CLCN6突变引起的West综合征的临床特征及遗传学分析(附1例报告)  

Clinical features and genetic analysis of West syndrome caused by CLCN6 mutations(report of one case)

作　　者：杨清梅 苏堂枫 陈丽卿 薛峥 徐三清 刘艳 YANG Qingmei;SU Tangfeng;CHEN Liqing(Department of Pediatrics Neurology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China)

机构地区：[1]华中科技大学同济医学院同济医院儿童神经内科,武汉430030 [2]华中科技大学同济医学院同济医院全科医学科,武汉430030

出　　处：《临床神经病学杂志》2025年第2期130-134,共5页Journal of Clinical Neurology

摘　　要：目的探讨CLCN6突变引起的West综合征(WS)的临床特征及遗传学特点。方法报道1例由CLCN6突变引起的WS并回顾文献,分析相关疾病的临床特征及基因突变的特点。结果本例男性患者7月龄起病,临床特征为痉挛发作、发育落后、EEG高度失律。11月龄时托吡酯和氯硝西泮联合使用控制发作,1岁时EEG正常,39月龄时自行停药无发作,但语言发育落后。全外显子组测序发现CLCN6新发错义突变(c.761T>C,p.F254S),该突变点具有高度保守性,多种在线预测软件判定为有害。根据美国医学遗传学与基因组学学会的指南,该变体被归类为可能致病(PS2+PM2+PP3)。回顾文献,共纳入3例(含本例)病例。临床特征包括痉挛发作(3/3,2例发展为强直-阵挛发作及肌阵挛发作)、智力/全面发育落后(3/3)、行为障碍(1/3)、睡眠障碍(1/3)、视力障碍(1/3)、小头畸形(2/3)、EEG高度失律(3/3),头部MRI蛛网膜下腔间隙扩大(2/3)。经治疗后,1例发作控制,2例发展为耐药性癫痫。CLCN6突变位点包括c.533A>C、c.599A>C及c.761T>C,均为新发错义突变,且均位于跨膜结构域中。结论CLCN6变异导致的WS神经发育预后不佳,且变异以新发错义突变为主,早期进行基因诊断有助于改善预后。Objective To investigate the clinical features and genetic characteristics of West syndrome(WS)caused by CLCN6 mutations.Methods A case of WS caused by CLCN6 mutations was reported.And the literatures were reviewed.The clinical features and gene mutation characteristics of CLCN6 associated WS were analyzed.Results This patient,a male,presented with symptoms at 7 months of age,and exhibited clinical features including spasms,developmental delay,and high-amplitude disorganized of EEG.At 11 months of age,a combination of topiramate and clonazepam controlled the seizures.By 1-year-old,the EEG normalized,and at 39 months of age,the patient discontinued medication without experiencing further seizures;however,language development remained delayed.Whole exome sequencing identified a de novo missense mutation in CLCN6(c.761T>C,p.F54S),which was highly conserved.Multiple online prediction tools classified this mutation as deleterious.According to the guidelines of the American college of medical genetics and genomics,this variant was classified as likely pathogenic(PS2+PM2+PP3).A literature review included three cases(including this one).Clinical features included spasms(3/3,with 2 cases evolved into tonic-clonic and myoclonic seizures),intellectual or global developmental delay(3/3),behavioral disorders(1/3),sleep disorders(1/3),visual impairment(1/3),microcephaly(2/3),high-amplitude disorganized of EEG(3/3),and enlarged subarachnoid spaces on head MRI(2/3).After treatment,seizures in one patient were controlled,while two cases developed drug-resistant epilepsy.The CLCN6 mutations reported include c.533A>C,c.599A>C,and c.761T>C,all of which are de novo missense mutations located in the transmembrane domains.Conclusions WS caused by CLCN6 mutations is associated with a poor neurodevelopmental prognosis.The mutations are primarily de novo missense mutations.Early genetic diagnosis is crucial for improving the prognosis.

关 键 词：CLCN6 WEST综合征 全外显子组测序 错义突变 

分 类 号：R742.1[医药卫生—神经病学与精神病学]