Glutaric aciduria type I and kynurenine pathway metabolites: a modified hypothesis

Glutaric aciduria type I is an inborn error of organic acid metabolism that demonstrates a particular temporal vulnerability (acute encephalopathic episodes in infancy) and a spatial vulnerability (acute striatal necrosis, focused on the putamen). Excitotoxic mechanisms involving 3-hydroxyglutaric acid as the major neurotoxin have been suggested. This paper proposes a role for metabolites of the kynurenine pathway in the pathogenic process and modifies the hypothesis of Heyes. Deficiency of glutaryl-CoA dehydrogenase blocking the glutarate pathway and activation of indoleamine 2,3-dioxygenase in macrophages/monocytes by intercurrent inflammation may increase flux down the kynurenine pathway towards the production of quinolinic acid. Quinolinic acid is neurotoxic and is an endogenous agonist at N-methyl-D-aspartate receptors. Synergistic excitation of these receptors by quinolinic acid and 3-hydroxyglutaric acid, which alone does not have sufficient potency, may be involved in the pathogenesis of striatal necrosis.