Kölker Stefan, Koeller David M, Okun Jürgen G, Hoffmann Georg F
Division of Metabolic and Endocrine Diseases, University Children's Hospital, Heidelberg, Germany.
Ann Neurol. 2004 Jan;55(1):7-12. doi: 10.1002/ana.10784.
Glutaryl-CoA dehydrogenase deficiency is an inherited organic aciduria with predominantly neurological presentation. Biochemically, it is characterized by an accumulation and enhanced urinary excretion of two key organic acids, glutaric acid and 3-hydroxyglutaric acid. If untreated, acute striatal degeneration is often precipitated by febrile illnesses during a vulnerable period of brain development in infancy or early childhood, resulting in a dystonic dyskinetic movement disorder. The mechanism underlying these acute encephalopathic crises has been partially elucidated using in vitro and in vivo models. 3-Hydroxyglutaric and glutaric acids share structural similarities with the main excitatory amino acid glutamate and are considered to play an important role in the pathophysiology of this disease. 3-Hydroxyglutaric acid induces excitotoxic cell damage specifically via activation of N-methyl-D-aspartate receptors. Furthermore, glutaric and 3-hydroxyglutaric acids indirectly modulate glutamatergic and GABAergic neurotransmission, resulting in an imbalance of excitatory and inhibitory neurotransmission. It also has been suggested that secondary amplification loops potentiate the neurotoxic properties of these organic acids. Probable mechanisms for this effect include cytokine-stimulated nitric oxide production, a decrease in energy metabolism, and reduction of cellular creatine phosphate levels. Finally, maturation-dependent changes in the expression of neuronal glutamate receptors may affect the vulnerability to 3-hydroxyglutaric and glutaric acid toxicity.
戊二酰辅酶A脱氢酶缺乏症是一种遗传性有机酸尿症，主要表现为神经系统症状。在生化方面，其特征是两种关键有机酸——戊二酸和3-羟基戊二酸在体内蓄积并在尿液中排泄增加。如果不进行治疗，在婴儿期或幼儿期脑发育的易损期，发热性疾病常诱发急性纹状体变性，导致肌张力障碍性运动障碍。利用体外和体内模型已部分阐明了这些急性脑病危机的潜在机制。3-羟基戊二酸和戊二酸与主要兴奋性氨基酸谷氨酸在结构上有相似之处，被认为在该疾病的病理生理学中起重要作用。3-羟基戊二酸通过激活N-甲基-D-天冬氨酸受体特异性地诱导兴奋性毒性细胞损伤。此外，戊二酸和3-羟基戊二酸间接调节谷氨酸能和γ-氨基丁酸能神经传递，导致兴奋性和抑制性神经传递失衡。也有人提出，继发性放大回路会增强这些有机酸的神经毒性特性。这种效应的可能机制包括细胞因子刺激的一氧化氮生成、能量代谢降低以及细胞内磷酸肌酸水平降低。最后，神经元谷氨酸受体表达的成熟依赖性变化可能会影响对3-羟基戊二酸和戊二酸毒性的易感性。
