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 4

Brain lysine accumulation, ketotic hypoglycemia, and increased glutaric acid levels correlate with age-dependent susceptibility to brain injury in weanling Gcdh–/– mice.

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Brain lysine accumulation, ketotic hypoglycemia, and increased glutaric ...
(A) Serum lysine, brain lysine, and brain glutaric acid levels, (B) serum and brain arginine and alanine levels, and (C) serum glucose (Glc) and β-hydroxybutyrate levels in weanling (4w) and adult (8w) Gcdh–/– mice (G–/–) and heterozygous controls (G–/+) on normal (ND) or lysine (Lys) diets. Amino acid differences are compared with heterozygous normal diet controls, and brain glutaric acid differences are compared with weanling Gcdh–/– normal diet controls. Mean ± SEM, *P < 0.01; **P < 0.001. n = 6 each group. (D) Twelve-day survival of adult (black circles, n = 20) and weanling (black diamonds, n = 20) Gcdh–/– mice on the lysine diet. (E) T2 maps (top) and T2-weighted images (bottom) of weanling Gcdh–/– mice. Color bar indicates T2 values (right side). Weanlings showed brain swelling, indicated by obliterated ventricles (black arrows; compare left with middle and right), and increased subdural fluid collection (red arrows, middle) at 48 hours of lysine diet exposure. At 6 days, surviving weanlings developed striatal lesions indicated by increased T2 signal (red arrows, right).