过度惊吓反应症1例临床及遗传学分析  

Clinical and genetic analysis of a child with hyperekplexia

作　　者：孙敏[1,3] 张新 徐那[1] 杨莉[1] 邱世彦 李玉芬[1] 徐丽云[1] Sun Min;Zhang Xin;Xu Na;Yang Li;Qiu Shiyan;Li Yufen;Xu Liyun(Department of Pediatric Neurology,Linyi People′s Hospital,Linyi 276003,China;Postgraduate Training Base of Jinzhou Medical University,Department of Pediatric Neurology,Linyi People′s Hospital,Linyi 276003,China;Department of Medical Ultrasound,Linyi People's Hospital,Linyi 276003,China)

机构地区：[1]临沂市人民医院小儿神经内科,临沂276003 [2]锦州医科大学研究生培养基地、临沂市人民医院小儿神经内科,临沂276003 [3]临沂市人民医院超声医学科,临沂276003

出　　处：《中华神经科杂志》2023年第7期780-786,共7页Chinese Journal of Neurology

基　　金：山东省医药卫生科技发展计划项目(2018WS399)。

摘　　要：目的分析1例过度惊吓反应症患儿的临床表型和基因测序结果,明确其遗传学病因。方法收集患儿临床资料,对其进行家系全外显子组测序,并对疑似致病变异进行患儿及其父母的Sanger测序验证及生物信息学分析。结果患儿女性,12岁,7月龄起病,因“发作性肢体僵硬11年余,加重半个月”于2022年7月4日就诊于临沂市人民医院小儿神经内科。临床表现为突然受到外界刺激后诉害怕,表情惊恐,喉中发声,肢体抖动数下后出现四肢僵直,偶伴呼吸暂停、嘴唇青紫,频繁时发作数次/d,每次持续1~30 min不等,早期头腹屈曲位可缓解。生长发育正常,头颅磁共振成像及发作期视频脑电图未见异常。全外显子测序结果显示患儿SLC6A5基因存在错义杂合突变c.643T>C(p.W215R),父母均未携带此突变,为未报道过的新生变异。根据美国医学遗传学与基因组学学会遗传变异分类标准及指南,该变异为可能致病性变异[PS2(经双亲验证的新发变异,且无家族史)+PM2(正常对照人群中未发现的变异)+PP3(多种软件预测出该变异会对基因或基因产物造成有害的影响)],位点高度保守,Swiss三维建模发现该突变氨基酸周围的氢键亦发生变化。结论过度惊吓反应症极其罕见且容易误诊,主要临床特征为对突然不能预期的外界刺激产生过度的惊吓反应(肢体抖动或惊跳),进而出现全身僵硬,生长发育正常,惊吓反应时视频脑电图正常。SLC6A5基因c.643T>C(p.W215R)可能致病性杂合错义变异是其遗传学病因。Objective To analyze the clinical phenotype and gene sequencing results of a child with hyperekplexia,and to clarify her genetic etiology.Methods The clinical information of the child was collected,and the whole exome sequencing of the child and her parents was performed.The suspected pathogenic variants were verified by Sanger sequencing and bioinformatics analysis.Results There was a 12 years old girl,who was hospitalized in the Department of Pediatric Neurology of Linyi People′s Hospital because of"paroxysmal limb stiffness for more than 11 years and aggravated for half a month"on July 4,2022.The girl showed exaggerated startle reflexes and generalized siffness in response to external sudden,unexpected stimuli,occasionally accompanied by apnea and cyanosis,frequent attacks occurred several times a day,lasting for 1-30 minutes,and early head and abdomen flexion can be relieved.She showed normal growth and development,no abnormality in brain magnetic resonance imaging and video electroencephalogram during seizure.The whole exome sequencing showed that there was a missense heterozygous mutation c.643T>C(p.W215R)in theSLC6A5 gene of the child.Neither of the parents carried this mutation,which was a novel and de novo variant.According to the guidelines of American College of Medical Genetics and Genomics,this variant was a likely pathogenic variant[PS2:de novo(both maternity and paternity confirmed)in the patient with the disease and no family history;PM2:undetected variants in the normal population;PP3:multiple softwares predicted that this mutation would have harmful effects on genes or gene products],and highly conserved.Swiss modeling found that the hydrogen bond of the modified amino acid also changed.Conclusion sHyperekplexia is relatively rare and prone to misdiagnosis.The main clinical features are excessive startle reflexes(limb shaking,or jumping)to unexpected external stimuli,resulting in overall stiffness,normal growth and development,and normal video electroencephalogram during the seizure.The likely

关 键 词：惊吓反应 误诊 错义变异 SLC6A5基因 

分 类 号：R741[医药卫生—神经病学与精神病学]