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Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I

Zinnanti, William J. and Lazovic, Jelena and Housman, Cathy and LaNoue, Kathryn and O'Callaghan, James P. and Simpson, Ian and Woontner, Michael and Goodman, Stephen I. and Connor, James R. and Jacobs, Russell E. and Cheng, Keith C. (2007) Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I. Journal of Clinical Investigation, 117 (11). pp. 3258-3270. ISSN 0021-9738. PMCID PMC2000809.

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Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I.

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Jacobs, Russell E.0000-0002-1382-8486
Additional Information:Copyright ©2007 by the American Society for Clinical Investigation. Received for publication January 25, 2007, and accepted in revised form July 16, 2007. Published Online October 11, 2007. We thank Alistair Barber and Rhona Ellis of the Penn State Microscopy Imaging Core facility for their expertise in confocal microscopy and Javad Towfighi, Victor Canfield, and Cathleen McNeill for critical review of the manuscript. This work was supported by grants from the Laverty and Oxford Foundations, the Jake Gittlen Cancer Research Foundation, the Pennsylvania Keystone Initiative Award, the Life Sciences Greenhouse, the Tobacco Settlement Fund, and NIH grants 6R24RR017331 (to K.C. Cheng), RO1 NS38641 (to K. LaNoue), and 1F32NS058164-01 and 1F32NS058164-01A1 (to J. Lazovic). Additionally the authors wish to acknowledge support of the Gordon and Betty Moore Foundation to the Caltech Brain Imaging Center and NCRR U24 RR021760 to R.E. Jacobs. Conflict of interest: The authors have declared that no conflict of interest exists.
Funding AgencyGrant Number
Laverty FoundationUNSPECIFIED
Oxford FoundationUNSPECIFIED
Jake Gittlen Cancer Research FoundationUNSPECIFIED
Pennsylvania Keystone InitiativeUNSPECIFIED
Life Sciences GreenhouseUNSPECIFIED
Tobacco Settlement FundUNSPECIFIED
NIHRO1 NS38641
Gordon and Betty Moore FoundationUNSPECIFIED
National Center for Research Resources (NCRR)U24 RR021760
Issue or Number:11
PubMed Central ID:PMC2000809
Record Number:CaltechAUTHORS:ZINjci07
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Official Citation:J. Clin. Invest. 117:3258–3270 (2007). doi:10.1172/JCI31617
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:9005
Deposited By: Archive Administrator
Deposited On:14 Oct 2007
Last Modified:02 Oct 2019 23:56

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