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Glutaryl\u2010CoA dehydrogenase deficiency (GDD) is an autosomal recessive disease characterized by the accumulation of glutaric and 3\u2010hydroxyglutaric acids in tissues and body fluids. Untreated patients commonly present with severe striatal degeneration during encephalopathic crises. Previous studies have highlighted primary excitotoxicity as a trigger of striatal degeneration. The aim of this PhD study was to investigate in detail tissue\u2010specific bioenergetic and biochemical parameters of GDD <jats:italic>in vitro<\/jats:italic>, <jats:italic>post mortem<\/jats:italic>, and in <jats:italic>Gcdh<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. The major bioenergetic finding was uncompetitive inhibition of \u03b1\u2010ketoglutarate dehydrogenase complex by glutaryl\u2010CoA. It is suggested that a synergism of primary and secondary excitotoxic effects in concert with age\u2010related physiological changes in the developing brain underlie acute and chronic neurodegenerative changes in GDD patients. The major biochemical findings were highly elevated cerebral concentrations of glutaric and 3\u2010hydroxyglutaric acid despite low permeability of the blood\u2013brain barrier for these dicarboxylic acids. It can be postulated that glutaric and 3\u2010hydroxyglutaric acids are synthesized <jats:italic>de novo<\/jats:italic> and subsequently trapped in the brain. In this light, neurological disease in GDD is not \u2018transported\u2019 to the brain in analogy with phenylketonuria or hepatic encephalopathy as suggested previously but is more likely to be induced by the intrinsic biochemical properties of the cerebral tissue and the blood\u2013brain barrier.<\/jats:p>","DOI":"10.1007\/s10545-007-0678-8","type":"journal-article","created":{"date-parts":[[2007,9,18]],"date-time":"2007-09-18T23:18:37Z","timestamp":1190157517000},"page":"673-680","source":"Crossref","is-referenced-by-count":16,"title":["Biochemistry and bioenergetics of glutaryl\u2010CoA dehydrogenase deficiency"],"prefix":"10.1002","volume":"30","author":[{"given":"S. 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