STXBP1基因相关脑病患儿的临床表型和基因变异分析

Clinical phenotypes and gene mutations analysis of children with STXBP1 gene-related encephalopathy

目的探讨STXBP 1基因相关脑病患儿的临床表型和基因变异情况。方法回顾性总结2015年10月至2022年5月收治的11例STXBP 1基因相关脑病患儿的临床资料,分析其临床表型、基因结果、治疗及疗效情况。结果11例患儿中男4例,女7例,10例患儿存在癫痫发作伴发育迟缓,1例患儿仅表现为发育迟缓。癫痫首发年龄为3天~1岁半,3个月以内起病者6例,3~12个月起病者3例,1岁以上起病者1例。常见的发作类型为痉挛和局灶发作。11例患儿均存在脑电图异常包括背景慢、多灶放电、爆发抑制和高度失律等。2例早期为大田原综合征,后期演变为婴儿痉挛症,5例为婴儿痉挛症,余为不能分型的癫痫综合征。4例患儿头颅MRI存在非特异性异常,包括髓鞘化发育落后、额颞部蛛网膜下隙增宽。所有患儿均存在STXBP1基因变异,共有11种突变类型,其中错义突变7例、移码突变1例、剪切突变1例、缺失突变2例,7例患儿的突变位点尚未见文献报道,分别为c.1694T>A、c.1115T>G、C.133_135del、C.1543 dupG、6-17号外显子杂合缺失、C.429+1 G>C、C.855 C>G及c.842_843 insGGACGACGGCCTGTGGATAGC ACT。随访中11例患儿均存在不同程度发育迟缓,2例患儿已死亡,4例患儿存在孤独症样表现。10例癫痫患儿均应用左乙拉西坦治疗,1例为单独应用完全缓解,5例患儿部分有效,4例患儿无效。3例患儿癫痫发作完全缓解,余7例为药物难治性癫痫。结论STXBP1脑病患儿发育迟缓相对严重,婴儿痉挛症表型最常见,癫痫治疗效果存在明显异质性,7个未报道突变位点丰富了STXBP1脑病的基因谱。

Objective To investigate the clinical phenotype and genetic characteristics of children with developmental and epileptic encephalopathy(DEE)caused by syntaxin-binding protein 1(STXBP 1)gene mutation.Methods The clinical data of 11 patient with STXBP 1 gene-related encephalopathy admitted to the Third Affiliated Hospital of Zhengzhou University from October 2015 to May 2022 were retrospectively reviewed,and their clinical phenotypes,gene outcomes,treatment and efficacy were analyzed.Results Of the 11 children,4 were males and 7 were females,10 had seizures with developmental delay and 1 showed only developmental delay.The age of onset of epilepsy was 3 days to 1.5 years,with 6 cases starting at less than 3 months,3 at 3-12 months,and 1 at more than 1 year of age.The common seizure types are epileptic spasm and focal seizure.All the 11 patients had the abnormal interictal electroencephalograms(EEG)including background slowness,multifocal discharge,suppression-burst,and hypsarrhythmia.Two cases had Otahara syndrome in the early stages,which evolved into infantile spasms in the later stages,five cases had infantile spasms,and the rest had epileptic syndromes that could not be typed.Four children had non-specific abnormalities on cranial MRI,including poor development of myelination,and widening of the subarachnoid space in the frontotemporal region.frontotemporal.All children had STXBP 1 gene variants,with a total of 11 variant types,including 7 missense variants,1 frameshift variant,1 splicing variant,and 2 deletion variants,and the variant loci of the 7 children have not been reported in the literature,which were c.1694T>A,c.1115T>G,C.133_135 del,C.1543 dupG,exons 6-17 heterozygous deletion,C.429+1G>C,C.855C>G and c.842_843 insGGACGACGGCCTGTGGGATAGCACT.During follow-up,11 patients had different degrees of developmental delay,2 patients had died,and 4 patients had autistic like features.Ten patients with epilepsy were treated with levetiracetam.One patient was seizure free with levetiracetam alone,5 patients showed partial response,and 4 patients showed no response on multitherapy.3 patients was seizure free,the remaining 7 patients were drug resistant epilepsy.Conclusion STXBP 1 generelated epilepsy usually occur to infant,and infantile spasm is the most common phenotype.There is significant heterogeneity in the therapeutic effect of epilepsy.Seven unreported mutation sites enriched the gene spectrum of STXBP 1 encephalopathy.