Integrated multi-omics profiling reveals novel molecular biomarkers and pathways associated with Fragile X-associated tremor/ataxia syndrome.

Introduction: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of premutation expansions (55-200 CGG repeats) in the fragile X messenger ribonucleoprotein 1 ( Methods: To address this critical gap, we performed an integrated multi-omics study combining plasma metabolomics (lipidomics, amine, and primary metabolites) with proteomics analyses in plasma and peripheral blood mononuclear cells (PBMCs) from FXTAS participants ( Results: Integrated analyses revealed molecular differences distinguishing FXTAS from HC, including alterations in metabolites related to energy metabolism (e.g., UDP-glucuronic acid, succinic acid, mannose), lipids (e.g., cholesterol, triglycerides, glycerophospholipids, ceramide), and selected amines (e.g., cystine, glycerophosphocholine, histidine). Proteomic analyses identified proteins associated with FXTAS clinical stage and CGG repeat size, implicating pathways related to mitochondrial function, immune-inflammatory signaling, and lipid metabolism. Comparative analysis of plasma and PBMC proteomes identified Basigin (CD147) and phospholipid transfer protein C2CD2 as overlapping candidate markers across biological matrices. Discussion: Although limited by sample size and the cross-sectional design, this exploratory study demonstrates the value of integrated, cross-matrix multi-omics profiling for identifying molecular patterns associated with advanced FXTAS. These findings reinforce prior mechanistic models and provide a foundation for future validation in larger, longitudinal cohorts.