Fabry disease: twenty novel alpha-galactosidase A mutations causing the classical phenotype

Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, re sults from the deficient activity of the lysosomal exoglycohydrolase, alpha -galactosidase A (EC 3.2.1.22; alpha -Gal A). The nature of the molecular lesions in the alpha -Gal A gene in 40 unrelated families with the classica l phenotype (absent alpha -Gal A activity) was determined in order to provi de precise heterozygote detection and prenatal diagnosis, and to explore po ssible genotype/ phenotype correlations. Genomic DNA was isolated from unre lated affected males, and the entire alpha -Gal A coding region and flankin g intronic sequences were analyzed by polymerase chain reaction (PCR) ampli fication and automated sequencing. Twenty new mutations were identified: M5 1K, D92N, D136H, F169S, C172F, L191Q, S247P, Q250X, P259R, G261D. T282N, R3 01P, W349X. T410K, 124delAT, 842delTAA, 1033delTC, 82insG, 893insG. and 903 insG. In the remaining 20 unrelated Fabry families, 17 previously reported mutations were detected. These studies further define the heterogeneity of mutations in the alpha -Gal A gene causing the classic Fabry disease phenot ype, and permit precise heterozygote detection and prenatal diagnosis.