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

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Journal of Inherited Metabolic Disease

Abstract

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.

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Authors and Affiliations

  1. Biochemistry, Endocrinology and Metabolism Units, Institute of Child Health, University College London, London, UK

    S. Varadkar

  2. Neurosciences Unit, Institute of Child Health, University College London, London, UK

    R. Surtees

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  1. S. Varadkar
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  2. R. Surtees
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Correspondence to R. Surtees.

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Varadkar, S., Surtees, R. Glutaric aciduria type I and kynurenine pathway metabolites: A modified hypothesis. J Inherit Metab Dis 27, 835–842 (2004). https://doi.org/10.1023/B:BOLI.0000045767.42193.97

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  • DOI: https://doi.org/10.1023/B:BOLI.0000045767.42193.97

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