LAUSR

BACKGROUND Fabry disease, an X-linked lysosomal storage disease, results from deficient α-galactosidase A (α-GalA) activity and the systemic accumulation of α-galactosyl-terminated glycosphingolipids. Two major phenotypes, "Classic" and "Later-Onset", lead to renal failure, and/or cardiac disease, and early demise. To date, the evolution and progression of the cardiac pathology and resultant clinical manifestations in family members of phenotype have not been well characterized. METHODS AND RESULTS In a Classic family with nine affected members (GLA mutation c.983delG), cardiac imaging, angiography, and cardiac biopsies were performed in four males and two heterozygous females. Tissues were examined histologically, ultrastructurally, and myocardial necrosis and apoptosis were evaluated by in situ ligation with hairpin probes. Increasing cardiac pathology correlated with ECG and cardiac magnetic resonance findings. Young affected males with "pre-hypertrophy" had 18-20μm cardiomyocyte diameters, <30% vacuolar areas in myocytes, and normal levels of necrosis and apoptosis. Patients with "moderate hypertrophy" (maximal wall thickness (MWT) ≤16mm) had 30-35μm cardiomyocyte diameters, ~45% vacuolar areas, and moderate levels of necrosis and apoptosis. In contrast, the oldest male with severe hypertrophy (MWT=21mm) had 38-40μm cell diameters, >60% vacuolar areas, and marked necrosis and apoptosis. CONCLUSION Progressive gender-specific cardiac pathology and clinical manifestations were documented in affected Classic family members. Increasing cardiomyocyte diameter was correlated with disease severity, age, and gender. Fibrosis was presumably caused by cell death of enlarged, substrate-engorged cardiomyocytes. These results support early enzyme therapy in Classic males to prevent/minimize irreversible cardiac damage.