsignsofMH[Metterleinetal2011b].
EvaluationofRelativesatRisk
Ifapathogenicvarianthasbeenidentifiedinthefamily,moleculargenetictestingofatrisk
relativesiswarrantedtoidentifythosewhoalsohavethepathogenicvariantandthuswillbenefit
fromavoidinganestheticagentsthatincreasetheriskforamalignanthyperthermiaepisode.
SeeGeneticCounselingforissuesrelatedtotestingofatriskrelativesforgeneticcounseling
purposes.
PregnancyManagement
IfapregnantwomanwithMHSrequiresnonemergentsurgeryduringthepregnancy,anon
triggeringanesthetic(local,nerveblock,epidural,spinalanesthesia,oratotalintravenousgeneral
anesthetic)shouldbeadministered.StandardAmericanSocietyofAnesthesiologistsmandated
monitoringshouldbeused,alongwithcoretemperaturemonitoring.Fetalmonitoringshould
followstandardguidelines.Dantroleneshouldnotbeadministeredinpreparationforsurgeryor
laboranddelivery.
Continuousepiduralanalgesiaishighlyrecommendedforlaboranddelivery.IfaCesarean
deliveryisindicatedinawomanwhodoesnothaveanepiduralcatheterinplace,neuraxial(spinal,
epidural,orcombinedspinalepidural)anesthesiaisrecommended,ifnototherwise
contraindicated.Ifageneralanestheticisindicated,atotalintravenousanesthetictechniqueshould
beadministered,withananesthesiamachinethathasbeenpreparedforanMHsusceptible
individual.
InthecaseofafetuswhosefatherisknowntobeMHsusceptiblebutwhosemotherisnotknown
tobeMHsusceptible,regionalanesthesiaorgeneralanesthesiawithouttriggeragentsis
recommended.
ForfurtherinformationregardingthemanagementofpregnantwomenwithMHS,see2009
guidelinesdevelopedbytheMalignantHyperthermiaAssociationoftheUnitedStates.
TherapiesUnderInvestigations
PreliminaryinvestigationbyLanneretal[2012]hasshownthat5aminoimidazole4carboxamide
ribonucleoside(AICAR)preventsheatinducedsuddendeathinaknockoutmousemodelofMH.
ThisfindingissuggestiveofpossibleeffectivenessofAICARintheprophylactictreatmentof
humanswithenhancedsusceptibilitytoexercise/heatinducedsuddendeathassociatedwith
mutationofRYR1.
SearchClinicalTrials.govforaccesstoinformationonclinicalstudiesforawiderangeofdiseases
andconditions.
GeneticCounseling
Geneticcounselingistheprocessofprovidingindividualsandfamilieswithinformationonthe
nature,inheritance,andimplicationsofgeneticdisorderstohelpthemmakeinformedmedicaland
personaldecisions.Thefollowingsectiondealswithgeneticriskassessmentandtheuseoffamily
historyandgenetictestingtoclarifygeneticstatusforfamilymembers.Thissectionisnotmeantto
addressallpersonal,cultural,orethicalissuesthatindividualsmayfaceortosubstitutefor
consultationwithageneticsprofessional.ED.
ModeofInheritance
Malignanthyperthermiasusceptibility(MHS)isinheritedinanautosomaldominantmanner.
RisktoFamilyMembers
Parentsofaproband
MostindividualsdiagnosedwithMHShaveaparentwithMHStheparentmaynothave
experiencedanepisodeofMH.
AprobandwithMHSmayhavethedisorderastheresultofadenovopathogenicvariant.
DenovopathogenicvariantshavebeendetectedtheproportionofindividualswithMHS
causedbydenovovariantsisunknown.
Recommendationsfortheevaluationofparentsofaprobandwithanapparentdenovo
pathogenicvariantincludecontracturetestingormoleculargenetictesting,ifavailableandif
thepathogenicvariantintheprobandhasbeenidentified.
Note:AlthoughmostindividualsdiagnosedwithMHShaveanaffectedparent,thefamilyhistory
mayappeartobenegativebecauseoffailuretorecognizethedisorderinfamilymembers,early
deathoftheparentbeforetheonsetofsymptoms,ordecreasedpenetranceoftheMHScausing
allele.
Sibsofaproband
Therisktothesibsoftheprobanddependsonthegeneticstatusoftheproband'sparents.
IfaparentoftheprobandhasMHS,therisktothesibsis50%.
Whentheparentsareclinicallyunaffectedbasedoncontracturetestingand/ormolecular
genetictesting,therisktothesibsofaprobandappearstobelow.
IfanMHScausingvariantcannotbedetectedinthegenomicDNAofeitherparent,two
possibleexplanationsaregermlinemosaicisminaparentoradenovopathogenicvariantin
theproband.Althoughnoinstancesofgermlinemosaicismhavebeenreported,itremainsa
possibility.
Offspringofaproband.EachchildofanindividualwithMHShasa50%chanceofinheriting
thepathogenicvariant.
Otherfamilymembersofaproband.Therisktootherfamilymembersdependsonthestatusof
theproband'sparents.Ifaparentisaffected,hisorherfamilymembersareatrisk.
Specificriskissues.RiskforMHispredominantlyaproblemundergeneralanesthesiawithtrigger
anesthetics.AverysmallnumberofindividualswithMHsusceptibilityappeartobeatriskforheat
strokeorexerciseinducedrhabdomyolysis.MHhasbeenreportedtooccurinindividualswithout
anestheticexposure[Tobinetal2001,Groometal2011].
RelatedGeneticCounselingIssues
SeeManagement,EvaluationofRelativesatRiskforinformationonevaluatingatriskrelativesfor
thepurposeofearlydiagnosisandtreatment.
Geneticheterogeneity.Evenifthesamepathogenicvariantisnotfoundinafamilymemberofan
individualwithacausativevariant,thefamilymembermaystillbeatriskforMH:inafew
families,afamilymemberhasbeenfoundtohaveavariantdifferentfromthatidentifiedinthe
proband[Monnieretal2003,Clarkeetal2010].
Considerationsinfamilieswithanapparentdenovopathogenicvariant.Whenneitherparent
ofaprobandwithanautosomaldominantconditionhasthepathogenicvariantorclinicalevidence
ofthedisorder,itislikelythattheprobandhasadenovopathogenicvariant.However,possible
nonmedicalexplanations,includingalternatepaternityormaternity(e.g.,withassisted
reproduction)orundisclosedadoptioncouldalsobeconsidered.
Familyplanning
Theoptimaltimefordeterminationofgeneticriskanddiscussionoftheavailabilityof
prenataltestingisbeforepregnancy.
Itisappropriatetooffergeneticcounseling(includingdiscussionofpotentialrisksto
offspringandreproductiveoptions)toyoungadultswhoareaffectedoratrisk.
DNAbankingisthestorageofDNA(typicallyextractedfromwhitebloodcells)forpossible
futureuse.Becauseitislikelythattestingmethodologyandourunderstandingofgenes,allelic
variants,anddiseaseswillimproveinthefuture,considerationshouldbegiventobankingDNAof
affectedindividuals.
PrenatalTestingandPreimplantationGeneticDiagnosis
Oncethepathogenicvarianthasbeenidentifiedinanaffectedfamilymember,prenataldiagnosis
forapregnancyatincreasedriskandpreimplantationgeneticdiagnosisarepossible.
Requestsforprenataltestingforpharmacogeneticconditionswhich(likeMHsusceptibility)have
effectivetreatmentandpreventionarenotcommon.Prenataltestingisgenerallynotoffered.
However,Girardetal[2006]reportedachilddiagnosedwithMHbasedonmoleculargenetic
testingoncordbloodobtainedatdelivery.
Resources
GeneReviewsstaffhasselectedthefollowingdiseasespecificand/orumbrellasupport
organizationsand/orregistriesforthebenefitofindividualswiththisdisorderandtheirfamilies.
GeneReviewsisnotresponsiblefortheinformationprovidedbyotherorganizations.For
informationonselectioncriteria,clickhere.
EuropeanMalignantHyperthermiaGroup(EMHG)
Dr.P.JaneHalsall,UniversityDepartmentofAnaesthesia,StJames'UniversityTrust
Hospital
BeckettStreet
ClinicalScienceBuilding
LeedsLS97TF
UnitedKingdom
Phone:+441132065274
Fax:+441132836972
Email:P.J.Halsall@leeds.ac.uk
www.emhg.org
MalignantHyperthermiaAssociationoftheUnitedStates(MHAUS)
11EastStateStreet
POBox1069
SherburneNY13460
Phone:8006449737(TollfreeEmergencyHotline)60767479013154647079
Fax:6076747910
Email:info@mhaus.org
www.mhaus.org
My46TraitProfile
Malignanthyperthermiasusceptibility
NorthAmericanMalignantHyperthermiaRegistry
TheNAMHRcollects,analyzes,anddisseminatesinformationonthepresentation,
diagnosis,treatment,andresponsetotreatmentofMHinaffectedindividuals.
Phone:8882747899(tollfree)
Email:bwb@pitt.edumcl2@pitt.eduadamskj2@upmc.edu
www.mhreg.org
MolecularGenetics
InformationintheMolecularGeneticsandOMIMtablesmaydifferfromthatelsewhereinthe
GeneReview:tablesmaycontainmorerecentinformation.ED.
TableA.
MalignantHyperthermiaSusceptibility:GenesandDatabases
Locus Gene Chromosome Protein LocusSpecific HGMD

Name Locus
MHS1 RYR1 19q13.2 Ryanodinereceptor LeidenMuscularDystrophy RYR1
1 pages(RYR1)
MHS2 Unknown 17q11.2q24 Unknown
MHS3 Unknown 7q21.2 Unknown
MHS4 Unknown 3q13.1 Unknown
MHS5 CACNA1S 1q32.1 Voltagedependent Calciumchannel,voltage CACNA1S
Ltypecalcium dependent,Ltype,alpha1S
channelsubunit subunit(CACNA1S)@
alpha1S LOVD
MHS6 Unknown 5p Unknown
Dataarecompiledfromthefollowingstandardreferences:genefromHGNCchromosomelocus,locusname,
criticalregion,complementationgroupfromOMIMproteinfromUniProt.Foradescriptionofdatabases
(LocusSpecific,HGMD)towhichlinksareprovided,clickhere.
TableB.
OMIMEntriesforMalignantHyperthermiaSusceptibility(ViewAllinOMIM)
114208 CALCIUMCHANNEL,VOLTAGEDEPENDENT,LTYPE,ALPHA1S
SUBUNITCACNA1S
145600 MALIGNANTHYPERTHERMIA,SUSCEPTIBILITYTO,1MHS1
154275 MALIGNANTHYPERTHERMIA,SUSCEPTIBILITYTO,2
180901 RYANODINERECEPTOR1RYR1
MolecularGeneticPathogenesis
ArelationshipbetweenMHandenvironmentalorexertionalheatstrokehasbeencorroborated
usinganimalmodelsofMH.IthaslongbeenknownthatpigswithMHSundergolethal
hypermetabolicepisodesfollowingprolongedelevationsinambienttemperature.Inaddition,heat
inducedMHreactionsintheabsenceoftriggeringanaestheticshavebeenreportedfor
heterozygousRYR1knockinmiceharboringeitherthep.Tyr522Ser[Cheluetal2006]or
p.Arg163Cys[Yangetal2006]MHScausingvariant.Themechanismforenhancedtemperature
sensitivityofthesemicewasshowntoresultfromSnitrosylationofRYR1increasingthe
temperaturesensitivityofthereleasechanneltoactivation,resultingininappropriatechannel
openingsandraisedintracellularcalciumlevels[Durhametal2008,Lanneretal2012].
TheMHS3locuswaslinkedtochromosome7q21q22.Atthislocus,thecandidategene
CACNA2D1,whichencodesasubunitoftheLtypevoltagedependentcalciumchannelthatis
intimatelyassociatedattheskeletalmuscletriadicjunctionswiththeryanodinereceptor,hadno
pathogenicvariantsinafamilylinkedtoMHS3[Schleithoffetal1999].LinkagetoMHS3wasnot
confirmedinstudiesofotherfamilieswithMHSandnoCACNA2D1pathogenicvarianthasyet
beenfoundinassociationwithMHS.
RYR1
Genestructure.RYR1consistsof106exons(twoofwhicharealternativelyspliced)
encompassingatotalof160kbandproducesoneofthelargestknownproteinswith5038amino
acids.Foradetailedsummaryofgeneandproteininformation,seeTableA,Gene.
Benignvariants.RYR1hasatleast16normalvariantsinthecodingregion[Gillardetal1992,
Brownetal2000].SeeTable4.
Pathogenicvariants.Morethan300pathogenicvariantsinRYR1havebeenassociatedwith
MHSand/orCCD.MostoftheRYR1pathogenicvariantsareprivate(i.e.,observedinonlyoneor
afewfamilies)thus,pathogenicvariantdetectionisamajorchallenge.AlmostallMHScausing
variantsaremissensevariantshowever,aninframedeletionofasingleaminoacid
(p.Glu2348del)inthecentralregionofRYR1[Sambuughinetal2005]andasinglenucleotide
deletionattheextremeCterminalendoftheprotein[Rossietal2007]havealsobeenreported.
SeeTable4andTable5(pdf).
Table4.
RYR1AllelicVariantsDiscussedinThisGeneReview
PredictedProtein
Variant DNANucleotide Reference
Change Reference
Classification Change Sequences
(Alias1)
Robinsonetal
c.2537C>T p.Ser846Leu
[2006]
Robinsonetal
c.4767A>C p.Gln1589Pro
[2006]
c.5360C>T p.Pro1787Leu Gillardetal[1992]
Benign c.6178G>T p.Gly2060Cys Gillardetal[1992]
Monnieretal
c.7648C>G p.Val2550Leu
[2000]
Robinsonetal
c.10747G>C p.Glu3583Gln
[2006]
c.11266C>G p.Gln3756Glu Brownetal[2000]
c.103T>C p.Cys35Arg Lynchetal[1997]
c.487C>T p.Arg163Cys Quaneetal[1993]
Monnieretal
c.488G>T p.Arg163Leu
[2005]
c.742G>A p.Gly248Arg Gillardetal[1992]
Sambuughinetal
c.2797G>A p.Ala933Thr
[2009]
c.1021G>Cor Quaneetal
p.Gly341Arg
c.1021G>A [1994b]
c.1201C>T p.Arg401Cys Davisetal[2002]
c.1209C>G p.Ile403Met Quaneetal[1993]
Quaneetal
c.1565A>C p.Tyr522Ser
[1994a]
Keatingetal
c.1654C>T p.Arg552Trp
[1997]
c.1840C>T p.Arg614Cys Gillardetal[1991]
c.1841G>T p.Arg614Leu Quaneetal[1997]
Sambuughinetal
c.4055C>G p.Ala1352Gly
[2009]
Sambuughinetal
c.6478G>A p.Gly2160Ser
[2009]
Manningetal
c.6488G>A p.Arg2163His
[1998b]
Manningetal NM_000540.2
c.6487C>T p.Arg2163Cys
[1998b] NP_000531.2
Manningetal
c.6502G>A p.Val2168Met
[1998b]
Manningetal
c.6617C>T p.Thr2206Met
[1998b]
Pathogenic
PredictedProtein
Variant DNANucleotide Reference
Change Reference
Classification Change Sequences
(Alias )
p.Glu2348del Sambuughinetal
c.7041_7043delGGA
(G2347del) [2001a]
Sambuughinetal
[2001b]
Rueffertetal
[2002]
Keatingetal
c.7300G>A p.Gly2434Arg
[1994]
c.7304G>A p.Arg2435His Zhangetal[1993]
c.7360C>T p.Arg2454Cys Brandtetal[1999]
c.7361G>A p.Arg2454His Baroneetal[1999]
Manningetal
[1998a]
Manningetal
[1998a]
Ferreiro&Fardeau
c.10579C>T p.Pro3527Ser
[2002]
c.11947C_T p.Arg3983Cys Groometal[2011]
Sambuughinetal
c.12881C>T p.Thr4294Met
[2009]
c.13513G_C p.Asp4505His Groometal[2011]
c.14477C>T p.Thr4826Ile Brownetal[2000]
c.14510delA p.Arg4837fsTer4839 Rossietal[2007]
Jungbluthetal
c.14545G>A p.Val4849Ile
[2002]
c.14693T>C p.Ile4898Thr Lynchetal[1999]
Noteonvariantclassification:Variantslistedinthetablehavebeenprovidedbytheauthors.GeneReviewsstaff
havenotindependentlyverifiedtheclassificationofvariants.
Noteonnomenclature:GeneReviewsfollowsthestandardnamingconventionsoftheHumanGenomeVariation
Society(www.hgvs.org).SeeQuickReferenceforanexplanationofnomenclature.
1. Variantdesignationthatdoesnotconformtocurrentnamingconventions
Normalgeneproduct.RYR1encodestheskeletalmusclecalciumreleasechannellocatedinthe
sarcoplasmicreticulum(SR)(alsoknownasryanodinereceptortype1).Thefunctionalchannelis
ahomotetramerof560kdsubunitsandreleasescalciumstoredintheSRinresponsetomembrane
depolarizationtransducedbythedihydropyridinereceptor(DHPR).Thecytoplasmicdomain,also
calledthefootstructure,isformedbythefirstapproximately4000aminoacidsandbridgesthegap
betweentheSRandthetransversetubularmembrane.Thelast1000aminoacidsformthe
transmembranedomainandcontainthepermeationpathwayandporeofthechannel
[Ramachandranetal2009].
Abnormalgeneproduct.MHScausingvariantsinRYR1causeCa2+releasechannelsinthe
sarcoplasmicreticulumtoexhibitanincreasedsensitivitytoactivationbybothendogenous(e.g.,
voltagesensor)andexogenous(e.g.,caffeine,halothane)triggers.Thisglobalhypersensitivityof
2+ 2+
theSRCa mechanismpredisposesskeletalmuscleuncontrolledCa2+releaseduringanMH
2+
event.
CACNA1S
Genestructure.Thegenespans90kbandconsistsof44exons.Foradetailedsummaryofgene
andproteininformation,seeTableA,Gene.
Pathogenicvariants.Afewdominantpathogenicvariantshavebeenidentifiedinseveralfamilies
withMHS[JurkatRottetal2000,Carpenteretal2009,Pironeetal2010,Toppinetal2010].
Threepathogenicvariants(p.Arg1086His,p.Thr1354Ser,andp.Arg174Trp)havebeen
functionallycharacterized[Weissetal2004,Pironeetal2010,Eltitetal2012].SeeTable6.
Table6.
CACNA1SPathogenicVariantsDiscussedinThisGeneReview
DNANucleotideChange PredictedProteinChange ReferenceSequences

NM_000069.2
NP_000060.2
c.520C>T p.Arg174Trp
c.4060A>T p.Thr1354Ser
Noteonvariantclassification:Variantslistedinthetablehavebeenprovidedbytheauthors.GeneReviewsstaff
havenotindependentlyverifiedtheclassificationofvariants.
Noteonnomenclature:GeneReviewsfollowsthestandardnamingconventionsoftheHumanGenomeVariation
Society(www.hgvs.org).SeeQuickReferenceforanexplanationofnomenclature.
Normalgeneproduct.CACNA1Sencodesthe1subunitofthepentameric(1,2,,and)
dihydropyridinereceptor(DHPR,alsotermedvoltagesensororLtypecalciumchannel)inskeletal
muscle.TheskeletalmuscleDHPRislocatedinthetransversetubulemembraneandacts
simultaneouslyasbothavoltagesensorforactivationoftheSRryanodinereceptorandasa
voltagedependentLtypeCa2+channel[Dirksen&Avila2002].The1subunitcontainsallthe
poreandgatingstructuresofthechannelandcomprisesfourhomologousrepeatsconnectedby
largecytoplasmicloops.Thefourthtransmembranesegmentofeachrepeat(S4)possesses
positivelychargedaminoacidsapproximatelyeverythirdresidueandcontributestothe"voltage
sensing"regionofthechannel.Sarcolemmaldepolarizationduringanactionpotentialinduces
voltagedrivenconformationalchangesintheS4segmentsoftheDHPRthatrapidlytriggerthe
openingofnearbySRCa2+releasechannels(ryanodinereceptorsorRyR1s).Althoughthe
intracellularloopthatlinksthesecondandthirdrepeat(IIIIIloop)playsacriticalrolein
mechanicalactivationofRyR1bytheDHPRfollowingdepolarization[Nakaietal1998],other
regionsoftheDHPR1[Leong&MacLennan1998]andsubunits[Chengetal2005]ofthe
DHPRhavealsobeensuggestedtointeractwithRyR1andinfluenceRyR1mediatedSRCa2+
release[Eltitetal2012].
Abnormalgeneproduct.ThreeofthefiveidentifiedMHScausingvariantsinCACNA1S
(p.Arg1086His,p.Arg1086Cys,andp.Arg1086Ser)resultinmutationofahighlyconserved
arginineresidueintheintracellularlooplinkingrepeatsIIIandIVoftheDHPR1subunit.Similar
tothatobservedforMHcausingvariantsinRYR1,thep.Arg1086Hispathogenicvariantin
CACNA1SincreasesthesensitivityoftheSRCa2+releasemechanismtoactivationbyboth
caffeineandvoltage[Weissetal2004].AfourthCACNA1Spathogenicvariant,p.Arg174Trp,was
identifiedinafamilywithMHthatdoesnotharboranRYR1pathogenicvariant[Carpenteretal
2009a].Thep.Arg174TrppathogenicvariantwasrecentlyproposedtosensitizeRyR1toMH
triggersbyenhancingbasalRyR1Ca2+leakoutoftheSR[Eltitetal2012].Finally,a
p.Thr1354SerpathogenicvariantlocatedintheIVS5S6extracellularporeloopwasshownto
2+
accelerateLtypeCa2+currentactivationinadditiontoincreasingthecaffeinesensitivityofRyR1
mediatedSRCa2+release[Pironeetal2010].
Thus,MHSissimilarlycausedbypathogenicvariantsinRYR1(MHS1)andboththe1(MHS5)
and2subunits(MHS3)oftheskeletalmuscleDHPR,proteinsthatareeachcriticallyinvolved
incoordinatingtheexcitationcontractionprocessinskeletalmuscle.Thisindicatesthatthe
pathogenesisofMHreflectsadysfunctioninthemuscleECcouplingprocessandthatMHS
resultingfrommutationoccurringatotherloci(e.g.,MHS2,MHS4,andMHS6)islikelyto
involvefunctionalalterationstootherproteinmembersofthereleasecomplex.
Calsequestrintype1(calsequestrin1)isanacidic,moderateaffinity,highcapacityCa2+binding
proteinlocatedintheterminalcisternaeofthesarcoplasmicreticulum.Theproteinisencodedby
CASQ1andfunctionstoconcentrateexchangeableCa2+ionsnearsitesofRYR1mediatedCa2+
release.Calsequestrin1isphysicallytetheredtoRYR1viatriadinandjunctin,forminga
quaternaryRYR1triadinjunctincalsequestrin1complexthatmodulatestheluminalCa2+
sensitivityoftheRYR1Ca2+releasechannel[Beardetal2004].Interestingly,genetically
engineeredmicelackingcalsequestrin1developnormally,butwhenanesthetizedwithMHtrigger
agentssuchashalothanedevelopmalignanthyperthermia.Thisfindingindicatesthatintracellular
hypercalcemiaoriginatingfrommanydifferentfundamentallydistinctetiologiescanresultinan
MHresponse[Daineseetal2009].
References
PublishedGuidelines/ConsensusStatements
NorthAmericanGuidelinesforTesting
1.LitmanRS,RosenbergH.Malignanthyperthermiaupdateonsusceptibilitytesting.
Availableonline.2005.Accessed12116.
2.SeiY,SambuughinN,MuldoonS.MalignanthyperthermiagenetictestinginNorth
AmericaWorkingGroupMeeting.Bethesda,Maryland.September45,2002.Available
online.2004.Accessed12116.
EuropeanGuidelinesforTesting
1.CarpenterD,RobinsonRL,QuinnellRJ,RingroseC,HoggM,CassonF,BoomsP,Iles
DE,HalsallPJ,SteeleDS,ShawMA,HopkinsPM.GeneticvariationinRYR1and
malignanthyperthermiaphenotypes.Availableonline.2009.Accessed12116.
2.RobinsonRL,HopkinsPM.Abreakthroughinthegeneticdiagnosisofmalignant
hyperthermia.Availableonline(registrationorinstitutionalaccessrequired).2001.Accessed
12116.
3.UrwylerA,DeufelT,McCarthyT,WestSEuropeanMalignantHyperthermiaGroup.
Guidelinesformoleculargeneticdetectionofsusceptibilitytomalignanthyperthermia.
Availableonline.2001.Accessed12116.[PubMed:11573677]
GuidelinesonDiagnosis,Management,andTransferofCarefromAmbulatorySurgery
Centers
1.GlahnKP,EllisFR,HalsallPJ,MllerCR,SnoeckMM,UrwylerA,WapplerFEuropean
MalignantHyperthermiaGroup.Recognizingandmanagingamalignanthyperthermia
crisis:guidelinesfromtheEuropeanMalignantHyperthermiaGroup.Availableonline.
2010.Accessed12116.[PubMed:20837722]
2.LarachMG,DirksenSJ,BelaniKG,BrandomBW,MetzKM,PolicastroMA,Rosenberg
H,ValedonA,WatsonCB.Creationofaguideforthetransferofcareofthemalignant
hyperthermiapatientfromambulatorysurgerycenterstoreceivinghospitalfacilities.
Availableonline.2012.Accessed12116.[PubMed:22052978]
NorthAmericanRecommendations
1.Mitochondrialmyopathiesandmalignanthyperthermiasusceptibility.Availableonline.
Accessed12116.
2.MHsusceptibilityandoperatingroompersonnel.Availableonline.Accessed12116.
3.Temperaturemonitoringduringsurgicalprocedures.Availableonline.Accessed12116.
4.Preparationofanesthesiaworkstationstoanesthetizemhsusceptiblepatients.Available
online.Accessed12116.
5.ParturientwithMHSpartner.Availableonline.Accessed12116.
6.AdverseeffectsofheatandexerciseinrelationtoMHsusceptibility.Availableonline.
Accessed12116.
LiteratureCited
1.AllenGC,LarachMG,KunselmanAR.Thesensitivityandspecificityofthecaffeine
halothanecontracturetest:areportfromtheNorthAmericanMalignantHyperthermia
Registry.TheNorthAmericanMalignantHyperthermiaRegistryofMHAUS.
Anesthesiology.199888:57988.[PubMed:9523799]
2.BaroneV,MassaO,IntravaiaE,BraccoA,DiMartinoA,TegazzinV,CozzolinoS,
SorrentinoV.MutationscreeningoftheRYR1geneandidentificationoftwonovel
mutationsinItalianmalignanthyperthermiafamilies.JMedGenet.199936:1158.[PMC
freearticle:PMC1734304][PubMed:10051009]
3.BeardNA,LaverDR,DulhuntyAF.Calsequestrinandthecalciumreleasechannelof
skeletalandcardiacmuscle.ProgBiophysMolBiol.200485:3369.[PubMed:15050380]
4.BetzenhauserMJ,MarksAR.Ryanodinereceptorchannelopathies.PflugersArch.
2010460:46780.[PMCfreearticle:PMC2885589][PubMed:20179962]
5.BradyJE,SunLS,RosenbergH.LiG.Prevalenceofmalignanthyperthermiadueto
anesthesiainNewYorkState,20012005.AnesthAnalg.2009109:11626.[PubMed:
19762744]
6.BrandomBW,LarachMG,ChenMS,YoungMC.Complicationsassociatedwiththe
administrationofdantrolene1987to2006:areportfromtheNorthAmericanMalignant
HyperthermiaRegistryoftheMalignantHyperthermiaAssociationoftheUnitedStates.
AnesthAnalg.2011112:111523.[PMCfreearticle:PMC3498049][PubMed:21372281]
7.BrandomBW,MuldoonSM.EstimationoftheIncidenceofMalignantHyperthermiaUsing
aCaptureRecaptureMethodintheUSA.AbstractA1267.LasVegas,NV:American
SocietyofAnesthesiologistsAnnualMeeting.2004.
8.BrandtA,SchleithoffL,JurkatRottK,KlinglerW,BaurC,LehmannHornF.Screeningof
theryanodinereceptorgenein105malignanthyperthermiafamilies:novelmutationsand
concordancewiththeinvitrocontracturetest.HumMolGenet.19998:205562.[PubMed:
10484775]
9.BrownRL,PollockAN,CouchmanKG,HodgesM,HutchinsonDO,WaakaR,LynchP,
McCarthyTV,StowellKM.Anovelryanodinereceptormutationandgenotypephenotype
correlationinalargemalignanthyperthermiaNewZealandMaoripedigree.HumMol
Genet.20009:151524.[PubMed:10888602]
10.CapacchioneJF,MuldoonSM.Therelationshipbetweenexertionalheatillness,exertional
rhabdomyolysis,andmalignanthyperthermia.AnesthAnalg.2009109:10659.[PubMed:
19617585]
11.CarpenterD,RingroseC,LeoV,MorrisA,RobinsonRL,HalsallPJ,HopkinsPM,Shaw
M.TheroleofCACNA1Sinpredispositiontomalignanthyperthermia.BMCMedGenet.
2009a10:104.[PMCfreearticle:PMC2770053][PubMed:19825159]
12.CarpenterD,RobinsonRL,QunnelRJ,RingroseC,HoggM,CasonF,BoomsP,IlesDE,
HalsallPJ,SteeleDS,ShawMA,HopkinsPM.GeneticvariationinRYR1andmalignant
hyperthermiaphenotypes.BrJAnaesth.2009b103:53848.[PubMed:19648156]
13.CheluMG,GoonasekeraSA,DurhamWJ,TangW,LueckJD,RiehlJ,PessahIN,Zhang
P,BhattacharjeeMB,DirksenRT,HamiltonSL.Heatandanesthesiainducedmalignant
hyperthermiainanRyR1knockinmouse.FASEBJ.200620:32930.[PubMed:
16284304]
14.ChengW,AltafajX,RonjatM,CoronadoR.Interactionbetweenthedihydropyridine
receptorCa2+channelbetasubunitandryanodinereceptortype1strengthensexcitation
contractioncoupling.ProcNatlAcadSciUSA.2005102:1922530.[PMCfreearticle:
PMC1323149][PubMed:16357209]
15.ClarkeNF,WaddellLB,CooperST,PerryM,SmithRL,KornbergAJ,MuntoniF,LillisS,
StraubV,BushbyK,GuglieriM,KingMD,FarrellMA,MartyI,LunardiJ,MonnierN,
NorthKN.RecessivemutationsinRYR1areacommoncauseofcongenitalfibertype
disproportion.HumMutat.201031:E154450.[PubMed:20583297]
16.DavisM,BrownR,DicksonA,HortonH,JamesD,LaingN,MarstonR,NorgateM,
PerlmanD,PollockN,StowellK.Malignanthyperthermiaassociatedwithexerciseinduced
rhabdomyolysisorcongenitalabnormalitiesandanovelRYR1mutationinNewZealand
andAustralianpedigrees.BrJAnaesth.200288:50815.[PubMed:12066726]
17.DArcyCE,BjorkstenA,YiuEM,BankierA,GilliesR,McLeanCA,ShieldLK,Ryan
MM.KingDenboroughsyndromecausedbyanovelmutationintheryanodinereceptor
gene.Neurology.200871:7767.[PubMed:18765655]
18.DaineseM,QuartaM,LyfenkoAD,PaoliniC,CanatoM,ReggianiC,DirksenRT,Protasi
F.Anestheticandheatinducedsuddendeathincalsequestrin1knockoutmice.FASEBJ.
200923:171020.[PMCfreearticle:PMC2698659][PubMed:19237502]
19.DirksenRT,AvilaG.Alteredryanodinereceptorfunctionincentralcoredisease:leakyor
uncoupledCa(2+)releasechannels?TrendsCardiovascMed.200212:18997.[PubMed:
12161072]
20.DirksenRT,AvilaG.DistincteffectsonCa2+handlingcausedbymalignanthyperthermia
andcentralcorediseasemutationsinRyR1.BiophysJ.200487:3193204.[PMCfree
article:PMC1304789][PubMed:15347586]
21.DowlingJJ,LillisS,AmburgeyK,ZhouH,AlSarrajS,BukSJ,WraigeE,ChowG,Abbs
S,LeberS,LachlanK,BaralleD,TaylorA,SewryC,MuntoniF,JungbluthH.King
Denboroughsyndromewithandwithoutmutationsintheskeletalmuscleryanodinereceptor
(RYR1)gene.NeuromusculDisord.201121:4207.[PubMed:21514828]
22.DukeAM,HopkinsPM,CalaghanSC,HalsallJP,SteeleDS.StoreoperatedCa2+entryin
malignanthyperthermiasusceptiblehumanskeletalmuscle.JBiolChem.2010285:25645
53.[PMCfreearticle:PMC2919128][PubMed:20566647]
23.DurhamWJ,AracenaParksP,LongC,RossiAE,GoonasekeraSA,BoncompagniS,
GilmanCP,GalvanDL,BakerM,ShirokovaN,ProtasiP,DirksenRT,HamiltonS.RyR1
SnitrosylationunderliesenvironmentalheatstrokeandsuddendeathinY522SRyR1
knockinmice.Cell.2008133:5365.[PMCfreearticle:PMC2366094][PubMed:
18394989]
24.EltitJM,BannisterRA,MouaO,AltamiranoF,HopkinsPM,PessahIN,MolinskiTF,
LpezJR,BeamKG,AllenPD.Malignanthyperthermiasusceptibilityarisingfromaltered
restingcouplingbetweentheskeletalmuscleLtypeCa2+channelandthetype1ryanodine
receptor.ProcNatlAcadSciUSA.2012109:79238.[PMCfreearticle:PMC3356662]
[PubMed:22547813]
25.FerreiroA,FardeauM.80thENMCInternationalWorkshoponMultiMinicoreDisease:1st
InternationalMmDWorkshop.1213thMay,2000,Soestduinen,TheNetherlands.
NeuromusculDisord.200212:608.[PubMed:11731287]
26.FortunatoG,BerrutiR,BrancadoroV,FattoreM,SalvatoreF,CarsanaA.Identificationofa
novelmutationintheryanodinereceptorgene(RYR1)inamalignanthyperthermiaItalian
family.EurJHumGenet.20008:14952.[PubMed:10757649]
27.GalliL,OrricoA,LorenziniS,CensiniS,FalcianiM,CovacciA,TegassinV,SorrentinoV.
Frequencyandlocalizationofmutationsinthe106exonsoftheRYR1genein50
individualswithmalignanthyperthermia.HumMutat.200627:830.[PubMed:16835904]
28.GenerB,BurnsJM,GriffinS,BoyerEW.Administrationofondansetronisassociatedwith
lethaloutcome.Pediatrics.2010125:e15147.[PubMed:20439600]
29.GillardEF,OtsuK,FujiiJ,DuffC,deLeonS,KhannaVK,BrittBA,WortonRG,
MacLennanDH.Polymorphismsanddeducedaminoacidsubstitutionsinthecoding
sequenceoftheryanodinereceptor(RYR1)geneinindividualswithmalignant
hyperthermia.Genomics.199213:124754.[PubMed:1354642]
30.GillardEF,OtsuK,FujiiJ,KhannaVK,deLeonS,DerdemeziJ,BrittBA,DuffCL,
WortonRG,MacLennanDH.Asubstitutionofcysteineforarginine614intheryanodine
receptorispotentiallycausativeofhumanmalignanthyperthermia.Genomics.199111:751
5.[PubMed:1774074]
31.GirardT,JhrM,SchaeferC,UrwylerA.Perinataldiagnosisofmalignanthyperthermia
susceptibility.Anesthesiology.2006104:13534.[PubMed:16732128]
32.GirardT,UrwylerA,CensierK,MuellerCR,ZorzatoF,TrevesS.Genotypephenotype
comparisonoftheSwissmalignanthyperthermiapopulation.HumMutat.200118:3578.
[PubMed:11668625]
33.GlahnKP,EllisFR,HalsallPJ,MllerCR,SnoeckMM,UrwylerA,WapplerF.,European
MalignantHyperthermiaGroup.Recognizingandmanagingamalignanthyperthermia
crisis:guidelinesfromtheEuropeanMalignantHyperthermiaGroup.BrJAnaesth.
2010105:41720.[PubMed:20837722]
34.GroomL,MuldoonSM,TangZZ,BrandomBW,BayarsaikhanM,BinaS,LeeHS,QiuX,
SambuughinN,DirksenRT.Identicaldenovomutationinthetype1ryanodinereceptor
geneassociatedwithfatal,stressinducedmalignanthyperthermiaintwounrelatedfamilies.
Anesthesiology.2011115:93845.[PMCfreearticle:PMC3203251][PubMed:21918424]
35.HayesJ,VeyckemansF,BissonnetteB.Duchennemusculardystrophy:anoldanesthesia
problemrevisited.PaediatrAnaesth.200818:1006.[PubMed:18184239]
36.HopkinsPM.Malignanthyperthermia:advancesinclinicalmanagementanddiagnosis.BrJ
Anaesth.200085:11828.[PubMed:10928000]
37.HopkinsPM,EllisFR,HalsallPJ.Evidenceforrelatedmyopathiesinexertionalheatstroke
andmalignanthyperthermia.Lancet.1991338:14912.[PubMed:1683922]
38.IbarraCA,WuS,MurayamaK,MinamiN,IchiharaY,KikuchiH,NoguchiS,Hayashi
YK,OchiaiR,NishinoI.MalignantHyperthermiainJapan.Anesthesiology.
2006104:114654.[PubMed:16732084]
39.JungbluthH.Multiminicoredisease.OrphanetJRareDis.20072:31.[PMCfreearticle:
PMC1947955][PubMed:17631035]
40.JungbluthH,MullerCR,HalligerKellerB,BrockingtonM,BrownSC,FengL,
ChattopadhyayA,MercuriE,ManzurAY,FerreiroA,LaingNG,DavisMR,RoperHP,
DubowitzV,BydderG,SewryCA,MuntoniF.AutosomalrecessiveinheritanceofRYR1
mutationsinacongenitalmyopathywithcores.Neurology.200259:2847.[PubMed:
12136074]
41.JungbluthH,SewryCA,MuntoniF.Coremyopathies.SeminPediatrNeurol.201118:239
49.[PubMed:22172419]
42.JurkatRottK,McCarthyT,LehmannHornF.Geneticsandpathogenesisofmalignant
hyperthermia.MuscleNerve.200023:417.[PubMed:10590402]
43.KaranSM,CrowlF,MuldoonSM.Malignanthyperthermiamaskedbycapnographic
monitoring.AnesthAnalg.199478:5902.[PubMed:8109781]
44.KeatingKE,GiblinL,LynchPJ,QuaneKA,LehaneM,HeffronJJ,McCarthyTV.
DetectionofanovelmutationintheryanodinereceptorgeneinanIrishmalignant
hyperthermiapedigree:correlationoftheIVCTresponsewiththeaffectedandunaffected
haplotypes.JMedGenet.199734:2916.[PMCfreearticle:PMC1050914][PubMed:
9138151]
45.KeatingKE,QuaneKA,ManningBM,LehaneM,HartungE,CensierK,UrwylerA,
KlausnitzerM,MullerCR,HeffronJJA,McCarthyTV.DetectionofanovelRYR1
mutationinfourmalignanthyperthermiapedigrees.HumMolGenet.19943:18558.
[PubMed:7849712]
46.KleinA,LillisS,MunteanuI,ScotoM,ZhouH,QuinlivanR,StraubV,ManzurAY,Roper
H,JeannetPY,RakowiczW,JonesDH,JensenUB,WraigeE,TrumpN,ScharaU,
LochmullerH,SarkozyA,KingstonH,NorwoodF,DamianM,KirschnerJ,LongmanC,
RobertsM,AuerGrumbachM,HughesI,BushbyK,SewryC,RobbS,AbbsS,Jungbluth
H,MuntoniF.Clinicalandgeneticfindingsinalargecohortofpatientswithryanodine
receptor1geneassociatedmyopathies.HumMutat.201233:9818.[PubMed:22473935]
47.KondoE,NishimuraT,KoshoT,InabaY,MitsuhashiS,IshidaT,BabaA,KoikeK,
NishinoI,NonakaI,FurukawaT,SaitoK.RecessiveRYR1mutationsinapatientwith
severecongenitalnemalinemyopathywithophthalmoplegiaidentifiedthroughmassively
parallelsequencing.AmJMedGenetA.2012158A:7728.[PubMed:22407809]
48.KraevaN,RiaziS,LokeJ,FrodisW,CrossanML,NolanK,KraevA,MaclennanDH.
Ryanodinereceptortype1genemutationsfoundintheCanadianmalignanthyperthermia
population.CanJAnaesth.201158:50413.[PubMed:21455645]
49.LannerJT,GeorgiouDK,DagninoAcostaA,AinbinderA,ChengQ,JoshiAD,ChenZ,
YarotskyyV,OakesJM,LeeCS,MonroeTO,SantillanA,DongK,GoodyearL,Ismailov
II,RodneyGG,DirksenRT,HamiltonSL.AICARpreventsheatinducedsuddendeathin
RyR1mutantmiceindependentofAMPKactivation.NatMed.201218:24451.[PMCfree
50.LarachMG,BrandomBW,AllenGC,GronertGA,LehmanEB.Cardiacarrestsanddeaths
associatedwithmalignanthyperthermiainNorthAmericafrom1987to2006:areportfrom
theNorthAmericanMalignantHyperthermiaRegistryoftheMalignantHyperthermia
AssociationoftheUnitedStates.Anesthesiology.2008108:60311.[PubMed:18362591]
51.LarachMG,DirksenSJ,BelaniKG,BrandomBW,MetzKM,PolicastroMA,Rosenberg
H,ValedonA,WatsonCB.,SocietyforAmbulatoryAnesthesiology.Malignant
HyperthermiaAssociationoftheUnitedStatesAmbulatorySurgeryFoundationSocietyfor
AcademicEmergencyMedicineNationalAssociationofEmergencyMedicalTechnicians.
Specialarticle:Creationofaguideforthetransferofcareofthemalignanthyperthermia
patientfromambulatorysurgerycenterstoreceivinghospitalfacilities.AnesthAnalg.
2012114:94100.[PubMed:22052978]
52.LarachMG,GronertGA,AllenGC,BrandomBW,LehmanEB.Clinicalpresentation,
treatment,andcomplicationsofmalignanthyperthermiainNorthAmericafrom1987to
2006.AnesthAnalg.2010110:498507.[PubMed:20081135]
53.LarachMG,LocalioAR,AllenGC,DenboroughMA,EllisFR,GronertGA,KaplanRF,
MuldoonSM,NelsonTE,OrdingH,etal.Aclinicalgradingscaletopredictmalignant
hyperthermiasusceptibility.Anesthesiology.199480:7719.[PubMed:8024130]
54.LeongP,MacLennanDH.ThecytoplasmicloopsbetweendomainsIIandIIIanddomains
IIIandIVintheskeletalmuscledihydropyridinereceptorbindtoacontiguoussiteinthe
skeletalmuscleryanodinereceptor.JBiolChem.1998273:2995864.[PubMed:9792715]
55.LiG,BradyJE,RosenbergH,SunLS.Excesscomorbiditiesassociatedwithmalignant
hyperthermiadiagnosisinpediatrichospitaldischargerecords.PaediatrAnaesth.
201121:95863.[PubMed:21722230]
56.LitmanRS,RosenbergH.Malignanthyperthermia:updateonsusceptibilitytesting.JAMA.
2005293:291824.[PubMed:15956637]
57.LynchPJ,KrivosicHorberR,ReyfordH,MonnierN,QuaneK,AdnetP,HaudecoeurG,
KrivosicI,McCarthyT,LunardiJ.Identificationofheterozygousandhomozygous
individualswiththenovelRYR1mutationCys35Arginalargekindred.Anesthesiology.
199786:6206.[PubMed:9066328]
58.LynchPJ,TongJ,LehaneM,MalletA,GiblinL,HeffronJJ,VaughanP,ZafraG,
MacLennanDH,McCarthyTV.Amutationinthetransmembrane/luminaldomainofthe
ryanodinereceptorisassociatedwithabnormalCa2+releasechannelfunctionandsevere
centralcoredisease.ProcNatlAcadSciUSA.199996:41649.[PMCfreearticle:
PMC22438][PubMed:10097181]
59.ManningBM,QuaneKA,LynchPJ,UrwylerA,TegazzinV,KrivosicHorberR,Censier
K,ComiG,AdnetP,WolzW,LunardiJ,MullerCR,McCarthyTV.Novelmutationsata
CpGdinucleotideintheryanodinereceptorinmalignanthyperthermia.HumMutat.
1998a11:4550.[PubMed:9450902]
60.ManningBM,QuaneKA,OrdingH,UrwylerA,TegazzinV,LehaneM,O'HalloranJ,
HartungE,GiblinLM,LynchPJ,VaughanP,CensierK,BendixenD,ComiG,HeytensL,
MonsieursK,FagerlundT,WolzW,HeffronJJ,MullerCR,McCarthyTV.Identificationof
novelmutationsintheryanodinereceptorgene(RYR1)inmalignanthyperthermia:
genotypephenotypecorrelation.AmJHumGenet.1998b62:599609.[PMCfreearticle:
PMC1376943][PubMed:9497245]
61.MarchantCL,EllisFR,HalsallPJ,HopkinsPM,RobinsonRL.Mutationanalysisoftwo
patientswithhypokalemicperiodicparalysisandsuspectedmalignanthyperthermia.Muscle
Nerve.200430:1147.[PubMed:15221887]
62.McCarthyTV,QuaneKA,LynchPJ.Ryanodinereceptormutationsinmalignant
hyperthermiaandcentralcoredisease.HumMutat.200015:4107.[PubMed:10790202]
63.MetterleinT,HartungE,SchusterF,RoewerN,AnetsederM.Sevofluraneasapotential
replacementforhalothaneindiagnostictestingformalignanthyperthermiasusceptibility:
resultsofapreliminarystudy.MinervaAnestesiol.2011a77:76873.[PubMed:21730923]
64.MetterleinT,ZinkW,KrankeE,HaneyaA,GrafB,KrankeP.Cardiopulmonarybypassin
malignanthyperthermiasusceptiblepatients:asystematicreviewofpublishedcases.J
ThoracCardiovascSurg.2011b141:148895.[PubMed:21376345]
65.MonnierN,FerreiroA,MartyI,LabarreVilaA,MezinP,LunardiJ.Ahomozygous
splicingmutationcausingadepletionofskeletalmuscleRYR1isassociatedwithmulti
minicorediseasecongenitalmyopathywithophthalmoplegia.HumMolGenet.
200312:11718.[PubMed:12719381]
66.MonnierN,KozakRibbensG,KrivosicHorberR,NivocheY,QiD,KraevN,LokeJ,
SharmaP,TegazzinV,FigarellaBrangerD,RomeroN,MezinP,BendahanD,PayenJF,
DepretT,MaclennanDH,LunardiJ.Correlationsbetweengenotypeandpharmacological,
histological,functional,andclinicalphenotypesinmalignanthyperthermiasusceptibility.
HumMutat.200526:41325.[PubMed:16163667]
67.MonnierN,KrivosicHorberR,PayenJF,KozakRibbensG,NivocheY,AdnetP,Reyford
H,LunardiJ.Presenceoftwodifferentgenetictraitsinmalignanthyperthermiafamilies:
implicationforgeneticanalysis,diagnosis,andincidenceofmalignanthyperthermia
susceptibility.Anesthesiology.200297:106774.[PubMed:12411788]
68.MonnierN,MartyI,FaureJ,CastiglioniC,DesnuelleC,SacconiS,EstournetB,Ferreiro
A,RomeroN,LaquerriereA,LazaroL,MartinJJ,MoravaE,RossiA,VanderKooiA,
VisserM,VerschuurenC,LunardiJ.Nullmutationscausingdepletionofthetype1
ryanodinereceptor(RYR1)arecommonlyassociatedwithrecessivestructuralcongenital
myopathieswithcores.HumMutat.200829:6708.[PubMed:18253926]
69.MonnierN,RomeroNB,LeraleJ,NivocheY,QiD,MacLennanDH,FardeauM,Lunardi
J.Anautosomaldominantcongenitalmyopathywithcoresandrodsisassociatedwitha
neomutationintheRYR1geneencodingtheskeletalmuscleryanodinereceptor.HumMol
Genet.20009:2599608.[PubMed:11063719]
70.NakaiJ,TanabeT,KonnoT,AdamsB,BeamKG.LocalizationintheIIIIIloopofthe
dihydropyridinereceptorofasequencecriticalforexcitationcontractioncoupling.JBiol
Chem.1998273:249836.[PubMed:9737952]
71.NishioH,SatoT,FukunishiS,TamuraA,IwataM,TsuboiK,SuzukiK.Identificationof
malignanthyperthermiasusceptibleryanodinereceptortype1gene(RYR1)mutationsina
childwhodiedinacarafterexposuretoahighenvironmentaltemperature.LegMed
(Tokyo)200911:1423.[PubMed:19223216]
72.ParnessJ,BandschappO,GirardT.Themyotoniasandsusceptibilitytomalignant
hyperthermia.AnesthAnalg.2009109:105464.[PubMed:19762732]
73.PaulPletzerK,YamamotoT,BhatMB,MaJ,IkemotoN,JimenezLS,MorimotoH,
WilliamsPG,ParnessJ.Identificationofadantrolenebindingsequenceontheskeletal
muscleryanodinereceptor.JBiolChem.2002277:3491823.[PubMed:12167662]
74.PironeA,SchredelsekerJ,TulucP,GravinoE,FortunatoG,FlucherBE,CarsanaA,
SalvatoreF,GrabnerM.Identificationandfunctionalcharacterizationofmalignant
hyperthermiamutationT1354SintheouterporeoftheCavalpha1Ssubunit.AmJPhysiol
CellPhysiol.2010299:C134554.[PMCfreearticle:PMC3006335][PubMed:20861472]
75.QuaneKA,HealyJM,KeatingKE,ManningBM,CouchFJ,PalmucciLM,DoriguzziC,
FagerlundTH,BergK,OrdingH,BendixenD,MortierW,LinzU,MullerCR,McCarthy
TV.Mutationsintheryanodinereceptorgeneincentralcorediseaseandmalignant
hyperthermia.NatGenet.19935:515.[PubMed:8220423]
76.QuaneKA,KeatingKE,HealyJM,ManningBM,KrivosicHorberR,KrivosicI,Monnier
N,LunardiJ,McCarthyTV.MutationscreeningoftheRYR1geneinmalignant
hyperthermia:detectionofanovelTyrtoSermutationinapedigreewithassociatedcentral
cores.Genomics.1994a23:2369.[PubMed:7829078]
77.QuaneKA,KeatingKE,ManningBM,HealyJM,MonsieursK,HeffronJJ,LehaneM,
HeytensL,KrivosicHorberR,AdnetP,EllisFR,MonnierN,LunardiJ,McCarthyTV.
Detectionofanovelcommonmutationintheryanodinereceptorgeneinmalignant
hyperthermia:implicationsfordiagnosisandheterogeneitystudies.HumMolGenet.
1994b3:4716.[PubMed:8012359]
78.QuaneKA,OrdingH,KeatingKE,ManningBM,HeineR,BendixenD,BergK,
KrivosicHorberR,LehmannHornF,FagerlundT,McCarthyTV.Detectionofanovel
mutationataminoacidposition614intheryanodinereceptorinmalignanthyperthermia.Br
JAnaesth.199779:3327.[PubMed:9389851]
79.RamachandranS,SerohijosAW,XuL,MeissnerG,DokholyanNV.Astructuralmodelof
theporeformingregionoftheskeletalmuscleryanodinereceptor(RyR1).PLoSComput
Biol.20095:e1000367.[PMCfreearticle:PMC2668181][PubMed:19390614]
80.RobinsonRL,AnetsederMJ,BrancadoroV,VanBroekhovenC,CarsanaA,CensierK,
FortunatoG,GirardT,HeytensL,HopkinsPM,JurkatRottK,KlingerW,KozakRibbens
G,KrivosicR,MonnierN,NivocheY,OlthoffD,RueffertH,SorrentinoV,TegazzinV,
MuellerCR.Recentadvancesinthediagnosisofmalignanthyperthermiasusceptibility:
Howconfidentcanwebeofgenetictesting?EurJHumGenet.200311:3428.[PubMed:
12700608]
81.RobinsonRL,BrooksC,BrownSL,EllisFR,HalsallPJ,QuinnellRJ,ShawMA,Hopkins
PM.RYR1mutationscausingcentralcorediseaseareassociatedwithmoreseveremalignant
hyperthermiainvitrocontracturetestphenotypes.HumMutat.200220:8897.[PubMed:
12124989]
82.RobinsonR,CarpenterD,ShawMA,HalsallJ,HopkinsP.MutationsinRYR1in
malignanthyperthermiaandcentralcoredisease.HumMutat.200627:97789.[PubMed:
16917943]
83.RobinsonRL,HopkinsPM.Abreakthroughinthegeneticdiagnosisofmalignant
hyperthermia.BritJAnaesth.200186:1668.[PubMed:11573654]
84.RosenbergH,AntogniniJF,MuldoonS.Testingformalignanthyperthermia.
85.RosenbergH,RueffertH.Clinicalutilitygenecardfor:malignanthyperthermia.EurJHum
Genet.2011:19.[PMCfreearticle:PMC3110041][PubMed:21248738]
86.RoseroEB,AdesanyaAL,TimarraCH,JoshiGP.Trenesandoutcomesofmalignant
hyperthermiaintheUnitedStates20002005.Anesthesiology.2009110:8994.[PubMed:
19104175]
87.RossiD,DeSmetP,LyfenkoA,GalliL,LorenziniS,FranciD,PetrioliF,OrricoA,
AngeliniC,TegazzinV,DirksenR,SorrentinoV.AtruncationoftheRYR1geneassociated
withcentralcorelesionsinskeletalmusclefibres.JMedGenet.200744:e67.[PMCfree
88.RueffertH,OlthoffD,DeutrichC,MeineckeCD,FrosterUG.Mutationscreeninginthe
ryanodinereceptor1gene(RYR1)inpatientssusceptibletomalignanthyperthermiawho
showdefiniteIVCTresults:identificationofthreenovelmutations.ActaAnaesthesiol
Scand.200246:6928.[PubMed:12059893]
89.SambuughinN,CapacchioneJ,BlokhinA,BayarsaikhanM,BinaS,MuldoonS.The
ryanodinereceptortype1genevariantsinAfricanAmericanmenwithexertional
rhabdomyolysisandmalignanthyperthermiasusceptibility.ClinGenet.200976:5648.
[PubMed:19807743]
90.SambuughinN,HolleyH,MuldoonS,BrandomBW,deBantelAM,TobinJR,NelsonTE,
GoldfarbLG.Screeningoftheentireryanodinereceptortype1codingregionforsequence
variantsassociatedwithmalignanthyperthermiasusceptibilityinthenorthamerican
population.Anesthesiology.2005102:51521.[PubMed:15731587]
91.SambuughinN,McWilliamsS,deBantelA,SivakumarK,NelsonTE.Singleaminoacid
deletionintheRYR1gene,associatedwithmalignanthyperthermiasusceptibilityand
unusualcontractionphenotype.AmJHumGenet.2001a69:2048.[PMCfreearticle:
PMC1226035][PubMed:11389482]
92.SambuughinN,NelsonTE,JankovicJ,XinC,MeissnerG,MullakandovM,JiJ,
RosenbergH,SivakumarK,GoldfarbLG.Identificationandfunctionalcharacterizationofa
novelryanodinereceptormutationcausingmalignanthyperthermiainNorthAmericanand
SouthAmericanfamilies.NeuromusculDisord.2001b11:5307.[PubMed:11525881]
93.SatoT,NishioH,IwataM.Kentotsuboi,TamuraA,MiyazakiT,SuzukiK.Postmortem
molecularscreeningformutationsinryanodinereceptortype1(RYR1)geneinpsychiatric
patientssuspectedofhavingdiedofneurolepticmalignantsyndrome.ForensicSciInt.
2010194:779.[PubMed:19931341]
94.SchleithoffL,MehrkeG,ReutlingerB,LehmannHornF.Genomicstructureandfunctional
expressionofahumanalpha(2)/deltacalciumchannelsubunitgene(CACNA2).Genomics.
199961:2019.[PubMed:10534405]
95.SeiY,SambuughinN,MuldoonS.MalignanthyperthermiagenetictestinginNorth
AmericaWorkingGroupMeeting.Bethesda,Maryland.September45,2002.
96.StewartSL,HoganK,RosenbergH,FletcherJE.IdentificationoftheArg1086Hismutation
inthealphasubunitofthevoltagedependentcalciumchannel(CACNA1S)inaNorth
Americanfamilywithmalignanthyperthermia.ClinGenet.200159:17884.[PubMed:
11260227]
97.TobinJR,JasonDR,ChallaVR,NelsonTE,SambuughinN.Malignanthyperthermiaand
apparentheatstroke.JAMA.2001286:1689.[PubMed:11448278]
98.TongJ,OyamadaH,DemaurexN,GrinsteinS,McCarthyTV,MacLennanDH.Caffeine
andhalothanesensitivityofintracellularCa2+releaseisalteredby15calciumrelease
channel(ryanodinereceptor)mutationsassociatedwithmalignanthyperthermiaand/or
centralcoredisease.JBiolChem.1997272:263329.[PubMed:9334205]
99.ToppinPJ,ChandyTT,GhanekarA,KraevaN,BeattieWS,RiaziS.Areportoffulminant
malignanthyperthermiainapatientwithanovelmutationoftheCACNA1Sgene.CanJ
Anaesth.201057:68993.[PubMed:20431982]
100.TuranA,MendozaML,GuptaS,YouJ,GottliebA,ChuW,SaagerL,SesslerDI.
Consequencesofsuccinylcholineadministrationtopatientsusingstatins.Anesthesiology.
2011115:2835.[PubMed:21606827]
101.UrwylerA,DeufelT,McCarthyT,WestS.,EuropeanMalignantHyperthermiaGroup.
Guidelinesformoleculargeneticdetectionofsusceptibilitytomalignanthyperthermia.BritJ
Anaesth.200186:2837.[PubMed:11573677]
102.VladutiuGD,IsacksonPJ,KaufmanK,HarleyJB,CobbB,ChristopherStineL,
WortmannRL.Geneticriskformalignanthyperthermiainnonanesthesiainduced
myopathies.MolGenetMetab.2011104:16773.[PMCfreearticle:PMC3171598]
[PubMed:21795085]
103.WapplerF,FiegeM,SteinfathM,AgarwalK,ScholzJ,SinghS,MatschkeJ,SchulteAm
EschJ.Evidenceforsusceptibilitytomalignanthyperthermiainpatientswithexercise
inducedrhabdomyolysis.Anesthesiology.200194:95100.[PubMed:11135728]
104.WeissRG,O'ConnellKM,FlucherBE,AllenPD,GrabnerM,DirksenRT.Functional
analysisoftheR1086HmalignanthyperthermiamutationintheDHPRrevealsan
unexpectedinfluenceoftheIIIIVlooponskeletalmuscleECcoupling.AmJPhysiolCell
Physiol.2004287:C1094102.[PubMed:15201141]
105.WilmshurstJM,LillisS,ZhouH,PillayK,HendersonH,KressW,MllerCR,NdondoA,
ClokeV,CullupT,BertiniE,BoennemannC,StraubV,QuinlivanR,DowlingJJ,AlSarraj
S,TrevesS,AbbsS,ManzurAY,SewryCA,MuntoniF,JungbluthH.RYR1mutationsare
acommoncauseofcongenitalmyopathieswithcentralnuclei.AnnNeurol.201068:717
26.[PubMed:20839240]
106.WuS,IbarraMC,MalicdanMC,MurayamaK,IchiharaY,KikuchiH,NonakaI,Noguchi
S,HayashiYK,NishinoI.CentralcorediseaseisduetoRYR1mutationsinmorethan90%
ofpatients.Brain.2006129:147080.[PubMed:16621918]
107.YangT,EsteveE,PessahIN,MolinskiTF,AllenPD,LpezJR.Elevatedresting[Ca2+]iin
myotubesexpressingmalignanthyperthermiaRyR1cDNAsispartiallyrestoredby
modulationofpassivecalciumleakfromtheSR.AmJPhysiolCellPhysiol.
2007292:C15918.[PubMed:17182726]
108.YangT,RiehlJ,EsteveE,MatthaeiKI,GothS,AllenPD,PessahIN,LopezJR.
PharmacologicandfunctionalcharacterizationofmalignanthyperthermiaintheR163C
RyR1knockinmouse.Anesthesiology.2006105:116475.[PubMed:17122579]
109.YangT,TaTA,PessahIN,AllenPD.Functionaldefectsinsixryanodinereceptorisoform1
(RyR1)mutationsassociatedwithmalignanthyperthermiaandtheirimpactonskeletal
excitationcontractioncoupling.JBiolChem.2003278:2572230.[PubMed:12732639]
110.ZhangY,ChenHS,KhannaVK,DeLeonS,PhillipsMS,SchappertK,BrittBA,Browell
AK,MacLennanDH.Amutationinthehumanryanodinereceptorgeneassociatedwith
centralcoredisease.NatGenet.19935:4650.[PubMed:8220422]
111.ZhouH,JungbluthH,SewryC,FengL,BertiniF,BushbyK,StraubV,RoperH,Rose
MR,BrockingtonM,KinaliM,ManzurA,RobbS,AppletonR,MessinaS,DAmicoA,
QuinlivanR,SwashM,MullerCR,BrownB,TrevesS,MuntoniF.Molecularmechanisms
andphenotypicvariationinRYR1relatedcongenitalmyopathies.Brain.2007130:202436.
[PubMed:17483490]
SuggestedReading
1.BrittBA,KalowW.Malignanthyperthermia:aetiologyunknown.CanAnaesthSocJ.
197017:31630.[PubMed:4317096]
2.HirsheyDirksenSJ,LarachMG,RosenbergH,BrandomBW,ParnessJ,LangRS,
GangadharanM,PezalskiT.Specialarticle:Futuredirectionsinmalignanthyperthermia
researchandpatientcare.AnesthAnalg.2011113:110819.[PMCfreearticle:
PMC3184381][PubMed:21709147]
3.LermanJ.Perioperativemanagementofthepaediatricpatientwithcoexistingneuromuscular
disease.BrJAnaesth.2011107Suppl1:i7989.[PubMed:22156273]
4.MacLennanDH,DuffC,ZorzatoF,FujiiJ,PhillipsM,KornelukRG,FrodisW,BrittBA,
WortonRG.Ryanodinereceptorgeneisacandidateforpredispositiontomalignant
hyperthermia.Nature.1990343:55961.[PubMed:1967823]
5.TorpyJM,LynmC,GlassRM.JAMApatientpage.Malignanthyperthermia.JAMA.
2005293:2958.[PubMed:15956641]
ChapterNotes
Acknowledgments
SupportedbygrantsfromtheNationalInstitutesofHealth(AR044657,AR053349and
AR052354toRTD).
AuthorHistory
RobertTDirksen,PhD(2006present)
SheilaRiazi,MD(2013present)
HenryRosenberg,MD(2003present)
NyamkhishigSambuughin,PhD(200320062010present)
RevisionHistory
31January2013(me)Comprehensiveupdatepostedlive
19January2010(me)Comprehensiveupdatepostedlive
12May2006(me)ComprehensiveupdatepostedtoliveWebsite
19December2003(me)ReviewpostedtoliveWebsite
19June2003(hr)Originalsubmission
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BookshelfID:NBK1146 PMID:20301325

Malignant Hyperthermia Susceptibility - GeneReviews® - NCBI Bookshelf

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Malignant Hyperthermia Susceptibility - GeneReviews® - NCBI Bookshelf

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1/8/2017 MalignantHyperthermiaSusceptibilityGeneReviewsNCBIBookshelf

Designation1 NorthAmericanProtocol EuropeanProtocol

Locus Gene Chromosome Protein LocusSpecific HGMD

DNANucleotideChange PredictedProteinChange ReferenceSequences

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