不明原因新生儿惊厥基因分析的临床研究

Clinical study on gene analysis of unexplained neonatal seizures

目的探讨不明原因新生儿惊厥的致病性基因突变和临床特点。方法选择2016年7月至2019年12月北京儿童医院新生儿中心收治的不明原因惊厥患儿进行回顾性分析,入选患儿均应用疾病基因靶向二代测序技术进行癫痫基因测序分析,并且临床资料完整。收集患儿临床表现、发作类型、辅助检查、治疗及预后等情况,对基因突变患儿的临床表型特点进行分析。结果共纳入49例不明原因惊厥患儿,其中23例存在明确致病性基因突变,男12例,女11例,起病时间1.0(0.2,2.0)d,生后0~1 d起病14例(60.9%),2~7 d起病7例(30.4%),>7 d起病2例(8.7%)。3例(13.0%)存在癫痫家族史。发作类型以强直发作(11/23,47.8%)、痉挛发作(6/23,26.1%)最常见。脑电图异常表现以暴发抑制和(或)高峰失律(15/23,65.2%)、存在明确痫样放电(3/23,13.0%)、低电压(3/23,13.0%)最常见。共发现致病性基因突变10个,其中KCNQ2基因突变最常见(12/23,52.2%),其次为STXBP1基因突变(3/23,13.0%)。23例患儿中的14例(14/23,60.9%)需要2种以上抗癫痫药物才能控制症状。随访时间1~36个月,随访期间发作缓解10例(10/23,43.5%),发作减少6例(6/23,26.1%),仍有4例(4/23,17.4%)在随访期间症状不能控制,其中3例(3/23,13.0%)放弃治疗后死亡。结论基因突变引起的新生儿惊厥发病早,KCNQ2基因突变最常见。对于不明原因的新生儿惊厥患儿可通过基因检测明确潜在致病突变,有助于临床疾病分型、治疗方案选择以及遗传咨询。

Objective To study the pathogenic gene mutation and clinical characteristics of unexplained neonatal seizures.Method Infants with unexplained seizures admitted to the Neonatal Center of Beijing Children's Hospital from July 2016 to December 2019 were retrospectively analyzed.All the children were tested by targeted second generation sequencing technique for epilepsy gene sequencing analysis,and the clinical data were intact.The clinical manifestations,seizure types,auxiliary examination,treatment and prognosis of the patients were collected,and the clinical phenotypic characteristics of patients with gene mutation were analyzed.Result A total of 49 children with unexplained seizures were included in the study,of which 23 had definite pathogenic gene mutations,including 12 males and 11 females.The median onset time was 1.0 day(0.2,2.0).14 cases(60.9%)had an episode within the first day of life,7 cases(30.4%)occurred at 2~7 days after birth,and 2 cases(8.7%)developed the disease 7 days after birth.3 cases(13.0%)had a family history of epilepsy.Tonic(11 cases,47.8%)and tonic clonic(6 cases,26.1%)were the most common types of seizures.The most common findings of EEG were burst suppression and/or hypsarrhythmia(15 cases,65.2%),definite epileptic wave(3 cases,13.0%)and low voltage(3 cases,13.0%).There were 10 epilepsy-related gene variations found in this study,KCNQ2 gene variation was the most frequent(12 cases,52.2%)among them,followed by STXBP1 gene variation(3 cases,13.0%).14 cases(60.9%)received more than two kinds of antiepileptic drugs to control the symptoms.During the follow-up period,10 cases(43.5%)relieved and episodes were reduced in 6 cases(26.1%).Another 4 cases(17.4%)were still out of control and 3 of them died after giving up treatment.Conclusion Neonatal seizures caused by gene mutations have early onset,usually within the first week of life.KCNQ2 gene mutations are the most common.For children with unexplained neonatal seizures,genetic test can be used to identify potential pathogenic mutations,which is helpful to clinical disease classification,treatment options and genetic counseling.