Graduate Interdisciplinary Program in Genetics, University of Arizona, Tucson, Arizona.
College of Nursing, University of Arizona, Tucson, Arizona.
Epilepsia. 2019 Aug;60(8):1711-1720. doi: 10.1111/epi.16288. Epub 2019 Jul 23.
To characterize a cohort of patients with SCN8A-related epilepsy and to perform analyses to identify correlations involving the acquisition of neurodevelopmental skills.
We analyzed patient data (n = 91) submitted to an online registry tailored to characteristics of children with SCN8A variants. Participants provided information on the history of their child's seizures, medications, comorbidities, and developmental skills based on the Denver II items. Spearman rank tests were utilized to test for correlations among a variety of aspects of seizures, medications, and neurodevelopmental progression.
The 91 participants carried 71 missense variants (41 newly reported) and three truncating variants. Ages at seizure onset ranged from birth to >12 months of age (mean ± SD = 5 months 21 days ± 7 months 14 days). Multiple seizure types with multimodal onset times and developmental delay were observed as general features of this cohort. We found a positive correlation between a developmental score based upon percentage of acquired skills and the age at seizure onset, current seizure freedom, and initial febrile seizures. Analyses of cohort subgroups revealed clear distinctions between patients who had a single reported variant in SCN8A and those with an additional variant reported in a gene other than SCN8A, as well as between patients with different patterns of regression before and at seizure onset.
This is the first study of an SCN8A patient cohort of this size and for which correlations between age at seizure onset and neurodevelopment were investigated. Our correlation studies suggest that variants of uncertain significance should be considered in assessing children with SCN8A-related disorders. This study substantially improves the characterization of this patient population and our understanding of the neurodevelopmental effects associated with seizures for SCN8A patients, and provides a clinical context at initial presentation that may be prognostic for developmental outcome.
对 SCN8A 相关性癫痫患者队列进行特征描述，并进行分析以确定与获得神经发育技能相关的相关性。
我们分析了提交给专门针对 SCN8A 变异儿童特征定制的在线注册的患者数据（n=91）。参与者根据丹佛二项式测试项目，提供了有关其孩子癫痫发作史、药物治疗、合并症和发育技能的信息。采用 Spearman 秩检验测试了各种癫痫发作、药物治疗和神经发育进展之间的相关性。
91 名参与者携带 71 个错义变异（41 个为新报告）和 3 个截断变异。发病年龄从出生到>12 个月（平均±标准差=5 个月 21 天±7 个月 14 天）。作为该队列的一般特征，观察到多种发作类型、多种发作起始时间和发育迟缓。我们发现，基于获得技能百分比的发育评分与发病年龄、当前无癫痫发作和初始热性惊厥之间呈正相关。对队列亚组的分析表明，SCN8A 中仅有一个报告变异的患者与除 SCN8A 之外的基因中报告了另一个变异的患者之间，以及在癫痫发作前和发作时具有不同退化模式的患者之间存在明显区别。
这是第一项对如此大规模的 SCN8A 患者队列进行的研究，并且对发病年龄与神经发育之间的相关性进行了研究。我们的相关性研究表明，在评估 SCN8A 相关疾病的儿童时，应考虑不确定意义的变异。这项研究极大地改善了该患者人群的特征描述和我们对 SCN8A 患者与癫痫相关的神经发育影响的理解，并为初始表现提供了一个可能对发育结果具有预后意义的临床背景。
