Clinical manifestation of patients with Fabry disease and R356W GLA variant

Background: The R356W GLA variant is an ultra-rare cause of Fabry disease (FD). The clinical manifestations of adult patients carrying this variant have never been reported. This study aims to describe the clinical phenotype of the R356W GLA variant. Methods: The cohort consisted of consecutive patients diagnosed with FD and carrying the R356W GLA variant. An observational, longitudinal, retrospective cohort study design was used. Clinical, laboratory, and imaging data have been collected from the baseline evaluation to the last clinical review. Results: Six families, including 36 patients with FD and the R356W GLA variant (age 41.1 ± 15.9 years, 67% females), were evaluated. Eleven patients (31%) showed left ventricular hypertrophy (LVH), and 6 (17%) had chronic kidney disease (CKD). Patients with LVH were older (53.4 ± 8.5 vs. 35.7 ± 15.5, p-value 0.001), showed a higher prevalence of CKD (45% vs. 4%, p-value 0.002), and worse structural and functional cardiac parameters at echocardiographic evaluation. During a median follow-up of 42 (IQR 21–98) months, one patient experienced advanced atrioventricular block requiring pacemaker implantation and one end-stage renal disease requiring dialysis. No patients experienced major adverse events. Conclusion: This study suggests that the R356W GLA variant could be a late-onset FD-causing variant with incomplete penetrance and predominantly cardiac manifestations.