PR002369 (Project)

Description:Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder caused by impaired catabolism of branched-chain amino acids (BCAAs), leading to severe systemic dysregulation. The disease has an incidence of approximately 1 in 185,000 live births in the general U.S. population, with much higher prevalence in the Mennonite communities (up to 1 in 140 live births in the latter due to the c.1312T>A p.Tyr438Asn BCKDHA founder mutation). Using a multi-omics approach integrating metabolomics, lipidomics, and proteomics, we analyzed blood samples from three MSUD patients on a BCAA-restricted diet, two post-liver transplantation patients, and six healthy controls. Gene ontology analysis highlighted enriched pathways in MSUD, including glycolysis, oxidative phosphorylation, and purine metabolism, revealing systemic metabolic imbalances. Lipidomics indicated disruptions in sphingolipids and lysophosphatidylcholines, which impact cellular signaling and membrane integrity. Liver transplantation corrected some abnormalities, but several metabolites and proteins remained dysregulated. Proteomic analysis revealed significant alterations in redox homeostasis, energy metabolism, and cytoskeletal organization, with only partial recovery post-transplantation. Post-translational modifications, such as methylation and cysteine oxidation, suggested ongoing oxidative stress and immune activation in the LT group. Elevated levels of L-isoleucine, L-valine, and their ketoacids persisted post-transplant, correlating with impaired amino acid metabolism, lipid remodeling, and protein folding. These findings provide comprehensive insight into MSUD-associated metabolic dysfunctions and highlight potential therapeutic targets to improve patient outcomes.