Genotype and phenotype in Fabry disease: analysis of the Fabry Outcome Survey

Abstract Aim: Mutations of the gene ( GLA ) encoding α‐galactosidase A are implicated in Fabry disease, a progressive, X‐chromosomal inherited lysosomal storage disorder. FOS – the Fabry Outcome Survey – was established as a long‐term surveillance study to describe the natural course of Fabry disease and its response to enzyme replacement therapy in a large cohort of European patients. Clinical phenotype, age of onset and course of Fabry disease are very variable, even within the same family, which makes it difficult to define a genotype–phenotype relationship by analysing individual patients. The FOS database contains detailed medical information on a large cohort of patients and thus has the potential to provide important information to address this question. Methods: At the time of analysis, information on 545 patients belonging to 157 families from nine European countries had been entered into the FOS database. A GLA mutation has been reported in 365 individuals (65% and 68% of all males and females, respectively) in FOS. These data were used to analyse the relationship between genotype and phenotype in Fabry disease. Results: A highly significant positive correlation was found between the age at entry into FOS and the FOS Severity Index in male patients with GLA missense mutations ( p <0.001) as well as in those carrying other types of mutations ( p <0.001). A positive correlation was also found between the age at entry into FOS and the number of affected organs in male patients with missense mutations, irrespective of whether the change in the amino acid side chain predicted in the α‐galactosidase A protein was classified as a conservative or non‐conservative change. Conclusion: The data presented here suggest that there is a correlation between genotype and clinical severity.