Fabry Disease - National Organization for Rare Disorders

Fabry disease is a rare inherited disorder of glycosphingolipid (fat) metabolism resulting from the absent or markedly deficient activity of the lysosomal ... ScrollToTopAboutNewsEventsContactPODCASTStoredonateMenuforPatientsandFamiliesInformation&ResourcesRareDiseaseInformationRareDiseaseVideoLibraryPatientandCaregiverResourceCenterInformationonClinicalTrialsandResearchStudiesGeneTherapyRareDiseaseCentersofExcellenceCOVID-19ResourcesHelptoAccessMedicationsPatientAssistanceProgramsOtherFinancialAssistanceConnectwithOthersFindaPatientOrganizationRareDiseaseDay®PatientStoriesTakeActionAttendEventsAdvocateSupportCloseforPatientOrganizationsJoinMembershipNetworkValueofMembershipMembershipCriteriaApplyforMembershipNonprofitResourcesMembershipBenefitsMembershipResourcesRareLaunch®WebinarSeriesDiversity,Equity&InclusionOtherWaystoPartnerGrowyourorganizationPatientRegistriesAdvocacyRareDiseaseDay®RDCA-DAP®MembershipProfilesAboutourMembersMemberListRareCancerCoalition®CloseforCliniciansandResearchersResourcesResourcesforMedicalProfessionalsRareDiseaseInformationResourcesforyourPatientsContinuingMedicalEducationResearchOpportunitiesResearchGrantProgramRequestsforProposalsResearchGrantRecipientsConnectLendYourExpertiseRareDiseaseDay®CloseNORDRareDiseaseAdvocacyNORD’sPolicyinActionIssueOverviewsNORDontheIssuesNORDStateReportCardNationalPartnershipsTakeActionLocallyJointheRareActionNetwork®ProjectRDACContactYourRepresentativesTakeActionRareInsights®RareInsights®5MythsAboutOrphanDrugsandtheOrphanDrugActCloseGetInvolvedDonateNowGiveWaystoGiveDonatetoResearchNORD®StoreEducateEducationalInitiativesRaiseAwarenessIdentifyRareDiseaseExpertsJoinParticipateinEventsBecomeaMemberRareCancerCoalition®EmploymentOpportunitiesCorporateCouncilAbouttheCorporateCouncilCurrentMembersCouncilCodeofConductJointheCouncilCloseHome/ForPatientsandFamilies/RareDiseaseInformation/FabryDiseaseRareDiseaseDatabase0-9•A•B•C•D•E•F•G•H•I•J•K•L•M•N•O•P•Q•R•S•T•U•V•W•X•Y•ZPrintFabryDiseaseNORDgratefullyacknowledgesJayaGanesh,MD,AssociateProfessor,GeneticsandGenomicMedicine,IcahnSchoolofMedicineatMountSinaiandR.J.Desnick,PhD,MD,DeanforGeneticandGenomicMedicine,ProfessorandChairmanEmeritus,IcahnSchoolofMedicineatMountSinai,andforassistanceinthepreparationofthisreport.SynonymsofFabryDiseasealpha-galactosidaseAdeficiencyAnderson-FabrydiseaseangiokeratomacorporisdiffusumangiokeratomadiffuseGLAdeficiencySubdivisionsofFabryDiseasetype1classicphenotypetype2later-onsetphenotypeGeneralDiscussionFabrydiseaseisarareinheriteddisorderofglycosphingolipid(fat)metabolismresultingfromtheabsentormarkedlydeficientactivityofthelysosomalenzyme,α-galactosidaseA(α-GalA).Thisdisorderbelongstoagroupofdiseasesknownaslysosomalstoragedisorders.Thisenzymaticdeficiencyiscausedbyalterations(mutations)intheα-galactosidaseA(GLA)genethatinstructscellstomaketheα-galactosidaseA(α-GalA)enzyme.Lysosomesfunctionastheprimarydigestivetractofcells.Enzymeswithinlysosomesbreakdownordigestparticularcompoundsandintracellularstructures.α-GalAfunctionstobreakdowncomplexsugar-lipidmoleculescalledglycolipids,specifically,globotriaosylceramide(GL-3orGb3),itsdeacylatedformLyso-GL-3/Gb3andrelatedglycolipids,byremovingtheterminalgalactosesugarfromtheendoftheseglycolipidmolecules.Theenzymedeficiencycausesacontinuousbuild-upofGL-3/Gb3andrelatedglycolipidsinthebody’scells,resultinginthecellabnormalitiesandorgandysfunctionthatparticularlyaffectsmallbloodvessels,theheartandkidneys(Desnick2001,Germain2010).TheGLAgeneislocatedontheX-chromosomeandtherefore,FabrydiseaseisinheritedasanX-linkeddisorder.Maleswiththetype1classicandtype2later-onsetphenotypes(seebelow)aretypicallysignificantlymoreseverelyaffectedthantheiraffectedfemalerelatives(Arends2017).Femalestypicallyhaveamorevariablecourseandmaybeasymptomaticorasseverelyaffectedastheirmalerelatives(seeGeneticssectionbelow).Therearetwomajordiseasephenotypes:type1“classic”andtype2“later-onset”subtypes.Bothleadtorenalfailure,and/orcardiacdisease,andearlydeath(Desnick2001,DesnickandBanikazemi2006,Arends2017,Doheny2018).Type1maleshavelittleornofunctionalα-GalAenzymaticactivity(<3%ofnormalmeanactivity),andmarkedaccumulationofGL-3/Gb3andrelatedglycolipidsincapillariesandsmallbloodvesselswhichcausethemajorsymptomsinchildhoodoradolescence.Theseincludeacroparesthesias(excruciatingpaininthehandsandfeetwhichoccurwithexercise,fevers,stress,etc.);angiokeratomas(clustersofredtobluerash-likediscolorationsontheskin);anhidrosisorhypohidrosis(absentormarkedlydecreasedsweating);gastrointestinalsymptomsincludingabdominalpainandcramping,andfrequentbowelmovements;andacharacteristiccornealdystrophy(star-burstpatternofthecorneaseenbyanslit-lampophthalmologicexamination)thatdoesnotaffectvision(Sher1979,Desnick2001).Withincreasingage,thesystemicGL-3/Gb3deposition,especiallyintheheartleadstoarrhythmias,leftventricularhypertrophy(LVH)andthenhypertrophiccardiomyopathy(HCM),andinthekidneystoprogressiveproteinuria,renalinsufficiency,andrenalfailure,and/ortocerebrovasculardiseaseincludingtransientischemicattacks(TIAs)andstrokes.Priortorenalreplacementtherapy(i.e.,dialysisandtransplantation)andenzymereplacementtherapy(ERT),theaverageageofdeathofaffectedmaleswiththetype1classicphenotypewas~40years(Columbi1967).Theincidenceofmaleswiththetype1classicphenotypeisabout1in40,000(Desnick2001),butvarieswithgeographicregionandrace,rangingfromabout~1in18,000to1in95,000basedonnewbornscreeningstudies(e.g.,Spada2006,Hwu2009,Burlina2018,andWasserstein2019).Incontrast,maleswiththetype2“later-onset”phenotype(previouslycalledcardiacorrenalvariants)haveresidualα-GalAactivity,lackGL-3/Gb3accumulationincapillariesandsmallbloodvessels,anddonotshowtheearlymanifestationsoftype1males(i.e.,theacroparesthesias,hypohidrosis,angiokeratomas,cornealdystrophy,etc).Theyexperienceanessentiallynormalchildhoodandadolescence,andtypicallypresentwithrenaland/orcardiacdiseaseinthethirdtoseventhdecadesoflife.Mosttype2later-onsetpatientshavebeenidentifiedbyenzymescreeningofpatientsincardiac,hemodialysis,renaltransplant,andstrokeclinics(Doheny2018),andrecentlybynewbornscreening(e.g.Spada2006,Hwu2009,Burlina2018,Wasserstein2019).Basedonthesescreeningstudiestheincidenceoftype2later-onsetdiseaseinmalesvariesbydemography,ethnicity,andrace,butisatleast5-10timesmorefrequentthanthatofthetype1malesfromthesameregion,ethnicgroup,orrace.Clinicalmanifestationsinheterozygousfemalesfromfamilieswiththetype1classicphenotypearevariableduetorandomX-chromosomalinactivation(Dobrovolny2005,Echevarria2015)andrangefromasymptomatictoassevereastype1classicmales(DesnickandBanikazemi2006,Arends2017).Type2heterozygotesmaybeasymptomaticordeveloprenalorcardiacmanifestationslaterinlife.Approximately90%oftype1heterozygoteshavethecharacteristiccornealdystrophy,whilethetype2heterozygousfemalestypicallylackthecharacteristiccornealfindingsorotherearlytype1manifestation(Desnick2001,DesnickandBanikazemi2006,Doheny2018).Thefrequencyandseverityofmanifestationsintype2heterozygousfemaleshasonlybeensystematicallyinvestigatedrecently,andtheyaretypicallylessfrequentandlessseverethanthoseseenintheirtype2malerelatives(Arends2017).NORDVideo:FabryDiseaseScrollbackuptorestoredefaultview.Signs&SymptomsType1ClassicPhenotypeThesignsandsymptomsofmaleswiththetype1classicphenotypetypicallybegininchildhoodoradolescence(Desnick2001,DesnickandBrady2004).Symptomsincreasewithageprimarilyduetotheprogressiveglycolipidaccumulationinthemicro-vascularsystem,kidneypodocytes,andcardiomyocytesleadingtokidneyinsufficiencyandfailure,heartdisease,and/orstrokes.Earlyandprogressiveclinicalsymptomsinclude:Acroparesthesias. Painisanearlysymptomofthetype1Classicsubtypeandmayoccurasearlyas2-8yearsofageinmales,andcanoccurduringchildhoodoradolescenceinfemaleheterozygotes,particularlyassociatedwithfevers.Affectedindividualsmayexperienceepisodesofsevereburningpaininthehandsandthefeet(acroparesthesia).Severeepisodesofpain(Fabry’scrises)maylastforhourstodaysandarefrequentlytriggeredbyexercise,fatigue,stress,and/orfever(Burlina2011).Anhidrosisorhypohidrosis. Type1malesandsometype1femaleshavedecreasedorabsentsweatproduction(hypohidrosisoranhidrosis)anddiscomfort(heatintolerance)inwarmtemperatures,withexercise,orfevers.Angiokeratomas. Earlysymptomsalsoincludetheappearanceofareddishtodark-blueskinrash,especiallyintheareabetweenthehipsandtheknees.Theseskinlesionsmaybeflatorraised.Theyoftenarefoundintheumbilicalareaorgenitalsoftype1males.Typically,malesandfemaleswiththetype2later-onsetphenotypedonothavethesecharacteristicskinlesions.Gastrointestinalproblems.GIsymptomsareanearlymanifestationoftype1FabryAbdominalcramping,frequentbowelmovements,anddiarrheamayalsooccur,particularlyafteralargemeal.Cornealdystrophy. Patientswiththetype1classicphenotypehaveabnormaldepositsofglycolipidsintheircorneasresultinginacharacteristicwhorl-likeopacity,whichcanbeseenbyslit-lampexaminationbyanexperiencedophthalmologist.Thesechangesdonotaffectvision.Bloodvesselsintheeyesmayappeartwisted(corkscrew-like;contorted)and/orslightlyenlarged(dilated)duetotheglycolipidaccumulationinthevesselwalls.AdditionalType1symptoms. OthersymptomsthatmaybeassociatedwithFabrydiseaseincludechronicfatigue,dizziness,headache,generalizedweakness,nausea,and/orvomiting,delayedpuberty,lackoforsparsehairgrowth,andrarelymalformationofthejointsofthefingers.Sometype1classicmaleshaveabnormalaccumulationoflymphinthefeetandlegsassociatedwithswelling(lymphedema).Inthesepatients,lymph,abodyfluidcontainingcertainwhitebloodcells,fats,andproteins,accumulatesoutsidebloodvesselsinspacesbetweencellsanddrainsorflowsbackintothebloodstreamvialymphvessels.Lymphedemaresultsfromdisruptionoflymph’snormaldrainageduetotheglycolipidaccumulationinthelymphaticvesselsandlymphnodes.CommonManifestationsinType1and2MalesWithadvancingageintype1males,typicallyinthethirdtofourthdecades,andintype2malesinthethirdtosixthdecades,theprogressiveGL-3/Gb3glycolipiddepositionleadstorenaland/orheartmanifestationsasdescribedbelow(Desnick2001,Arends2017).Manyofthetype2later-onsetmaleswholacktheearlymanifestationsseeninthetype1males,aredetectedinrenal,heart,orstrokeclinics(Nakao1995,2003;Doheny2018).Patientswiththetype2later-onsetsubtypetypicallydonothavetheskinlesions(angiokeratoma),sweatnormally,donotexperiencetheFabrypainorcrises,anddonothaveheatintoleranceorcornealinvolvement.Theseindividualsdevelopheartorkidneydiseaselaterinadultlife.Signsofprogressiveorganinvolvementinclude:Renaldysfunction.ProgressivedecreaseinrenalfunctionisduetotheprogressiveaccumulationofGL-3/Gb3inthekidneys,particularlyintheendothelialcells,smoothmusclecellsandpodocytes(Najafian2013;Tondel2008,2013).Thereishistologicalevidenceofthisaccumulationandensuingcellularandvascularinjurytorenaltissuebeginninginchildhoodandadolescence(Tondel2008,2013;Najafian2013)intype1classicmalesandfemales.Intype1classicmales,thedeclineintypicallybeginswithpodocyteinvolvementandmicroalbuminurialeadingtofrankproteinuria,increasinglossoffunction(decreasingglomerularfiltrationrateorGFR),allleadingtokidneyfailureandtheneedfordialysisortransplantationtypicallyby35to45yearsofage.Intype2males,kidneyinvolvementtypicallyoccursinthefourthdecadeorlater,butsomepatientsdonotdeveloprenalfailure(Meehan2004).Kidneyinvolvementintype1femaleheterozygotesismorevariable.Onlyabout10-15%oftype1femalesdevelopkidneyfailure.Itisnotclearwhatpercentageoftype2femalesdeveloprenalfailure,ifany(Arends2017).Cardiacdisease.GL-3/Gb3depositioncanbefoundinallcardiactissues,includingvalves,cardiomyocytes,nerves,andcoronaryarteries(Desnick1976).Heartdiseaseincludesheartenlargement,typicallyleftventricularhypertrophy(LVH)leadingtohypertrophiccardiomyopathy(HCM),rhythmabnormalities(arrhythmias),andheartfailure(Frustaci2017).LVHoccursinabout20%ofmalesandfemaleswithanaverageageofdiagnosisintheearly20sto40samongtype1malesandlate30sto40samongtype1femaleheterozygotes.Earlyheartinvolvementintype1malestypicallyincludesarrhythmiasandmitralinsufficiencyintheir20sfollowedbyLVHleadingtoHCM.Type2later-onsetmalesdevelopsimilarheartmanifestationsastype1males,butatolderagesandmaybefirstdiagnosedincardiacclinicsamongpatientswithLVHorHCM(Doheny2018).Heterozygousfemaleswiththetype1phenotypeoftenhavesinusbradycardiaasanearlyfindingandmaymoreseverelyaffectedheterozygotescandevelopLVHprogressingtoHCM.Cerebrovascularcomplications. AsaresultoftheprogressiveGL-3/Gb3depositionintheheartleadingtoatrialfibrillationandinthesmallbloodvesselsinthebrain,about7%ofmalesand4%offemaleswithFabrydisease,particularlythosewiththetype1phenotype,experienceischemicorhemorrhagicstrokes,occurringtypicallyinthefourthdecadeoflifeorlater(Fellgiebel2006,Wilcox2008).Respiratoryabnormalities:Accumulationofglycosphingolipidsandconsequentfibrosiscancauseinterstitiallungdisease.Pathologicalchangesandtissueremodelingmayinvolvebothalveoliandthebronchialtreeleadingtorestrictivelungdisease,obstructiveairwaydisease,oramixtureofobstructiveandrestrictivedisease.(Svensson2015).Respiratorysymptomsmayoccurindependentofcardiovasculardiseaseinthesepatients.Otherpathology:Hearingloss,tinnitus,dizzinessandvertigopotentiallyduetoGL-3/Gb3depositioninvestibularstructuresand/orauditoryneuropathyarecommonlyreportedinadultpatientsandwhilethesearenotlifethreatening,contributetodiseaseburdenandnegativelyaffectqualityoflife.Depressionhasbeenreportedandaportionofthesecases,especiallyTypeIClassicmales,wereclassifiedashavingseveredepression.(Cole2007)CausesGeneticsFabrydiseaseiscausedbyalterations(mutations)inthealpha-galactosidaseA(GLA)genelocatedontheX-chromosome.Chromosomesarefoundinthenucleusofallcells.Theycarrythegeneticcharacteristicsofeachindividualinthousandsofspecificsegments,called“genes”thatspanthelengthofthechromosomes.Eachofthesegeneshasaspecificfunctioninthebody.Humanchromosomesareorganizedinpairs,numberedfrom1through22,withthe23rdpairofX-andY-chromosomesformalesandtwoX-chromosomesforfemales.Individualsinheritonechromosomeineachpairfromeachparent.Therefore,inX-linkeddisordersincludingFabrydisease,diseasetraitsontheX-chromosomecanbemaskedorreducedinfemalesbythenormalgeneontheotherX-chromosome.Morespecifically,becauseonlyonefunctioningX-chromosomeisrequiredinmalesandfemales,oneoftheX-chromosomesineachcellofafemaleisessentially“turnedoff”,usuallyinarandompattern(randomX-chromosomeinactivation).ThismeansthatinX-linkeddisorders,somecellswillhavetheX-chromosomewiththemutated“Fabry”geneactivated,whileotherswillhavetheX-chromosomewiththefunctioning,normalgeneactivated.Therefore,inFabrydiseasethesymptomsandseverityoforganinvolvementaredependentonthepercentageofcellsinthetissue/organwheretheX-chromosomewiththeGLAgenemutationisactive,butwithnoormarkedlydecreasedfunction,whichpartiallyexplainswhythediseaseseverityinfemalesismorevariablethanintheiraffectedmalerelatives.SincemaleshaveonlyoneX-chromosome,ifamalehastheX-chromosomewiththeGLAgenemutation,hewillbeaffectedwiththedisorder.Therefore,type1classicandtype2later-onsetmaleswithFabrydiseasearemoreuniformlyaffected,whereassymptomsinfemales,duetorandomX-inactivation,mayrangefromasymptomaticorasseverelyaffectedastheiraffectedmalerelatives(Dobrovolny2005,Echevarria2016)MaleswithX-linkedFabrydiseasetransmittheGLAgenemutationtoalltheirdaughters,whoareheterozygotes,butnevertotheirsons.Femaleheterozygoteshavea50percentriskoftransmittingthediseasetoeachoftheirchildren,bothdaughtersandsons,witheachpregnancy.TheGLAgenenormallyinstructsthebody’scellstomaketheα-GalAenzyme,whichbreaksdowntheaccumulatingglycolipids(GL-3/Gb3)inthecell’slysosomes.FabrydiseaseiscausedbymutationsintheGLAgene.Thereareover965reportedmutationsintheGLAgenethatareresponsibleforFabrydisease(Stenson2017;HumanGeneMutationDatabase;http://www.hgmd.org),causingthetype1or2phenotypes.Twodatabasesprovidephenotypeassignmentsforallreportedmutations:dbFGP.organdFabry-Database.org(Saito2011).Thus,theseverityandrangeofsymptomsmayvaryamongindividualsdependingontheGLAmutationintheirfamily.Somemutationsmarkedlyaltertheenzymesuchthatithaslittletonoactivity.Thesemutationscausethetype1classicsubtype(e.g.,Eng1997,Shabber2006),whileothermutationsresultinasmallamountofresidualenzymeactivityandthetype2later-onsetsubtype(e.g.,vonScheidt1991,Eng1997,Nakao2003,Spada2006).ThesignsandsymptomsofFabrydiseasedevelopduetoabsentormarkedlydeficientα-GalAenzymaticactivity.Patientswiththetype1classicphenotype,whohavenoorverylowactivitylevels(lessthan3%ofnormal),accumulatetheGL-3/Gb-3glycolipidsubstance(andrelatedglycolipids)inmosttissuesofthebody,especiallysmallbloodvessels,andcertaincellsintheheartandkidneys.Patientswiththetype2later-onsetphenotypehaveresidualenzymeactivity(3-15%ofmeannormalactivity,Desnick2001),alsoaccumulateGL-3/Gb3,buttoalesserextentandataslowerrate.Theytendtohaveasomewhatlesssevereformofthedisease,butmaleswiththetype2subtypeultimatelydevelopseverecardiacdiseaseand/orrenalfailure.TherearealsomutationsintheGLAgenethatarebenignanddonotcauseFabrydisease(e.g.,Froissart2003,Doheny2018)AffectedPopulationsFabrydiseaseisararepan-ethnicdisorder,meaningthatitoccursinallracialandethnicpopulationsaffectingmalesandfemales.Itisestimatedthattype1classicFabrydiseaseaffectsapproximatelyonein40,000males.Thetype2later-onsetphenotypeismorefrequent,thanthetype1phenotypeby3-10fold,andinsomepopulationsmayoccurasfrequentlyasabout1in1,500to4,000males(Spada2006,Hwu2009,Chien2012).DataemergingfromthenewbornscreeningstudiessuggeststhattheincidenceofFabrydiseasevariesindifferentgeographicregions(Spada2006,Hwu2009,Burlina2018,Wasserstein2019).Already,newbornscreeningforFabrydiseasehasbeeninitiatedinseveralstatesintheUSA.RelatedDisordersSymptomsofthefollowingdisorderscanbesimilartothoseofFabrydisease.Comparisonsmaybeusefulforadifferentialdiagnosis:Schindlerdiseaseisarareinheritedmetabolicdisordercharacterizedbyadeficiencyofthelysosomalenzymealpha-N-acetylgalactosaminidase(alpha-NAGA),whichleadstoanabnormalaccumulationofcertaincomplexcompounds(glycosphingolipidsandoligosaccharides)inmanytissuesofthebody(Schindler1989).Schindlerdiseaseisinheritedasanautosomalrecessivedisorder.TherearethreetypesofSchindlerdisease.Theclassicformofthedisorder,knownasSchindlerdisease,typeI,hasaninfantileonset.Affectedindividualsappeartodevelopnormallyuntilapproximatelyoneyearofage,whentheybegintolosepreviouslyacquiredskillsthatrequirethecoordinationofphysicalandmentalactivities(developmentalregression).Additionalneurologicalandneuromuscularsymptomsmaybecomeapparent,includingdiminishedmuscletone(hypotonia)andweakness;involuntary,rapideyemovements(nystagmus);visualimpairment;andepisodesofuncontrolledelectricalactivityinthebrain(seizures).Withcontinuingdiseaseprogression,affectedchildrentypicallydeveloprestrictedmovementsofcertainmusclesduetoprogressivelyincreasedmusclerigidity,severeintellectualdisability,hearingandvisualimpairment,andalackofresponsetostimuliintheenvironment.TypeIISchindlerdiseasealsoknownasKanzakidisease,istheadult-onsetformwithsymptomspresentinginthesecondorthirddecadeoflife(Kanzaki1993).Thedisorderischaracterizedbyangiokeratoma,askinlesionanddistributionsimilartothatseenintype1classicFabrydisease.Presentationmayalsoincludelymphedema,intellectualimpairment,anddistinctfacialfeaturesincludingmildlycoarsefeatures,thicklips,adepressednasalbridgeandanenlargedtipofthenose.TypeIIISchindlerdiseaseisanintermediateformthedisorder.Symptomscanrangefrommoreseriousintellectualimpairment,neurologicaldysfunctionandseizurestomilderneurologicalandpsychiatricissuessuchasspeechandlanguagedelaysandmildautism-likesymptoms.(Formoreinformationonthisdisorder,choose“Schindler”asyoursearchtermintheRareDiseaseDatabase.)Gaucherdiseaseisoneofthemostcommonofthelipidstoragediseasesandischaracterizedbytheabnormalaccumulationofcertainfattysubstancesinvariousorgansofthebody(Balwani2010).Symptomsdevelopduetoadeficiencyintheenzymeglucocerebrosidaseandmayincludeenlargementoftheliver(hepatomegaly)andspleen(splenomegaly),ageneralfeelingofillhealth(malaise),visualdifficulties,abdominalswelling,severebonepainandbonedisease.Gaucherdiseaseisinheritedasanautosomalrecessivetrait.(Formoreinformationonthisdisorder,choose“Gaucher”asyoursearchtermintheRareDiseaseDatabase.)Fucosidosisisanextremelyrareinheritedlysosomalstoragediseasecharacterizedbyadeficiencyoftheenzymealpha-L-fucosidase.Thereareatleasttwotypesoffucosidosis(i.e.,type1andtype2),determinedmainlybytheseverityoftheenzymedeficiencyandresultingsymptoms.Thesymptomsoffucosidosistype1,themostsevereformofthedisease,maybecomeapparentasearlyassixmonthsofage.SymptomsmayincludeaskinlesionsimilartoFabrydisease(angiokeratoma),progressivedeteriorationofthebrainandspinalcord(centralnervoussystem),intellectualdisability,lossofpreviouslyacquiredintellectualskills,andgrowthretardationleadingtoshortstature.Otherphysicalfindingsandfeaturesbecomeapparentovertime,includingmultipledeformitiesofthebones(dysostosismultiplex),coarsefacialfeatures,enlargementoftheheart(cardiomegaly),enlargementoftheliverandspleen(hepatosplenomegaly),and/orepisodesofuncontrolledelectricalactivityinthebrain(seizures).Additionalsymptomsmayincludeincreasedordecreasedperspirationand/ormalfunctionofthegallbladderand/orsalivaryglands.Fucosidosisisinheritedasanautosomalrecessivetrait.(Formoreinformationonthisdisorder,choose“fucosidosis”asyoursearchtermintheRareDiseaseDatabase.)Erythromelalgiaisarareconditionthatprimarilyaffectsthefeetand,lesscommonly,thehands.Itischaracterizedbyintenseburningpainofaffectedextremities,severeredness,andincreasedskintemperaturethatmaybeepisodicoralmostcontinuousinnature.(Formoreinformationonthisdisorder,choose“Erythromelalgia”asyoursearchtermintheRareDiseaseDatabase.)DiagnosisTheclinicaldiagnosisofthetype1classicphenotypecanbemadeclinicallybyphysicianswhorecognizethecharacteristicfindingsofepisodicpainintheextremities,absentordecreasedsweating(anhidrosisorhypohidrosis),typicalskinlesions(angiokeratoma),gastrointestinalabnormalities,andthecornealdystrophyinchildhoodoradolescence(Desnick2003).Thediseaseprogressestorenalinsufficiency,and/orheartandcerebrovasculardiseaseinadulthood.Intype2males,thediagnosisisoftenmissed,andmaybemadeinadulthoodwhenthecardiacand/orkidneydiseasebecomesmanifest.Manymaleswiththetype2later-onsetphenotypehavebeendiagnosedbyscreeningpatientsinhemodialysis,cardiac,andstrokeclinics(Doheny2018).Thediagnosisofbothtype1and2malesisconfirmedbydemonstratingtheenzymedeficiencyandbyidentifyingthespecificGLAgenemutation.Femaleheterozygotescanhaveα-GALAenzymaticactivityfrommarkedlydecreasedtovaluesinthenormalrange.Therefore,heterozygousfemalesareonlyaccuratelydiagnosedbydemonstratingthespecificα-galactosidaseA(GLA)genemutation.Earlyprenataldiagnosisatabout10weeksofpregnancycanbemadebyα-GalAenzymeandGLAmutationanalysesofvilliobtainedbychronicvillussampling,orbyamniocentesisatabout15weeksofgestationbydeterminingtheα-GalAenzymeactivityanddemonstratingthefamily-specificGLAmutation(Desnick2007).PreimplantationgeneticdiagnosisisavailablewhenthefamilialmutationintheGLAgeneisknown.Newbornscreeningstudieshaveidentifiedaffectedmalesbydemonstratingthereducedα-GalAactivityindriedbloodspotsfollowedbyGLAgenesequencing(e.g.,Spada2006,Burlina2018,Wasserstein2019).StandardTherapiesTreatmentFabrydiseasecausesmulti-organdysfunctionandpatientsneedacomprehensive,multi-disciplinarytreatmentplanthatisindividuallytailoredandincludesspecifictherapiesthattargetabnormalsubstrateaccumulationandadjuvanttherapiesthataddressend-organdamage(Ortiz2018).Enzymereplacementtherapy(ERT)isthecornerstonefortreatmentofFabrydiseaseandsyntheticenzyme,producedbyrecombinantDNAtechnology,isinfusedintravenously.Twoformsoftherecombinantenzymeareavailable,agalsidasealpha(Replagal®,Shirepharmaceuticals)andagalsidasebeta(Fabrazyme®,SanofiGenzyme).FabrazymeistheonlyERTapprovedbytheFoodandDrugAdministration(FDA)in2003.BothReplagalandFabrazymeareavailableinEuropeandotherregionsoftheworld.ERTreplacesthemissingenzymeandreducestheaccumulatedglycolipidsincellsthroughoutthebody.Double-blind,placebo-controlledPhase3and4clinicaltrialshavedemonstratedthesafetyandeffectivenessofFabrazyme(Eng2001A,2001B;Banikazemi2007,Fellgiebel2014,Germain2015).ERThasbeenshowntosloworpreventthedeclineofrenalfunctionespeciallyifinitiatedearlybeforeadvancedkidneydamage,improveneuropathicpainandheatintolerance(Eng2001,Germain2015).GlobotriaosylceramideaccumulationisclearedfromvariouscelltypesinthekidneyfollowingERT(Tondel2013,Skrunnes2017).EarlyinitiationofERTisimportantespeciallyintype1classicallyaffectedmales.ERTinitiationiscurrentlyrecommendedfortype1Classicmaleswithclnicalmanifestationsatanyage,orifasymptomatic,byage15(Hopkin2016,Ortiz2018).Recombinantenzyme“biosimilars”areavailableincertaincountriesincludingKoreaandJapan.Severalotherrecombinantenzymepreparationsareinclinicaldevelopment.Anoraltherapy,Galafold(migalastat,AmicusTherapeutics)wasapprovedintheEU(2017)andintheUS(2018)totreatadultswithFabrydisease.Thedrugisapharmacologicchaperonethatcanbindto,stabilize,andenhancetheresidualenzymaticactivityofcertainmissensemutations(DesnickandSchuchman2002,Benjamin2017).Clinicalstudieshavedemonstratedtheeffectivenessofthisapproach(Germain2016).Futurestudieswilldeterminetheclinicalandbiochemicaleffectivenessofspecificmissensemutationswithresidualactivity.Adjuncttherapiesincludelowdailydosesofdiphenylhydantoin,carbamazepine,orneurontin,tohelptomanagetheacroparesthesia(Burlina2011).Otherlatercomplications(e.g.,kidneyfailureorheartproblems)shouldbetreatedsymptomaticallyafterconsultationwithaphysicianwhoisexperiencedinthecareofpatientswithFabrydisease.Hemodialysisandkidney(renal)transplantationmaybenecessaryincasesthathaveprogressedtokidneyfailure(Thadhani2002,Ersözlü2018).Geneticcounselingisrecommendedforaffectedindividualsandtheirfamilies.InvestigationalTherapiesTrialsofgenetherapyarealsounderway.InformationoncurrentclinicaltrialsispostedontheInternetatwww.clinicaltrials.gov.AllstudiesreceivingU.S.governmentfunding,andsomesupportedbyprivateindustry,arepostedonthisgovernmentwebsite.ForinformationaboutclinicaltrialsbeingconductedattheNIHClinicalCenterinBethesda,MD,contacttheNIHPatientRecruitmentOffice:Toll-free:(800)411-1222TTY:(866)411-1010Email:[email protected]SomecurrentclinicaltrialsalsoarepostedonthefollowingpageontheNORDwebsite:https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/Forinformationaboutclinicaltrialssponsoredbyprivatesources,inthemain,contact:www.centerwatch.comFormoreinformationaboutclinicaltrialsconductedinEurope,contact:https://www.clinicaltrialsregister.eu/ContactforadditionalinformationaboutFabrydisease:InternationalCenterforFabryDiseaseIcahnSchoolofMedicineatMountSinaiFifthAvenueat100thStreetNewYork,NY10029(212)659-6700Toll-free:1-866-FABRY-MDSupportingOrganizationsFabrySupport&InformationGroup108NE2ndStreetSuiteCConcordia,MO64020-0510USAPhone:(660)463-1355Email:[email protected]Website:http://www.fabry.orgInternationalCenterforFabryDiseaseMountSinaiSchoolofMedicineFifthAvenueat100thStreetNewYork,NY10029USAPhone:(212)659-6700Toll-free:(866)322-7963Email:[email protected]Website:http://www.mssm.edu/research/programs/international-center-for-fabry-diseaseMetabolicSupportUKUnit11-12GwenfroTechnologyPark,CroesnewyddRdWrexham,WalesLL137YPUnitedKingdomPhone:0124420758108452412173Email:[email protected]Website:https://www.metabolicsupportuk.org/NationalFabryDiseaseFoundation4301ConnecticutAve.N.W.,Suite404Washington,DC20008-2369Toll-free:(800)651-9131Email:[email protected]Website:http://www.fabrydisease.org/ProyectoPideunDeseoMéxico,i.a.p.Altadena#59-501NápolesBenitoJuárez,03810México,D.F.Phone:525555432447Email:[email protected]Website:http://www.pideundeseo.orgReferencesTEXTBOOKSDesnickR,IoannouY,EngC.Alpha-GalactosidaseAdeficiency:Fabrydisease.In:ScriverCR,BeaudetAL,SlyWS,ValleD,eds.TheMetabolicandMolecularBasesofInheritedDisease.8thed.NewYork,NY:McGraw-Hill;2001:3733-3774.JOURNALARTICLESArends,M,etal.CharacterizationofClassicalandNonclassicalFabryDisease:AMulticenterStudy.JAmSocNephrol.2017;28:1631-1641.BalwaniM,FuerstmanL,KornreichR,EdelmannL,DesnickRJ.TypeIGaucherdisease:Significantdiseasemanifestationsin“asymptomatic”homozygotes.ArchInternMed.2010;170:1463-1469.BanikazemiM,etal.Agalsidase-betatherapyforadvancedFabrydisease:Arandomizedtrial.AnnInternMed.2007;146:77-86.BenjaminER,etal.ThevalidationofpharmacogeneticsfortheidentificationofFabrypatientstobetreatedwithmigalastat.2017;19:430-443.BurlinaAB,PoloG,SalviatiL,DuroG,ZizzoC,DardisA,etc.NewbornscreeningforlysosomalstoragedisordersbytandemmassspectrometryinNorthEastItaly.JInheritMetabDis.2018;41:209-219.BurlinaAP,SimsKB,PoliteiJM,BennettGJ,BaronR,SommerC,MøllerAT,HilzMJ.EarlydiagnosisofperipheralnervoussysteminvolvementinFabrydiseaseandtreatmentofneuropathicpain:thereportofanexpertpanel.BMCNeurol.2011;11:61.ColeAl,LeePJ,HughesD,DeeganPB,WaldekS,LachmanRH.DepressioninadultswithFabrydisease:Acommonandunder-diagnosedproblem.JInheritMetabDis.2007;30:943–951ChienYH,Ni-ChunL,HianSC,DesnickRJ,HwuWL:Fabrydisease:Incidenceofthecommonlater-onsetα-galactosidaseAIVS4+919G>AmutationinTaiwanesenewborns–SuperiorityofDNA-basedtoenzyme-basednewbornscreeningforcommonmutations.MolMed.2012;18:780-784.ColumbiA,KostyalA,BracherR,GloorF,MazziR,ThölenH.Angiokeratomacorporisdiffusum–fabryDisease.HelvMedActa.1967;34:67-83DesnickRJ,SchuchmanEH.Enzymereplacementandenhancementtherapies:Lessonsfromlysosomaldisorders.NatureRevGenet.2002;3:954-966.DesnickRJ,etal.Fabrydisease,anunder-recognizedmultisystemicdisorder:expertrecommendationsfordiagnosis,management,andenzymereplacementtherapy.AnnInternMed.2003;138:338-346.DesnickRJ,BradyRO.Fabrydiseaseinchildhood.J.Pediatr.2004;144:520-526.DesnickRJandBanikazemiM.Fabrydisease:Clinicalspectrumandevidence-basedenzymereplacementtherapy.NephrolTher.2006;Suppl2:S172-S185.DesnickRJ.PrenataldiagnosisofFabrydisease.PrenatDiag.2007;27:693-694.DobrovolnyR,etal.RelationshipbetweenX-inactivationandclinicalinvolvementinFabryheterozygotes.Elevennovelmutationsinthealpha-galactosidaseAgeneintheCzechandSlovakpopulation.JMolMed(Berl).2005;83:647-54.DohenyD,SrinivasanR,PagantS,ChenB,YasudaM,DesnickRJ.:Fabrydisease:PrevalenceofaffectedmalesandheterozygoteswithpathogenicGLAmutationsidentifiedbyscreeningrenal,cardiacandstrokeclinics,1995-2017.J.MedGenet.2018;55:261-268.EchevarriaL,etal.X-chromosomeinactivationinfemalepatientswithFabrydisease.ClinGenet.2016;89:44-54.EngCM,AshleyGA,BurgertTS,EnriquezAL,D’SouzaM,DesnickRJ.Fabrydisease:Thirty-fivemutationsintheα-galactosidaseAgeneinpatientswithclassicandvariantphenotypes.MolMed.1997;3:174-182.EngCM,etal.Aphase1/2clinicaltrialofenzymereplacementinFabrydisease:pharmacokinetic,substrateclearance,andsafetystudies.AmJHumGenet.2001A;68:711-722.EngCM,etal.Safetyandefficacyofrecombinanthumanalpha-galactosidaseAreplacementtherapyinFabry’sdisease.NEnglJMed.2001B;345:9-16.ErsözlüS,etal.Long-termoutcomesofkidneytransplantationinFabrydisease.Transplantation.2018;102:1924-1933.FellgiebelA,etal.CNSmanifestationsofFabry’sdisease.LancetNeurol.2006;5:791-795.FellgiebelA,GartenschlägerM,WildbergerK,ScheurichR,DesnickRJ,SimsK:EnzymereplacementtherapystabilizedwhitematterlesionprogressionwithFabrydisease.CerebrovascDis.2014;38:448-456.FroissartR,GuffonN,VanierMT,DesnickRJ,MaireI.Fabrydisease:D313Yisanalpha-galactosidaseAsequencevariantthatcausespseudodeficientactivityinplasma.MolGenetMetab.2003;80:307-314.FrustaciA,ChimentiC,DohenyD,Desnick,RJ:EvolutionofcardiacpathologyinclassicFabrydisease:Progressivecardiomyocyteenlargementleadstoincreasedcelldeathandfibrosis,andcorrelateswithseverityofventricularhypertrophy.IntJCardiol.2017;248:257-262.GermainDP,etal.Fabrydisease.OrphanetJRareDis.2010;5:30.GermainDP,etal.Ten-yearoutcomeofenzymereplacementtherapywithagalsidasebetainpatientswithFabrydisease.JMedGenet.2015;52:353-358.GermainDP,etal.TreatmentofFabry’sDiseasewiththePharmacologicChaperoneMigalastat.NEnglJMed.2016;375:545-555.HopkinRJ,JefferiesJL,LaneyDA,LawsonVH,MauerM,TaylorMR,WilcoxWR;FabryPediatricExpertPanel.ThemanagementandtreatmentofchildrenwithFabrydisease:AUnitedStates-basedperspective.MolGenetMetab.2016;117:104-113.HwuWL,etal.NewbornscreeningforFabrydiseaseinTaiwanrevealsahighincidenceoftheLater-OnsetGLAmutationc.936+919G>A(IVS4+919G>A).HumMutat.2009;30:1397-1405.KanzakiT,YokotaM,IrieF,HirabayashiY,WangAM,DesnickRJ.Angiokeratomacorporisdiffusumwithglycopeptiduriaduetodeficientlysosomalα-N-acetylgalactosaminidaseactivity:Clinical,morphologicandbiochemicalstudies.ArchDermatol.1993;129:460-465.MeehanS,JusantoT,RydelJJ,DesnickRJ.Fabrydisease:Renalinvolvementlimitedtopodocytepathologyandproteinuriainaseptuagenariancardiacvariant.Pathologicandtherapeuticimplications.AmJKidneyDis.2004;43:164-171.NajafianB,MauerM,HopkinRJ,SvarstadE.RenalcomplicationsofFabrydiseaseinchildren.PediatrNephrol.2013;28:679-687.NakaoS,etal.AnatypicalvariantofFabry’sdiseaseinmenwithleftventricularhypertrophy.NEnglJMed.1995;333:288-293.NakaoS,etal.Fabrydisease:Detectionofundiagnosedhemodialysispatientsandidentificationofa“renalvariant”phenotype.KidneyInt.2003;64:801-807.OrtizA,etal.Fabrydiseaserevisited:Managementandtreatmentrecommendationsforadultpatients.MolGenetMetab.2018;123:416–427.SaitoS,OhnoK,SakurabaH.Fabry-database.org:databaseoftheclinicalphenotypes,genotypesandmutantα-a-galactosidaseAstructuresinFabrydisease.JHumGenet.2011;56:467-468.SchiffmannR,etal.Fabrydisease:progressionofnephropathy,andprevalenceofcardiacandcerebrovasculareventsbeforeenzymereplacementtherapy.NephrolDialTransplant.2009;24:2102-2111.SchindlerD,etal.Neuroaxonaldystrophyduetolysosomalα-N-acetylgalactosaminidasedeficiency.Clinical,pathologicandbiochemicaldelineation.NEnglJMed.1989;320:1735-1740.ShabbeerJ,YasudaM,BensonSD,DesnickRJ.Fabrydisease:identificationof50novelalpha-galactosidaseAmutationscausingtheclassicphenotypeandthree-dimensionalstructuralanalysisof29missensemutations.HumGenomics.2006;2:297-309.SherNA,LetsonRD,DesnickRJ.TheocularmanifestationsinFabry’sdisease.ArchOphthalmol.1979;97:671-676.SkrunesR,etal.ReaccumulationofglobotriaosylceramideinpodocytesafteragalsidasedosereductioninyoungFabrypatients.NephrolDialTransplant.2017;32:807-813.SpadaM,etal.HighincidenceofLater-OnsetFabrydiseaserevealedbynewbornscreening.AmJHumGenet.2006;79:31-40.Stenson,PD,etal.TheHumanGeneMutationDatabase:TowardsaComprehensiveRepositoryofInheritedMutationDataforMedicalResearch,GeneticDiagnosisandNext-GenerationSequencingStudies.HumGenet.2017;136:665-77.Svensson,CK,Feldt-RasmussenU,BackerV.Fabrydisease,respiratorysymptoms,andairwaylimitation–asystematicreview.EurClinRespirJ.2015;2:1-8.ThadhaniR,etal.PatientswithFabrydiseaseondialysisintheUnitedStates.KidneyInt.2002;61:249-255.TøndelC,BostadL,HirthA,SvarstadE.RenalbiopsyfindingsinchildrenandadolescentswithFabrydiseaseandminimalalbuminuria.AmJKidneyDis.2008;51:767-776.TøndelC,BostadL,LarsenKK,HirthA,VikseBE,HougeG,SvarstadE.:AgalsidasebenefitsrenalhistologyinyoungpatientswithFabrydisease.JAmSocNephrol.2013;24:137-148.WassersteinMP,etal.TheNewYorkpilotnewbornscreeningprogramforlysosomalstoragediseases:ReportoftheFirst65,000Infants.GenetMed.2019;21:631-640WilcoxWR,etal.FemaleswithFabrydiseasefrequentlyhavemajororganinvolvement:LessonsfromtheFabryRegistry.MolGenetMetab.2008;93:112-128.vonScheidtW,etal.AnatypicalvariantofFabry’sdiseasewithmanifestationsconfinedtothemyocardium.NEnglJMed.1991;324:395-399.YearsPublished1986,1994,1995,1997,1998,1999,2001,2002,2003,2004,2007,2009,2012,2015,2019TheinformationinNORD’sRareDiseaseDatabaseisforeducationalpurposesonlyandisnotintendedtoreplacetheadviceofaphysicianorotherqualifiedmedicalprofessional.ThecontentofthewebsiteanddatabasesoftheNationalOrganizationforRareDisorders(NORD)iscopyrightedandmaynotbereproduced,copied,downloadedordisseminated,inanyway,foranycommercialorpublicpurpose,withoutpriorwrittenauthorizationandapprovalfromNORD.Individualsmayprintonehardcopyofanindividualdiseaseforpersonaluse,providedthatcontentisunmodifiedandincludesNORD’scopyright.NationalOrganizationforRareDisorders(NORD)55KenosiaAve.,DanburyCT06810•(203)744-0100ReportIndexSynonymsSubdivisionsGeneralDiscussionSigns&SymptomsCausesAffectedPopulationsRelatedDisordersStandardTherapiesInvestigationalTherapiesSupportingOrganizationsReferencesRelatedContentNORDPatientAssistanceNORDstrivestoopennewassistanceprogramsasfundingallows.Ifwedon'thaveaprogramforyounow,pleasecontinuetocheckbackwithus.LearnMore>NORDVideo:RareDiseaseFactsNORDProgramAlonewearerare.Togetherwearestrong.®SignUpforNORDNews!FollowNORD×