Cardiomyopathy in Fabry disease: insights in the pathogenesis and new treatment options

Download in PDF

Fabry disease (FD) is a rare inherited lysosomal storage disorder caused by pathogenic mutations in the GLA gene that result in deficient α-galactosidase A (α-Gal A) activity and accumulation of glycosphyngolipids in the heart and other tissues. Cardiac involvement in FD is characterized by left ventricular hypertrophy and myocardial fibrosis underlying rhythm and conduction disorders and heart failure with preserved left ventricular ejection fraction. Recent data suggests a role for myocardial inflammation in addition to glycosphyngolipid accumulation in the development of cardiomyopathy in patients with FD. Myocardial imaging, particularly with cardiac magnetic resonance, is essential for early diagnosis and sta16 ging of Fabry cardiomyopathy. Enzyme replacement therapy (ERT), if started earlier prior to the irreversible damage of the heart and other organs, can prevent progression of cardiomyopathy and reduces the risk of cardiovascular outcomes. Migalastat that was recently approved in Europe and North America for the treatment of FD in adult patients with amenable GLA variants is a chaperone molecule increasing the residual α-Gal A activity. Therapeutic strategies currently in development include substrate reduction and gene therapies.