Pathomechanisms of Neurodegeneration in Glutaryl-CoA Dehydrogenase Deficiency

Stefan Kölker, David Koeller, Jürgen G. Okun, Georg F. Hoffmann

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

Glutaryl-CoA dehydrogenase deficiency is an inherited organic aciduria with predominantly neurological presentation. Biochemically, it is characterized by an accumulation and enhanced urinary excretion of two key organic acids, glutaric acid and 3-hydroxyglutaric acid. If untreated, acute striatal degeneration is often precipitated by febrile illnesses during a vulnerable period of brain development in infancy or early childhood, resulting in a dystonic dyskinetic movement disorder. The mechanism underlying these acute encephalopathic crises has been partially elucidated using in vitro and in vivo models. 3-Hydroxyglutaric and glutaric acids share structural similarities with the main excitatory amino acid glutamate and are considered to play an important role in the pathophysiology of this disease. 3-Hydroxyglutaric acid induces excitotoxic cell damage specifically via activation of N-methyl-D-aspartate receptors. Furthermore, glutaric and 3-hydroxyglutaric acids indirectly modulate glutamatergic and GABAergic neurotransmission, resulting in an imbalance of excitatory and inhibitory neurotransmission. It also has been suggested that secondary amplification loops potentiate the neurotoxic properties of these organic acids. Probable mechanisms for this effect include cytokine-stimulated nitric oxide production, a decrease in energy metabolism, and reduction of cellular creatine phosphate levels. Finally, maturation-dependent changes in the expression of neuronal glutamate receptors may affect the vulnerability to 3-hydroxyglutaric and glutaric acid toxicity.

Original languageEnglish (US)
Pages (from-to)7-12
Number of pages6
JournalAnnals of Neurology
Volume55
Issue number1
DOIs
StatePublished - Jan 2004

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Synaptic Transmission
Corpus Striatum
Excitatory Amino Acids
Acids
Phosphocreatine
Movement Disorders
Glutamate Receptors
N-Methyl-D-Aspartate Receptors
Energy Metabolism
Glutamic Acid
Nitric Oxide
Fever
3-hydroxyglutaric acid
Glutaric Acidemia I
Cytokines
Brain
glutaric acid
In Vitro Techniques

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Pathomechanisms of Neurodegeneration in Glutaryl-CoA Dehydrogenase Deficiency. / Kölker, Stefan; Koeller, David; Okun, Jürgen G.; Hoffmann, Georg F.

In: Annals of Neurology, Vol. 55, No. 1, 01.2004, p. 7-12.

Research output: Contribution to journalArticle

Kölker, Stefan ; Koeller, David ; Okun, Jürgen G. ; Hoffmann, Georg F. / Pathomechanisms of Neurodegeneration in Glutaryl-CoA Dehydrogenase Deficiency. In: Annals of Neurology. 2004 ; Vol. 55, No. 1. pp. 7-12.
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