Andersons pediatric cardiology 1555

undertakenandholdssomepromise.54

MucopolysaccharidosisTypeVI(MaroteauxLamySyndrome)
Deficiencyofarylsulfatasebresultsinaninabilitytohydrolyzethesulfate
groupsindermatansulfate.TheclinicalpictureissimilartothatofHurler
syndrome,butnormalintelligenceisusual.Althoughsevereinitsclassicalform,
mildervariationsexist.Affectedinfantscanpresentacutelywith
cardiomyopathy.55Themitralandaorticvalvesarefrequentlyinvolvedandthe
diseaseistypicallyprogressive.Regurgitationistheprimaryvalvedisorder,but
stenosisoracombinationorstenosisandregurgitationwillbecomemore
commonovertime.Valvardysfunctionsevereenoughtonecessitatereplacement
hasbeennotedinyoungadults.56Leftventricularaneurysmhasalsobeen
reported.57Deathusuallyoccursinthethirddecade.Theconditionisinheritedin
anautosomalrecessivefashion,althoughsomecaseshavebeenpresumedtobe
X-linked.58Enzymereplacementtherapywithhumanrecombinantarylsulfatase
bhasbeenstudiedandfoundtobeeffectiveintermsofarrestingtheprogression
ofcardiacvalvediseasewhenstartedlateinlife,butitispostulatedthatitmay
haveevenbetterefficacyifstartedinearlyinfancy.59,60

MucopolysaccharidosisTypeVII(SlySyndrome)
Deficiencyofβ-glucuronidaseresultsinaclinicalsyndromeofextremely
variableseverity.Includedinthefeaturesarecoarsefacies,cornealclouding,
abdominalandinguinalhernias,puffyhandsandfeet,hepatosplenomegaly,and
asmallthoracolumbarhump.Cardiovascularmanifestationsinclude
hypertension,aorticaneurysm,valvethickening,aorticregurgitation,obstructive
arterialdiseaseincludingcoronaryinvolvement,andcardiomyopathy.61–63Fetal
hydropshasalsobeenreported.64Thisextremelyrareconditionisinheritedin
autosomalrecessivefashion.Durationofsurvivalvarieswidelyanddependson
theseverityofthedisease.Deathasearlyas30monthshasoccurredinonechild
withseveredisease.Animalstudiesinvolvingenzymereplacementtherapyhave
beenperformedandareencouragingintermsofimprovingthecardiovascular

changesassociatedwiththisdisease.65


Mucolipidoses
Themucolipidosespresentwithclinicalfeaturessimilartothe
mucopolysaccharidosesbutarebiochemicallydistinct.LeroyandDemars66
observedinclusionsinculturedfibroblaststhatoccupiedthewholecytoplasmic
spaceapartfromtheGolgiapparatus.Itwasbecauseofthisthatthename
inclusion-cell,ori-cell,diseasewascoined.Thecauseofthelysosomalstorage
defectisdeficiencyofseveralacidhydrolasesinthelysosome,butthisisnotthe
primaryproblem,sincetheplasmaaboundsintheseacidhydrolases(albeitin
unstableforms).Theproblemisfailuretolocatethehydrolaseswithinthe
lysosome.Failureofphosphorylationofmannoseresiduesofthehydrolasesis
theprimarydefect.Hydrolaseswithoutmannose6-phosphatecomponentsare
thennotrecognizedbythelysosomeandarenottransportedacrossthe
lysosomalmembrane,particularlyinconnectivetissue.Inthisway,inclusioncelldiseaseandpseudo-Hurlerpolydystrophydifferfromsialidosis(previously
calledmucolipidosistypeI),wherethereisasinglelysosomalenzymedefect.
MucolipidosestypesII(inclusion-celldisease)andIII(pseudo-Hurler
polydystrophy)resultfromadeficiencyofuridinediphosphate(udp)-nacetylglucosamine:lysosomalenzymen-acetylglucosamine-1phosphotransferase.Thedegreetowhichthisenzymeisdeficientdeterminesthe
ultimatephenotype.Diagnosisissuggestedbyclinicalfeaturesresembling
mucopolysaccharidosesbutwithouttheirbiochemicalabnormalities.Findingsof
highserumlevelsofβ-hexosaminidases,iduronatesulfatase,andarylsulfatase
arediagnostic.Thecharacteristicenzymaticdeficienciesinfibroblastscanbe
identifiedinculturedcells.

MucolipidosisTypeII(Inclusion-CellDisease,ICellDisease)
Inclusion-celldiseaseisanautosomalrecessiveconditionthatresultsfroma
severedeficiencyofthephosphotransferaseenzymeduetospecificgene
mutationsthatresultinamarkedreductioninenzymeactivity.Variousdefectsin
thegeneencodingthisenzymehavebeendiscoveredinpatientswiththis

disorder.67Patientswithinclusion-celldiseasepresentwithclinicalfeaturesvery
similartothoseofHurlersyndrome.Hepatosplenomegalyisnotsoobvious,
whereasstrikinggingivalhypertrophyisafeaturenotencounteredinHurler
syndrome.Furthermore,thediseasebecomesevidentearlierthandoesHurler


syndrome.Cornealcloudingistherule.Theskeletalandjointabnormalities,
togetherwithmyocardialinfiltration,usuallyleadtodeathbytheageof5years
eitherfromrespiratorycausesorcardiacfailure.Allchildrenhavecardiac
involvement,frequentlywiththickeningandinsufficiencyofthemitralvalve
and,lessfrequently,theaorticvalve.68Asymmetricseptalhypertrophyhasbeen
reported.69Treatmentofthecardiacmanifestationsisusuallysupportive,
althoughsurgicalmanagementofvalveinvolvementhasbeenreported.70Also,
successwithallogeneicstemcelltransplantationintermsofdiseaseprogression
hasbeenreportedinasmallnumberofcases.71

MucolipidosisTypeIII(Pseudo-Hurler
Polydystrophy)
MucolipidosistypeIIIisanautosomalrecessiveconditionthatislesssevere,
andalsolesscommon,thantypeIIandisduetoadeficiencyofthesame
phosphotransferaseenzyme.However,inthistypetheenzymeactivityisless
severelyreducedandthemanifestationsarelesssevere.Thereissignificant
variabilityintheclinicalseverityofthisdisease.72Thisislikelyduetovarious
geneticdefectsleadingtodifferentlevelsofenzymeactivity.Patientsareusually
sparedthejointmanifestationsearlyinlife(unlikethosewithinclusion-cell
disease)andoftenpresentwithjointstiffnessattheageof4or5years.Growth
ismoderatelyretardedandcornealcloudingispresentbytheageof7or8years.
Thepatientsaredisabledbycarpaltunnelsyndromeanddestructionofthehip
joints.Cardiacinvolvement,typicallygradualthickeningandeventual
regurgitationofthemitralandaorticvalves,doesoccurbutisusuallynot

sufficientlyseveretocauseclinicalproblems.Patientswithpseudo-Hurler
polydystrophygenerallysurviveintothefourthdecade.Morerecently,with
advancesinunderstandingofthegeneticsofthedisease,mucolipidosishasbeen
subcategorizedintotypeIIIα/βandtypeIIIgammaasthedeficientenzymeis
theproductoftwogenes.Thefirstencodestheαandβsubunitsandthesecond
encodesthegammasubunit.Despitethis,thetwosubtypeshavesimilar
manifestations.73,74

DisordersofGlycoproteinDegradation
Specificlysosomalenzymaticdeficienciesresultinfailureofdegradationof