Fig. 7.11 Gaucherdiseaseinvolvingthebonemarrow.(A)Gauchercellswithabundantlipid-laden“wrinkled”cytoplasm.(B)ElectronmicrographofGauchercellswithelongateddistendedlysosomes.(Courtesy of Dr. Matthew Fries,Department of Pathology,University of Texas Southwestern Medical Center,Dallas,Texas.) with coarse facial features, clouding of the cornea, joint stiffness, and mental retardation. Urinary excretion of the accumulated mucopolysaccharides often is increased. With all of these disorders except one, the mode of inheritance is autosomal recessive; the exception, Hunter syndrome, is an X-linked recessive disease. Of the seven recognized variants, only two well-characterized syndromes are discussed briefly here.
MPS type I, also known as Hurler syndrome, is caused by a deficiency of α-L-iduronidase. In Hurler syndrome, affected children have a life expectancy of 6 to 10 years, and death is often a result of cardiac complications. Accumulation of dermatan sulfate and heparan sulfate is seen in cells of the mononuclear phagocyte system, in fibroblasts, and within endothelium and smooth muscle cells of the vascular wall. The affected cells are swollen and have clear cytoplasm, resulting from the accumulation of material positive for periodic acid–Schiff staining within engorged, vacuolated lysosomes. Lysosomal inclusions also are found in neurons, accounting for the mental retardation.
MPS type II or Hunter syndrome, differs from Hurler syndrome in its mode of inheritance (X-linked), the absence of corneal clouding, and often its milder clinical course. As in Hurler syndrome, the accumulated mucopolysaccharides in Hunter syndrome are heparan sulfate and dermatan sulfate, but this results from a deficiency of L-iduronate sulfatase. Despite the difference in enzyme deficiency, an accumulation of identical substrates occurs because breakdown of heparan sulfate and dermatan sulfate requires both α-L-iduronidase and the sulfatase; if either one is missing, further degradation is blocked. Diagnosis is made by measuring the level of enzyme in leukocytes. DNA diagnosis is not routinely employed because of the large number of alellic mutations.
Tay-SachsdiseaseiscausedbyaninabilitytometabolizeGM2gangliosidesbecauseofalackoftheβ subunitoflysosomalhexosaminidase.GM2gangliosidesaccumulateintheCNSandcauseseverementalretardation,blindness,motorweakness,anddeathby2to3yearsofage.
Niemann-PickdiseasetypesAandBarecausedbyadeficiencyofsphingomyelinase.Inthemoresevere,typeAvariant,accumulationofsphingomyelininthenervoussystemresultsinneuronaldamage.Sphingomyelinalsoisstoredinphagocyteswithintheliver,spleen,bonemarrow,andlymphnodes,causingtheirenlargement.IntypeB,neuronaldamageisnotpresent.
Niemann-PickdiseasetypeCiscausedbyadefectincholesteroltransportandresultantaccumulationofcholesterolandgangliosidesinthenervoussystem.Affectedchildrenexhibitataxia,dysarthria,andpsychomotorregression.
Gaucherdiseaseresultsfromlackofthelysosomalenzymeglucocerebrosidaseandaccumulationofglucocerebrosideinmononuclearphagocyticcells.Inthemostcommon,type1variant,affectedphagocytesbecomeenlarged(Gauchercells)andaccumulateinliver,spleen,andbonemarrow,causing hepatosplenomegalyandboneerosion.Types2and3arecharacterizedbyvariableneuronalinvolvement.