Genotype-Phenotype Spectrum of 52 Mexican Patients With Fabry Disease: A Novel GLA Variant With Atypical Phenotype

Fabry disease (FD) is a rare lysosomal type 3 disorder with an X-linked inheritance pattern caused by pathogenic variants in the GLA gene. This study aimed to describe the genotype and phenotype of 52 Mexican patients with FD.

We included 12 patients with clinical and molecular diagnosis of FD treated at our institution and 40 FD Mexican patients already reported in the literature.

The most frequent manifestations were acroparesthesias (71.2%), hypohidrosis or anhidrosis (48.1%), heat intolerance (46.2%), and proteinuria (42.3%). Renal and neurological manifestations were more prevalent in males than females. Cardiac involvement included hypertrophic cardiomyopathy and Wolf-Parkinson-White arrhythmia. Cornea verticillata was seen in 14 patients (26.9%) and angiokeratomas in 15 (28.8%). We identified 14 variants in the GLA gene in Mexican patients with FD. We found a novel variant GLA c.122C>G that causes an atypical FD phenotype with predominantly neurological involvement in two unrelated patients, one of them with a forthright clinical and radiological overlap of Multiple Sclerosis and normal biological biomarkers, thus requiring a renal biopsy that helped confirm the diagnosis of FD.

The genotype and phenotype of Mexican patients with FD are similar to other populations. Atypical phenotype of FD, such as the one associated with the novel variant c.122C>G, can be a diagnostic challenge, as it can be mixed up with MS. Our findings confirm the limitations of noninvasive diagnostic methods and the necessity of the renal biopsy when the clinical suspicion of FD is high.