Disrupted synaptic gene expression in Fabry disease: Findings from RNA sequencing

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency in the enzyme α-galactosidase A. This defect leads to the progressive accumulation of glycosphingolipids, resulting in kidney, heart, and nervous system damage, which contributes to significant morbidity and mortality. Early diagnosis is essential to prevent irreversible damage and optimize treatment strategies. Recent research aims to provide a better understanding of FD pathophysiology to improve management approaches. This study is an international, multicenter, cross-sectional analysis that used RNA sequencing (RNA-seq) to compare blood samples from 50 FD patients and 50 age- and sex-matched healthy controls. The objective was to identify gene expression patterns and investigate secondary cellular pathways affected by lysosomal dysfunction. Among the more than 400 differentially expressed genes detected, 207 were protein-coding genes, most of which were overexpressed in the FD cohort. Functional enrichment analysis highlighted processes related to synaptic function, specifically concerning chemical synaptic transmission and membrane potential regulation. Identified genes included those related to voltage-gated ion channels, neurotransmitter receptors, cell adhesion molecules, scaffold proteins, and proteins associated with synaptic vesicles and neurotrophic signaling, all linked to lipid rafts. Notable identified genes included those encoding voltage-gated potassium channel genes (KCNQ2, KCNQ3, KCNMA1) and ionotropic receptor genes involved in glutamatergic (GRIN2A, GRIN2B) and GABAergic systems (GABRA4, GABRB1, GABRG2, GABRQ). These findings suggest that lysosomal dysfunction contributes to synaptic defects in FD, paving the way for further research into the role of synaptic pathology and lipid rafts in the underlying pathogenesis and clinical outcomes in FD.