WWOX基因相关发育性癫痫性脑病患儿基因型及临床表型特点  

Genotype and phenotype of WWOX gene related developmental and epileptic encephalopathy

作　　者：王婷 程苗苗 刘文玮 谭全桢 刘昌昊 杨莹 杨小玲[1] 张月华[1] Wang Ting;Cheng Miaomiao;Liu Wenwei;Tan Quanzhen;Liu Changhao;Yang Ying;Yang Xiaoling;Zhang Yuehua(Neurological Department of Children's Medical Center,Peking University First Hospital,Beijing 100176,China)

机构地区：[1]北京大学第一医院儿童医学中心神经内科,北京100176

出　　处：《中华儿科杂志》2024年第8期752-757,共6页Chinese Journal of Pediatrics

基　　金：国家重点研发计划(2023YFC2706300, 2023YFC2706301)。

摘　　要：目的总结WWOX基因相关发育性癫痫性脑病患儿的基因型及临床表型特点。方法病例系列研究。收集2019年6月至2023年12月在北京大学第一医院儿童医学中心神经内科就诊的12例WWOX基因相关发育性癫痫性脑病患儿的临床资料, 分析其基因变异特点、临床表型、辅助检查结果以及治疗和预后情况。结果 12例患儿中男7例、女5例, 癫痫起病年龄中位数为1.8月龄, 范围为10日龄至6月龄。患儿癫痫发作类型多样, 包括局灶性发作10例, 癫痫性痉挛9例, 强直发作4例, 肌阵挛发作1例;9例患儿有多种发作类型。12例患儿均有小头畸形及全面发育迟缓。视频脑电图显示背景活动减慢6例, 高度失律6例, 多灶性放电6例, 局灶性放电1例;监测到癫痫性痉挛8例, 强直发作4例, 肌阵挛发作1例。头颅磁共振成像可见双侧额颞区蛛网膜下腔增宽5例, 脑沟深3例, 双侧侧脑室增宽2例, 胼胝体发育不良5例, 脑白质髓鞘化延迟3例。12例患儿表型均符合发育性癫痫性脑病诊断, 其中8例诊断为婴儿癫痫性痉挛综合征。12例WWOX基因变异均为复合杂合变异, 共包含20个变异位点、片段缺失或染色体缺失, 其中11个变异位点(p.Ala149Thr、p.Arg156Ser、p.R167Tfs*8、p.Leu186Val、c.605+5G>A、p.Trp218*、p.His263Arg、p.Leu275fs*19*1、p.N285Kfs*10、p.Ser304Tyr、p.Met326Arg)及1个片段缺失(loss1 exon2-8)尚未见报道。末次随访年龄为11月龄至5岁3月龄, 1例1岁10月龄死亡, 其余11例患儿经过多种抗癫痫发作药物治疗后, 2例发作控制、9例癫痫发作未控制。结论 WWOX基因变异相关发育性癫痫性脑病患儿均在6月龄内起病, 部分可早到新生儿期, 常见癫痫发作类型包括局灶性发作和癫痫性痉挛, 均有小头和全面发育迟缓, 多为药物难治性癫痫。Objective:To summarize the genotype and clinical phenotype of children with WWOX gene related developmental and epileptic encephalopathy(DEE).Methods:Case series studies.The clinical data of 12 children with WWOX gene related DEE who were admitted to the Neurological Department of Children′s Medical Center,Peking University First Hospital from June 2019 to December 2023 were analyzed.The children′s characteristics of gene variation,clinical phenotype,auxiliary examination results,treatment and prognosis were analyzed.Results:Among 12 children with WWOX gene related DEE,there were 7 boys and 5 girls,the age of seizure onset ranged from 10 days to 6 months(median 1.8 months).Multiple seizure types were observed,including focal seizures in 10 cases,epileptic spasms in 9 cases,tonic seizures in 4 cases,myoclonic seizures in 1 case.Among 12 cases,9 cases had multiple seizure types.All 12 cases showed microcephaly and global developmental delay.Video electroencephalography showed slowed background activity in 6 cases,hyperarrhythmia in 6 cases,multifocal discharges in 6 cases,and focal discharges in 1 case.Epileptic spasms were detected in 8 cases,tonic seizures in 4 cases and myoclonic seizures in 1 case.Brain magnetic resonance imaging showed bilateral frontotemporal subarachnoid space widening in 5 cases,deep sulci in 3 cases,bilateral ventricular enlargement in 2 cases,callosal hypoplasia in 5 cases,and delayed white matter myelination in 3 cases.The phenotypes of 12 cases were consistent with the diagnosis of DEE,and 8 of them were diagnosed with infantile epileptic spasm syndrome.All the WWOX gene variants in 12 cases were complex heterozygous variants,including 20 variants,11 variants and 1 large intragenic WWOX gene deletion(p.Ala149Thr,p.Arg156Ser,p.R167Tfs*8,p.Leu186Val,c.605+5G>A,p.Trp218*,p.His263Arg,p.Leu275fs*19*1,p.N285Kfs*10,p.Ser304Tyr,p.Met326Arg,loss1 exon2-8)had not been reported previously.The age of last follow-up ranged from 11 months to 5 years and 3 months.During the follow-up,1 case died a

关 键 词：癫痫 基因 WWOX 发育性癫痫性脑病 发育迟缓 

分 类 号：R742.1[医药卫生—神经病学与精神病学]