Dravet综合征的临床特点分析及SCN1A基因新突变

目的 分析Dravet综合征的临床特点,并对新诊断患儿进行SCN1A基因筛查,寻找基因突变.方法收集3例Dravet综合征患儿临床资料,留取例1患儿血样标本,提取外周血白细胞基因组DNA,对SCN1A全部外显子进行PCR扩增,通过变性高效液相色谱法对PCR产物进行突变片段筛查,对于变性高效液相色谱法筛查有异常的片段利用双脱氧法进行基因测序.利用基因序列分析软件进行测序结果分析.结果 1.Dravet综合征3例患儿的共同表现:均在1岁内起病;初以热性惊厥起病,1岁后逐渐转变为无热惊厥;发作形式包括肌阵挛、阵挛、不典型失神发作等;对药物治疗反应差,随病程进展出现精神运动发育迟缓或倒退;发作间歇期EEG可见尖慢波、棘慢波、多棘慢波发放或伴阵发.2.基因筛查结果发现SCN1A基因新突变c.2867T>G,可导致所编码氨基酸改变(M956R),经检索(截至2010年11月)尚未见该位点突变报道.结论 Dravet综合征是以热性惊厥起病但预后差的癫(癎)性脑病,临床应注意与热性惊厥鉴别.Dravet综合征患儿发病与SCN1A基因突变有相关性.     

Epilepsy with a de novo missense mutation in the sodium channel a1 subunit: a case report

Most epilepsies are characterized as "idiopathic" because of the lack of a known cause. Nevertheless, recently, there has been significant progress in the molecular genetics of idiopathic epilepsy. Mutations in gene-encoding ion channels were found to be the underlying disorder in all idiopathic epilepsies with a known molecular basis. Missense mutations in the voltage-gated sodium channel a1 subunit gene (SCN1A) were firstly identified in patients with generalized epilepsy with febrile seizures plus additional symptoms (GEFS + ). Subsequently, mutations of SCN1A were also found in patients with severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome, and in patients with borderline SMEI (SMEB), a milder form of Dravet syndrome. We describe a case of a new missense de novo mutation of SCN1A in a child with the clinical features of borderline SMEI syndrome.     

Paternal germline mosaicism of a SCN2A mutation results in Ohtahara syndrome in half siblings

Ohtahara syndrome is a devastating early infantile epileptic encephalopathy caused by mutations in different genes. We describe a patient with Ohtahara syndrome who presented on the first day of life with refractory tonic seizures and a suppression-burst pattern on EEG. The patient developed severe microcephaly, and never achieved any developmental milestones. He died at the age of 5 years. A de novo missense mutation (c. 4007C>A, p.S1336Y) in SCN2A was found. Interestingly, the father has another son with Ohtahara syndrome from a different mother. The half brother carries the same SCN2A mutation, strongly suggesting paternal gonadal mosaicism of the mutation. The broad clinical spectrum of SCN2A mutations now includes Ohtahara syndrome. This is the first report of familial Ohtahara syndrome due to a germline mosaic SCN2A mutation. Somatic mosaicism, including germline, has been described in several epileptic encephalopathies such as Dravet syndrome, KCNQ2 neonatal epileptic encephalopathy, SCN8A epileptic encephalopathy and STXBP1 related Ohtahara syndrome. Mosaicism should be considered as one of the important inheritance patterns when counseling parents with a child with these devastating diseases.     

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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.     

Molecular genetics of infantile nervous system channelopathies

Inherited or de novo mutations in at least a dozen genes encoding ion channels may present as paroxysmal disorders during the neonatal period or first year of life. These channelopathies include genes encoding voltage-gated channels specific for sodium (SCN1A, SCN2A, SCN1B, SCN9A) and potassium (KCNQ2, KCNQ3) which account for a variety of epilepsy phenotypes ranging from mild, such as Benign familial neonatal seizures (BFNS) to severe, such as Dravet syndrome (severe myoclonic epilepsy of infancy, SMEI) and the rare and unusual syndrome paroxysmal extreme pain disorder (PEPD). Ligand-gated channels involved include the GABA(A) receptor in a variety of epilepsy phenotypes and the human glycine receptor. Mutations in five genes encoding subunits of this receptor and accessory molecules underlie hyperekplexia or stiff-baby syndrome. All these conditions are rare but correct diagnosis is of value not only for genetic counselling but to allow the specific treatment which is available.     

婴儿严重肌阵挛癫痫的临床特征和基因突变分析

目的 探讨婴儿严重肌阵挛癫癎(SMEI)的临床特点和基因诊断.方法分析13例SMEI患儿的临床和脑电图(EEG)特点及钠离子通道SCN1A基因突变筛查结果.结果男10例,女3例.8例有热性惊厥和癫痫家族史.惊厥起病年龄2～9个月,平均5.6个月.首次发作为热性惊厥9例.13例在病程早期均以反复发热诱发的全面性或一侧性阵挛或强直阵挛发作为主,其中8例有热性惊厥持续状态.出现无热惊厥的年龄为2～21个月.病程中均出现多种发作类型.发作均有热敏感的特点,诱发因素包括发热、洗热水澡和疫苗接种.起病后出现智力发育落后11例.共济失调5例,锥体束征阳性2例.EEG在1岁前多数正常,1岁后出现全导或局灶放电.头颅MBI检查异常2例.13例均应用多种抗癫痫药治疗,发作均未完全控制.卡马西平和拉莫三嗪使部分患儿发作加重.10例发现有SCN1A基因突变.结论 SMEI的临床特点是:1岁以内起病,首次发作常为热性惊厥;1岁以后出现多种发作形式和智力发育落后;发作具有热敏感的特点;EEG早期正常,以后出现全导或局灶放电.筛查SCN1A基因突变有助于早期明确诊断,指导选择抗癫癎药物.     

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??Objective??To study the clinical features and SCN1A gene mutation in a familial inherited Dravet syndrome family with dizygotic twins. Methods??The clinical manifestations of dizygotic twins with Dravet syndrome and GEFS + mother were summarized and SCN1A gene was sequenced. The relationship between genotype-phenotype of SCN1A gene and Dravet syndrome was analyzed by literature. Results??The dizygotic twins and their mother have de novo SCN1A gene mutant c.3624A??T??p.R1208S?? at the second loop of Na+ channel α subunit. This is very rare compared to the usual mutation domain at S4 or S5-S6. It is the first report in China that Dravet syndrome dizygotic twins inherited SCN1A gene mutation from their mother who was diagnosed as GEFS+. Point mutations of SCN1A were more common??accounting for 93.8%. The relationships between phenotype-genotype were very complex??since other pathogenic factors may be involved in. Conclusion??It is the first report in China that SCN1A gene mutation in a familial inherited Dravet syndrome with dizygotic twins and found a de novo SCN1A gene mutation of c.3624A??T??p.R1208S????which is located at the very rare region of the protein.     

Dravet syndrome: The main issues

Dravet syndrome (DS) is a severe form of infantile onset epilepsy characterized by multiple seizure types, prolonged convulsive seizures and frequent episodes of status epilepticus. Seizures precipitated by fever are a main characteristic. Affected children exhibit normal early development. Cognitive impairment, behavioral disturbances with hyperactivity and sometimes autistic traits occur after seizure onset. Seizures persist into adulthood but become less frequent. In about 85% of patients, a mutation of the SCN1A gene is present. DS fully illustrates the concept of epileptic encephalopathy. However, it is difficult to determine the causative role of the underlying sodium channel dysfunction and that of the consequent seizures in influencing cognitive outcome. An overwhelmingly high number of SCN1A mutations have been associated with DS. Intragenic or whole gene deletions, duplications and amplifications are additional rare molecular mechanisms. Most mutations are de novo, but familial mutations also occur. Somatic mosaic mutations should be considered when estimating the recurrence. MRI imaging is usually normal, and no neuropathologic signature of the condition seems to exist. In heterozygous Scn1a+/? mice, GABAergic interneurons exhibit substantially reduced sodium current density with reduced ability for sustained action potential firing. GABAergic output is reduced and excitability of downstream synaptic targets increased. Stiripentol was effective in combination with valproate and clobazam in two pivotal phase III trials. Phenytoin, carbamazepine, and lamotrigine can worsen seizures and should be avoided. Prospective studies will clarify to what extent earlier diagnosis and efforts at seizure control with the most appropriate drug combinations will reduce clinical deterioration.     

Crisis con fiebre en el primer año de vida: ¿epilepsia del espectro Dravet?

IntroductionDravet syndrome is a drug resistant epilepsy which starts in the first year of life with febrile seizures, followed by cognitive impairment and epilepsy with multiple seizure types. Diagnosis has been typically made at the age of three to four years, but earlier diagnosis is now possible as clinical features are better recognised and molecular diagnosis is available.Patients and methodsWe studied a series of 14 children with Dravet syndrome or Dravet spectrum epilepsy. A screening test, developed by other authors to distinguish the febrile seizures in Dravet syndrome from febrile seizures from other origin, was applied to the clinical features of the seizures occurring during the first year of life in our patients.ResultsClinical suspicion of Dravet spectrum epilepsy was possible in 100% of children in our series. Moreover, taking into consideration only the first seizure, 79% of patients scored sufficiently to detect Dravet syndrome.ConclusionsDravet syndrome can be recognised during the first year of life. It is important that physicians are made aware of these clinical criteria capable to distinguish febrile seizures in Dravet syndrome from febrile seizures of other origin, and set up a protocol to collect appropriate data regarding febrile seizures occurring in the first year of life.     

Diagnosis and long-term course of Dravet syndrome

Dravet syndrome is a severe infantile-onset epilepsy syndrome with a distinctive but complex electroclinical presentation. A healthy, developmentally normal infant presents at around 6 months of age with convulsive status epilepticus, which may be hemiclonic or generalized; seizures may be triggered by fever, illness or vaccination. The infant typically has further episodes of status epilepticus every month or two, often triggered by fever. Other seizure types including focal dyscognitive seizures, absence and myoclonic seizures develop between 1 and 4 years. Atonic drop attacks and episodes of non-convulsive status may occur. Early development is normal but slows in the second year. Developmental regression may occur, particularly with status epilepticus. EEG studies are initially normal, but after 2 years they show generalized spike-wave and polyspike-wave activity with multifocal discharges. Photosensitivity may be seen. Imaging is normal or shows non-specific findings such as atrophy.Dravet syndrome is associated with mutations of the gene encoding the alpha-1 subunit of the sodium channel, SCN1A, in >70% of patients. These include sequencing mutations and copy number variant anomalies; 90% of mutations arise de novo. PCDH19 mutational analysis is a second-tier test for girls with a Dravet-like picture who do not have SCN1A mutations.Outcome is poor, with intellectual disability in most patients and ongoing seizures. Intellectual impairment varies from severe in 50% patients, to moderate and mild intellectual disability each accounting for 25% cases. Rare patients have normal intellect. The long-term course involves ongoing, brief nocturnal convulsions and a characteristic deterioration in gait.     

热性惊厥、GEFS＋、Dravet综合征与疫苗接种的关系

对患有神经系统疾病儿童进行疫苗接种决策对于人们尤其是儿科医生来说是个棘手的问题,医生和家长们担心出现不良反应(如惊厥、疫苗脑病等)或考虑患儿存在热敏感性惊厥疾病的病史,担心疫苗接种导致惊厥发作,从而倾向于不给或不推荐其接种疫苗,而热性惊厥、GEFS＋、Dravet综合征这类热敏感性疾病是最常见的惊厥性疾病之一,其发病机制被证实多与SCN 钠离子亚通道基因突变导致功能缺失相关。对于FS、GEFS、以及Dravet综合征的患儿,疫苗接种可能会导致发热,引起惊厥,但疫苗接种并不会使他们的预后变差。     

早发性癫痫脑病伴运动障碍5例临床特征分析

目的　探讨早发性癫痫脑病伴运动障碍患儿临床特点，提高认识，正确诊治。方法　收集2013年9月至 2017年9月华中科技大学同济医学院附属武汉儿童医院神经内科收治的早发性癫痫脑病伴运动障碍患儿5例，对其临床资料进行回顾性分析。结果　共收集5例患儿，男1例，女4例。1例运动障碍表现为手舞足蹈样动作，2例为运动障碍震颤、共济失调混杂，1例为四肢震颤伴有手腕部交替扭曲动作，1例为肌张力不全伴有震颤、言语不清表现。4例基因检测为阳性，1例为SCN1A基因突变，2例为PRRT2基因突变，1例为SLC2A1基因突变。经治疗，2例控制，效果好，3例效果差。结论　早发性癫痫脑病伴运动障碍，容易漏诊或误诊为癫痫发作，与遗传有一定关联，致病基因为PRRT2、SLC2A1基因。SCN1A基因突变相关性早发性癫痫脑病伴运动障碍相对少见。部分患儿治疗效果好。     

Electroclinical features of epileptic encephalopathy caused by SCN8A mutation

Voltage‐gated sodium channel Na_v1.6, encoded by the gene SCN8A, plays a crucial role in controlling neuronal excitability. SCN8A mutations that cause increased channel activity are associated with seizures. We describe a patient with epileptic encephalopathy caused by de novo SCN8A mutation (c.5614C>T, p.Arg1872Trp). Seizures began 10 days after birth at which time brain magnetic resonance imaging (MRI) and electroencephalography (EEG) were normal. Seizure recurrence increased with age, leading to the development of frequent status epilepticus from 1 year of age. Seizure type included generalized tonic seizures and focal motor seizures. EEG first showed focal epileptic activity at the age of 4 months, and thereafter showed multifocal spikes. Serial MRI demonstrated brain atrophy, which appeared to progress with seizure aggravation. Clinical features that may give a clue to the diagnosis include normal EEG despite frequent seizures in early infancy and an increase in epileptic activity that occurs with aging.     

Novel SCN1A mutations in Indonesian patients with severe myoclonic epilepsy in infancy

Background: Severe myoclonic epilepsy in infancy (SMEI) and borderline SMEI (SMEB) are caused by a mutation in SCN1A, which encodes a voltage‐gated sodium channel α1‐subunit protein. Although many mutations in SCN1A have been associated with clinical features of SMEI or SMEB from different ethnic groups, there have been no such reports from the South‐East Asian populations so far. Methods: Patients 1 and 2 were Indonesian children diagnosed as having SMEI and SMEB based on their clinical features. SCN1A was screened for mutations using a combination of polymerase chain reaction and denaturing high‐performance liquid chromatography. Nucleotide substitutions were confirmed on direct sequencing. Results: In patient 1, a G‐to‐A heterozygous transition was detected at nucleotide 4834 (c.4834G>A) in exon 25, leading to substitution of valine with isoleucine at amino acid position 1612 (p.V1612I) in the SCN1A protein. In patient 2 a T‐to‐G heterozygous transversion was identified at nucleotide 5266 (c.5266T>G) in exon 26, leading to substitution of cysteine with glycine at amino acid 1756 (p.C1756G) in the SCN1A protein. Both amino acid substitutions might disrupt these highly conserved regions in species from drosophila to human, leading to dysfunction of the protein. p.V1612I and p.C1756G were determined as disease‐causing mutations due to their absence in the control population. Conclusion: The first cases of SMEI and SMEB are reported in South‐East Asian populations. Two novel SCN1A mutations are also identified in these patients, p.V1612I and p.C1756G, which may lead to neuronal excitability or convulsions.     

基于规范化诊治与管理的234例儿童癫性脑病病例系列报告

目的 探讨儿童癫性脑病(EE)的病因及预后。方法 回顾性分析儿童EE的临床资料,行病因学分析,并随访其疗效及预后。结果 234例EE患儿,包括West综合征92例,Dravet综合征53例,Lennox-Gastaut综合征32例,Landau-Kleffner综合征15例,大田原综合征13例,伴睡眠期持续棘慢波的癫性脑病10例,肌阵挛-失张力癫2例,Rasmussen综合征2例,15例未能归为已知的癫综合征。病因：遗传相关67.9%（基因诊断明确为遗传性31.2%）,结构性12.0%,感染性4.7%,代谢性和免疫性各0.9%,病因不明19.2%。治疗有效率：药物33.8%（79/234）,生酮饮食47.3%（35/74）,外科手术60.0%（3/5）,迷走神经刺激术（VNS）44.4%（4/9）;综合治疗（单纯药物治疗或在药物治疗基础上行生酮饮食/外科手术/VNS治疗）有效率48.7%。预后：发病后首次智能发育评估,223例（95.3%）存在发育异常;治疗后（随访病程中位数44月）智能发育随访,215例（91.9%）存在发育异常。结论 遗传性病因是EE的首要病因,仅1/3抗癫药物治疗有效,随访发现智能发育异常率高,总体预后不良。     

Cardiac ion channel gene mutations in sudden infant death syndrome

Sudden infant death syndrome (SIDS) is multifactorial and may result from the interaction of a number of environmental, genetic, and developmental factors. We studied three major genes causing long QT syndrome in 42 Japanese SIDS victims and found five mutations, KCNQ1-K598R, KCNH2-T895M, SCN5A-F532C, SCN5A-G1084S, and SCN5A-F1705S, in four cases; one case had both KCNH2-T895M and SCN5A-G1084S. All mutations were novel except for SCN5A-F532C, which was previously detected in an arrhythmic patient. Heterologous expression study revealed significant changes in channel properties of KCNH2-T895M, SCN5A-G1084S, and SCN5A-F1705S, but did not in KCNQ1-K598R and SCN5A-F532C. Our data suggests that nearly 10% of SIDS victims in Japan have mutations of the cardiac ion channel genes similar to in other countries.     

Hepatic coma culminating in severe brain damage in a child with a SCN1A mutation

An 11 months old boy, developed liver failure after febrile status epilepticus while being treated with valproic acid for myoclonic epilepsy and recurrent partial and generalized seizures. The diagnosis of Alpers-Huttenlocher disease was considered. A muscle biopsy showed mitochondrial dysfunction. Mitochondrial DNA depletion was ruled out. Sequencing of the polymerase gamma gene (POLG1) did not detect any mutations.Sequencing of the alpha-1 subunit gene of the voltage-gated neuronal sodium channel (SCN1A) revealed a novel, de novo amino acid change p.Val 1637 Glu.This case expands the spectrum of clinical presentations related to mutations in SCN1A. We warn that children with SCN1A mutations may be at risk for developing liver failure following status epilepticus, due to mitochondrial dysfunction.     

STXBP1基因突变致癫性脑病8例病例系列报告

目的 总结STXBP1基因突变所致的癫性脑病的临床表现及基因突变特点。方法 回顾性分析2011年12月30日至2018年1月31日于复旦大学附属儿科医院就诊且基因诊断为STXBP1基因突变的癫性脑病患儿的临床特点、基因检测结果、治疗和疗效。结果 8例STXBP1基因突变致癫性脑病患儿进入本文分析,男、女各4例,起病年龄为生后2 d至6月龄（中位数为生后15 d）。8例均存在发育落后,均有不同程度的反应欠佳、眼示踪较差,2例角弓反张,1例皮肤黝黑、阴囊着色较深。脑电图波形：4例为暴发抑制,3例为高峰失律,1例为两侧较多痫样放电。2例行DST（智力及发育筛查）,DQ（发育商）和MI（智商指数）均<50。1例合并先天性喉软骨发育不良,腹部B超示肾上腺皮质均质性增大。1例合并孤独症。8例共检测到7个STXBP1基因突变位点,其中错义突变4个,无义突变2个,移码突变1个。c.1216C>T (p.R406C)、c.246G>A（p.K82K）、c.1702G>A(p.G568S)和 c.54delG位点此前未被人类基因突变数据库(HGMD)收录,经软件预测均为有害突变;c.1439C>T（p.P480L）、c.585 C>G( p.Y195X)和c.1162C>T（p.R388X）为HGMD已收录的致病位点。4例诊断为大田原综合征,3例为WEST综合征,1例为不能分类的癫综合征。经过单药或联合治疗,5例得到临床发作控制,3例表现为药物难治性癫。结论 STXBP1基因突变相关的癫性脑病是严重的儿童神经系统疾病,肾上腺增大可能为其新的表型之一。     

Hypokalemic periodic paralysis; two different genes responsible for similar clinical manifestations

Primary hypokalemic periodic paralysis (HOKPP) is an autosomal dominant disorder manifesting as recurrent periodic flaccid paralysis and concomitant hypokalemia. HOKPP is divided into type 1 and type 2 based on the causative gene. Although 2 different ion channels have been identified as the molecular genetic cause of HOKPP, the clinical manifestations between the 2 groups are similar. We report the cases of 2 patients with HOKPP who both presented with typical clinical manifestations, but with mutations in 2 different genes (CACNA1Sp.Arg528His and SCN4A p.Arg672His). Despite the similar clinical manifestations, there were differences in the response to acetazolamide treatment between certain genotypes of SCN4A mutations and CACNA1S mutations. We identified p.Arg672His in the SCN4A gene of patient 2 immediately after the first attack through a molecular genetic testing strategy. Molecular genetic diagnosis is important for genetic counseling and selecting preventive treatment.     

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??Objective??To analyze the clinical features and the results of genetic diagnosis in children with hypokalemic renal tubular diseases. Methods??The clinical data of 38 patients with hypokalemic renal tubular diseases were analyzed retrospectively??who were treated in Children’s Hospital Affiliated to Shanghai Jiao Tong University from Jan. 2010 to Jan. 2016. Results??Totally 38 patients with hypokalemic renal tubular diseases were enrolled in this study. There were 18 cases of renal tubular acidosis??RTA?? including 17 cases of type??RTA and 1 case of type?? RTA. There were 11 cases of Bartter syndrome??5 cases of Gitelman syndrome and 4 cases of Fanconi syndrome. The common clinical manifestations of hypokalemic renal tubular diseases included myasthenia??nausea??vomiting??polydipsia??polyurine and growth retardation. One case of Fanconi syndrome progressed to chronic Kidney disease??phase ????while the other
children had normal renal function. Glomerular proteinuria was found in 1??1 and 3 children with Bartter syndrome??Gitelman syndrome and Fanconi syndrome??respectively. Additionally??1 case with Fanconi syndrome has tubular proteinuria. However??urinary trace proteins associated with glomerular and tubular injury commonly elevated in these hypokalemic renal tubular diseases. Genetic analysis showed a new potential heterozygous mutations of ATPV0A4 in type??RTA and three heterozygous mutations of SLC12A3 in Gitelman syndrome. Conclusion??The clinical symptoms vary in patients and are featured mainly by myasthenia??nausea??vomiting??polydipsia??polyurine and growth retardation. Glomerular and tubular injuries are commonly found in hypokalemic renal tubular diseases. Moreover??genetic diagnosis may be helpful in diagnosis??treatment and genetic counseling.