The ketogenic diet compensates for AGC1 deficiency and improves myelination
The ketogenic diet compensates for AGC1 deficiency and improves myelination
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DOI：
10.1111/epi.13193
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发表时间：
2015-11-01
期刊：
影响因子：
5.6
通讯作者：
Wedell, Anna
中科院分区：
文献类型：
--
作者：
Dahlin, Maria;Martin, Daniel A.;Wedell, Anna
脑谷氨酸盐-谷氨酸盐载体（AGC 1）在神经元中特异性表达，在神经元中其将天冬氨酸盐从线粒体转运至胞质溶胶，并且作为苹果酸盐-天冬氨酸盐穿梭的一部分在将烟酰胺腺嘌呤二核苷酸（NADH）还原当量转移至线粒体中起作用。AGC 1的功能缺陷是先天性代谢缺陷的基础，其表现为严重的肌张力减退、精神发育停滞和几个月大的癫痫发作。在AGC 1缺乏症中，由于缺乏N-乙酰天冬氨酸（NAA）而导致继发性髓鞘形成不足，这通常是由神经元中天冬氨酸的乙酰化产生的，并且是相邻少突胶质细胞合成脂肪酸所必需的。基于AGC 2缺乏的经验，我们预测糖酵解减少应该补偿代谢缺陷，并允许AGC 1缺乏恢复髓鞘形成。因此，通过引入生酮饮食，在6岁的AGC 1缺乏症患者中开始碳水化合物限制。反应是戏剧性的，临床和放射学。精神发育显示明显改善，磁共振成像（MRI）显示髓鞘形成恢复。这是第一个成功治疗继发性髓鞘形成不足的报告。由于AGC 1是由神经元线粒体呼吸链产生的质子梯度驱动的，因此该结果通常与继发性髓鞘形成不足具有潜在相关性。
The brain aspartate-glutamate carrier (AGC1) is specifically expressed in neurons, where it transports aspartate from the mitochondria to the cytosol, and plays a role in transfer of nicotinamide adenine dinucleotide (NADH)-reducing equivalents into the mitochondria as a part of the malate-aspartate shuttle. Deficient function of AGC1 underlies an inborn error of metabolism that presents with severe hypotonia, arrested psychomotor development, and seizures from a few months of age. In AGC1 deficiency, there is secondary hypomyelination due to lack of N-acetylaspartate (NAA), which is normally generated by acetylation of aspartate in the neuron and required for fatty acid synthesis by the adjacent oligodendrocyte. Based on experiences from AGC2 deficiency, we predicted that reduced glycolysis should compensate for the metabolic defect and allow resumed myelination in AGC1 deficiency. Carbohydrate restriction was therefore initiated in a patient with AGC1 deficiency at 6 years of age by introducing a ketogenic diet. The response was dramatic, clinically as well as radiologically. Psychomotor development showed clear improvement, and magnetic resonance imaging (MRI) indicated resumed myelination. This is the first successful treatment of secondary hypomyelination reported. Because AGC1 is driven by the proton gradient generated by the neuronal mitochondrial respiratory chain, the results have potential relevance for secondary hypomyelination in general.