Fabry Disease

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding the enzyme alpha-galactosidase A (alpha-Gal A). Deficient or absent alpha-Gal A leads to progressive accumulation of globotriaosylceramide (Gb3, also called GL-3) and its deacylated form globotriaosylsphingosine (lyso-Gb3) within lysosomes of vascular endothelial cells, podocytes, cardiomyocytes, renal tubular cells, and dorsal root ganglia neurons. This progressive Gb3 deposition drives organ damage through several mechanisms: vascular endothelial dysfunction (promoting thrombosis and vasculopathy), cardiac hypertrophy (Gb3 infiltration of cardiomyocytes causes left ventricular hypertrophy mimicking hypertrophic cardiomyopathy), renal injury (podocyte and tubular cell damage causing progressive proteinuria and CKD leading to ESRD), and peripheral nervous system involvement (small fiber neuropathy causing the characteristic acroparesthesias). Because Fabry disease is X-linked, MALES (hemizygous) are classically more severely affected with earlier onset (childhood to adolescence), while FEMALES (heterozygous carriers) have variable severity due to random X-inactivation (lyonization) -- some carrier females are asymptomatic while others have severe disease. The classic male phenotype presents in childhood with episodic burning pain in the hands and feet (acroparesthesias), angiokeratomas (dark red papules clustered on...