Brain Advance Access published online on March 17, 2009
Brain, doi:10.1093/brain/awp024
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease
1 Penn State College of Medicine, Hershey, PA, USA 2 Department of Biology, California Institute of Technology, Pasadena, CA, USA 3 Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA 4 Program in Biochemistry and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA 5 Biomed Research & Technologies, Inc., Wexford, PA, USA 6 Departments of Anesthesiology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA 7 Department of Pathology and Jake Gittlen Cancer Research Foundation, Penn State College of Medicine, Hershey, PA, USA 8 Department of Cellular and Molecular Physiology and Biochemistry, Penn State College of Medicine, Hershey, PA, USA
Correspondence to:
William J. Zinnanti, Penn State College of Medicine, Box 149, 500 University Drive, Hershey, 17033 PA, USA E-mail: wzinnanti{at}gmail.com
Maple syrup urine disease (MSUD) is an inherited disorder of branched-chain amino acid metabolism presenting with life-threatening cerebral oedema and dysmyelination in affected individuals. Treatment requires life-long dietary restriction and monitoring of branched-chain amino acids to avoid brain injury. Despite careful management, children commonly suffer metabolic decompensation in the context of catabolic stress associated with non-specific illness. The mechanisms underlying this decompensation and brain injury are poorly understood. Using recently developed mouse models of classic and intermediate maple syrup urine disease, we assessed biochemical, behavioural and neuropathological changes that occurred during encephalopathy in these mice. Here, we show that rapid brain leucine accumulation displaces other essential amino acids resulting in neurotransmitter depletion and disruption of normal brain growth and development. A novel approach of administering norleucine to heterozygous mothers of classic maple syrup urine disease pups reduced branched-chain amino acid accumulation in milk as well as blood and brain of these pups to enhance survival. Similarly, norleucine substantially delayed encephalopathy in intermediate maple syrup urine disease mice placed on a high protein diet that mimics the catabolic stress shown to cause encephalopathy in human maple syrup urine disease. Current findings suggest two converging mechanisms of brain injury in maple syrup urine disease including: (i) neurotransmitter deficiencies and growth restriction associated with branched-chain amino acid accumulation and (ii) energy deprivation through Krebs cycle disruption associated with branched-chain ketoacid accumulation. Both classic and intermediate models appear to be useful to study the mechanism of brain injury and potential treatment strategies for maple syrup urine disease. Norleucine should be further tested as a potential treatment to prevent encephalopathy in children with maple syrup urine disease during catabolic stress.
Key Words: Maple syrup urine disease; metabolic decompensation; cerebral oedema; MRI; branched-chain amino acids
Abbreviations:
KG, alpha-ketoglutarate; KGDH, alpha-ketoglutarate dehyrdrogenase; KIC, alpha-ketoisocaproate; BCAA, branched-chain amino acid; BCAT, branched-chain aminotransferase; LAT1, LNAA transporter; LNAA, large neutral amino acid; MSUD, maple syrup urine disease
.
Received October 21, 2008. Revised January 14, 2009. Accepted January 19, 2009.
*These authors contributed equally to this work.