Progress in pathogenesis of glutaric aciduria type I

Abstract

Glutaric aciduria type I is an autosomal recessive disorder resulting from glutaryl-CoA de- hydrogenase（GCDH） deficiency. Untreated patients commonly present with severe striatal degeneration and ex- trapyramidal sequelae during encephalopathic crises. GCDH deficiency leads to accumulation of glutaric acid and 3-hydroxyglutaric acid in tissues and body fluids （especially in brain）, which are neurotoxic. There is no correla- tion between residual enzyme activity caused by mutations in GCDH and phenotype. The pathogenesis of glutaric aciduria type I is complicated. Previous studies have demonstrated that glutaric and 3-hydroxyglutaric acids are synthesized in central nervous system and trapped because of limiting transport across the blood-brain barrier. The studies on metabolite-mediated neurotoxicity mainly focus on excitotoxicity,impairment of energy metabo- lism and oxidative stress. In addition, activation of astrocyte, vascular derangements,inflammatory processes may be a synergism of neurotoxicity. Key words: Glutaric aciduria; Neurotoxicity; Excitotoxicity; Impairment of energy metabolism; Oxida- tive stress