The unsolved puzzle of neuropathogenesis in glutaric aciduria type I

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• 作者：Paris  ; Jafari^a ; Olivier  ; Braissant^b ; Luisa  ; Bonaf&eacute ; ^a ; Diana  ; Ballhausen^a ;   ; ^{diana.ballhausen@chuv.ch}
• 关键词：Glutaric aciduria type I ; Glutaryl-CoA dehydrogenase ; Neuropathogenesis ; Excitotoxicity ; Oxidative stress ; Energy failure
• 刊名：Molecular Genetics and Metabolism
• 出版年：2011
• 出版时间：December 2011
• 年：2011
• 卷：104
• 期：4
• 页码：425-437
• 全文大小：701 K

文摘

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¨Cdyskinetic 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¨Cbrain 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.