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


Corresponding author: R. Schiffmann, MD, National Institutes of Health, Building 10, Room 3D03, 9000 Rockville Pike, Bethesda, MD 20892-1260, USA. Tel.: +1 301 4961465; fax: +1 301 4808354; e-mail:


Fabry disease is an X-linked recessive disorder caused by a deficiency in the lysosomal enzyme α-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 α-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 α-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 α-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.