Immuno-Inflammatory Profiling and Complement Activation in Fabry Disease: A Cross-Sectional Study

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A deficiency, leading to glycosphingolipid accumulation and progressive organ damage. Beyond substrate storage, low-grade inflammation and complement activation have been increasingly implicated in FD pathogenesis, yet a comprehensive characterization of this immuno-inflammatory profile is lacking. In this exploratory cross-sectional study, fifteen patients with FD and fifteen age- and sex-matched healthy controls (HCs) were assessed using a broad panel of systemic inflammatory, humoral immunity/complement, hematological, and endothelial biomarkers, integrated through univariate analysis (Cliff's delta, δ), penalized least absolute shrinkage and selection operator (LASSO) regression, and unsupervised hierarchical clustering. Fibrinogen (δ = 0.60, 95% confidence interval (CI) 0.24-0.88), sTNFR2 (δ = 0.48, 95% CI 0.08-0.80), complement C4 (δ = 0.53, 95% CI 0.13-0.84), and lymphocyte count (δ = 0.52, 95% CI 0.15-0.85) showed the largest between-group effect sizes among the immuno-inflammatory biomarkers assessed, with higher levels in FD. Fibrinogen and sTNFR2 were the most stable predictors in LASSO bootstrap resampling (selected in 75.0% and 69.5% of iterations, respectively), and unsupervised clustering segregated FD from HCs with high accuracy (90% FD enrichment in the high-biomarker cluster; p < 0.001). These convergent findings indicate that FD is characterized by a distinct low-grade immuno-inflammatory profile dominated by innate immune and complement activation.