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Progressivedepositionofglycosphingolipidmeansthatthecardiacproblems
themselvesarealsoprogressive.Sinceconcomitantrenalinvolvementoccurs,
thecardiaceffectsareexacerbatedby,forexample,renalhypertension.The
clinicalcourseinthemalehomozygoteisoneofsteadydeteriorationduring
earlyadultlife,deathbeingduetocardiacorrenaldisease.Theheterozygote
femaleexperienceslittlelimitationofstyleandlengthoflife.Thediagnosiscan
beconfirmed(andheterozygotesidentified)bydemonstratingtheenzymic
deficiencyinleukocytesandbyanabnormallyhighcontentofaccumulated
substratesintearsorurinarysediment.Prenataldiagnosisisavailable.Enzyme
replacementtherapywasfirstreportedin2002,112andpositiveeffectsoncardiac
involvementareevident.113Fabrydiseaseshouldbeconsideredwhenever
unexplainedleftventricularhypertrophyisdiscovered,asearlydiagnosisand
initiationofenzymereplacementtherapyhasshownclearbenefit.114

Gangliosidoses
Thegangliosidosesarelysosomalstoragediseasescharacterizedby
accumulationofgangliosidesgm1orgm2(orrelatedconjugates)owingto
deficiencyofspecificlysosomalhydrolases.Theenzymedeficientingm1
gangliosidosisisacidβ-galactosidase.Deficiencyofhexosaminidaseaorb(or
both)oradeficiencyofanenzymeactivatorresultsingm2gangliosidosis.

Gm1Gangliosidosis
Therearemanyenzymaticandclinicalsubdivisionsofgm1gangliosidosis.The
genelocusisontheshortarmofchromosome3.Mutationatthislocusresultsin
absenceofenzymeactivityforacidβ-galactosidase,leadingtoaccumulationof
gm1gangliosideinthebrainandviscera.Thewidevariationinclinicalpicture
hasresultedinabroadclassificationofinfant,juvenile,andadultforms.All
formsofgm1gangliosidosisareinheritedasautosomalrecessivetraits.
Theinfantformisarapidlyprogressivediseasecharacterizedbyhypotonia,
poorfeeding,andfailuretomakemotororintellectualprogress.Progressive
neurologicdeteriorationresultsinspasticquadriplegiaordecerebraterigidity.

Rarefiedbonesandbeakedvertebraearesomeoftheskeletallesions
encountered.AsinTay-Sachsdisease(seelater),acherry-redspotisseeninthe
macularregionoftheretina.Deathusuallyoccursbytheageof3years,


frequentlyfrombronchopneumonia.Theheartisfrequentlyinvolved.The
spectrumfromCHFwithsystolicdysfunctiontoisolatedvalvethickeninghas
beenobserved.115,116Neonatalasciteshasalsobeenreported.117Cardiac
involvementusuallyincludescardiomegalyonchestradiography,leftventricular
hypertrophyontheechocardiogram,andCHF.118Interestingly,patientswithgm1
gangliosidosishaveadefectinthesameenzymethatisinvolvedinpatientswith
Morquiosyndrometypeb.Theclinicalheterogeneityamongpatientswiththis
enzymaticdefectisunclearbutisprobablyrelatedtoresidualactivityofthe
enzyme,postprocessingoftheenzyme,andotherproteinsinvolvedsuchas
saposinb.119Anoveltreatmentstrategyisunderinvestigationinvolving
molecularchaperones,substancesthatstabilizetheconfigurationofdefective
enzymesandenablethemtoremainenzymaticallyactive.120Treatmentina
mousemodeldemonstratedimprovedenzymeactivity121andareducedquantity
ofsubstrateinneuronaltissues;however,noviabletherapyforhumansyet
exists.122,123

Gm2Gangliosidoses
Thegm2gangliosidosesareautosomalrecessiveconditionsthatresultinvariable
deficiencyofhexosaminidase,thelocusforwhichhasbeenmappedtotheqarm
ofchromosome5.Thisenzyme,whichiscomposedoftwosubunits(αandβ),
comesintwoforms.Hexosaminidasea(foundinthecentralnervoussystem)is
composedofanα-andβ-subunit,andhexosaminidaseb(foundinperipheral
tissues)iscomposedoftwoβsubunits.Thusthegm2gangliosidosesresultfrom
adefectineithertheα-subunit(Tay-Sachsdisease,severedeficiencyof
hexosaminidasea)ortheβ-subunit(Sandhoffdisease,withseveredeficiencyof

bothtypesaandboftheenzyme).Thejuvenileandadult(chronic)gm2
gangliosidosesresultfromlessseveredeficienciesofhexosaminidasetypea.
Treatmentforthesedisordersisstillunderinvestigationusinganimalmodels.
Effortshaveincludedgenetherapy,substratereductiontherapy,andbone
marrowtransplantation,althoughnoneofthesetreatmentshasyettoshowclinic
benefitinhumans.124–127
Tay-SachsDisease.
Tay-Sachsdiseaseisthemostcommonofthegangliosidoses;itpresentswith
motorweaknessinthefirst6monthsoflife.Thereisprogressivemotorand


mentaldeterioration,withconvulsions,spasticityanddecerebraterigidity.Death
usuallyoccursbytheageof3years,themostfrequentcausebeing
bronchopneumonia.Thechildrenhavedoll-likefacies.Examinationoftheretina
showsthetypicalcherry-redmacula,whichlaterbecomesbrown.Cardiac
accumulationofsubstrateisusual;however,saveforaprolongedQTinterval
andnonspecificT-wavechanges,cardiacmanifestationsarerare.Althoughthe
hallmarkofthediseaseiscentralnervoussystemaccumulationofgm2
ganglioside,evidenceofperipheralandautonomicnervoussysteminvolvement
hasbeenreportedinpatientswithchronicdisease.128
SandhoffDisease.
SandhoffdiseaseissimilartoTay-Sachsdiseaseinitspresentationandcourse
butisbiochemicallydistinct.Clinicallyrelevantcardiacinvolvementisrare,but
acardiomyopathyhasbeendescribed,alongwiththickeningofthemitralvalve
anditstensionapparatus.129AnotherseparatereportdescribesacaseofCHF
duetoaorticandmitralvalvethickeningwithseveremitralregurgitation.130The
coronaryarteriesmayalsobenarrowed.131Aswithgm1gangliosidoses,the
inheritanceisautosomalrecessive.