Andersons pediatric cardiology 1557

Sphingolipidoses
SphingomyelinLipidosis(Niemann-Pick
Disease)
InNiemann-Pickdisease,thereisaccumulationofsphingomyelininthecellsas
aresultofdeficiencyofsphingomyelinase(typeaandb).Aseconddistinctform
(typec)wasrecentlydiscovered,whicharisesfromthedefectivefunctionof
cholesteroltransport.99Theprimarycellsaffectedarethoseofmonocytemacrophagelineageastheyarefrequentlyemployedinthemetabolicturnover
ofthesesubstances.Intypea,patientsexhibithepatosplenomegalyininfancy
andprofoundcentralnervoussysteminvolvement.Theseindividualsrarely
survivebeyond3yearsofage.Typebpatientsalsohavehepatosplenomegaly
alongwithpathologicalterationsintheirlungs,butthereareusuallynocentral
nervoussystemsigns.Intypec,psychosispredominatesinitially.100Manyof
thesepatientsareofAshkenaziJewishheritage.Thediseaseischaracterizedby
hepatosplenomegalyandtheoccurrenceoffoamstoragecellsinmanytissues.
Theheartisnotusuallyaffected,butoneinfantwithacuteneuronopathicdisease
hadendocardialfibroelastosis.101Sincetherewerenostoragecellsintheheart,
however,thismayhavebeenachanceassociation.Lipidprofileabnormalities
havealsobeendescribedinchildrenwithNiemann-Pickdiseasetypesaandb,
possiblyleadingtoprematureatherosclerosis.102Lowlevelsofhigh-density
lipoproteincholesterolwasthemostconsistentfinding,whereaselevated
triglyceridesandlevelsoflow-densitylipoproteincholesterolwereseenin
approximatelytwo-thirds.Theseabnormalitieswerenotedatanearlyageand
mayreflectderangedcholesterolmetabolisminthesecellsasaresultof
sphingomyelinaccumulation.Niemann-Pickdiseaseinmostofitsformsis
inheritedinanautosomalrecessivefashion.

Glucosylceramidosis(GaucherDisease)
Gaucherdiseaseisthemostcommoninheriteddisorderofglycolipid
metabolism.Inhisoriginaldescription,103PhillippeGaucherascribedthe
changestoaprimaryepitheliomaofthespleen.Thereisexcessiveaccumulation
ofglucosylceramideincellsofthereticuloendothelialsysteminorgans

throughoutthebody,resultingfromdeficiencyoftheenzyme
glucocerebrosidase,whichcleavesglucosefromglucocerebroside.Although


over150differentmutationsofthegeneencodingglucocerebrosidasehavebeen
described,thediseaseoccursinthreevarietiesbasedonthepresenceorabsence
ofneurologicmanifestationsandtheirrateofprogression.Thefirst(typeI,the
chronicnonneuronopathicform)canbediagnosedatanyageandisthemost
commonform.Itischaracterizedbyhypersplenism,hepatomegaly(with
evidenceofabnormalliverfunction),andskeletallesions(includingaseptic
necrosisofthefemoralhead).Otherlongbonesandvertebraemayalsobe
eroded.Inpatientswiththistypeofdisease,cardiacinvolvementmaybeseen,
withmyocardialinfiltrationorrestrictivepericardialdisease.104Themost
frequentlyencounteredcardiacproblem,however,iscorpulmonalesecondaryto
pulmonaryinvolvement.Mitralandaorticstenosisandinsufficiencycanalsobe
seen,105andseverevalvarandaorticarchcalcificationhasbeenreported.106The
courseisvariable.Deathmayoccurinearlychildhoodor,particularlywhenthe
onsetislate,theremaybeanormallifeexpectancy.Furthervariabilityis
apparentlytheconsequenceofthenonneuronopathicformatonsetchangingto
oneoftheotherformswithpoorerprognosis.
Theacuteneuronopathicform(typeII)isusuallyrecognizedwithinthe
secondhalfofthefirstyearoflife.Neurologicinvolvementisevidentearly,
afflictingparticularlythecranialnervesandextrapyramidaltracts.The
mechanismofdeathisusuallyarespiratoryinfection,since—owingto
incoordinationofthenasopharynx—aspirationiscommon.
Thesubacuteneuronopathicform(typeIII)fallsbetweentheacuteand
chronicforms.Theneurologicinvolvementrendersitlessbenignthanthe
chronicvariant,butitscourseusuallystretchesovermanyyears.
AlthoughdescribingGaucherdiseaseintermsofthreedistinctphenotypesis
convenient,theactualobservedbehaviorofthisdiseaseismuchlesswell

defined.Patientswiththesamegenotypecanhavewidelydifferingphenotypes,
andpatientsevenwithinaparticulartypecanhavemarkedlydifferingclinical
courses.Thus,althoughthegeneticdefectsleadingtoGaucherdiseasearebeing
elucidatedandincludeover150specificmutationsalreadyidentified,the
genotype-phenotypelinkisstillquiteunclear.
ThediagnosisofGaucherdiseaseisconfirmedbythefindingoftypical
storagecellsinthebonemarroworbyliverbiopsy.TheGauchercellislarge
andlipid-laden.Thecytoplasmisdescribedashavinga“wrinkledtissuepaper”
or“crumpledsilk”appearance.Thenucleusiseccentric.Thesecellsmustbe
differentiatedfromcellsfoundinmultiplemyeloma,leukemia,thalassemia,and
congenitaldyserythropoieticanemia.Demonstrationoftheenzymicdeficiency


inculturedskinfibroblastsorinleukocytesconfirmsthediagnosis.Treatment
optionsincludebonemarrowtransplantationandgenetherapyinrarecases,but
enzymereplacementtherapyhasbecomethestandardofcareinthemajorityof
cases.Infact,typeIGaucherdiseasewasthefirstlysosomalstoragedisorderfor
which,in1991,aneffectiveenzymereplacementtherapywasdeveloped.107
Improvementinthevisceralorganinvolvementiscommon,butneurologic
damageisgenerallynotresponsivetoexogenousenzymetherapy.Allthree
variantsareinheritedasautosomalrecessivetraits.Intrauterinediagnosisis
available,andheterozygotescanbeidentifiedatleastfortheacuteandchronic
types.

α-GalactosidaseaDeficiency(FabryDisease)
Deficiencyofα-galactosidase,alysosomalenzyme,resultsintheaccumulation
ofphosphosphingolipidsinthelysosomesofmanytissuesandalsointhebody
fluids.Themostfrequentlyaffectedtissueisthevascularendothelium.The
diseaseisofX-linkedinheritance,butheterozygouswomencanshowsevere
manifestationsofthedisease.108Thegenelocusfortheenzymeisonthelong

armoftheX-chromosome.
Thediseaseusuallypresentsinchildhoodinthemalehomozygote,oftenwith
periodiccrisesofseverepainofburningcharacter,whichusuallystartsinthe
handsandfeet.Crisesoccurmostusuallyintheafternoon.Suchcrises,which
becomelessfrequentandseverewithtime,may,however,befollowedby
eruptionofskinlesions,angiokeratomas,andtypicalopacitiesofthecorneaand
thelens.Theangiokeratomasareclustersofdark-redtopurplepunctatelesions,
whichareusuallyflatorslightlyraised.Theyoccurmostfrequentlybetweenthe
umbilicusandthekneesanddonotblanchonpressure.Hyperkeratosisand
hypohydrosisusuallyaccompanytheangiokeratomas.Ocularlesionsinclude
typicalcreamywhorl-likeopacitiesinthecornea.Theyarefrequentlyfoundin
thefemaleheterozygoteaswellasthemalehomozygote.Cardiacdiseaseis
manifestwithincreasingage.Myocardialischemiaandinfarctionarecommon
andaresecondarytothevascularlesions.Mitralregurgitationandaorticstenosis
arethemostfrequentlyencounteredvalvarlesions.109Infiltrationofthe
conductiontissuesalsooccurs.ThisresultsinprogressiveshorteningofthePR
interval,asinotherstoragediseasesthataffectthespecializedatrioventricular
conductionaxis.110Myocardialdepositioncanbedetectedechocardiographically
bythedemonstrationofseptalandleftventricularwallthickening.111