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Glutaric aciduria type I and kynurenine pathway metabolites: A modified hypothesis
Author(s) -
Varadkar S.,
Surtees R.
Publication year - 2004
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1023/b:boli.0000045767.42193.97
Subject(s) - quinolinic acid , kynurenine pathway , kynurenine , kynurenic acid , neurotoxin , indoleamine 2,3 dioxygenase , chemistry , agonist , biochemistry , pharmacology , receptor , biology , glutamate receptor , tryptophan , amino acid
Summary : 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.