[Genetics of Fabry disease: diagnostic and therapeutic implications]

Fabry disease (FD, OMIM 301500) is an X-linked inborn error of metabolism due to mutations in the gene encoding a-galactosidase A, a lysosomal enzyme. FD is an X-linked disease and affected males are more severely affected than females. In Fabry disease, the penetrance and the severity index of the phenotype are high in males, while expressivity and severity index appears highly variable and often "intermediate" in heterozygous females. Classic definitions of X-linked recessive and dominant inheritance neither reflect the variable expressivity, nor take into account the multiple mechanisms that can lead to disease expression in heterozygous females. The use of the terms X-linked recessive and dominant should probably be abandoned, and Fabry disease simply described as following 'X-linked' inheritance. Due to random X-chromosomal inactivation, enzymatic detection of carriers is often inconclusive. Molecular testing of females at-risk to be carriers is therefore mandatory for accurate genetic counselling. The GLA gene has been cloned and more than 300 mutations have been identified. Most of them are private and have been identified in only one family