Amitriptyline use in individuals with KCNQ2/3 gain-of-function variants: A retrospective cohort study

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY Epilepsia Pub Date : 2025-02-17 DOI:10.1111/epi.18310

Matthias De Wachter, Charissa Millevert, Joost Nicolai, Elisabeth Cats, Gerhard Kluger, Mathieu Milh, Robin Cloarec, Steffen Syrbe, Katrijn Arts, Katrien Jansen, Magdalena Krygier, Robert Smigiel, Stephane Auvin, Kern Olofson, Cathrine Elisabeth Gjerulfsen, Berten Ceulemans, Rikke S. Møller, Allan Bayat, Sarah Weckhuysen

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Abstract

Objective

Heterozygous gain-of-function (GOF) variants in KCNQ2 and KCNQ3, encoding the voltage-gated potassium channel subunits Kv7.2 and Kv7.3, lead to neurodevelopmental disorders for which no established treatments are available. Amitriptyline, an antidepressant, blocks Kv7.2/Kv7.3 and has previously been reported to be effective in a single individual with a KCNQ2 GOF variant. We designed a retrospective, single-arm, multicenter study to investigate the effects of amitriptyline in a real-world setting.

Methods

We used a 7-point Likert scale to measure seizure frequency, clinical examination, motor function, alertness, skill acquisition, communication, mood, behavior, self-care, sleep, tiredness, and electroencephalogram at baseline, after a minimum of 6 weeks of intervention, and, if applicable, after discontinuation. Adverse events were assessed in all participants, and the effectiveness of the treatment was evaluated in 11 individuals who received a minimum dosage of .5 mg/kg/day for at least 6 weeks. Data were collected from October 2023 to August 2024.

Results

Thirteen individuals, eight with a pathogenic KCNQ2 GOF variant and five with a pathogenic KCNQ3 GOF variant, were included. Nine were female, and the median age at start of amitriptyline was 7.1 years (range = 1.5–20 years). Eleven individuals received a minimum dosage of .5 mg/kg/day for at least 6 weeks. The median dosage of amitriptyline administered was 1 mg/kg/day, with a median treatment duration of 29 weeks. Although amitriptyline was ineffective in two individuals (18%), eight (72%) demonstrated at least minimal improvement in two or more domains, with improvements in alertness and communication being the most frequently reported. In those with reported improvements, amitriptyline was discontinued in four individuals, but continued improvements were seen, to the same or greater extent compared to treatment. The remaining five individuals are on continued treatment because of perceived benefits.

Significance

Overall, the effect of amitriptyline remains unclear, and formal n-of-1 trials are needed to investigate the precise effects of amitriptyline in KCNQ GOF-related neurodevelopmental disorders.

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阿米替林在KCNQ2/3功能获得变异患者中的应用：一项回顾性队列研究

目的：编码电压门控钾通道亚基Kv7.2和Kv7.3的KCNQ2和KCNQ3的杂合功能获得（GOF）变异导致神经发育障碍，目前尚无成熟的治疗方法。阿米替林（Amitriptyline）是一种抗抑郁药，可阻断Kv7.2/Kv7.3，此前曾报道对KCNQ2 GOF变异的单个个体有效。我们设计了一项回顾性、单臂、多中心研究，以调查阿米替林在现实环境中的作用。方法：我们采用7点李克特量表，在干预至少6周后，如果适用，在停止干预后，测量癫痫发作频率、临床检查、运动功能、警觉性、技能获得、沟通、情绪、行为、自我保健、睡眠、疲劳和基线脑电图。对所有参与者的不良事件进行了评估，并对11名接受最低剂量为每天0.5 mg/kg至少6周的个体进行了治疗效果评估。数据收集时间为2023年10月至2024年8月。结果：共纳入13例患者，其中8例为致病性KCNQ2 GOF变异，5例为致病性KCNQ3 GOF变异。9例为女性，阿米替林开始治疗时的中位年龄为7.1岁（范围为1.5-20岁）。11例患者接受最低剂量为每天0.5 mg/kg，持续至少6周。阿米替林的中位剂量为1mg /kg/天，中位治疗持续时间为29周。尽管阿米替林对两人（18%）无效，但8人（72%）在两个或多个领域表现出至少最小的改善，其中警惕性和沟通能力的改善是最常见的报道。在报告有改善的患者中，有4人停用阿米替林，但与治疗相比，持续改善的程度相同或更大。剩下的五个人继续接受治疗，因为他们认为有好处。意义：总的来说，阿米替林的作用尚不清楚，需要正式的n-of-1试验来研究阿米替林在KCNQ gof相关神经发育障碍中的确切作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Epilepsia 医学-临床神经学

CiteScore

10.90

自引率

10.70%

发文量

319

审稿时长

2-4 weeks

期刊介绍： Epilepsia is the leading, authoritative source for innovative clinical and basic science research for all aspects of epilepsy and seizures. In addition, Epilepsia publishes critical reviews, opinion pieces, and guidelines that foster understanding and aim to improve the diagnosis and treatment of people with seizures and epilepsy.