Abstract
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by insufficient activity of α-galactosidase A (α-Gal A) encoded by GLA. The enzymatic defect causes the progressive accumulation of sphingolipids in various tissues and body fluids, causing systemic disorders. We report a rare familial case of inherited cardiac FD associated with a novel double mutation in the GLA gene: W24R and N419D. A young man with severe obesity was admitted for heart failure (HF) with the diagnosis of dilated cardiomyopathy. Left ventricular hypertrophy was suspected during HF treatment after discharge, and in association with his mother's family history of cardiac diseases and sudden death, the etiology of the hypertrophy was re-examined. Very low α-Gal A activity confirmed the diagnosis of FD. Gene mutation analysis of GLA demonstrated a double mutation: W24R and N419D. Proband analysis revealed the same double mutation in his mother. Although she had no signs or symptoms of FD, we detected mild accumulation of globotriaosylsphingosine. The good laboratory practice-validated assay using HEK293 cells showed that the double mutation was amenable to migalastat, a pharmacological chaperone stabilizing α-Gal A. This case highlights a novel double gene mutation in GLA (W24R and N419D) identified in a family with FD. Although clinical significance of each mutation remains unknown, its combination might work synergistically to attain or augment pathogenicity.