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

J Clin Invest. 2007 Nov;117(11):3258-70. doi: 10.1172/JCI31617.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology*
  • Amino Acid Metabolism, Inborn Errors* / diet therapy
  • Amino Acid Metabolism, Inborn Errors* / pathology
  • Amino Acid Metabolism, Inborn Errors* / physiopathology
  • Animals
  • Brain Diseases, Metabolic, Inborn* / diet therapy
  • Brain Diseases, Metabolic, Inborn* / pathology
  • Brain Diseases, Metabolic, Inborn* / physiopathology
  • Child
  • Diet
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Glucose / metabolism
  • Glucose / therapeutic use
  • Glutamic Acid / metabolism
  • Glutarates / metabolism*
  • Glutaryl-CoA Dehydrogenase / genetics
  • Glutaryl-CoA Dehydrogenase / metabolism*
  • Homoarginine / metabolism
  • Homoarginine / therapeutic use
  • Humans
  • Lysine / metabolism
  • Lysine / therapeutic use
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Neurons / metabolism
  • Neurons / pathology
  • Neurons / ultrastructure
  • Nuclear Magnetic Resonance, Biomolecular
  • Tryptophan / metabolism
  • gamma-Aminobutyric Acid / metabolism


  • Glutarates
  • Homoarginine
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Tryptophan
  • Glutaryl-CoA Dehydrogenase
  • glutaric acid
  • Glucose
  • Lysine