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glycoproteinswithconsequentaccumulationofglycoproteinsinmanytissues,
especiallythenervoussystem.Theybecamerecognizedwhenpatientswith
presentationssimilartothosewiththemucopolysaccharidoseswerefoundto
havebiochemicallydistinctdiseases.
Thefiveprimarydisordersofglycoproteindegradation,mannosidosis,
fucosidosis,sialidosis,galactosialidosis,andaspartylglycosaminuria,canallbe
diagnosedbydemonstrationoftheenzymedefectinculturedfibroblasts.
Prenataldiagnosisisoftenpossible.

Mannosidosis
Deficiencyofα-mannosidaseisarare,autosomalrecessivedisorderthatresults
intheaccumulationofoligosaccharides,astheirdegradationisdependenton
lysosomalactivityofthisenzyme.Oligosaccharidesareexcretedintheurine.
Severaldefectsinthegeneencodingα-mannosidasehavebeendiscovered.The
specificdefectmayresultindecreasedenzymesynthesis,decreasedenzyme
activitywithinthelysosomalenvironment,decreasedlocalizationoftheenzyme
withinthelysosome,orfaultyposttranslationalmodificationoftheenzyme.The
patientspresentwithfeaturessuggestiveofmucopolysaccharidosisbuthavean
increasedsusceptibilitytoinfections.Progressivementalretardationistypical.
EarlyonsetofthediseasecategorizedastypeIisassociatedwithincreased
severity.Deathoccursbetween3and10yearsofage.Late-onsetdisease(type
II)runsamorebenigncourse.Cardiacmanifestationsarenotfrequently
reported.However,ashortPRintervalhasbeenreportedinseveralpatients.The
mechanismforthisisunknown.75Treatmenthasbeenattemptedwithbone
marrowtransplantation,andstrategiescurrentlyunderinvestigationinclude
variousformsofenzymereplacementtherapy.76

Fucosidosis
Deficiencyofα-L-fucosidaseresultsintheaccumulationoffucosylated
oligosaccharidesandglycolipids.Twoclinicaltypesarerecognized.Thefirst
typepresentsininfancywithcoarsefacies,growthretardation,mental

retardation,andneurologicdeterioration.Convulsionsandrespiratoryinfections
oftenoccur.Thesecondtypehasamorebenigncourseandalateronset.
Cardiomegaly,probablyaspartofageneralizedvisceromegaly,isthemost
commoncardiacfeaturebutisbenign.Thesetwotypesprobablyrepresentboth


endsofacontinuumthatisdictatedbyapatient'sspecificenzymeactivityas
determinedbyhisorherspecificgenedefect.Bonemarrowtransplantationhas
beenperformedwithgoodresults,andfurtherexperimentationwithenzyme
replacementtherapyisongoing.77,78

Sialidosis
Thebasicdefectinsialidosisisdeficiencyofα-neuraminidase,with
accumulationofsialoglycoconjugates.Twoformsexist.Thefirstisoflateonset
andpatientsareofnormalappearancebutdevelopthecherry-redspot
myoclonussyndrome.Decreasedvisualacuityisassociatedwithacherry-red
spotinthemacularregion.Neurologic(andoccasionalrenal)manifestations
dominatetheclinicalpicture.Thesecondtypehasanearlyonset,evenon
occasionbeingobviousatbirth.Thepatientshavecoarsefeaturesand
enlargementofvariousorgansincludingtheheart.Echocardiographyhasshown
anincreasedleftventricularwallthicknessalongwiththickeningofthemitral
valve.79Thereisgreatvariabilityinthespectrumofseverity,eveninthegroup
withearlyonset.Survivalbeyond20yearsisrare;occasionally,however,
affectedsubjectsarestillborn.Fetalhydropshasbeenreportedasapresenting
feature.80Sialidosisisinheritedinautosomalrecessivefashion.Enzyme
replacementtherapyandgenetransfertreatmentsareunderinvestigation.81

Galactosialidosis
Ingalactosialidosis,patientshaveadefectintheproductionoflysosomal
protectiveprotein/cathepsinA,whichhelpstoformastableandactivated

complexwithβ-galactosidaseandα-neuraminidase.82Thusthesymptomsarea
combinationofthoseseeninsialidosisandMorquiosyndrome,theseverityof
whichislikelydeterminedbythespecificgeneticdefectanditsoveralleffecton
theproductionoffunctionallevelsoftheprotein.Aninfantileformhasbeen
described,83andthereappearstobeafairamountofclinicalvariationevenin
thosediagnosedasinfants.84Structuralcongenitalheartdiseasehasbeen
reportedinpatientswithgalactosialidosis,85butthecardiacmanifestationsare
usuallysimilartothoseseeninMorquiosyndromeandsialidosis,withaorticand
mitralvalvethickening,86whichisprogressive.87Recentlytheroleofthese
enzymesandprotectiveprotein/cathepsinAinelastogenesishasbeguntobe
unraveled,helpingtofurtherexplainthephenotypeassociatedwiththesegenetic


disorders.88Althoughnospecifictreatmentyetexists,earlyworkhasbegunon
therapiesinvolvingenzymereplacementorgenetransfer.89–91

Aspartylglycosaminuria
Aspartylglycosaminuriaisalysosomalstoragediseaseduetoadefectiveor
deficientglycosylasparaginase.Thisenzymeisrequiredforcompletebreakdown
ofasparagine-linkedglycoproteinswithinthelysosome.92Accumulationofthese
glycoproteinresiduesleadstosevereandprogressiveneurologicimpairment.It
isassociatedwithcoarsefeatures,jointlaxity,andearlyrapidsomaticgrowth
followedbyareducedadolescentgrowthspurtleadingultimatelytoshortstature
andmentalretardation.Animalmodelsdemonstrateresidueaccumulationwithin
theheart,butclinicalcardiacinvolvementdoesnotappeartopredominate.
Therapyviaenzymereplacementiscurrentlybeingstudiedinanimal
models.93,94

AcidLipaseDeficiency(WolmanDiseaseand
CholesterolEsterStorageDisease)

Lysosomalacidlipaseisnecessaryforthecleavageoftriglyceridesand
cholesterolestersfromlipoproteinsdeliveredtothelysosome.Completeor
partialdeficiencyoflysosomalacidlipaseresultsinaccumulationofcholesterol
inmosttissuesofthebody.Thediseaseoccursintwoforms.Wolmandisease,
withcompleteabsenceofenzymaticactivity,isadiseaseofinfancypresenting
withvomiting,diarrhea,hepatosplenomegaly,failuretothrive,anemia,and
calcificationoftheadrenalglands.Cardiacmanifestationsarenotusually
evident,butmicroscopicexaminationofthearteriesshowsexcessfattydeposits.
Hepatomegalyisfrequentlytheonlysigninthemilderformofthedisease,
cholesterolesterstoragedisease,althoughprematureatherosclerosisisalso
seen.95ThediagnosisofWolmandiseaseissuggestedbytheassociationof
hepatosplenomegalywithadrenalcalcification.Definitivediagnosisofeither
diseasecanbemadebyassessingacidlipaseactivityinculturedskinfibroblasts.
Thediseaseisinheritedinautosomalrecessivefashion.Successfultreatment
withhematopoieticstemcell,bonemarrow,andcordbloodtransplantationhas
beenreported.96–98