Molecular genetic, biochemical, and clinical studies in three families with cardiac Fabry's disease

The variant form of Fabry's disease, called cardiac Fabry's disease, which has left ventricular hypertrophy as its main clinical manifestation is not uncommon. Because there has been no pedigree analysis in families with card iac Fabry's disease, we performed gene analyses, enzyme assays, and cardiac evaluations in 3 distinct families with cardiac Fabry's disease. Gene anal yses were performed in all 18 members of 3 families including 3 male proban ds. Five hemizygotes and 6 heterozygotes were identified. Plasma alpha -gal actosidase A activity was measured in all 18 family members. Echocardiograp hy and electrocardiography were performed in the 5 hemizygotes and in 5 of the 6 heterozygotes. The proband and 3 heterozygotes from a pedigree with a mutation in exon 6 of the alpha -galactosidase A sequence leading to a Met 296IIe substitution showed a decrease in alpha -galactosidase A activity. I n a separate pedigree, a proband and his hemizygous brother, with a mutatio n in exon 2 leading to a Glu66Gln substitution, had ct decrease in alpha -g alactosidase A activity, whereas 3 heterozygotes had normal values. In the third pedigree, a decrease in alpha -galactosidase A activity was observed in 2 hemizygotes who have a mutation in exon 1 leading to an Ala20Pro subst itution. Although all 5 hemizygotes exhibited left ventricular hypertrophy on echocardiography, all 5 heterozygotes lacked this finding. Because plasm a alpha -galactosidase A activity was normal in some heterozygotes with car diac Fabry's disease, gene analysis is essential for an accurate diagnosis. Patients with cardiac Fabry's disease thus show an x-linked form of hypert rophic cardiomyopathy. (C) 2001 by Excerpta Medico, Inc.