[Molecular genetics of inherited metabolic diseases--its application to the investigation of pathogenesis and the diagnosis of Fabry disease].

Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from the deficient activity of the lysosomal hydrolase, alpha-galactosidase. Patients with classic Fabry disease of early onset show diverse clinical manifestations caused by generalized vasculopathy. Recent clinical and enzymatic examinations have revealed another form of this disease; progressive cardiomyopathy of late onset without other systemic signs or symptoms. Efforts were directed to identify the specific mutations in the alpha-galactosidase gene and to clarify the phenotype/genotype correlations. A variety of mutations, including deletions, nonsense mutations, splicing mutations and amino acid substitutions caused the classic form of Fabry manifestations, which resulted in the complete deficiency of alpha-galactosidase activity. Single base substitutions were detected in the upstream region of alpha-galactosidase gene exon 6, which resulted in residual enzyme activity. The degree of the expressed residual enzyme activity might determine the clinical phenotypes. Heterozygotes were successfully identified by gene analysis and immunofluorescence imaging diagnosis using confocal laser scanning microscopy.