Lysosomal storage disorders

The lysosome is the cell's degradative organelle, filled with acid hydrolases that break down sphingolipids, glycosaminoglycans, glycogen, and other macromolecules. When one of those enzymes is deficient, its specific substrate cannot be cleared and instead accumulates within lysosomes. Cells swell with undegraded material, function declines, and the affected organs enlarge or degenerate. Most lysosomal storage disorders are autosomal recessive; the notable exceptions are Fabry disease and Hunter syndrome, which are X-linked recessive.

The sphingolipidoses are the largest group. Tay-Sachs disease reflects hexosaminidase A deficiency with GM2 ganglioside accumulation, producing a cherry-red macular spot and neurodegeneration without hepatosplenomegaly. Niemann-Pick disease, from sphingomyelinase deficiency, also shows a cherry-red spot but with hepatosplenomegaly and foam cells. Gaucher disease, the most common lysosomal storage disorder, results from glucocerebrosidase deficiency and produces macrophages with a crumpled tissue paper appearance, hepatosplenomegaly, and bone pain. Krabbe disease and metachromatic leukodystrophy both cause demyelination, while Fabry disease produces angiokeratomas, neuropathic pain in the hands and feet, and progressive renal failure.

The mucopolysaccharidoses accumulate glycosaminoglycans. Hurler syndrome, from alpha-L-iduronidase deficiency, causes coarse facial features, corneal clouding, and developmental delay. Hunter syndrome results from iduronate sulfatase deficiency and is milder, X-linked, and characteristically lacks corneal clouding. Pompe disease sits at the boundary of two categories: it is a glycogen storage disease caused by acid alpha-glucosidase deficiency within the lysosome, and it prominently affects cardiac muscle. Diagnosis rests on enzyme assay and genetic testing, and enzyme replacement therapy exists for several of these conditions.

USMLE Step 1 tests lysosomal storage disorders heavily in biochemistry. The reliable strategy is to memorize the enzyme, the accumulated substrate, the inheritance pattern, and one or two distinguishing clinical findings for each disease — the exam most often presents a vignette and asks for the deficient enzyme.