NOVEL FRAMESHIFT MUTATION IN A HETEROZYGOUS WOMAN WITH FABRY DISEASE AND END-STAGE RENAL-FAILURE

It is generally accepted that Fabry disease (angiokeratoma corporis di ffusum) is an X-linked disorder resulting from the deficient activity of the lysosomal enzyme alpha-galactosidase. In males, the enzymatic d efect leads to accumulation of glycosphingolipids, particularly in the kidney which causes end-stage renal disease. We report here a woman w ho presented in 1987 with focal and segmental glomerulosclerosis and r equired hemodialysis 4 years later when her son was evaluated for prot einuria. In these patients morphologic, biochemical, and genetic inves tigations were performed to explore the possibility of a hereditary re nal disorder. Ultrastructural examination of the son's renal biopsy sp ecimen revealed lamellated osmiophilic inclusions in the glomeruli, ty pical of Fabry disease. Four months after kidney transplantation in th e mother, a graft biopsy specimen also revealed dense lamellated inclu sions on electron microscopy. The leukocyte alpha-galactosidase activi ty was 0.008 mu mol/min . 10(9) cells in the son and 0.070 in the moth er (range 0.100-0.500 mu mol/min . 10(9) cells). The diagnosis of Fabr y disease was confirmed in both patients by the identification by DNA sequencing of a novel mutation in the alpha-galactosidase gene: one si ngle base pair deletion in exon 3 (7317delA). In conclusion: (1) end-s tage renal disease may occur in heterozygous women with Fabry disease; (2) morphologic lesions due to glycosphingolipid accumulation may be observed in the renal allograft after transplantation, and (3) DNA ana lysis confirmed the diagnosis by demonstrating a frameshift mutation, which has as yet not been reported.