细胞周期蛋白依赖性激酶样5(CDKL5)缺乏症(CDD)是由CDKL5基因的致病变体引起的发育性脑病。这种独特的疾病包括早期婴儿发作难治性癫痫,低张力,发育性智力和运动障碍,和皮质视觉障碍。我们根据CDKL5卓越中心的系统文献回顾和经验,回顾了CDD的临床表现和遗传变异。我们提出了最低诊断标准。致病变异包括缺失,截断,拼接变体,和错觉变体。致病性错义变体仅发生在激酶结构域内或影响剪接位点。CDKL5蛋白在脑中广泛表达,主要在神经元中,在细胞增殖中起作用,神经元迁移,轴突生长,树突形态发生,和突触发育。CDD的分子生物学揭示了精准治疗的机遇,正在进行或计划进行2期和3期临床试验,以评估疾病特异性和疾病改善治疗。
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the gene CDKL5. This unique disorder includes early infantile onset refractory epilepsy, hypotonia, developmental intellectual and motor disabilities, and cortical visual impairment. We
review the clinical presentations and genetic variations in CDD based on a systematic literature
review and experience in the CDKL5 Centers of Excellence. We propose minimum diagnostic criteria. Pathogenic variants include deletions, truncations, splice variants, and missense variants. Pathogenic missense variants occur exclusively within the kinase domain or affect splice sites. The CDKL5 protein is widely expressed in the brain, predominantly in neurons, with roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis, and synapse development. The molecular biology of CDD is revealing opportunities in precision therapy, with phase 2 and 3 clinical trials underway or planned to assess disease specific and disease modifying treatments.