Molecular Basis

Lysosomes contain numerous acid hydrolases that catabolize the “leftover” proteins, nucleic acids, and carbohydrates that are the result of normal growth and metabolism (Figure 1). Each lysosomal enzyme is part of a complex pathway that reduces macromolecules into smaller components, which will be reused by the cell or eventually eliminated from the body.

The absence of one enzyme causes a bottleneck in the catabolic pathway, leading to the progressive accumulation of intermediate metabolic products within the lysosome. The missing enzyme in Fabry disease is α-GAL, which cleaves α-galactosyl bonds in neutral glycosphingolipids. The predominant intermediate metabolic product that accumulates is

GL-3, and, to a lesser extent, galabiosylceramide. A primary source of GL-3 is postulated to be the membranes of senescent erythrocytes, which contain the glycosphingolipid precursor globoside^[1]. Fabry patients with blood types AB or B also accumulate blood group B glycosphingolipids. GL-3, galabiosylceramide, and blood group B substances are deposited throughout the bodies of Fabry patients, and are especially prominent in the lysosomes of endothelial, perithelial, and smooth muscle cells of blood vessels, where they bulge into the lumen, causing vessel narrowing and dilatation (Figure 2) that progresses to ischemia and infarction^[2]. Under polarization microscopy, the lipid deposits appear birefringent (Figure 3).

Figure 1. Biosynthesis and Trafficking of Lysosomal Enzymes
Most newly synthesized lysosomal enzymes are recognized by the mannose-6-

References
1. Dawson G, Sweeley CC. In vivo studies on glycosphingolipid metabolism in porcine blood. J Biol Chem 1970; (245)2:410-6

2. Desnick RJ, Ioannou YA, Eng CM. α-Galactosidase A deficiency: Fabry disease. In: The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill, 2001;3733-74.