Overview Function digest endosomal material via digestive enzymes glycosylases lipases proteases all are acid hydrolases which function at low pH found in all cells higher concentrations in phagocytic cells Forms primary lysosomes newly formed from the trans-Golgi waiting to receive endocytosed material secondary lysosomes aka phagolysosome formed when primary lysosomes fuse with endocytic vesicles Lysosomal Storage Disease (by Deficient Enzymes) Sphingolipidoses Sphingomyelinase deficient in Niemann-Pick disease sphingomyelin accumulates histiocytes look "foamy" presentation hepatosplenomegaly anemia cherry red spots on macula death < 3 years failure to thrive neurodegeneration inheritance AR risk ↑ in Ashkenazi Jews α-galactosidase A deficient in Fabry disease ceramide trihexose accumulates presentation peripheral neuropathy especially in hands and feet angiokeratomas small purple blemishes on skin impaired sweating, either hypo- or anhidrosis cardiovascular disease renal disease inheritance XR β-galactocerebrosidase deficient in Krabbe disease galactocerebroside accumulates presentation hyperactive reflexes optic atrophy developmental delay presence of globoid cells large multinucleated cells that contain PAS positive inclusions inheritance AR β-glucocerebrosidase deficient in Gaucher disease glucocerebroside accumulates in cells of phagocytic cells histiocytes (dendritic cells) look like wrinkled tissue paper called Gaucher's cells presentation three types type I most common hepatosplenomegaly aseptic necrosis of heads of long bones mild anemia possible to live a normal lifespan type II "infantile Gaucher" CNS involved death < 1 year type III "juvenile Gaucher" severity < type II inheritance AR risk ↑ in Ashkenazi Jews Hexosaminidase A deficient in Tay-Sachs disease GM2 ganglioside accumulates lysosomes with onion skin presentation CNS degeneration blindness cherry red spot on macula startle reflex death < 4 years similar to Niemann-Pick but without hepatosplenomegaly inheritance AR risk ↑ in Ashkenazi Jews Arylsulfatase A deficient in metachromatic leukodystrophy cerebroside sulfate accumulates presentation demyelination in CNS and PNS resulting in ataxia and dementia inheritance AR Mucopolysaccharides α-L-iduronidase deficient in Hurler syndrome heparan sulfate and dermatan sulfate accumulates in heart and liver presentation gargoyle-like facies corneal clouding progressive mental retardation inheritance AR Iduronate sulfatase deficient in Hunter syndrome heparan sulfate and dermatan sulfate accumulates presentation severity < than Hurler's aggressive behavior remember: hunter's are aggressive corneal clouding absent inheritance XR Other Lysosomal Disorders I (inclusion)-cell disease cause proteins marked for localization to lysosomes are post-translationally modified in the Golgi mannose residues are phosphorylated by N-acetylglucosamine-phosphotransferase enzyme defect in N-acetylglucosamine-phosphotransferase causes I-cell disease without mannose-6-phosphate designation, the enzymes are secreted instead of being targeted to the lysosome cells cannot degrade endocytosed material and inclusion bodies build up intracellularly presentation high plasma levels of lysosomal enzymes skeletal abnormalities restricted joint movement psychomotor retardation early death coarse facial features no treatment Chédiak–Higashi syndrome cause primary lysosomes of leukocytes cannot fuse with phagosomes due to inability of microtubles to polymerize also affects immune cell chemotaxis presentation ↑ infections especially S. aureus partial albinism peripheral neuropathy inheritance AR