Stratification of Fabry mutations in clinical practice: a closer look at α-galactosidase A-3D structure.

Background Fabry disease (FD) is an X-linked lysosomal storage and multi-system disorder due to mutations in the alpha-galactosidase A (alpha-GalA) gene. We investigated the impact of individual amino acid exchanges in the alpha-GalA 3D-structure on the clinical phenotype of FD patients. Patients and methods We enrolled 80 adult FD patients with alpha-GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the alpha-GalA 3D-structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD-specific treatment. Results Patients with active site or buried mutations showed a severe phenotype with multi-organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. alpha-GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P P < 0.05 in women) whilst lyso-Gb3 levels were higher (P < 0.01 in men; <0.05 in women). Conclusions The type of amino acid exchange location in the alpha-GalA 3D-structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.