Department of Pediatric Neurology, Reference Center for Rare Epilepsies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades Hospital, Paris, France.
Imagine Institute, Mixed Unit of Research 1163, University of Paris, Sorbonne University, Paris, France.
Epilepsia. 2020 Nov;61(11):2461-2473. doi: 10.1111/epi.16679. Epub 2020 Sep 21.
OBJECTIVE: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. METHODS: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature. RESULTS: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. SIGNIFICANCE: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.
目的：我们旨在描绘 KCNB1 脑病患者的表型谱和长期预后。
方法：我们通过国际合作收集了 KCNB1 致病性变异患者的遗传、临床、脑电图和影像学数据，并得到了家族协会“KCNB1 法国”的支持。患者被分为发育性和癫痫性脑病（DEE）或发育性脑病（DE）。此外，我们还回顾了已发表的病例，并提供了我们系列中年龄大于 12 岁的患者以及文献中的长期预后。
结果：我们的系列包括 36 名患者（21 名男性，中位年龄=10 岁，范围=1.6 个月至 34 岁）。20 名患者（56%）患有 DEE，伴有婴儿期起病的癫痫发作（发作起始=10 个月，范围=10 天至 3.5 岁），而 16 名患者（33%）患有 DE，起病较晚，癫痫发作在 10 名患者中（发作起始=5 岁，范围=18 个月至 25 岁），6 名患者无癫痫发作。与 DE 患者相比，DEE 患者的认知障碍更为严重。对 36 名来自我们系列和 9 份报告中的 37 名已发表个体的 73 名 KCNB1 致病性变异患者的分析显示，所有患者均存在发育迟缓，67%（n=41/61）存在严重至重度智力残疾，56%（n=32/57）存在自闭症特征。22 名年龄大于 12 岁的患者（我们系列中的 14 名和已发表的 8 名患者）的长期预后显示认知、精神和行为预后较差。癫痫发作的病程各不相同。与截断变异相比，错义变异与更频繁和更严重的癫痫发作相关。
意义：我们的研究描述了 KCNB1 脑病的表型谱，从严重的 DEE 到伴有或不伴有癫痫的 DE 不等。尽管 DEE 患者的认知障碍更为严重，但大多数患者的长期预后较差，且错义变异与更严重的癫痫发作预后相关。进一步了解疾病机制应有助于开发靶向治疗，这对于改善神经发育预后非常有必要。
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