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Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease

Zinnanti, William J. and Lazovic, Jelena and Griffin, Kathleen and Skvorak, Kristen J. and Paul, Harbhajan S. and Homanics, Gregg E. and Bewley, Maria C. and Cheng, Keith C. and LaNoue, Kathryn F. and Flanagan, John M. (2009) Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease. Brain, 132 (4). pp. 903-918. ISSN 0006-8950.

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Maple syrup urine disease (MSUD) is an inherited disorder of branched-chain amino acid metabolism presenting with lifethreatening 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 branchedchain 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.

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Additional Information:© 2009 The Author(s).Received October 21, 2008. Revised January 14, 2009. Accepted January 19, 2009. Advance Access publication March 17, 2009.We thank Dr Alistair Barber and Rhona Ellis of the Penn State Microscopy Imaging Core facility for their expertise in confocal microscopy. This work is dedicated to the memory of Rhona Ellis for her endless encouragement and admiration of the young scientist.Keystone Innovation Zone; Ben Franklin Technology Partners; the Jake Gittlen Cancer Research Foundation and the International Organization for Glutaric Aciduria; MSUD Family Support Group; Scott Foster Metabolic Disease Fund; National Institutes of Health grants (1F32NS058164 to J.L.; 6R24RR017331 to K.C.C.; and RO1 NS38641 to K.F.L.); Pennsylvania Tobacco Settlement funds (to K.C.C.).
Funding AgencyGrant Number
Keystone Innovation ZoneUNSPECIFIED
Ben Franklin Technology PartnersUNSPECIFIED
Jake Gittlen Cancer Research FoundationUNSPECIFIED
International Organization for Glutaric AciduriaUNSPECIFIED
MSUD Family Support GroupUNSPECIFIED
Scott Foster Metabolic Disease FundUNSPECIFIED
NIHRO1 NS38641
Pennsylvania Tobacco Settlement fundsUNSPECIFIED
Subject Keywords:Maple syrup urine disease; metabolic decompensation; cerebral oedema; MRI; branched-chain amino acids
Issue or Number:4
Record Number:CaltechAUTHORS:20090701-093636602
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14472
Deposited By: Lindsay Cleary
Deposited On:11 Aug 2009 18:06
Last Modified:03 Oct 2019 00:50

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