STXBP1脑病患儿临床特征及遗传学特点

Clinical and genetic characteristics of children with STXBP1 encephalopathy

目的探讨突触融合蛋白结合蛋白1(STXBP1)基因变异所导致的STXBP1脑病患儿的临床特征及基因变异情况。方法回顾性总结首都儿科研究所附属儿童医院2014年1月至2019年6月收治的15例STXBP1脑病患儿的临床资料,分析其遗传学病因及治疗转归情况。结果15例患儿中男11例、女4例,年龄2月龄至5岁9月龄,其中14例患儿存在癫痫发作伴发育落后表现,1例仅表现为发育落后。癫痫发作起病年龄为2日龄~19月龄,≤1岁发病11例。常见的发作类型为强直、痉挛。7例患儿诊断为大田原综合征或婴儿痉挛症。11例癫痫患儿存在间歇期脑电图异常包括多脑区癫痫样放电、爆发抑制图形及高峰失律图形等。7例患儿存在头颅磁共振成像异常,包括髓鞘化不良、脑白质容积少、胼胝体缺如或发育不全等。随访2个月至4年9个月,3例癫痫发作完全缓解,6例部分缓解,5例无效。8例患儿单独或联合使用左乙拉西坦,6例有效。5例存在痉挛发作的患儿加用氨己烯酸,4例有效。15例患儿均存在不同程度的发育迟缓,4例患儿存在孤独症样表现。所有患儿均存在STXBP1基因变异,共有15种变异类型,其中错义变异8例、无义变异1例、移码变异5例、复杂变异1例。其中有5例患儿的变异位点未见报道,分别为c.1038_1039delCC、c.172delG、c.348_351dupTGAA、c.1193A>G、c.1769C>T。结论发育迟缓和癫痫是STXBP1脑病主要的、独立的表型特征。STXBP1基因变异以新发错义变异为主。在控制癫痫发作方面,左乙拉西坦和氨己烯酸可能更为有效。

Objective To investigate the clinical and genetic characteristics of developmental and epileptic encephalopathy(DEE)caused by syntaxin-binding protein 1(STXBP1)gene mutation.Methods The clinical data,gene variation and treatment outcome of 15 children with STXBP1 encephalopathy admitted to Children′s Hospital Affiliated to Capital Institute of Pediatrics from January 2014 to June 2019 were analyzed retrospectively.Results Among 15 patients,11 were male and 4 were female,age ranged from 2 months to 69 months.The clinical manifestations of 14 children were epilepsy and developmental delay(DD)and the remaining one showed developmental delay without seizure.The onset age of epilepsy ranged from two days to 19 months and 11 of them experienced the first attack before 1 year of age.The common seizure types were epileptic spasms and tonic seizures.Seven patients were diagnosed with Ohtahara syndrome or West syndrome.Epileptic form discharges were observed in the interictal electroencephalograms(EEG)of 11 patients,including multifocal discharges,suppression-burst and hypsarrhythmia.The brain magnetic resonance imaging of 7 children were abnormal,including myelin dysplasia,less white matter,lack of corpus callosum or hypoplasia.The follow-up time ranged from 2 months to 57 months,after the last follow-up,3 cases were seizure free,6 children showed partial response and the other 5 patients had no response on multitherapy.Six of 8 patients showed good responses to levetiracetam(LEV)monotherapy or in combination with other antiepileptic drugs(AEDs).Vigabatrin(VGB)was applied to 5 patients with epileptic spasms and 4 of them showed response.All patients showed different degrees of developmental delay while four of them showed autistic features.STXBP1 gene mutations were identified in all cases and there were 15 types of gene variations,including 8 missense mutations,1 nonsense mutation,5 frame shift mutations and 1 complex mutation.Five novel mutations were unreported before,including c.1193A>G,c.172delG,c.1769C>T,c.1038_1039delCC,c.348_351dupTGAA.Conclusions Development delay and epilepsy are the major and independent clinical phenotypes in children with STXBP1 encephalopathy.The variation of STXBP1 gene is mainly de novo.Levetiracetam and vigabatrin may be more effective in epilepsy control than other AEDs.