Division of Neurology, Departments of Neurology and Pediatrics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, 3501 Civic Center Blvd, Philadelphia, PA, 19104, USA.
Danish Epilepsy Centre, Filadelfia, Dianalund,, DK 4293, Denmark.
Neurotherapeutics. 2019 Jul;16(3):848-857. doi: 10.1007/s13311-019-00739-y.
Pathogenic variants in KCNT1 represent an important cause of treatment-resistant epilepsy, for which an effective therapy has been elusive. Reports about the effectiveness of quinidine, a candidate precision therapy, have been mixed. We sought to evaluate the treatment responsiveness of patients with KCNT1-related epilepsy. We performed an observational study of 43 patients using a collaborative KCNT1 patient registry. We assessed treatment efficacy based upon clinical seizure reduction, side effects of quinidine therapy, and variant-specific responsiveness to treatment. Quinidine treatment resulted in a > 50% seizure reduction in 20% of patients, with rare patients achieving transient seizure freedom. Multiple other therapies demonstrated some success in reducing seizure frequency, including the ketogenic diet and vigabatrin, the latter particularly in patients with epileptic spasms. Patients with the best quinidine response had variants that clustered distal to the NADP domain within the RCK2 domain of the protein. Half of patients did not receive a quinidine trial. In those who did, nearly half did not achieve therapeutic blood levels. More favorable response to quinidine in patients with KCNT1 variants distal to the NADP domain within the RCK2 domain may suggest a variant-specific response.
KCNT1 中的致病变体是治疗耐药性癫痫的一个重要原因，而目前仍缺乏有效的治疗方法。关于候选精准治疗药物奎尼丁的疗效报告结果不一。我们试图评估 KCNT1 相关癫痫患者的治疗反应。我们对使用 KCNT1 患者登记处的 43 名患者进行了一项观察性研究。我们根据临床癫痫发作减少情况、奎尼丁治疗的副作用以及针对特定变异的治疗反应来评估治疗效果。奎尼丁治疗使 20%的患者癫痫发作减少了 >50%，极少数患者实现了短暂的癫痫无发作。其他多种疗法在降低癫痫发作频率方面也取得了一定的成功，包括生酮饮食和氨己烯酸，后者在癫痫性痉挛患者中尤其有效。对奎尼丁反应最好的患者的变异体位于 NADP 结构域内的 RCK2 结构域的远端。一半的患者未接受奎尼丁试验。在接受试验的患者中，近一半患者未达到治疗性血药浓度。在 RCK2 结构域内 NADP 结构域远端的 KCNT1 变异体患者中对奎尼丁反应更好，这可能提示存在针对特定变异体的反应。
