Table 1 Clinical profiles of common lysosomal storage diseases
Disease | Gene/defective protein | Function | Clinical symptoms (in vivo phenotypes) | Biochemical/cellular pathology | Available therapiesa |
|---|---|---|---|---|---|
Pompe disease | GAA/acid alpha-glucosidase | Degrading glycogen in cellular vacuoles | Cardiac and respiratory failure; muscle weakness | Glycogen storage; autophagic build-up | Myozyme; Lumizyme; DNJ (trial) |
Sphingolipidoses | |||||
Fabry disease | GLA/alpha-galactosidase A | Hydrolyzing the terminal alpha-galactosyl moieties from glycolipids and glycoproteins | Cardiovascular problems; renal failure; pain and paresthesia in the extremities | Increase levels of GB3; laminated alternate electron-dense and lucent layers (Zebra bodies) in the Cytoplasm | Fabrazyme; Replagal; DGJ (trial) |
Gaucher disease | GBA/acid beta-glucocerebrosidase | Cleavage of the glucosylceramide to ceramide and glucose | Hepatosplenomegaly; pancytopenia; skeletal(type 1 and 3) or neurological problems (type 2 and 3) | Tubular structures in arrays inside dilated lysosomes under EM | Cerezyme; Zavesca (miglustat; NB-DNJ); isofagomine (trial) |
Niemann-Pick disease, type A and B | SMPD1/acid sphingomyelinase | Converting sphingomyelin to ceramide | Hepatosplenomegaly; cherry-red maculae; pneumonia | Abnormal lipid profiles; lamellar inclusions under EM | rhASM (for type B, trial, not published) |
Metachromatic leukodystrophy | ARSA/arylsufatase A | Hydrolyzing cerebroside sulfate to cerebroside and sulfate | Progressive neurological dysfunction; demyelination | Metachromatic deposits in the nervous system | BMT (may delay progress); rhARSA (for those who have received HSCT, trial, not published) |
Krabbe disease(Globoid cell leukodystrophy) | GALC/beta-galactocerebrosidase | Hydrolyzing the galactose ester bonds of galactosylceramide | Diffuse neurological dysfunction; sensorimotor peripheral neuropathy | Accumulation of galactosylsphingosine in all tissues, filamentous and curvilinear inclusions | HSCT; BMT |
Mucopolysaccharidoses (MPS): representative types | |||||
Hurler syndrome (MPS IH) | IDUA/alpha-L-iduronidase | Hydrolyzes the terminal alpha-L-iduronic acid residues of the glycosaminoglycans | Hepatosplenomegaly; heart diseases; dysostosis multiplex; mental retardation | Accumulation of dermatan sulfate and heparan sulfate | HSCT; Aldurazyme |
Hunter syndrome (MPS II) | IDS/iduronate sulfatase | Lysosomal degradation of heparan sulfate and dermatan sulfate | Growth deficiency; coarse face; stiff joints; mental retardation | Accumulation of dermatan sulfate and heparan sulfate | BMT; Elaprase |
Sanfilippo syndrome B (MPS IIIB) | NAGLU/alpha-N-acetylglucosaminidase | Lysosomal degradation of heparan sulfate | Severe neurodegeneration; coarse face; mild organomegaly | Accumulation of heparan sulfate; abnormal Ca+2 homeostasis; Golgi abnormalities; abnormal neurite outgrowth | Miglustat (NB-DNJ, trail) |
Sly syndrome (MPS VII) | GUSB/beta-glucuronidase | Lysosomal degradation of glucuronic acid-containing glycosaminoglycans | Heart disease; dysostosis multiplex; hepatosplenomegaly; hydrops fetalis; mental retardation | Progressive lysososmal storage in many tissues because of accumulation of dermatan sulfate and heparan sulfate | BMT |
Lipid storage disease | |||||
Niemann-Pick disease, type C | NPC1/NPC1 protein | Regulating intracellular cholesterol trafficking | Hepatosplenomegaly; neurological deterioration | Low-cholesterol esterification; lamellar | Zavesca (miglustat; NB-DNJ) |
Ceroid lipofuschinosis, neuronal, type 1 | PPT1/palmitoyl-protein thioesterase | Removing palmitate from cysteine residues during | Myoclonus; spasticity; ophthalmic problems; mental deterioration | Granular osmiophilic cytoplasmic deposits in cells under EM | Cystagon (cysteamine bitartrate) combined with N-acetylcysteine (trial); neural stem cells (trial) |
Mucolipidosis | |||||
I-cell disease | GNPTAB/N-Acetylglucosaminyl-phosphotransferase alpha and beta subunits | Catalyzing the synthesis of the M-6-P determinant on lysosomal hydrolases | Alveolar ridge hypertrophy; dysostosis multiplex; heart failure; joint limitation; thick tight skin; mental retardation | Increased lysosomal enzyme secretion; membrane-bound vacuoles containing electron-lucent or fibrillogranular contents | BMT |
Oligosaccharidosis | |||||
Fucosidosis | FUCA1/alpha-L-fucosidase | Degrading fucose-containing glycoproteins and glycolipids | Angiokeratoma; psychomotor retardation; coarse face; dysostosis multiplex | Increased oligosaccharide secretion; elevated sweat chloride; vacuolated lymphocytes | HSCT; BMT |
Transport defects through the lysosomal membrane | |||||
Cystinosis | CTNS/cystinosin | Transporting cystine out of lysosomes | Failure to thrive; renal tubular Fanconi syndrome; hepatosplenomegaly; skeletal problems | Characteristic crystals within lysosomes causing cell expansion | Cystagon (cysteamine bitartrate) |
Defective vesicular traffic | |||||
Chediak-Higashi syndrome | CHS1/LYST protein | Regulating protein trafficking to and from lysosomes | Recurrent pyogenic infections; ophthalmic problems; hepatosplenomegaly; neurological dysfunction | Giant granules in muscle cells; giant lysosomes; altered vesicular fusion; defective antigen presentation | BMT; HSCT |