title: The unsolved puzzle of neuropathogenesis in glutaric aciduria type I.
abstract: Glutaric aciduria type I (GA-I) is a cerebral organic aciduria caused by deficiency of glutaryl-Co-A dehydrogenase (GCDH). GCDH deficiency leads to accumulation of glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA), two metabolites that are believed to be neurotoxic, in brain and body fluids. The disorder usually becomes clinically manifest during a catabolic state (e.g. intercurrent illness) with an acute encephalopathic crisis that results in striatal necrosis and in a permanent dystonic-dyskinetic movement disorder. The results of numerous in vitro and in vivo studies have pointed to three main mechanisms involved in the metabolite-mediated neuronal damage: excitotoxicity, impairment of energy metabolism and oxidative stress. There is evidence that during a metabolic crisis GA and its metabolites are produced endogenously in the CNS and accumulate because of limiting transport mechanisms across the blood-brain barrier. Despite extensive experimental work, the relative contribution of the proposed pathogenic mechanisms remains unclear and specific therapeutic approaches have yet to be developed. Here, we review the experimental evidence and try to delineate possible pathogenetic models and approaches for future studies.
authors.affiliation: Inborn Errors of Metabolism, Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Paris
authors.initials: P
authors.lastname: Jafari
authors.forename: Olivier
authors.initials: O
authors.lastname: Braissant
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafé
authors.forename: Diana
authors.initials: D
authors.lastname: Ballhausen
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001928:Brain Diseases, Metabolic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D018683:Excitatory Amino Acid Agents / Q000378:metabolism; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D009928:Organ Specificity; D018384:Oxidative Stress; D009435:Synaptic Transmission
chemical_list: D018683:Excitatory Amino Acid Agents; D050770:Glutaryl-CoA Dehydrogenase