SYNGAP1基因相关神经系统表型谱及基因变异特点

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...     

Mowat-Wilson综合征5例癫痫相关的临床特点

目的总结Mowat-Wilson综合征(MWS)患儿癫痫相关的临床特点, 提高对此病的认识。方法回顾性分析2020年6至12月就诊于北京大学第一医院的5例MWS患儿的癫痫相关临床特点, 总结其癫痫发作的起病年龄、临床表现、脑电图、头颅磁共振成像(MRI)、ZEB2基因变异等特点及抗癫痫发作药物(ASM)的疗效。结果 5例患儿中男3例、女2例, 癫痫发作起病年龄为6月龄至4岁。4例患儿表现为局灶性发作, 局灶性发作表现多样, 但均表现为局灶运动性发作;1例患儿表现为癫痫性痉挛发作。5例患儿均表现出特殊面容, 不同程度的智力障碍、发育迟缓以及多种先天畸形。4例患儿脑电图表现为背景节律减慢和后头部为主的癫痫样放电, 1例患儿脑电图病初为高度失律, 后表现为后头为主的多灶性放电。2例患儿头颅磁共振成像有异常, 分别表现为胼胝体发育不良和白质发育落后。5例患儿均为ZEB2基因新生杂合变异携带者, 无义变异4例, 移码变异1例。随访14～20个月, 3例癫痫发作控制超过1年, 2例癫痫发作控制超过6个月;2例单用丙戊酸, 2例联合应用丙戊酸。结论癫痫发作是MWS的常见临床表型, 以局灶性运动性发作...     

CHD2基因相关癫痫的临床特点和遗传学分析

目的 研究CHD2基因变异相关癫痫患者的临床表型及基因型特点。方法 对6例CHD2基因变异相关癫痫患者的临床表现、脑电图、基因特点及抗癫痫发作药物疗效等进行回顾性总结分析。结果 6例患儿中男5例、女1例,癫痫起病年龄为1岁8个月至12岁。癫痫发作类型包括局灶性发作及全面性强直阵挛发作各3例次,眼睑肌阵挛伴或不伴失神发作2例次,不典型失神发作、痉挛发作、肌阵挛发作及强直发作各1例次。3例诊断为癫痫综合征,其中2例为Jeavons综合征,1例为Lennox-Gastaut综合征;2例具有光敏性。共患病中智力障碍6例,注意力缺陷多动障碍3例,孤独症谱系疾病2例,精神障碍1例。6例CHD2基因变异中4例为新发突变,2例为母源;其中无义突变3例,错义突变2例,片段缺失1例。末次随访年龄5岁至15岁10月龄,5例患儿抗癫痫药物规律治疗,4例有效,其中2例癫痫发作控制超2年,1例控制1年8月。结论 癫痫发作是CHD2基因变异的常见表型,癫痫起病年龄差别较大,表型为Jeavons综合征者预后不良,丙戊酸钠对CHD2基因变异相关癫痫疗效相对较好。精神障碍为罕见临床表型。     

OPHN1 基因突变致X 连锁智力障碍1 例报告及文献复习

目的探讨X连锁智力障碍的临床表型与基因型的关系。方法回顾分析1例癫痫伴智力障碍患儿的临床资料以及全外显子捕获测序结果。结果男性患儿,9岁。生后4个月发现发育迟缓,5个月癫痫发作,4岁时智力发育障碍,7岁时视力检查提示高度近视。脑电图提示癫痫样放电;头颅磁共振提示大枕大池;韦氏儿童智力量表评估示总智商49。基因检测发现患儿OPHN1基因第19号外显子存在移码突变c.1641delA(p.K547fs*5),家系共分离验证发现其母亲携带该变异位点。该变异位点既往未见报道。根据ACMG指南,其为致病性变异。患儿经抗癫痫药物丙戊酸钠联合拉莫三嗪治疗,效果好。结论 OPHN1移码突变c.1641delA(p.K547fs*5)为患儿X连锁智力障碍的致病基因,临床表型为癫痫、中度智力低下、高度近视、大枕大池。     

SYNGAP1 基因变异致癫痫伴认知发育障碍3 例临床分析

目的探讨SYNGAP1基因变异致儿童癫痫伴认知发育障碍的临床特点。方法收集并分析2017—2019年确诊的3例SYNGAP1变异相关癫痫患儿的临床资料以及对患儿及父母的全外显子二代测序及Sanger验证结果。结果 3例患儿中,男2例、女1例,均为儿童期起病。癫痫发作分别表现为眼睑肌阵挛伴失神,肌阵挛、失张力,局灶性发作。3例患儿均有认知异常,其中1例有刻板、攻击行为,缺少眼神交流和社会性交往。患儿父母及家系成员无惊厥及发育障碍。3例患儿均检测到SYNGAP1基因存在新发杂合变异,均为常染色体显性遗传,分别为6号外显子c.623delC(p.P208Qfs*15)、1号外显子c.67+1GA(splicing)、13号外显子c.2158GA(p.Asp720Asn),其中13号外显子错义变异患儿为局灶性发作。结论 SYNGAP1基因变异可导致癫痫伴认知发育障碍,癫痫发作具有临床多样性。     

SLC6A1基因变异相关儿童癫痫5例病例系列报告

背景：SLC6A1基因编码γ 氨基丁酸（GABA）转运蛋白GAT 1,该基因变异可降低GAT 1活性,影响突触间隙GABA的重摄取,在癫、智力障碍和孤独症谱系障碍等神经系统疾病的发病中起重要作用。 目的：总结SLC6A1基因变异相关儿童癫的临床表型及基因变异情况。 设计：病例系列报告。 方法：回顾性收集2007年12月至2021年10月复旦大学附属儿科医院神经科诊治的SLC6A1基因变异相关癫患儿的临床资料,总结其临床表现、治疗效果及基因检测结果,并检索文献,总结已报道SLC6A1基因变异与临床表型的关系。 主要结局指标：临床表型和SLC6A1基因突变位点。 结果：5例患儿纳入分析,男4例,女1例,起病年龄1~3岁,癫发作类型包括：肌阵挛发作4例,失神发作3例,肌阵挛 失张力发作2例,全面性强直阵挛发作1例。5例均存在精神运动发育落后,其中语言发育落后突出。随访5例患儿中4例无发作,丙戊酸单药治疗、丙戊酸联合左乙拉西坦治疗各2例。5例均携带SLC6A1基因杂合变异,且均为新发突变,其中错义变异3个,剪接变异和无义变异各1个。c.1379T>G (p.L460R)、c.1485G>A (p.W495X)尚未见报道。CAT 1蛋白胞外结构域EC3 4和跨膜区TM7是致病性或可能致病性错义变异致氨基酸改变的集中区域。 结论：SLC6A1基因变异所致癫多在幼儿期起病,癫发作类型多样,丙戊酸对其癫发作疗效好,但大多数患儿伴精神运动发育落后。新变异的发现丰富了SLC6A1基因变异谱。     

SYNGAP1基因相关儿童癫痫临床特点和基因分析

目的总结SYNGAP1基因相关儿童癫痫的临床特点。方法回顾性收集首都医科大学附属北京儿童医院神经内科2017年3月至2020年10月就诊的13例SYNGAP1基因变异相关癫痫患儿, 并进行随访, 对其临床特点、脑电图、头颅影像学、基因结果、治疗等进行总结。结果 13例患儿(男4例、女9例)随访到12例, 末次随访年龄5岁7月龄(3岁1月龄至9岁)。癫痫发作起病年龄为2岁(4月龄至3岁), 发作类型包括眼睑肌阵挛伴或不伴失神(9例)、肌阵挛发作(5例)、不典型失神(4例)、可疑失张力发作(4例)、跌倒发作(6例, 具体发作类型不详), 发作频率每日数次到百余次。4例表型类似肌阵挛-失张力综合征。10例发作有诱因, 包括进食(5例)、情绪(5例)、发热(3例)、声音(2例)、劳累(2例)等。10例患儿脑电图提示9例发作间期广泛性或局灶性痫样放电, 监测到不典型失神4例、肌阵挛发作2例和眼睑肌阵挛伴失神发作1例。12例中9例加用丙戊酸钠均有效(发作减少50%以上), 5例联用左乙拉西坦3例有效, 至末次随访3例发作相对控制(6个月至1年1个月), 余7例仍有发作(数日1次或每日数次)。13例...     

良性癫痫伴中央颞区棘波变异型的临床特点及治疗策略

目的 探讨儿童良性癫痫伴中央颞区棘波(BECT)变异型的临床特点及治疗策略.方法 回顾分析2010年1月至2015年1月就诊于本院的15例BECT变异型患儿的临床资料.结果 15例BECT变异型患儿的起病年龄中位数为5岁7个月(1岁1个月~10岁);病程9个月~7年.87.0%(13/15例)患儿符合BECT变异型Ⅰ型的临床表现.88.0%(10/12例)随访儿童存在一定程度的学习障碍,所有患儿脑电图均显示一侧或双侧中央、顶区和(或)中、后颞区(Rolandic区)散在的棘慢波或棘波发放,睡眠后明显增多.33%(5/15例)患儿合并不典型失神,47%(7/15例)患儿清醒期可监测到负性肌阵挛的发作,同期可明确发现相应的脑电图改变.丙戊酸钠加用左乙拉西坦、丙戊酸钠加用氯硝西泮和丙戊酸钠加用左乙拉西坦及氯硝西泮为较为常用的抗癫痫药物组合.对于口服抗癫痫药物无效的患儿可予甲泼尼龙冲击治疗.结论 BECT变异型均伴有明显的脑电图恶化,认识其临床和脑电图变化的特点及规律,可提高对BECT变异型的诊断.抗癫痫药物目的不仅是控制临床发作,更重要的是减少脑电图的异常放电.     

CHD2基因变异相关癫痫临床特点分析

目的 分析CHD 2基因变异相关癫痫患儿的临床特点。方法 通过对7例CHD 2基因变异相关癫痫患儿的长期随访观察,分析总结其临床特点及治疗方案效果评价。结果 7例患儿癫痫发作中位起病年龄为3岁2个月。5例患儿病程中出现2种及以上的发作类型,以全面强直阵挛发作为主。7例患儿有程度不等的运动、智力及语言发育落后,1例有孤独症倾向。5例患儿发作间期脑电图监测到异常放电,4例有临床发作。头颅MRI均无特异性改变。4例患儿需加用2种以上抗癫痫药物,治疗后发作次数减少;1例患儿对抗癫痫药物不敏感,最后启动生酮饮食治疗,目前无发作。末次随访年龄为2～7岁,其中3例发作控制半年以上,丙戊酸和左乙拉西坦是治疗CHD2基因变异相关癫痫的有效药物。结论 CHD2基因变异相关癫痫患儿起病年龄较早,发作类型多样,多为难治性癫痫,预后较差,应尽早治疗干预。     

结节性硬化症儿童智力障碍高危因素研究

目的探讨致结节性硬化症(TSC)智力障碍的临床高危因素。方法回顾分析2016年12月至2020年11月TSC专病队列6～16岁患儿的临床资料,采用韦氏智力测试量表评估智商(IQ),应用儿童青少年简易国际神经心理学访谈量表(MINI-KID)筛查、诊断TSC相关的神经精神障碍性疾病。采用多因素logistic回归寻找智力障碍高危因素。结果入组患儿共95例,85例(89.4%)检出TSC1/TSC2基因变异,其中TSC1基因变异27例,TSC2变异58例。67例(70.5%)合并智力障碍(IQ70);76例(80.0%)发生癫痫;79例(83.2%)共患神经精神障碍性疾病,共筛查出16种神经精神障碍性疾病。TSC相关神经精神障碍性疾病、癫痫、抗癫痫药物(≥2种)、较早的癫痫发病年龄(2岁)、较频繁的癫痫发作频率(每月发作1次以上)与智力障碍显著相关。结论智力障碍是TSC最常见和最主要的特征之一;神经精神障碍性疾病和癫痫是TSC患儿智力障碍的高危因素。     

DNMT3A基因相关Tatton-Brown-Rahman综合征1例报道并文献复习

该文报道1例DNMT3A基因变异导致的Tatton-Brown-Rahman综合征（TBRS）的临床及遗传学特征。患儿女，8个月14 d，主要临床表现为精神运动发育迟缓、肌张力减退、脑室扩大和小脑扁桃体下疝。经基因分析发现该患儿存在DNMT3A基因新发杂合变异c.134C > T (p.A45V)，其父母该位点为野生型，根据ACMG指南判定为可能致病性变异，既往未见文献报道，符合常染色体显性遗传。该患儿确诊为TBRS。该病多数预后较好，过度生长和智力障碍是最常见的临床表现；行为/精神问题、脊柱侧弯和无热惊厥是TBRS可能的并发症。对于表现为过度生长和智力障碍的患儿，需考虑TBRS可能，必要时进行基因诊断，以免漏诊。     

葡萄糖转运子1缺陷综合征运动障碍特点和诊疗分析

目的 探讨葡萄糖转运子1缺陷综合征（GLUT1-DS）的临床特征和诊疗方法,分析运动障碍的诊断意义。方法 收集4例GLUT1-DS患儿的临床资料,分析其临床特点和治疗随访情况。结果 4例中男2例、女2例,起病年龄2~15个月。表现为运动障碍、癫癎发作和发育迟缓,均以癫癎发作为首诊原因。4例均有持续性共济失调、肌张力异常和构音障碍,2例有持续性震颤,发作性肢体瘫痪和眼球运动障碍各2例,劳累易诱发发作性症状。4例患儿的脑脊液葡萄糖及其与血糖的比值均降低。4例均检测到SLC2A1基因突变,均接受生酮饮食治疗,生酮比3：1~2：1,发作性症状5周内完全缓解。结论 对于合并多样化运动障碍的智力运动发育迟缓的癫癎患儿需考虑GLUT1-DS,生酮饮食的生酮比维持在3：1~2：1可起效。     

Neuroimaging in mental retardation

Objective : To determine the diagnostic yield of neuroimaging ina cohort of children with mental retardation of unknown origin.Methods: Neuroimaging was performed in a total of 47 patients with developmental delay/mental retardation, where no etiologic diagnosis could be made following clinical examination and preliminary investigations.Results : Thirty (63.82%) children had abnormal neuroimaging findings of which 19 (42.42%) were specific abnormalities useful in arriving at etiological diagnosis. Positive outcome of neuroimaging increased with the severity of mental retardation and in presence of microcephaly and neurologic deficits other than mental retardation.Conclusion : Neuroimaging should be the standard clinical practice for a child with global developmental delay where no cause is apparent after examination and relevant investigations.     

应用聚合酶链反应-单链构象多态性技术分析结节性硬化症基因突变

目的 检测结节性硬化症基因外显子突变。方法 应用聚合酶链反应-单链构象多态性（PCR-SSCP）技术分析28例结节性硬化症患者TSC1和TSC2基因外显子突变情况。结果 28例中有4例发生TSC1基因突变,其中包括1个无义突变,2个错义突变和1个移码突变;有13例患者发生TSC2基因突变,其中包括2个无义突变,2个移码突变,1个缺失和8个错义突变,有2例患者在TSC1及TSC2基因上均发生突变,另有2例患者在TSC2核苷位1960上出现同样突变,TSC1突变患者和TSC2突变患者之间临床表现无明显差异。结论 突变广泛分布于TSC1及TSC2基因各个外显子上,没有集聚于某个外显子,基因突变不能反映疾病的临床表现及严重程度。     

Epilepsy and Mental Retardation Following Febrile Seizures In Childhood

ABSTRACT. In an unselected group of children who were seen following an initial febrile convulsion, the frequency of subsequent afebrile seizures was 3.5% and of mental retardation 1%. The most common afebrile seizure type was generalized major (86%). About 3/4 of the children who developed afebrile seizures did so by three years and all by five years following the initial febrile seizure. The children with afebrile seizures differed from those without afebrile seizures in the frequency of neonatal abnormality, family history of mental retardation, focal initial febrile convulsions, and delay in psychomotor milestones before the initial febrile seizure. Only about 1/3 of the children who developed afebrile seizures ever had a recurrent febrile convulsion and none had complex recurrent febrile seizures. Half the children with mental retardation had histories of delay in psychomotor milestones prior to the initial febrile seizure, and no child with mental retardation had any seizure longer than five minutes. The administration of daily phenobarbital did not reduce the frequency of epilepsy, in spite of a significant reduction in the incidence of recurrent febrile seizures. There remains no evidence that the prevention of recurrent febrile convulsions significantly decreases the frequency of afebrile seizures or mental retardation.     

Detection of a novel silent deletion,a missense mutation and a nonsense mutation in TCOF1

Background: Treacher Collins syndrome (TCS) is a disorder of craniofacial development, that is caused by mutations in the TCOF1 gene. TCS is inherited as an autosomal dominant trait, and haploinsufficiency of the TCOF1 gene product treacle is proposed to be etiologically involved. Methods: Mutational analysis of the TCOF1 gene was done in 10 patients diagnosed with TCS using single‐strand conformation polymorphism and direct sequencing. Results: Among these 10 patients, a novel 9 bp deletion was found, together with a previously reported 2 bp deletion, a novel missense mutation and a novel nonsense mutation in three different families. Familial studies allowed judgment of whether these abnormal findings were responsible for the TCS phenotype, or not. The 9 bp deletion of three amino acids Lys‐Glu‐Lys (1378–1380), which was located in the nuclear localization domain of treacle, seemed not essential for the treacle function. In contrast, the novel mutation of Ala26Val is considered to affect the LisH domain, an important domain of treacle. All of the mutations thus far detected in exon 5 have resulted in frameshift, but a nonsense mutation was detected (Lys159Stop). Conclusion: The information obtained in the present study provides additional insights into the functional domains of treacle.     

Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex

Background

Epilepsy appears in 70–80% of patients with tuberous sclerosis complex, most commonly in the first year of age. Early manifestation of epilepsy is associated with drug-resistant epilepsy and mental retardation in more than 80% of patients. Clinical epileptic seizures are preceded by deterioration of EEG recording thus infants with high risk of epilepsy can be identified.

Aims

We hypothesized that preventative antiepileptic treatment of infants with multifocal activity on EEG might lower the incidence of drug-resistant epilepsy and mental retardation.

Methods

Forty-five infants with early diagnosis of tuberous sclerosis complex were included in the open-label study. They were divided in two groups: standard (n = 31) and preventative one (n = 14). In standard group the antiepileptic treatment was launched early, but after the onset of seizures. In preventative group medication was commenced when active epileptic discharges were seen on EEG, but before the onset of clinical seizures. Children were followed till the end of 2 years of age.

Results

At 24 months of age mental retardation was significantly more frequent and severe in “standard” vs “preventative” group (48% vs 14%; p = 0.031; mean IQ score 68.7 vs 92.3; p < 0.05). The “preventative” group was characterized by higher ratio of seizure-free patients (93% vs 35%; p = 0.004), lower incidence of drug-resistant epilepsy (7% vs 42%; p = 0.021) and lower number of patients requiring polytherapy (21% vs 55%; 0.039) than the “standard group.

Conclusions

Preventative antiepileptic treatment of infants with tuberous sclerosis complex and high risk of epilepsy markedly improves their neurodevelopmental outcome and reduces the incidence of drug-resistant seizures.     

Macrocephalic mental retardation associated with a novel C-terminal <Emphasis Type="Italic"> MECP2</Emphasis> frameshift deletion

We report a novel C-terminal MECP2 frameshift deletion (1135_1142delCCCGTG CC) in a 19-year-old woman with mental retardation and epilepsy. Preservation of language capabilities, purposeful hand use and sufficient locomotion implied an atypical variant of Rett syndrome (OMIM 312750). Occipito-frontal head circumference was large at birth (36 cm; SDS 1.7) and increased until adulthood (58.5 cm; SDS 2.3). Conclusion: Our observation indicates that head size and head growth are of limited reliability in the diagnosis of MECP2-associated phenotypes.     

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??Objective??To study the clinical features and SCN1A genes detection results in children with Dravet syndrome in order to provide reference for clinical treatment. Methods??The clinical data??SCN1A genes reports and antiepileptic drug effects of 60 DS children who were diagnosed from December 2013 to December 2015 were collected from the Children’s Hospital of Fudan University. Results??The onset of seizures occured during 1-9 months with a median of 6 months and 83.3% of patients were febrile seizures at frist onset??they were heat sensitive??and hot water bath induced seizures in 63.3%??38/60??. There were multiple phenotypes??including generalized tonic-clonic seizures??95.0%??57/60????partial seizures??alternating unilateral seizure????78.3%??47/60????status epilepticus??65.0%,39/60????myoclonic seizures??65.0%??39/60????and atypical absence ??63.3%??38/60??. Seizure ouccurred most frequently??2-3 times per month?? in 1-3 years of age. The median age of mental retardation was 18 months. The number of mental retardation and the positive rate of EEG increased with age. Dravet syndrome were intractable. In patients who used sodium ion blocking drugs 40.0%??24/60?? children had aggravated seizures. 80.0%??48/60?? patients had SCN1A mutation with missense and nonsense mutation accounting for over a half. There was no correlation between SCN1A mutations and onset age??sex??seizure type or seizure frequency. Conclusion??Dravet syndrome is a childhood-onset epileptic encephalopathy??which is not rare in the national seizure center. The positive rate of SCNIA mutation is high??which can help the diagnosis of DS. Anti-epiletic drug treatment for DS is difficult and the misuse of drugs is in a high proportion??so the diagnosis and treatment level still needs to be improved.