Dravet综合征患儿SCN1A基因突变特点与其临床表型的相关性及药物疗效

Relationship between mutation characteristics of SCN1A gene in Dravet syndrome and its clinical phenotype and drug efficacy

目的探讨SCN1A基因突变的Dravet综合征(DS)患儿不同突变特点与临床表型的相关性及药物疗效。方法收集2014年1月至2018年5月在郑州大学第三附属医院小儿神经内科确诊为DS患儿的临床资料,采集患儿及其父母外周血,提取DNA,采用二代高通量基因测序对患儿行癫痫基因包检测,对其父母采用Sanger测序进行家系验证,基因突变阴性患儿采用多重连接探针扩增技术(MLPA)检测SCN1A基因大片段变异,根据年龄对患儿采用Gesell量表或韦氏儿童智力量表(C-WISC)行智力评估。结果共收集50例DS患儿,其中38例SCN1A基因突变阳性,突变率为76.0%(38/50例),以错义突变[50.0%(19/38例)]、移码突变[28.9%(11/38例)]为主。50例患儿平均起病年龄为6.00月龄;68.0%(34/50例)的患儿首次发作以发热(>37.5 ℃)诱发,60.0%(30/50例)的患儿有热水浴惊厥发作史;74.0%(37/50例)的患儿有惊厥持续状态;80.0%(40/50例)的患儿有丛集样发作;92.0%(46/50例)的患儿有≥2种发作类型;30.0%(15/50例)轻度智力落后,38.0%(19/50例)中度智力落后,14.0%(7/50例)重度智力落后;24.0%(12/50例)的患儿1岁前即出现脑电图发作间期异常,脑电图异常的平均年龄为30.12个月;药物有效率排名前3位的为托吡酯[70.0%(28/40例)]、丙戊酸钠[48.0%(24/50例)]、氯硝西泮或氯巴占[45.7%(16/35例)];截断突变组患儿肌阵挛及不典型失神发作出现的时间均早于错义突变组(14.75个月比21.20个月,16.82个月比26.00个月),差异均有统计学意义(均P<0.05);截断突变组患儿丛集样发作比例高于错义突变组[94.7%(18/19例)比63.2%(12/19例)],差异有统计学意义(P<0.05);起病年龄、发作类型、惊厥持续状态比例、智力落后程度、1岁前脑电图异常比例及发作频率与SCN1A基因突变方式及突变位点差异无统计学意义(均P>0.05)。结论DS患儿SCN1A基因突变率高,SCN1A基因突变特点与DS临床表型有一定相关性;托吡酯为DS患儿常用药物中最有效的药物。

Objective To explore the relationship between different mutation characteristics and clinical phenotype of children with Dravet syndrome (DS) with SCN1A gene mutation, and to summarize the drug efficacy. Methods The clinical data of children diagnosed as DS from the Department of Pediatrics Neurology, the Third Affi-liated Hospital of Zhengzhou University from January 2014 to May 2018 were collected.The peripheral blood DNA of the children was detected by adopting next generation sequencing for epilepsy-related gene-panel, while the parents′ were screened by using Sanger sequencing for family verification.Multiple ligation-dependent probe amplification technology was used to detect large fragment variation of SCN1A gene if the mutations of the children were negative.The Gesell scale and cavity Wechsler intelligence scale for children(C-WISC) were used to evaluate the intelligence of children. Results A total of 50 cases of DS were collected, 38 cases of them were positive for SCN1A mutation, and the mutation rate was 76.0%(38/50 cases), of which, the missense mutation[50.0%(19/38 cases)] and frameshift mutation[28.9%(11/38 cases)] were dominant.The average onset age of 50 patients was 6 months, of which onset of seizures was triggered by fever(temperature>37.5 ℃) in 68.0%(34/50 cases)of children, the history of seizures in hot baths was found in 60.0%(30/50 cases) of children, status epilepticus was found in 74.0%(37/50 cases), cluster-like episodes was found in 80.0%(40/50 cases),≥2 seizure types was found in 92.0%(46/50 cases). Mental retarda-tion was found in most of the children, of which 30.0%(15/50 cases) were mild mental retardation, 38.0%(19/50 cases) were moderate mental retardation, 14.0%(7/50 cases)were severe intelligence retardation.Interictal abnormalities of electroencephalogram(EEG) before 1 year old was found in 24.0%(12/50 cases), and the average age of EEG abnormalities was 30.12 months old;the top three drug efficacy rates were 70.0%(28/40 cases) of Topiramate, 48.0%(24/50 cases) of Sodium Valproate, 45.7%(16/35 cases) Clonazepam or Clobazam.The time of onset of myoclonus and atypical absence of the truncation mutation group was earlier than that of the missense mutation group(14.75 months vs.21.20 months;16.82 months vs.26.00 months), and the difference was statistically significant(P<0.05). The proportion of clustered episodes in the truncation mutation group was higher than that in the missense mutation group [94.7%(18/19 cases)vs.63.2%(12/19 cases)], and the difference was statistically significant (P<0.05). There was no significant correlation between the SCN1A gene mutation (type and position) and age of onset, type of seizure, proportion of convulsion persistence, the mental development or abnormal proportion of EEG and seizure frequency before 1 year old(all P>0.05). Conclusions The SCN1A gene mutation rate is high in children with DS, and the SCN1A gene mutation characteristics has a certain correlation with DS clinical phenotype.Topiramate is the most effective drug among children with DS.