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.
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