Developmental and epileptic encephalopathies are devastating disorders characterized by epilepsy, intellectual disability, and other neuropsychiatric symptoms, for which available treatments are largely ineffective. Following a precision medicine approach, we show for KCNA2-encephalopathy that the K+ channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the KV1.2 subunit in vitro, by reducing current amplitudes and negative shifts of steady-state activation and increasing the firing rate of transfected neurons. In n-of-1 trials carried out in nine different centers, 9 of 11 patients carrying such variants benefitted from treatment with 4-aminopyridine. All six patients experiencing daily absence, myoclonic, or atonic seizures became seizure-free (except some remaining provoked seizures). Two of six patients experiencing generalized tonic-clonic seizures showed marked improvement, three showed no effect, and one worsening. Nine patients showed improved gait, ataxia, alertness, cognition, or speech. 4-Aminopyridine was well tolerated up to 2.6 mg/kg per day. We suggest 4-aminopyridine as a promising tailored treatment in KCNA2-(gain-of-function)–encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment.

中文翻译：

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对于功能获得性 KCNA2 脑病患者，4-氨基吡啶是一种很有前景的治疗选择。

发育性和癫痫性脑病是以癫痫、智力残疾和其他神经精神症状为特征的破坏性疾病，可用的治疗方法在很大程度上是无效的。根据精准医学方法，我们针对 KCNA2 脑病表明，K+ 通道阻滞剂 4-氨基吡啶可以通过降低电流幅度和稳态负移来拮抗由体外 KV1.2 亚基变异引起的功能获得缺陷。状态激活和增加转染神经元的放电率。在九个不同中心进行的 n-of-1 试验中，携带此类变异的 11 名患者中有 9 名受益于 4-氨基吡啶治疗。每天经历失神、肌阵挛或失张力性癫痫发作的所有六名患者都没有癫痫发作（除了一些剩余的诱发性癫痫发作）。经历全身强直-阵挛性癫痫发作的六名患者中有两名表现出明显改善，三名没有效果，一名恶化。九名患者的步态、共济失调、警觉性、认知或言语有所改善。4-氨基吡啶耐受性良好，高达每天 2.6 mg/kg。我们建议 4-氨基吡啶作为 KCNA2-（功能获得）脑病的有前途的定制治疗，并提供在线工具帮助医生选择适合这种治疗的功能获得突变患者。