Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I. Journal   The Journal of clinical investigation. Citation   J Clin Invest. 117(11):3258-70 Publication date   2007 Nov Authors   Zinnanti WJ Lazovic J Housman C LaNoue K O'Callaghan JP Simpson I Woontner M Goodman SI Connor JR Jacobs RE Cheng KC Investigators   Keith C. Cheng James R. Connor Kathryn F. LaNoue Ian A. Simpson Grants   United States NINDS 1F32NS058164-01 United States NINDS 1F32NS058164-01A1 United States NCRR 6R24RR017331 United States NINDS R01 NS38641 United States NCRR U24 RR021760 Abstract   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.