摘要
背景SMARCA2基因变异可导致不同神经发育障碍疾病表型。目的总结SMARCA2相关疾病的临床特征和遗传学特点。设计病例系列报告。方法纳入中南大学湘雅医院儿科2017年1月至2021年12月收录进“儿童智力障碍/发育落后临床大数据”和“儿童癫癎临床大数据”数据库的0~18岁、SMARCA2基因变异为致病或可能致病,且首次就诊后有随访记录的病例。收集患儿人口学信息,母孕史、出生史和既往史,癫癎发作形式和频率,抗癫癎发作治疗的药物及剂量,查体和脑电图及生长发育评估资料;末次随访截止至2022年1月。结合既往文献报道,总结SMARCA2相关疾病临床及遗传学特征。主要结局指标癫癎发作频率。结果6例SMARCA2相关疾病患儿中,男女各3例,例1~5诊断为Nicolaides-Baraitser综合征(NCBRS),例6诊断为Lennox-Gastaut综合征(LGS)。随访时间为1.75(0.58~3.25)年。均否认既往高热惊厥病史、其他颅内病变病史及家族类似病史。均存在不同程度发育落后。癫癎发作中位起病年龄为9(8~19)月龄。例6癫癎发作表现为痉挛发作、强直痉挛、不典型失神发作及肌阵挛发作;例1~5全面性强直阵挛发作4例,局灶性发作3例,痉挛发作2例,丛集发作2例,癫癎持续状态1例。例1~5均有特殊面容,表现为三角脸、长睫毛、鼻梁低平、长人中;均身材矮小、小头畸形;例6仅表现为鼻梁低平。6例经丙戊酸钠、促肾上腺皮质激素、氯巴占和左乙拉西坦等抗癫癎发作药物治疗,2例发作完全控制,4例显著好转。均为SMARCA2(NM_003070)新生杂合错义突变,例1~5错义变异均位于ATP酶/C末端解旋结构域,例6位于小解旋酶/SANT相关结构域。例1~6变异位点依次为:c.2554G>A/致病、c.2564G>A/致病、c.3394G>A/致病、c.2551G>A/致病、c.2830C>A/可能致病、c.1399C>T/可能致病,例3~6突变位点未见报道。结论SMARCA2基因变异导致以NCBRS为主要表型的神经发育障碍性疾病。SMARCA2相关神经发育障碍疾病具有一定的基因型-表型关联特征,共同特征为发育落后/智力障碍和癫癎,NCBRS患儿还存在特殊粗糙面容和发育畸形,语言落后突出。
Background SMARCA2 gene mutations can lead to different neurodevelopmental disorders.Objective To summarize the clinical and genetic characteristics of SMARCA2 related disorders.Design Case Series Report.Methods Cases were enrolled who met the following inclusion criteria:aged 0-18 years who were included in the databases of Clinical Big Data of Children with Mental Disorders/Developmental Delays and Clinical Big Data of Children with Epilepsy in the Department of Pediatrics,Xiangya Hospital,Central South University from January 2017 to December 2021;the genetic test results showed that the SMARCA2 gene mutation was pathogenic or likely pathogenic;there were follow-up records after the first visit.Children's demography information,maternal pregnancy history,birth history and past history,seizure types and frequency,anti-seizure medications,physical examination,EEG,growth and development assessment data were collected.The last follow-up was January 2022.Based on previous literature reports,the clinical and genetic characteristics of SMARCA2 related diseases were summarized.Main outcome measures Frequency of epileptic seizures.Results Among the 6 cases of SMARCA2 related nervous system disease,3 cases were male and 3 cases were female.Case 6 was diagnosed as Lennox-Gastaut syndrome(LGS),and case 1-5 were diagnosed as Nicolaides-Baraitser syndrome(NCBRS).The follow-up period was 1.75(0.58-3.25)years.They all denied any previous history of heat shock,other intracranial lesions,or similar family history.All had varying degrees of developmental delay.The median onset age of seizure was 9(8-19)months.In case 6,seizures manifested as spasms,tonic spasm,atypical absence seizure and myoclonus seizure.In cases 1-5,there were four instances of generalized tonic-clonic seizures,three instances of focal seizures,two instances of spasms,two instances of cluster seizures,and one instance of status epilepticus.All five cases exhibited distinct facial characteristics,such as a triangular face,prominent eyelashes,broad nasal base,and broad philtrum.Additionally,they all presented with stunted growth and microcephaly.In contrast,case six only displayed a broad nasal base.Six cases were treated with antiepileptic drugs such as sodium valproate,adrenocorticotropin,chlorhexidine,and levetiracetam.The seizures were completely controlled in two cases,and significant improvement was observed in four cases.All were detected with SMARCA2(NM_003070)de novo heterozygous missense mutation.The missense mutations were located in the ATPase/C-terminal Helicase domain in cases 1 to 5,and were in HSA domain in case 6.The missense variation in cases 1 to 6 is:c.2554G>A/pathogenic,c.2564G>A/pathogenic,c.3394G>A/pathogenic,c.2551G>A/pathogenic,c.2830C>A/likely pathogenic,c.1399C>T/likely pathogenic.Cases 3-6 have not been reported.Conclusions The SMARCA2 gene mutation can lead to neurodevelopmental disorders with NCBRS as the main phenotype.There are genotype-phenotype associations in SMARCA2 related neurodevelopmental disorders.The common features including developmental delay/intellectual disability and epilepsy.Children with NCBRS also have special rough facial features and developmental abnormalities,and prominent language deficits.
作者
刘方云
彭盼
吴腾辉
陈晨
尹飞
彭镜
LIU Fangyun;PENG Pan;WU Tenghui;CHEN Chen;YIN Fei;PENG Jing(Department of Pediatrics,Xiangya Hospital,Central South University,Changsha 410000;Clinical Research Center for Children Neurodevelopmental Disabilities of Hunan Province,Changsha 410000,China)
出处
《中国循证儿科杂志》
CSCD
北大核心
2023年第2期137-141,共5页
Chinese Journal of Evidence Based Pediatrics
基金
国家自然科学基金面上项目:82071462。
