A monogenic etiology can be identified in up to 40% of people with severe epilepsy. To address earlier and more appropriate treatment strategies, clinicians are required to know the implications that specific genetic causes might have on pathophysiology, natural history, comorbidities, and treatment choices. In this narrative review, we summarize concepts on the genetic epilepsies based on the underlying pathophysiologic mechanisms and present the current knowledge on treatment options based on evidence provided by controlled trials or studies with lower classification of evidence. Overall, evidence robust enough to guide antiseizure medication (ASM) choices in genetic epilepsies remains limited to the more frequent conditions for which controlled trials and observational studies have been possible. Most monogenic disorders are very rare and ASM choices for them are still based on inferences drawn from observational studies and early, often anecdotal, experiences with precision therapies. Precision medicine remains applicable to only a narrow number of patients with monogenic epilepsies and may target only part of the actual functional defects. Phenotypic heterogeneity is remarkable, and some genetic mutations activate epileptogenesis through their developmental effects, which may not be reversed postnatally. Other genes seem to have pure functional consequences on excitability, acting through either loss- or gain-of-function effects, and these may have opposite treatment implications. In addition, the functional consequences of missense mutations may be difficult to predict, making precision treatment approaches considerably more complex than estimated by deterministic interpretations. Knowledge of genetic etiologies can influence the approach to surgical treatment of focal epilepsies. Identification of germline mutations in specific genes contraindicates surgery while mutations in other genes do not. Identification, quantification, and functional characterization of specific somatic mutations before surgery using CSF liquid biopsy or after surgery in brain specimens will likely be integrated in planning surgical strategies and reintervention after a first unsuccessful surgery as initial evidence suggests that mutational load may correlate with the epileptogenic zone. Promising future directions include gene manipulation by DNA or mRNA targeting; although most are still far from clinical use, some are in early phase clinical development.

高达 40% 的严重癫痫患者可发现单基因病因。为了制定更早、更合适的治疗策略，临床医生需要了解特定遗传原因可能对病理生理学、自然史、合并症和治疗选择产生的影响。在这篇叙述性综述中，我们根据潜在的病理生理机制总结了遗传性癫痫的概念，并根据对照试验或证据分类较低的研究提供的证据介绍了当前治疗方案的知识。总体而言，足以指导遗传性癫痫的抗癫痫药物（ASM）选择的证据仍然仅限于可以进行对照试验和观察研究的更常见的情况。大多数单基因疾病非常罕见，ASM 对它们的选择仍然基于观察性研究和早期（通常是轶事）精准治疗经验得出的推论。精准医学仍然仅适用于少数单基因癫痫患者，并且可能仅针对部分实际功能缺陷。表型异质性是显着的，一些基因突变通过其发育效应激活癫痫发生，这种效应在出生后可能无法逆转。其他基因似乎对兴奋性具有纯粹的功能性影响，通过功能丧失或获得功能效应发挥作用，并且这些可能具有相反的治疗意义。此外，错义突变的功能后果可能难以预测，使得精准治疗方法比确定性解释估计的要复杂得多。对遗传病因的了解可以影响局灶性癫痫的手术治疗方法。特定基因中种系突变的鉴定表明不能进行手术，而其他基因中的突变则不然。手术前使用脑脊液液体活检或手术后脑标本的特定体细胞突变的识别、量化和功能表征可能会被纳入规划手术策略和第一次不成功手术后的重新干预中，因为初步证据表明突变负荷可能与致癫痫相关。区。有前景的未来方向包括通过 DNA 或 mRNA 靶向进行基因操作；尽管大多数距离临床使用还很远，但有些正处于临床开发的早期阶段。