Objective:

Genetic variants of the neuronal nicotinic acetylcholine receptor (nAChR) cause autosomal dominant sleep-related hypermotor epilepsy. Approximately 30% of autosomal dominant sleep-related hypermotor epilepsy patients are medically intractable. In preclinical models, pathogenic nAChR variants cause a gain of function mutation with sensitivity to acetylcholine antagonists and agonists. Nicotine modifies the activity of nAChRs and can be used as targeted therapy.

Methods:

We reviewed next-generation sequencing epilepsy panels from a single laboratory (GeneDx) from patients at Children’s Medical Center Dallas between 2011 and 2015 and identified patients with nAChR variants. Retrospective review of records included variant details, medical history, neuroimaging findings, and treatment history.

Results:

Twenty-one patients were identified. Four patients were prescribed nicotine patches for intractable seizures. Three of 4 patients had a clinical response, with >50% seizure reduction.

Conclusions:

Treatment with a nicotine patch can be an effective therapy in epilepsy patients with nAChR gene variants. We propose consideration of transdermal nicotine treatment in intractable epilepsy with known nAChR variants as an experimental therapy. Further clinical trials are needed to fully define therapeutic effects.

中文翻译：

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尼古丁：针对 nAChR 基因变异引起的癫痫的靶向治疗

客观的：

神经元烟碱型乙酰胆碱受体 (nAChR) 的遗传变异导致常染色体显性遗传睡眠相关过度运动性癫痫。大约 30% 的常染色体显性遗传睡眠相关过度运动性癫痫患者在医学上是顽固的。在临床前模型中，致病性 nAChR 变异导致对乙酰胆碱拮抗剂和激动剂敏感的功能获得突变。尼古丁会改变 nAChRs 的活性，可用作靶向治疗。

方法：

我们回顾了 2011 年至 2015 年达拉斯儿童医疗中心患者的单个实验室 (GeneDx) 的下一代测序癫痫面板，并确定了具有 nAChR 变异的患者。对记录的回顾性审查包括变异细节、病史、神经影像学发现和治疗史。

结果：

确定了 21 名患者。4 名患者服用尼古丁贴剂治疗顽固性癫痫发作。4 名患者中有 3 名出现临床反应，癫痫发作减少 50% 以上。

结论：

使用尼古丁贴剂治疗具有 nAChR 基因变异的癫痫患者可能是一种有效的治疗方法。我们建议考虑在已知 nAChR 变体的顽固性癫痫中使用经皮尼古丁治疗作为实验疗法。需要进一步的临床试验来充分确定治疗效果。