Phenotypic expression and outcomes in patients with the Arg301Gln GLA variant in Anderson-Fabry disease

Abstract Introduction: The Arg301Gln variant in the GLA gene has been poorly described in the literature. The few reports demonstrate different patterns of presentation of both classical and non-classical Anderson–Fabry (FD) disease, which develops later in life and with less organ damage. The aim of this study was to analyse the penetrance, clinical phenotype, and biochemical profile of an international cohort of patients carrying the Arg301Gln genetic variant in the GLA gene. Methods: This is a retrospective observational multicentre study of patients carrying the Arg301Gln variant in the GLA gene associated with FD disease. Results: Forty-nine Arg301Gln GLA carriers, 41% male, were analysed. The penetrance was 63% in the entire cohort and 1.5 times higher in men. The mean age of onset of symptoms was 41 years; men presented symptoms earlier and with a shorter delay to diagnosis compared to women. The classic presentation affected only 20% of the cohort, with no differences between sexes. During follow-up, almost 20% of the patients presented some type of non-fatal cardiovascular event (stroke, need for dialysis, heart failure, and arrhythmias requiring intracardiac devices), predominantly affecting men. Only a few women had normal levels of α-galactosidase A enzyme activity; residual levels were the most common finding. The incidence of combined events, including all causes of death, was 33%, and the cumulative incidence of all-cause mortality was 9%. Conclusions: Patients carrying the Arg301Gln variant in the GLA gene have a high penetrance of cardiorenal involvement with the clinical onset of the disease in middle age, and only a very low proportion showed the classical clinical presentation of FD. As in other X-linked diseases, males were more affected by severe cardiovascular and renal events. This genotype–phenotype correlation could be useful from a practical clinical point of view and for future decision-making.