Inborn Errors of Metabolism, Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, 1011 Lausanne, Switzerland.
Mol Genet Metab. 2011 Dec;104(4):425-37. doi: 10.1016/j.ymgme.2011.08.027. Epub 2011 Sep 2.
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.
Ⅰ 型戊二酸血症（GA-I）是一种脑有机酸血症，由谷氨酰辅酶 A 脱氢酶（GCDH）缺乏引起。GCDH 缺乏导致戊二酸（GA）和 3-羟基戊二酸（3-OHGA）两种代谢物在脑和体液中积累，这两种代谢物被认为具有神经毒性。该疾病通常在分解代谢状态（如并发疾病）下表现出临床症状，伴有急性脑病危象，导致纹状体坏死和永久性张力障碍性运动障碍。大量体外和体内研究的结果指出了与代谢物介导的神经元损伤相关的三个主要机制：兴奋性毒性、能量代谢障碍和氧化应激。有证据表明，在代谢危机期间，GA 和其代谢物在中枢神经系统内源性产生，并由于血脑屏障的转运机制受限而积累。尽管进行了广泛的实验工作，但所提出的发病机制的相对贡献仍不清楚，尚未开发出特定的治疗方法。在这里，我们回顾了实验证据，并试图描绘可能的发病模型和未来研究的方法。
