Clinical and Molecular Characterization of the GLA c.1124G>C (p.Gly375Ala) Variant in Colombian Patients with Fabry Disease: A Retrospective Cohort Study

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, resulting in deficient α-galactosidase A activity and progressive multi-organ involvement. The GLA c.1124G>C (p.Gly375Ala) variant is currently classified as a variant of uncertain significance (VUS), with scarce evidence regarding its clinical expression, particularly in Latin American populations. In this context, we aimed to characterize the demographic, clinical, biochemical, and therapeutic features of Colombian patients with FD carrying this variant.

Methods: We conducted a retrospective observational cohort study including all patients with FD harboring the GLA c.1124G>C (p. Gly375Ala) variant evaluated at Hospital Universitario San José de Popayán between 2015 and 2023. Data were extracted from medical records, including demographics, organ involvement (cardiac, neurologic, renal, dermatologic, and others), enzymatic activity, plasma lyso-Gb3 levels, treatment history, and follow-up outcomes. Descriptive and sex-stratified analyses were performed.

Results: Sixteen patients were identified (50% male; mean age 40±13.5 years), predominantly from rural and low socioeconomic backgrounds. Mean age at diagnosis was similar between sexes. Enzymatic activity was reduced in both males and females, with residual activity observed across the cohort. Plasma lyso-Gb3 levels were normal or mildly elevated. Renal involvement was more frequent in males, with higher creatinine levels (p=0.035). Multisystem involvement was common (93.8%), with a median of four affected systems. Dermatologic manifestations were most frequent, followed by central and peripheral nervous system and cardiac involvement. Treatment discontinuation occurred in 10 patients, mainly due to access barriers; therapy switching was documented in five cases.

Conclusions: Although classified as a VUS, the GLA c.1124G>C variant was associated with a late-onset, predominantly oligo systemic phenotype with variable expressivity, consistent with non-classic FD. Healthcare access limitations emerged as key determinants of treatment continuity, underscoring the need for variant-specific characterization and improved care pathways in underserved populations.