Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I
William J. Zinnanti, … , Russell E. Jacobs, Keith C. Cheng
William J. Zinnanti, … , Russell E. Jacobs, Keith C. Cheng
Published October 11, 2007
Citation Information: J Clin Invest. 2007;117(11):3258-3270. https://doi.org/10.1172/JCI31617.
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Research Article Neuroscience

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

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.

Authors

William J. Zinnanti, Jelena Lazovic, Cathy Housman, Kathryn LaNoue, James P. O’Callaghan, Ian Simpson, Michael Woontner, Stephen I. Goodman, James R. Connor, Russell E. Jacobs, Keith C. Cheng

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Figure 9

Glx and GABA depletion detected by 1H NMR spectroscopy correlates with treatment success.

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Glx and GABA depletion detected by 1H NMR spectroscopy correlates with t...
(A) Comparison of 1H NMR spectra from weanling Gcdh–/– mice on a normal (left) or lysine diet (middle) or with combined glucose/homoarginine treatment (right) indicates a large decrease in the Glx peak (red arrow, center) and a smaller decrease in NAA after 48 hours of lysine diet exposure that was prevented by combined treatment (right). Multiple resonance peaks for GABA are not indicated. (B) Glx/Cr ratio, GABA/Cr ratio, and NAA/Cr ratio detected by 1H NMR spectroscopy in weanling Gcdh–/– mice on the lysine diet or with indicated treatments. Data are reported as percentage of normal diet control. Mean ± SEM, *P < 0.03. n = 4 per group. Lower left panel indicates voxel location used to acquire NMR spectroscopy data.