An Atypical Variant of Fabry's Disease with Manifestations Confined to the Myocardium

Abstract

FABRY'S DISEASE is an X-linked recessive disorder resulting from deficient activity of the lysosomal hydrolase α-galactosidase A.¹-³ The enzymatic defect leads to the progressive accumulation of neutral glycosphingolipids with terminal α-galactosyl moieties (particularly globotriaosylceramide) in the lysosomes of vascular endothelial and smooth-muscle cells throughout the body. In classically affected males, who have no detectable α-galactosidase A activity, the onset of disease manifestations occurs in childhood or adolescence and is characterized by severe acroparesthesias, angiokeratoma, corneal opacities, and hypohidrosis. The cardiac manifestations result from the accumulation of globotriaosylceramide in the myocytes, leading to myocardial failure; in coronary endothelial cells, resulting in myocardial infarction; and in valvular fibroblasts, leading predominantly to mitral insufficiency.⁴-¹⁰ Hypertrophic obstructive cardiomyopathy and the development of a pattern of dilated cardiomyopathy have been described.^11,12 Affected hemizygotes may have angina, a short PR interval,¹³ ST-segment changes,¹⁴ or all three features. The course of the disease is progressive, and with advancing age complications of myocardial, renal, or cerebral vascular disease may occur in male patients. Before the introduction of renal transplantation and hemodialysis, the average age of affected hemizygous males at death (usually caused by renal failure) was 41 years.¹ With successful treatment of the renal insufficiency, subsequent disease manifestations result from slowly progressive myocardial infiltration. In contrast, men with atypical variants of the disorder, who have residual α-galactosidase A activity, are asymptomatic or have mild symptoms.^1,15-²¹ Heterozygous female carriers of the disease-causing gene usually have no symptoms or minimal disease involvement and have a normal life span.