OBJECTIVE Patients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments. METHODS We recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information. RESULTS We identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI. CONCLUSION Our patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.

中文翻译：

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日本致病性CDKL5变异患者的临床表现和癫痫治疗

目的 具有致病性细胞周期蛋白依赖性激酶样 5 基因 (CDKL5) 变异的患者被称为 CDKL5 缺陷症 (CDD)。本研究旨在描述日本 CDD 患者的临床特征并阐明可能的适当治疗方法。方法 我们从大约 1,100 名日本发育性和癫痫性脑病患者的队列中招募了具有致病性或可能致病性 CDKL5 变异的患者，这些患者接受了遗传分析。我们回顾性地审查了临床、脑电图、神经影像学和遗传信息。结果 我们确定了 29 名患者（21 名女性，8 名男性）。所有患者都表现出严重的发育迟缓，尤其是男性。在 15 名患者中观察到不自主运动。没有抗癫痫药物 (AED) 通过单一疗法实现无癫痫发作。2 名患者使用丙戊酸钠，1 名患者使用氨己烯酸，1 名患者使用拉莫三嗪，癫痫发作频率降低 ≥ 50% 的 AEDs。在使用拉莫三嗪、溴化钾和左乙拉西坦期间观察到癫痫发作加重。促肾上腺皮质激素（ACTH）是最有效的治疗方法。生酮饮食（KD）、胼胝体切开术和迷走神经刺激并没有改善大多数患者的癫痫发作频率，但 KD 在其中一个方面非常有效。磁共振成像 (MRI) 上的脑萎缩程度反映了疾病的严重程度。与女性相比，男性在 MRI 上的运动发育水平较低，脑萎缩更严重。结论与之前的研究相比，我们的患者表现出更严重的整体发育迟缓，并且患有顽固性癫痫，可能是因为之前的研究男性人数较少。需要进一步研究来研究 CDD 的适当治疗方法，例如 AED 多药治疗或涉及 ACTH、KD 和 AED 的联合治疗。