摘要：

目的: 总结IQSEC2基因变异致非典型Rett综合征合并发育性癫痫性脑病的临床及遗传学特点。方法与结果: 安徽省儿童医院2020年5月至2022年4月诊断与治疗4例IQSEC2基因变异致非典型Rett综合征合并发育性癫痫性脑病患儿，男性2例，女性2例且为同卵双生子；发病前均有全面性发育迟缓，2岁时逐渐出现频繁拍手、咬手、睡眠紊乱（睡眠增多或难以入睡）、磨牙等非典型Rett综合征表现，后逐渐出现发育倒退及癫痫发作，癫痫发作首发年龄为2岁2个月至2岁10个月，均以全面性强直-阵挛发作发病，病程2~11个月时出现痉挛发作，3例（例2、例3、例4）伴局灶性发作。4例视频脑电图背景均为4~6 Hz θ波，发作间期为广泛性多灶性尖慢复合波。3例（例2、例3、例4）头部MRI可见异常征象，以脑沟增深为主。全外显子组测序提示IQSEC2基因致病性变异和可能致病性变异，2例（例1、例2）为IQSEC2基因c.608dup（p.Gln204Profs*35）移码突变，2例（例3、例4）为IQSEC2基因c.2231C > A（p.Ser744Ter）和c.2521C > T（p.Gln841Ter）无义突变，4例突变位点国内外均未见报道。4例均接受多种抗癫痫发作药物治疗。末次随访年龄4岁3个月至6岁3个月，均无法独行，无主动语言，例1患儿3年无癫痫发作，例2、例4偶有发作，例3至今仍发作频繁。结论: IQSEC2基因变异可表现为非典型Rett综合征，伴难治性痉挛发作，男女均有严重表型，同一突变位点临床表型严重程度不一。本研究丰富了IQSEC2基因变异谱和临床表型谱，扩展了Rett综合征及发育性癫痫性脑病的遗传谱，为疾病的临床诊疗及后续研究提供了指导。

关键词: Rett综合征, 癫痫, 基因, 突变

Abstract:

Objective: Summarize the clinical and genetic characteristics of atypical Rett syndrome and developmental epileptic encephalopathy caused by IQSEC2 gene variation. Methods and Results: From May 2020 to April 2022, Anhui Provincial Children's Hospital diagnosed and treated 4 children with atypical Rett syndrome and developmental epileptic encephalopathy caused by IQSEC2 gene variation, including 2 males and 2 females were a pair of identical twins. They all had comprehensive developmental delay before onset. At the age of 2 years, all cases gradually exhibited clinical manifestations of atypical Rett syndrome, such as frequent clapping, biting, sleep disorders (increased sleep or difficulty falling asleep), and grinding teeth, followed by developmental regression and seizures. The initial age of epilepsy was from 2 years and 2 months to 2 years and 10 months. All cases started with generalized tonic-clonic seizure, with epileptic spasm occurring between 2 and 11 months of course. Case 2, Case 3 and Case 4 were also accompanied by focal seizures. Four cases with VEEG background of 4-6 Hz θ wave, the VEEG during the interictal phase was a broad multifocal sharp slow complex wave. In Case 2, Case 3 and Case 4, MRI was abnormal, mainly with increased depth of cerebral hemispheric sulcus and gyrus. The whole exome sequencing suggested pathogenicity and possible pathogenic variations in the IQSEC2 gene, Case 1 and Case 2 were frameshift mutations of c. 608dup (p. Gln204Profs*35), while Case 3 and Case 4 were nonsense mutations of c. 2231C > A (p. Ser744Ter) and c. 2521C > T (p. Gln841Ter), respectively. The four mutation sites have not been reported domestically or internationally. All cases received treatment with multiple antiepileptic seizure medicine. The last follow-up age was from 4 years and 3 months to 6 years and 3 months. All cases were unable to walk alone and had no active language. There were no seizures in Case 1 for 3 years, occasional seizures in Case 2 and Case 4, and frequent seizures in Case 3. Conclusions: IQSEC2 gene variation can manifest as atypical Rett syndrome, which can be accompanied by refractory epileptic spasms. Both males and females have severe phenotypes, and the severity of clinical phenotypes at the same mutation site varies. Our report enriches the variation spectrum and clinical phenotype spectrum of the IQSEC2 gene, expands the genetic spectrum of Rett syndrome and developmental epileptic encephalopathy, and provides value for the clinical diagnosis, treatment and subsequent research of this disease.

Key words: Rett syndrome, Epilepsy, Genes, Mutation