Identification of fifteen novel mutations and genotype-phenotype relationship in Fabry disease

Fabry disease is an X-linked recessive disorder caused by a deficiency in t he lysosomal enzyme alpha -galactosidase A, which results in a progressive multisystem disease. Most families have private mutations and no general co rrelation between genotype and disease manifestations has. Forty-nine patients (47 males and 2 females) from 36 affected families were selected for the study. Their evaluation included clinical examination, id entification of alpha -galactosidase A gene mutations and residual enzymati c activity. For mutation detection, each exon with flanking intronic sequen ces was amplified by polymerase chain reaction (PCR) from the patient's gen omic DNA and sequenced. Analysis of the resulting sequences was conducted t o identify structural defects in the gene. Each of the Fabry patients carri ed a mutation in the alpha -galactosidase A gene. Fifteen mutations were no vel. They included missense mutations (M51K, Y123M, G261D), nonsense point mutations (E251X) and small insertions or deletions creating a premature tr anslational termination signal (P6X, D93X, W162X, K240X, H302X, I303X, L403 X, S345X, G375X. F396X). Residual alpha -galactosidase A activity was signi ficantly 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 Fa bry disease. A significant genotype-phenotype relationship was found.