Novel Frameshift Mutation in a Heterozygous Woman with Fabry Disease and End-Stage Renal Failure

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Abstract
It is generally accepted that Fabry disease (angiokeratoma corporis diffusum) is an X-linked disorder resulting from the deficient activity of the lysosomal enzyme α-galactosidase. In males, the enzymatic defect leads to accumulation of glycosphingolipids, particularly in the kidney which causes end-stage renal disease. We report here a woman who presented in 1987 with focal and segmental glomerulosclerosis and required hemodialysis 4 years later when her son was evaluated for proteinuria. In these patients morphologic, biochemical, and genetic investigations were performed to explore the possibility of a hereditary renal disorder. Ultrastructural examination of the son’s renal biopsy specimen revealed lamellated osmiophilic inclusions in the glomeruli, typical of Fabry disease. Four months after kidney transplantation in the mother, a graft biopsy specimen also revealed dense lamellated inclusions on electron microscopy. The leukocyte α-galactosidase activity was 0.008 µmol/min·109 cells in the son and 0.070 in the mother (range 0.100-0.500 µmol/min·109 cells). The diagnosis of Fabry disease was confirmed in both patients by the identification by DNA sequencing of a novel mutation in the α-galactosidase gene: one single base pair deletion in exon 3 (7317delA). In conclusion: (1) end-stage 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 analysis confirmed the diagnosis by demonstrating a frameshift mutation, which has as yet not been reported.

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