Inflammation and autophagy impairment in presymptomatic pediatric patients with Fabry disease identified by newborn screening

Fabry disease (FD) is a lysosomal storage disorder caused by a deficiency of α-galactosidase A. Although the accumulation of glycosphingolipids occurs very early, clinical manifestations are often delayed. Little is known about the cellular changes that occur in the presymptomatic phase and may progressively cause damage. To this aim, we evaluated inflammatory markers, cellular stress, and autophagy in presymptomatic pediatric patients with FD identified through newborn screening. We conducted a cross-sectional study of 12 male presymptomatic FD patients with a mean age of 3.11 years. We measured plasma cytokine levels (IL1β, TNFα, and IL6) by ELISA. In six patients we also analyzed cellular stress (p-p38) and autophagy markers (LC3, Beclin, Atg3, Atg5, Atg7, Atg12, and Atg16L) by Western blot in peripheral blood mononuclear cells. We observed elevated levels of IL1β and TNFα in 10/12 and 11/12 patients, respectively. P-p38 activation increased by an average of 1.31-fold (SD 1) compared to controls. Autophagy markers showed significant reductions, with LC3-II levels decreasing by an average of 53% (SD 54%). Upstream autophagy mediators (Beclin, Atg3, Atg5, Atg7, Atg12, and Atg16L) were also reduced. This study is the first to demonstrate the presence of inflammation and autophagy inhibition in pediatric presymptomatic FD patients. These findings provide new insights into the early pathogenesis of FD and suggest potential biomarkers for disease progression. • Inflammation and autophagy impairment are present in presymptomatic Fabry disease. • Inflammatory cytokines IL-1β and TNF-α are increased. • Increased p-p38 activation indicates cellular stress. • Reduced LC3-II levels, unlike symptomatic patients, point to inhibited autophagy. • Upstream autophagy markers also decreased, confirming inhibited autophagic flux.