Previously Unreported in Women Galactosidase Alpha Pro409Ser Variant Is Associated With Fabry Disease.

Abstract

Fabry disease is a rare X-linked lysosomal storage disorder involving a deficiency in α- galactosidase A. This condition results in an impaired ability to metabolize globotriaosylceramide in the glycosphingolipid metabolic pathway, which accumulates within tissues throughout the body. Fabry disease affects 1 in 40 000 to 117 000 men with an unknown prevalence in women.1 Clinical presentations can be variable, ultimately resulting in potentially severe end-organ damage. In light of the variability in clinical presentation and rarity of the disease, initial misdiagnosis is common with a mean delay to diagnosis of between 13.7 and 16.3 years from symptom onset.1 Typical manifestations can include cutaneous lesions (angiokeratoma corporis), peripheral neuropathy, cerebrovascular accidents, proteinuria, renal insufficiency, and cardiac dysfunction.2,3 Cardiac manifestations include increased ventricular wall thickness, heart failure, valvular thickening and dysfunction, and coronary artery disease.2,3 Accurate and early diagnosis is imperative because early treatment with agalsidase β had been demonstrated to reduce the incidence of major adverse outcomes, including renal failure, stroke, cardiac events, and death.2 A 50-year-old woman presented to our institution with a recent onset of worsening exertional shortness of breath, fatigue, and chest tightness on a background of a presumptive diagnosis of hypertrophic cardiomyopathy made 10 years before. Her family history was significant for ischemic heart disease in her father and brother and valvular disease in her sister, but there was no known family history of hypertrophic cardiomyopathy. There were no other systemic symptoms, and clinical examination revealed a holosystolic murmur without other features of systemic disease, including cornea verticillata. Baseline renal function was normal with a creatinine of 0.8 mg/dL. Echocardiography (Figure 1A and 1B) demonstrated severe concentric increase in left ventricular wall thickness with systolic anterior motion of the mitral valve leaflets resulting in severe left ventricular outflow tract …