SYNGAP1基因相关神经系统表型谱及基因变异特点

Study of SYNGAP1 gene-related neurological phenotypes spectrum and characteristics of gene variation

目的总结SYNGAP1基因变异患儿神经系统表型谱及基因变异特点。方法回顾性收集2015年5月至2022年3月在北京大学第一医院儿科门诊就诊的23例SYNGAP1基因变异患儿临床资料,对其临床表型、基因变异特点及治疗预后进行分析。结果23例SYNGAP1基因变异患儿中,男7例、女16例,23例均为新生变异,其中错义变异9例,无义变异7例,移码变异6例,剪切位点变异1例。23例均有发育落后,其中21例(91.3%,21/23)患儿有癫痫发作,癫痫发作起病年龄为8个月~5岁(中位起病年龄2岁1月)。发作类型包括不典型失神8例,眼睑肌阵挛伴或不伴失神6例,肌阵挛发作6例,失张力发作3例,痉挛发作2例,全面强直阵挛发作1例。脑电图提示背景活动慢于同龄儿,发作间期广泛性放电22例,无异常放电1例。23例头颅磁共振成像均未见异常。癫痫综合征表型诊断为眼睑肌阵挛伴失神4例,婴儿痉挛症1例,Doose综合征1例,热性惊厥1例。3例(13%,3/23)有孤独症样表现。21例有癫痫发作的患儿中,20例口服抗癫痫发作药物(ASM),7例发作控制1年以上,其中用丙戊酸6例,左乙拉西坦3例,拉莫三嗪2例,托吡酯1例,其中4例患儿联合2~3种ASM。13例发作未控制,1例热性惊厥患儿未用药。结论SYNGAP1基因变异均为新生变异,变异类型主要包括错义、无义、插入及缺失变异,少数为剪切位点变异。SYNGAP1基因变异相关临床特点为均有发育落后;90%以上有癫痫发作,少数有孤独症样表现。癫痫多在儿童早期起病,发作类型多样,常见发作类型为不典型失神、眼睑肌阵挛伴或不伴失神和肌阵挛发作。癫痫综合征表型包括眼睑肌阵挛伴失神、婴儿痉挛症和Doose综合征,少数表型为热性惊厥。癫痫治疗应选择广谱ASM。

Objective To summarize the neurological phenotypes spectrum and characteristics of SYNGAP1 gene variation in children.Methods The clinical data of 23 children with SYNGAP1 gene variation were retrospectively collected in the pediatric outpatient of Peking University First Hospital from May 2015 to March 2022,their clinical phenotypes,gene variations characteristics and treatment prognosis were analyzed.Results Among the 23 children with SYNGAP1 gene variation,there were 7 male and 16 female,and 23 were all de novo variations,including 9 missense variations,7 nonsense variations,6 frame-shifting variations,and 1 splicing site variation.All 23 patients had developmental retardation,of which 21(91.3%,21/23)had seizures with onset age ranging from 8 months to 5 years(median onset age being 2 years and 1 month).The types of seizures included atypical absence in 8 cases,eyelid myoclonic seizures with or without absence in 6 cases,myoclonic seizures in 6 cases,atonic seizures in 3 cases,epileptic spasm in 2 cases,and general tonic-clonic seizures in 1 case.The EEG background activity was slow in all patients.Twenty-two patients had generalized discharges during the interictal period and 1 patient had no abnoamal discharges.MRI was normal in all 23 cases.The phenotype of epilepsy syndrme included,eyelid myoclonus with absence(4 cases),infantile spasm(1 case),and Doose syndrome(1 case).One patient was diagnosed with febrile seizures.Three patients(13%,3/23)had autistic features.Among the 21 children with seizures,20 were treated with anti-seizure mes(ASM).Seizures were controlled in 7 patients for over ayear,and the medicines used were valproic acid(6),levetiracetam(3),lamotrigine(2),and topiramate(1)Among them,4 were also given 2 to 3 ASMs.Thirteen patients had uncontrolled seizures.One patient with febrile seizures didn't use ASM.Conclusion All SYNGAP1 gene variations are in a few cases are de novo,and the types of variations mainly include missense,nonsense,and frame shift variations,and splicing site variations are in a few cases.The clinical features of SYNGAP1 gene variation include developmental delay,more than 90%have epileptic seizures,and a few have autistic features.Epilepsy starts in early childhood,multiple seizure types can be observed,and the common seizure types include atypical absence,eyelid myoclonus with or without absence,and myoclonic seizures.Phenotypes of epilepsy syndromes include eyelid myoclonus with absence,infantile spasm,and Doose syndrome.A few are febrile seizures.Broad spectrum ASM should be selected for the treatment of SYNGAP1 related epilepsy.