Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

Int J Mol Sci. 2020 Oct 11;21(20):7490. doi: 10.3390/ijms21207490.


Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by decreased activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), which catalyzes the irreversible catabolism of branched-chain amino acids (BCAAs). Current management of this BCAA dyshomeostasis consists of dietary restriction of BCAAs and liver transplantation, which aims to partially restore functional BCKDC activity in the periphery. These treatments improve the circulating levels of BCAAs and significantly increase survival rates in MSUD patients. However, significant cognitive and psychiatric morbidities remain. Specifically, patients are at a higher lifetime risk for cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorder. Recent literature suggests that the neurological sequelae may be due to the brain-specific roles of BCAAs. This review will focus on the derangements of BCAAs observed in the brain of MSUD patients and will explore the potential mechanisms driving neurologic dysfunction. Finally, we will discuss recent evidence that implicates the relevance of BCAA metabolism in other neurological disorders. An understanding of the role of BCAAs in the central nervous system may facilitate future identification of novel therapeutic approaches in MSUD and a broad range of neurological disorders.

Keywords: amino acid metabolism; branched-chain amino acid; maple syrup urine disease; metabolic disorder; neurological disorder.

Publication types

  • Review

MeSH terms

  • Amino Acids, Branched-Chain / metabolism*
  • Aspartic Acid / metabolism
  • Brain / metabolism*
  • Brain / pathology
  • Central Nervous System / metabolism
  • Disease Susceptibility
  • Glutamic Acid / metabolism
  • Humans
  • Lactic Acid / metabolism
  • Maple Syrup Urine Disease / etiology*
  • Maple Syrup Urine Disease / metabolism*
  • Maple Syrup Urine Disease / pathology
  • Metabolic Networks and Pathways
  • Nervous System Diseases / etiology
  • Nervous System Diseases / metabolism


  • Amino Acids, Branched-Chain
  • Aspartic Acid
  • Lactic Acid
  • Glutamic Acid