Journal of Inherited Metabolic Disease

, Volume 35, Issue 1, pp 71–79

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

Authors

    • Department of Neurology and Neurological SciencesStanford University School of Medicine
  • Jelena Lazovic
    • Department of RadiologyUniversity of California Los Angeles
Branched-Chain Amino Acids

DOI: 10.1007/s10545-011-9333-5

Cite this article as:
Zinnanti, W.J. & Lazovic, J. J Inherit Metab Dis (2012) 35: 71. doi:10.1007/s10545-011-9333-5
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Abstract

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.

Abbreviations

αKG

Alpha-ketoglutarate

αKGDH

Alpha-ketoglutarate dehydrogenase

αKIC

Alpha-ketoisocaproate

BBB

Blood-brain barrier

BCAA

Branched-chain amino acid

BCAT

Branched-chain aminotransferase

BCATc

BCAT cytosolic

BCATm

BCAT mitochondrial

BCKA

Branched-chain keto acid

BCKDH

Branched-chain keto acid dehydrogenase

CoA

Coenzyme A

LNAA

Large neutral amino acid

LAT1

LNAA transporter 1

MSUD

Maple syrup urine disease

PCr

Phosphocreatine

PDH

Pyruvate dehydrogenase

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© SSIEM and Springer 2011