Journal of Inherited Metabolic Disease

, Volume 35, Issue 1, pp 71–79 | Cite as

Interrupting the mechanisms of brain injury in a model of maple syrup urine disease encephalopathy

Branched-Chain Amino Acids


Maple syrup urine disease (MSUD) was first recognized as an inherited lethal encephalopathy beginning in the first week of life and associated with an unusual odor in the urine of affected children. It was later confirmed as a deficiency of branched-chain keto acid dehydrogenase (BCKDH), which is the second step in branched-chain amino acid (BCAA) breakdown. MSUD is characterized by BCAA and branched-chain keto acid (BCKA) accumulation. BCAAs are essential amino acids and powerful metabolic signals with severe consequences of both deprivation and accumulation. Treatment requires life-long dietary restriction and monitoring of BCAAs. However, despite excellent compliance, children commonly suffer metabolic decompensation during intercurrent illness resulting in life-threatening cerebral edema and dysmyelination. The mechanisms underlying brain injury have been poorly understood. Recent studies using newly developed mouse models of both classic and intermediate MSUD have yielded insight into the consequences of rapid BCAA accumulation. Additionally, these models have been used to test preliminary treatments aimed at competing with blood-brain barrier transport of BCAA using norleucine. Assessment of biochemical changes with and without treatment suggests different roles for BCAA and BCKA in the mechanism of brain injury.





Alpha-ketoglutarate dehydrogenase




Blood-brain barrier


Branched-chain amino acid


Branched-chain aminotransferase


BCAT cytosolic


BCAT mitochondrial


Branched-chain keto acid


Branched-chain keto acid dehydrogenase


Coenzyme A


Large neutral amino acid


LNAA transporter 1


Maple syrup urine disease




Pyruvate dehydrogenase


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Copyright information

© SSIEM and Springer 2011

Authors and Affiliations

  1. 1.Department of Neurology and Neurological SciencesStanford University School of MedicineStanfordUSA
  2. 2.Department of RadiologyUniversity of California Los AngelesLos AngelesUSA

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