Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I.
Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I.
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I型戊二酸血症的年龄依赖性易感性机制及新治疗策略。
DOI：
10.1172/jci31617
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Cheng,KeithC
中科院分区：
文献类型：
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作者：
Zinnanti,WilliamJ;Lazovic,Jelena;Housman,Cathy;LaNoue,Kathryn;O'Callaghan,JamesP;Simpson,Ian;Woontner,Michael;Goodman,StephenI;Connor,JamesR;Jacobs,RussellE;Cheng,KeithC
戊二酸血症I型（GA-I）是一种遗传性赖氨酸和色氨酸代谢疾病，表现为纹状体病变，解剖学和症状与亨廷顿病相似。受影响的儿童通常在与非特异性疾病相关的分解代谢状态下遭受急性脑损伤。损伤和年龄依赖性易感性的机制尚不清楚，缺乏预示脑损伤的诊断标志物阻碍了干预工作。使用GA-I小鼠模型，我们发现病理事件始于神经元室，而未成熟大脑中赖氨酸积累的增加导致戊二酸产量增加，导致年龄依赖性损伤。谷氨酸和GABA耗竭与脑内戊二酸积累相关，可通过质子核磁共振（1H NMR）谱作为体内监测的诊断标志物。阻断脑赖氨酸摄取可降低戊二酸水平和脑损伤。这些发现提供了我们认为可能用于人类GA-I的新的监测和治疗策略。
Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I.