Metabolic epilepsies arise in the context of rare inborn errors of metabolism (IEM), notably glucose transporter type 1 deficiency syndrome, succinic semialdehyde dehydrogenase deficiency, pyruvate dehydrogenase complex deficiency, nonketotic hyperglycinemia, and mitochondrial cytopathies. A common feature of these disorders is impaired bioenergetics, which through incompletely defined mechanisms result in a wide spectrum of neurological symptoms, such as epileptic seizures, developmental delay, and movement disorders. The ketogenic diet (KD) has been successfully utilized to treat such conditions to varying degrees. While the mechanisms underlying the clinical efficacy of the KD in IEM remain unclear, it is likely that the proposed heterogeneous targets influenced by the KD work in concert to rectify or ameliorate the downstream negative consequences of genetic mutations affecting key metabolic enzymes and substrates—such as oxidative stress and cell death. These beneficial effects can be broadly grouped into restoration of impaired bioenergetics and synaptic dysfunction, improved redox homeostasis, anti‐inflammatory, and epigenetic activity. Hence, it is conceivable that the KD might prove useful in other metabolic disorders that present with epileptic seizures. At the same time, however, there are notable contraindications to KD use, such as fatty acid oxidation disorders. Clearly, more research is needed to better characterize those metabolic epilepsies that would be amenable to ketogenic therapies, both experimentally and clinically. In the end, the expanded knowledge base will be critical to designing metabolism‐based treatments that can afford greater clinical efficacy and tolerability compared to current KD approaches, and improved long‐term outcomes for patients.

中文翻译：

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适合生酮治疗的代谢性癫痫：适应症、禁忌症和潜在机制

代谢性癫痫发生在罕见的先天性代谢障碍 (IEM) 的背景下，特别是葡萄糖转运蛋白 1 型缺乏综合征、琥珀酸半醛脱氢酶缺乏症、丙酮酸脱氢酶复合物缺乏症、非酮症高甘氨酸血症和线粒体细胞病。这些疾病的一个共同特征是生物能量学受损，其通过不完全定义的机制导致广泛的神经系统症状，例如癫痫发作、发育迟缓和运动障碍。生酮饮食 (KD) 已成功用于不同程度地治疗此类病症。虽然 KD 在 IEM 中的临床疗效的潜在机制仍不清楚，受 KD 影响的提议的异质靶标很可能协同工作，以纠正或改善影响关键代谢酶和底物的基因突变的下游负面后果——例如氧化应激和细胞死亡。这些有益作用可以大致分为恢复受损的生物能量学和突触功能障碍、改善氧化还原稳态、抗炎和表观遗传活性。因此，可以想象，KD 可能被证明对其他伴有癫痫发作的代谢紊乱有用。然而，与此同时，使用 KD 存在明显的禁忌症，例如脂肪酸氧化障碍。显然，需要更多的研究来更好地表征那些适合生酮疗法的代谢性癫痫，无论是在实验上还是在临床上。