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

  • Branched-Chain Amino Acids
  • Published:
Journal of Inherited Metabolic Disease

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.

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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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Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Room H3160, Stanford, CA, 94305, USA

    William J. Zinnanti

  2. Department of Radiology, University of California Los Angeles, Los Angeles, CA, 90095, USA

    Jelena Lazovic

Authors
  1. William J. Zinnanti
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  2. Jelena Lazovic
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Correspondence to William J. Zinnanti.

Additional information

Communicated by: Jörn Oliver Sass

Competing interest: None declared

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Zinnanti, W.J., Lazovic, J. Interrupting the mechanisms of brain injury in a model of maple syrup urine disease encephalopathy. J Inherit Metab Dis 35, 71–79 (2012). https://doi.org/10.1007/s10545-011-9333-5

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  • DOI: https://doi.org/10.1007/s10545-011-9333-5

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