Beyond bile acids synthesis: metabolomics profiling highlights extensive metabolic dysregulation and treatment response in CTX.

backgroundCerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder caused by variants in CYP27A1 leading to loss of sterol-27-hydroxylase activity. Sterol-27-hydroxylase generates two classes of bioactive signaling molecules: bile acids and oxysterols. The broader metabolic consequences resulting from perturbations in bile acid and oxysterol signaling and their reversibility with FDA-approved treatment chenodeoxycholic acid (CDCA), are not fully described.

methodsTo establish a comprehensive map of metabolic consequences of CTX, we performed large-scale, untargeted plasma metabolomics in a single subject with CTX, both before and after 6 months of CDCA therapy, and compared results with a reference cohort of over 1100 individuals. Data were analyzed for significant metabolite changes and pathway alterations.

resultsUntreated CTX exhibited marked depletion of bile acid intermediates and elevations in sterol precursors, consistent with the known enzymatic block in this pathway. Metabolomics highlighted additional pathways affected by bile acid and oxysterol signaling such as fatty acid metabolism, NAD

conclusionsThis study exposes the comprehensive nature of metabolic disturbance in CTX beyond the bile acids pathway, revealing perturbations in bile acids, steroids, fatty acids, phospholipids and NAD+ synthesis and highlights the dynamic early response to CDCA therapy. The metabolomic profile of untreated CTX can be leveraged for diagnostic screening. These findings report new candidate biomarkers for diagnosis and monitoring and underscore the potential of metabolomics to uncover broader metabolic consequences in rare disease.