Abstract:

Objective The aim of this study was to summarize the phenotypic spectrum，treatment and prognosis of epilepsy caused by SCN8A variants. Methods The features of clinical phenotypes and genotypes of epilepsy children with SCN8A variants detected by next-generation sequencing were analyzed.The treatment and prognosis of all patients were followed up. Results Totally 80 epilepsy children with heterozygous SCN8A variants were collected，including 39 males，and 41 females.56 different variation types were identified，including 52 missense variants（one patient with mosaic variant），3 splicing site variants，and 1 insertion variant.76 patients had de novo variants，4 patients had inherited variants.22 variants were not reported previously.The seizure onset age ranged from the first day of life to 6 years and 4 months（Medium：4 months）.There are various types of epileptic seizures.The common seizure types included focal seizures（76.2%，61/80）， generalized tonic-clonic seizures（26.2%，21/80），and epileptic spasms（20.0%，16/80）.81.2%（65/80） of patients had developmental delay.Two patients comorbid with autism spectrum disorder. The EEG exhibited slow background activity（30.0%，24/80）.Interictal EEG showed multifocal discharges（21.3%，17/80），generalized discharges（20.0%，16/80），focal discharges（5%，4/80），and hypsarrhythmia（6.3%，5/80）. Electrical status epilepticus in slow wave sleep（ESES） was monitored in one patient. Seizures were captured in 35 patients. Brain MRI was abnormal in some patients （57.5%，46/80），including enlargement of subarachnoid spaces in the frontal and temporal region，enlargement of bilateral lateral ventricle，delayed myelination of white matter，agenesis of corpus callosum，and brain atrophy.Totally13 patients were diagnosed with infantile epileptic spasms syndrome，52 patients with unclassified developmental and epileptic encephalopathy（DEE），15 patients with self-limited （familial）infantile epilepsy（SeLIE）.The last follow-up age was ranged from 7 months to 14 year and 6 months（medium：5 year and 11 moths）. 21（26.2%）patients were seizure free. Two patients were died. 57 patients still had seizures at last followed up. Conclusion The variants of most SCN8A-related epilepsy patients were missense variants.The onset of seizure starts during infancy，with focal seizures being the most common seizure types. The phenotypic spectrum varies widely，ranging from mild SeLIE to severe DEE. The efficacy of sodium channel blocker is better than other anti-seizure drugs，but most patients are with refractory epilepsy.

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目的 总结 SCN8A 基因变异相关癫痫的表型谱及预后。方法　对2013年9月至2024年12月在北京大学第一医院儿童医学中心儿童神经内科门诊及病房二代测序发现的 SCN8A 基因变异相关癫痫患儿的临床表型和基因变异特点进行分析，并对预后进行随访。结果 共收集80例 SCN8A 变异的癫痫患儿，其中男39例、女41例。共检测到56种不同类型的变异，其中错义变异52种（1例为嵌合变异），剪切变异3种，插入变异1种。76例为新生变异，4例为遗传性变异。22种变异位点尚未见报道。癫痫起病年龄为1 d 至6岁4月龄（中位起病年龄4月龄）。癫痫发作类型多样，常见的发作类型包括局灶性发作（76.2%，61/80），全面强直—阵挛发作（26.2%，21/80），癫痫性痉挛（20.0%，16/80）。81.2%（65/80）的患儿有发育落后，2例有孤独症谱系障碍表现。脑电图可出现背景节律减慢（30.0%，24/80），发作间期监测到多灶性放电（21.3%，17/80），广泛性放电（20.0%，16/80），局灶性放电（5.0%，4/80），高峰失律（6.3%，5/80），1例可见睡眠期癫痫性电持续状态（ESES），35例监测到临床发作。头颅磁共振成像（MRI）可出现异常（57.5%，46/80），包括额颞区蛛网膜下腔增宽、侧脑室增宽、脑白质髓鞘化延迟、胼胝体发育不良、脑萎缩。诊断为婴儿癫痫性痉挛综合征13例，不能分类的发育性癫痫性脑病52例，自限性（家族性）婴儿癫痫15例。80例患儿末次随访年龄为7月龄至14岁6月龄（中位随访年龄5岁11月龄），癫痫发作完全缓解21例（26.2%），2例死亡，其余57例末次随访仍有发作。结论 SCN8A 基因变异相关癫痫以错义变异为主，多在婴儿期发病，局灶性发作最常见，临床表型谱广，包括预后良好的自限性（家族性）婴儿癫痫和预后不良的发育性癫痫性脑病。

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