Plasma multi-omics analysis reveals very long chain ceramides as validated biomarkers of Friedreich's ataxia

Friedreichs Ataxia (FRDA) is an autosomal neurodegenerative disease caused by the deficiency of the protein frataxin. Frataxin is a critical enzyme in the assembly of iron-sulfur clusters that are cofactors for several metabolic enzymes. To identify metabolic features that could be used as potential biomarkers for FRDA in plasma, we performed a multi-omics analysis using a discovery-validation cohort design. We combined metabolomics, lipidomics and proteomics from several liquid chromatography-high resolution mass spectrometry platforms. The analyses revealed that FRDA patients compared to healthy controls and unaffected carriers had dysregulated sphingolipids metabolism, phospholipid metabolism, citric acid cycle, amino acid metabolism, and apolipoprotein metabolism. Using an ROC, the decreased very long chain ceramides can distinguished FRDA patients from healthy controls with AUC from 0.75 to 0.85. Using induced pluripotent stem cell differentiated cardiomyocytes (iPSC-CMs), we demonstrated that frataxin deficiency preferentially affected ceramide synthase (CerS2), enriching long chain ceramides, and depleting very long chain ceramides. The ceramide metabolism was differentially regulated in two of the affected tissues in FRDA: heart and muscles. A machine-learning model improved the prediction of FRDA using the combination of three plasma metabolites (AUC > 0.9). In conclusion, decreased very long chain ceramides are reliable plasma biomarkers for FRDA patients. One Sentence SummaryNew plasma lipids biomarkers of Friedreichs Ataxia (FRDA) were validated using a discovery-validation design with two independent cohorts.