Fabry disease is an X-linked recessive disorder caused by a deficiency in the lysosomal
enzyme alpha-galactosidase A, which results in a progressive multisystem disease. Most families have private mutations and no general correlation between genotype and disease manifestations has been described to date. Forty-nine patients (47 males and 2 females) from 36 affected families were selected for the study. Their evaluation included clinical examination, identification of
alpha-galactosidase A gene mutations and residual enzymatic activity. For mutation detection, each exon with flanking intronic sequences was amplified by polymerase chain reaction (PCR) from the patient's genomic
DNA and sequenced. Analysis of the resulting sequences was conducted to identify structural defects in the gene. Each of the Fabry patients carried a mutation in the
alpha-galactosidase A gene. Fifteen mutations were novel. They included missense mutations (M51K, Y123M, G261D), nonsense point mutations (E251X) and small insertions or deletions creating a premature translational termination signal (P6X, D93X, W162X, K240X, H302X, I303X, L403X, S345X, G375X, F396X). Residual
alpha-galactosidase A activity was significantly lower in patients with
neuropathic pain (p=0.01) and in patients with mutations leading to a nonconservative
amino acid change (p=0.04). Our findings emphasize the wide variety of genetic mechanisms leading to
Fabry disease. A significant genotype-phenotype relationship was found.