Advancing the Biochemical Understanding of Maple Syrup Urine Disease and the Impact of Liver Transplantation: A Pilot Study

Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder causing impaired branched-chain amino acid (BCAA) catabolism and systemic metabolic dysregulation. MSUD has an incidence of approximately 1 in 185,000 U.S. births, with much higher prevalence in the Mennonite communities (up to 1 in 400 live births due to the c.1312T > A p.Tyr438Asn BCKDHA founder mutation). Using a multiomic approach integrating metabolomics, lipidomics, and proteomics, we analyzed blood samples from three patients on a BCAA-restricted diet (MSUDDR), two MSUD patients who received liver transplants (MSUDLT), and six healthy controls. Gene ontology analysis of integrated omics data confirmed systemic metabolic imbalances in MSUD, highlighting increases in glycolysis, oxidative phosphorylation, and purine metabolism. Lipidomic analysis revealed disruptions in sphingolipids and lysophosphatidylcholines, affecting signaling and membrane integrity. Liver transplantation corrected some abnormalities, but key metabolites and proteins remained altered. Proteomic analysis revealed significant alterations in redox homeostasis, energy metabolism, and cytoskeletal organization with partial recovery post-transplantation. Post-translational modifications indicated ongoing oxidative stress and immune activation in the MSUDLT 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 insights into MSUD-associated metabolic dysfunction and highlight potential therapeutic targets.