Fabry's Cardiomyopathy: Diagnosis, Pathophysiology and the Role of Enzyme Replacement Therapy

Fabry disease is an X-linked abnormality of glycosphingolipid metabolism that results in systemic deposition of sphingolipid, especially in the vascular endothelium and myocardium, which leads to left ventricular hypertrophy (LVH), endothelial dysfunction, and valvular disease. Both males and females are affected with the disorder, but females have a delayed presentation. Fabry disease is an important cause of undiagnosed ven- tricular hypertrophy in the absence of systemic hypertension and aortic stenosis. These patients present with heart failure, arrhythmias, and valvular heart disease. The develop- ment of LVH and adverse ventricular remodeling heralds a poor prognosis. The diagno- sis is established by measuring plasma α-galactosidase activity and confirmed by genetic analysis. Genetic counseling is available. In patients with Fabry's cardiomyopathy, enzyme replacement therapy (ERT) significantly slows the progression of LVH without significant effects on endothelial dysfunction. This issue of Cardiology Rounds reviews the diagno- sis, pathophysiology, cardiovascular (CV) symptoms, and treatment of Fabry disease. Fabry disease (FD or Fabry-Anderson disease) is a life-threatening lysosomal storage dis- order due to an X-linked inborn metabolic defect of the lysosomal enzyme, α-galactosidase A (α-Gal A). This deficiency leads to the progressive accumulation of the glycosphingolipid, globotriaosylceramide (Gb3), within vulnerable cells, tissues, and organs, including those of the cardiovascular system, 1-3 and results in endothelial dysfunction, ventricular hypertrophy, and valvular heart disease. 2-4 Two variants of FD exist: the classic variant, which is early- onset and presents with angiokeratomas and painful peripheral neuropathy; and the late variant, which is characterized by the development of end-organ damage, including renal, cardiac, and cerebrovascular disease. Although FD has been considered an orphan disease with an estimated prevalence of ∼1 in 50,000 males, recent data suggest that the true inci- dence of α-Gal A deficiency is 1 in ∼3,100, with an 11:1 ratio of patients with the late-onset phenotype variant compared with the classic phenotype. This suggests that the late-onset phenotype of FD may be underdiagnosed among males with cardiac, cerebrovascular, and/or renal disease. 5 Hemozygous male patients have a marked reduction in detectable α-Gal A activity, while affected heterozygous females tend to have a higher level of enzyme activity. Hence, in comparison to men, affected women tend to develop symptoms later and survive for at least 10-15 years longer. Diagnosis