染色体2q24.3微缺失相关癫痫遗传学与临床特点研究

Genetics and clinical phenotypes of epilepsy associated with chromosome 2q24.3 microdeletion

目的总结染色体2q24.3微缺失相关癫痫患儿遗传学与临床表型特点。方法回顾性研究,收集2017年3月至2022年7月在北京大学第一医院儿科13例2q24.3微缺失的患儿,对其临床表现、脑电图及头颅影像学特点进行总结。结果13例2q24.3微缺失癫痫患儿缺失片段大小为0.18~7.31 Mb,缺失区域包含的主要致病基因为SCN3A、SCN2A、TTC21B、SCN1A和SCN9A基因。13例患儿中男7例、女6例,癫痫的起病年龄为3.3(2.5,6.0)月龄。13例患儿癫痫发作类型多样,其中局灶性发作13例、全面强直-阵挛发作6例、肌阵挛发作3例、痉挛发作和强直发作各2例。发作有热敏感9例,有癫痫持续状态6例。1例智力、运动发育正常,余12例有不同程度的发育迟缓。6例有颅面部异常,1例有右手拇指六指畸形,1例有多系统受累。脑电图显示发作间期局灶性放电3例,多灶性放电5例,多灶性兼有广泛性放电1例。头颅磁共振成像检查13例患儿中额颞区蛛网膜下腔增宽4例、侧脑室扩大4例、脑白质髓鞘化延迟1例。诊断符合Dravet综合征5例。末次随访年龄为2.5(1.4,5.5)岁,其中1例癫痫发作已控制1年以上,其余12例仍有发作。结论2q24.3微缺失相关癫痫患儿主要与SCN3A、SCN2A和SCN1A基因缺失有关,癫痫发作多在婴儿早期起病,发作类型多样,以局灶性发作和全面强直-阵挛发作多见,发作多数有热敏感特点,易发生癫痫持续状态,患儿有智力、运动发育迟缓,含有SCN2A和SCN3A基因缺失的患儿表型重于仅含SCN1A基因缺失的患儿。

Objective To summarize the genetics and clinical phenotypes of epilepsy children with 2q24.3 microdeletion.Methods All the patients with 2q24.3 microdeletion were retrospectively collected at the Pediatric Department of Peking University First Hospital from March 2017 to July 2022.The features of clinical manifestations,electroencephalogram(EEG),and neuroimaging were analyzed.Results There were 13 patients with 2q24.3 microdeletion were included.All 13 patients had de novo copy number variation(CNV)with a deletion size ranged 0.18-7.31 Mb.The main pathogenic genes in the region were SCN3A,SCN2A,TTC21B,SCN1A and SCN9A genes.Among the 13 patients,7 were boys,and 6 were girls.The onset age of epilepsy was 3.3(2.5,6.0)months.Multiple seizure types were observed,including focal seizures in 13 patients,generalized tonic-clonic seizures(GTCS)in 6 patients,myoclonic seizures in 3 patients,epileptic spasm in 2 patients,and tonic seizures in 2 patients.Seizures were fever sensitivity in 9 patients.Status epilepticus was observed in 6 patients.One case had normal mental motor development and 12 cases had different degrees of developmental delay.Six patients had craniofacial abnormality,1 had six-finger deformity of the right thumb,and 1 had multiple system abnormalities.EEG showed focal discharge in 3 cases,multifocal discharges in 5 cases,multifocal and generalized discharges in 1 case.Brain magnetic resonance imaging(MRI)showed enlargement of subarachnoid spaces in the frontal and temporal region in 4 patients,enlargement of lateral ventricle in 4 patients and delayed myelination of white matter in 1 patient.Dravet syndrome was diagnosed in 5 cases.The age at the last follow-up were 2.5(1.4,5.5)years,1 patient was seizure free longer than 1 year,and 12 patients still had seizures.Conclusions The epilepsy associated with 2q24.3 microdeletion is mainly induced by the deletion of SCN3A,SCN2A and SCN1A genes.The seizure onset age of 2q24.3 microdeletion related epilepsy was in infancy.Multiple seizure types are observed and the common seizure types include focal seizures and GTCS.Most patients have fever sensitivity and status epilepticus.Most patients have developmental delay.The phenotype of patients with deletion of SCN3A and SCN2A gene is more severe than that of patients with deletion of SCN1A gene only.