Cardiac involvement in Anderson-Fabry disease

Anderson-Fabry disease results from hereditary deficiency of the lysosomal enzyme alpha-galactosidase A. This disease is marked by progressive intracellular accumulation of globotriaosylceramide (Gb(3)) and digalactosylceramide, the major glycosphingolipid substrates of alpha-galactosidase A. Many cell types are affected, including renal epithelial cells, myocardial cells and neuronal cells, endothelial cells, pericytes, and vascular smooth muscle cells (1). Cardiac involvement in Anderson-Fabry disease (AFD) is frequent, due to structural and functional changes related to glycosphingolipid deposition in the myocardium, valves, and conduction system. Deposition of Gb(3) in the heart is similar to deposition in other organs (2). It may be found in all cardiac tissues, with the greatest concentrations occurring in the left ventricular myocardium, the mitral valve, and the left atrium. In contrast, increased deposition of digalactosylceramide was found only in the lungs and right heart tissues (3). Accumulation of Gb(3) in the heart leads to an increase in ventricular wall thickness, mitral valve prolapse (4), and electrocardiographic abnormalities, including various degrees of atrioventricular conduction block, tachyarrhythmias, and ST-segment/T-wave abnormalities (5). Rarely, in the so-called "cardiac-variant," cardiomyopathy is the principle manifestation of AFD (6). Little is known about the timing of onset of cardiac involvement or its progression relative to other end-organ manifestations of AFD. This may be the result of the heterogeneous clinical symptoms leading to delayed diagnosis and because of uncertainty regarding the true incidence of the cardiac variant of AFD, which was mostly diagnosed by postmortem examinations. Indeed, AFD may account for up to 3% of men with hypertrophic cardiomyopathies, suggesting that the cardiac variant may be more common than previously thought (7). Clinical manifestations of AFD have been reported in female heterozygotes, but these complications were felt to be uncommon and usually mild. For example, it has been estimated that severe manifestations occur in only approximately 1% of female carriers (8). In a recent study however, 12% of patients with AFD being treated with dialysis in the United States were female (9) (See Obrador et al. in this issue). Furthermore, pedigree examination in female carriers suggested that cardiac involvement by AFD was more frequent than previously expected. Of 21 carriers investigated by a questionnaire, 19% had left ventricular hypertrophy: 48% from valvular disease and 33% from arrhythmias (10). By comparison, 88% of hemizygous males had left ventricular hypertrophy, and 29% had valvular disease (11). In our own patient population of 20 heterozygous females, 55% had cardiomyopathy and 60% had electrocardiographic abnormalities (12). Although there are gender-related differences, cardiac involvement by AFD appears to increase with age in both hemizygotes and heterozygotes, and thus careful monitoring for cardiac disease in patients of both genders is warranted.