Febrile seizures and genetic epilepsy with febrile seizures plus (GEFS+)

Aim. To review the literature about febrile seizures and GEFS plus with special emphasis on management and outcome. Methods. Selected literature review. Results. Febrile seizures are the most common convulsive event in humans, occurring in 2–6% of the population. The aetiology is complex with strong evidence for a heterogeneous genetic predisposition interacting with fever of any cause, with certain viral infections having a greater effect. A large amount of literature has established that febrile seizures have no long‐term consequences on cognition or behaviour. Unfortunately, about 40% of children with a first febrile seizure will have a recurrence. The strongest predictor of recurrence is age <14–16 months at the time of the first febrile seizure. Epilepsy follows febrile seizures in ～3% cases, with the concepts of simple and complex febrile seizures providing relatively weak prediction. Very prolonged febrile seizures may lead to mesial temporal sclerosis and temporal lobe epilepsy although the degree of risk remains uncertain. Investigations beyond establishing the cause of the provoking fever are nearly always unnecessary. Treatment is mainly reassurance and there is some evidence that parents eventually “come to grips” with the fear that their children are dying during a febrile seizure. Antipyretic medications are remarkably ineffective to prevent recurrences. Daily and intermittent prophylactic medications are ineffective or have unacceptable side effects or risks. “Rescue” benzodiazepines may prevent prolonged recurrences for selected patients with a first prolonged febrile seizure although this has not been proven. Genetic epilepsy with febrile seizures plus (GEFS+) is a complex autosomal dominant disorder usually caused by mutations in SCN1A (a voltage‐gated sodium channel). One third of patients have febrile seizures only; two thirds have a variety of epilepsy syndromes, both focal and generalized. Conclusions. Febrile seizures may distress parents but rarely have any long‐term consequences. Reassurance is the only treatment for the vast majority. Identifying patients with GEFS plus may lead to further investigations and counselling.     

Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit SCN1B

Generalized epilepsy with febrile seizures plus (GEFS(+)) is an important childhood genetic epilepsy syndrome with heterogeneous phenotypes, including febrile seizures (FS) and generalized epilepsies of variable severity. Forty unrelated GEFS(+) and FS patients were screened for mutations in the sodium channel beta-subunits SCN1B and SCN2B, and the second GEFS(+) family with an SCN1B mutation is described here. The family had 19 affected individuals: 16 with typical GEFS(+) phenotypes and three with other epilepsy phenotypes. Site-specific mutation within SCN1B remains a rare cause of GEFS(+), and the authors found no evidence to implicate SCN2B in this syndrome.     

Neuronal voltage-gated ion channels are genetic modifiers of generalized epilepsy with febrile seizures plus

Mutations in the neuronal voltage-gated sodium channel genes SCN1A and SCN2A are associated with inherited epilepsies, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (severe myoclonic epilepsy of infancy). The clinical presentation and severity of these epilepsies vary widely, even in people with the same mutation, suggesting the action of environmental or genetic modifiers. To gain support for the hypothesis that genetic modifiers can influence clinical presentation in patients with SCN1A-derived GEFS+, we used mouse models to study the effect of combining the human GEFS+ mutation SCN1A-R1648H with SCN2A, KCNQ2, and SCN8A mutations. Knock-in mice heterozygous for the R1648H mutation (Scn1a(RH/+)) have decreased thresholds to induced seizures and infrequent spontaneous seizures, whereas homozygotes display spontaneous seizures and premature lethality. Scn2a(Q54) transgenic mice have a mutation in Scn2a that results in spontaneous, adult-onset partial motor seizures, and mice carrying the Kcnq2-V182M mutation exhibit increased susceptibility to induced seizures, and rare spontaneous seizures as adults. Combining the Scn1a-R1648H allele with either Scn2a(Q54) or Kcnq2(V182M/+) results in early-onset, generalized tonic-clonic seizures and juvenile lethality in double heterozygous mice. In contrast, Scn8a mutants exhibit increased resistance to induced seizures. Combining the Scn1a-R1648H and Scn8a-med-jo alleles restores normal thresholds to flurothyl-induced seizures in Scn1a(RH/+) heterozygotes and improved survival of Scn1a(RH/RH) homozygotes. Our results demonstrate that variants in Scn2a, Kcnq2, and Scn8a can dramatically influence the phenotype of mice carrying the Scn1a-R1648H mutation and suggest that ion channel variants may contribute to the clinical variation seen in patients with monogenic epilepsy.     

Generalised epilepsy with febrile seizures plus (GEFS+): molecular analysis in a restricted area

Purpose  

Mutation analysis of the SCN1B, SCN1A and GABRG2 genes in children affected by Genetic (Generalised) Epilepsy with Febrile Seizures plus (GEFS⁺) and their affected and some unaffected family members, coming from a restricted geographic area, was performed.     

全身性癫癎伴高热惊厥附加症致病基因的连锁定位研究

目的　定位全身性癫癎伴高热惊厥附加症的致病基因。方法　采用全基因组扫描的连锁分析方法对全身性癫癎伴高热惊厥附加症4个家系进行研究。结果　在染色体5q34多点连锁分析显示最大LOD值为3. 815。染色体单体型分析将连锁范围缩小至D5S820至D5S1476之间4. 0厘摩(cM)的区域。结论　全身性癫癎伴高热惊厥附加症致病基因定位在染色体5q34。     

全面性癫癎伴热性惊厥附加症的临床和脑电图特征分析

目的探讨全面性癫伴热性惊厥附加症(GEFS )的临床和脑电图(EEG)特点。方法收集4个GEFS 的家系资料,通过详细的调查建立完善的家系谱,并对受累者的临床资料、EEG进行分析总结。结果4个家系共有60名成员,其中受累者20例,表现为FS者5例,FS 者7例,FS 与失神发作2例,FS 与肌阵挛发作1例,FS 与失神和肌阵挛发作1例,此例患者发作间期EEG呈现局灶性癫放电和全面性癫放电共存的现象,1例表现为FS 和部分性发作,其发作间歇期EEG呈现中央中颞棘波灶,个体诊断符合良性罗兰多区癫。另外,受累者有肯定的临床发作,但是由于不能收集到可靠的发作表现资料,无法进行发作分类者3例。受累者神经系统检查以及头颅CT或磁共振成像(MRI)检查均未见异常。结论GEFS 的正确诊断需要注重个体,立足于整个家系进行,其临床发作谱还包括部分性发作,脑电图也有局灶的癫样放电。良性罗兰多区癫也许是GEFS 的一个新表现型。     

Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation.

BACKGROUND: Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant syndrome characterized by febrile seizures (FS) and a variety of afebrile generalized seizure types. GEFS+ has previously been linked to mutations in two genes encoding the voltage-gated sodium channel alpha-subunit (SCN1A) and beta1-subunit (SCN1B). We studied a large family with FS and partial as well as generalized seizure types. METHODS: All but two living affected family members were interviewed and examined. Information on deceased affected family members was sought. EEG for 11 affected family members and one unaffected family member were obtained. Genetic linkage analysis and mutation screening of SCN1A were performed on blood samples from 16 affected individuals and their first-degree relatives. RESULTS: There were 27 affected family members; 18 were alive at the time of the study. All affected family members had FS; seven had FS only, and 19 also had afebrile seizures. Eleven individuals continued to have FS beyond 6 years of age. FS were complex in 12 family members, usually with prolonged duration. The index patient had right temporal lobe epilepsy and hippocampal sclerosis. Four other patients had strong historical evidence of temporal lobe epilepsy, and three others had nonlocalizing evidence of partial epilepsy. Pedigree analysis indicated autosomal dominant transmission. All affected individuals who were tested and one asymptomatic individual had a sodium channel mutation of SCN1A, an A-->C transversion at nucleotide 3809 resulting in the substitution of lysine 1270 by threonine in the D3/S2 segment (designated as K1270T). CONCLUSIONS: Our findings indicate that partial epilepsy preceded by FS can be associated with sodium channel mutations and may represent a variant of GEFS+.     

Role of the sodium channel SCN9A in genetic epilepsy with febrile seizures plus and Dravet syndrome

Mutations of the SCN1A subunit of the sodium channel is a cause of genetic epilepsy with febrile seizures plus (GEFS⁺) in multiplex families and accounts for 70–80% of Dravet syndrome (DS). DS cases without SCN1A mutation inherited have predicted SCN9A susceptibility variants, which may contribute to complex inheritance for these unexplained cases of DS. Compared with controls, DS cases were significantly enriched for rare SCN9A genetic variants. None of the multiplex febrile seizure or GEFS⁺ families could be explained by highly penetrant SCN9A mutations.     

Genetic screening of two Tunisian families with generalized epilepsy with febrile seizures plus

Background and purpose:  Febrile Seizure can be associated with heterogeneous epilepsy phenotypes regrouped in a syndrome called generalized epilepsy with febrile seizures plus (GEFS+). The aim of this report is to search for the gene responsible for GEFS+ in two affected Tunisian families.
Methods:  Microsatellite marker analysis was performed on the known FS and GEFS+ loci. According to the results obtained by statistical analyses, GABRG2 on GEFS+3 locus and SCN1A on GEFS+2 locus were considered as two of the potential candidate genes and were tested for mutations by direct sequencing.
Results and conclusions:  The mutation analysis and statistical test of the GABRG2 gene revealed a disease association with rs211014 in intron 8 (χ² = 5.25, P =  0.021). A sequencing analysis of the SCN1A gene was performed for the two tested families and showed a known mutation (c.1811G>A) and a putative disease-associated haplotype in only one family. Our results support that SCN1A is the responsible gene for GEFS+ in one of the two studied Tunisian families and suggest a positive association of an intronic SNP in the GABRG2 gene in both families.     

GABRG2在全面性癫痫伴热性惊厥附加症中的研究

目的 研究全面性癫痫伴热性惊厥附加症患者的GABRG2基因突变。方法 对10个家系先症者的GABRG2基因进行体外扩增及测序分析。结果 未发现相关突变。结论 GABRG2基因突变在我国北方汉族人并不普遍。     

全面性癫癎伴热性惊厥附加症的临床和遗传学特点(附9家系报告)

目的探讨全面性癫癎伴热性惊厥附加症(GEFS+)的临床和遗传学特点。方法回顾性分析9个GEFS+家系的临床资料。结果本组9例先证者中男7例,女2例;起病年龄1~3岁;发作类型均为全面性强直-阵挛发作(GTCS)。其中,1例为GTCS,4例为热性惊厥(FS),4例为热性惊厥附加症(FS+)。脑电图检查示6例有典型疒间样波,1例有θ波,2例无异常。9个GEFS+家系184人中共有患者45例,男32例,女13例;男性发病比率(34.4%)明显高于女性发病比率(14.3%)(P<0.05)。其中,2例为GTCS,39例为FS,4例为FS+。家系系谱图分析显示,17例患者(37.8%)父母一方或双方患病,符合常染色体显性遗传;28例患者(62.2%)父母不发病或发病情况不详,但其近亲中至少有2例或以上患者。结论 GEFS+的脑电图不一定有异常波。GEFS+具有遗传异质性,本组中男性显著多于女性,不完全符合常染色体显性遗传。     

中国10个全面性癫痫伴热性惊厥附加症家系的临床特征分析

目的探讨中国全面性癫痫伴热性惊厥附加症(generalized epilepsy with febrile seizure plus,GEFS+)家系的临床特征。方法通过门诊就诊、个人访视、电话等方式,对10个GEFS+家系所有成员进行详细临床资料收集,包括家系图谱、有无发作、发作形式以及检查结果等。结果10个家系共有140名成员接受了调查(其中3名去世,由亲属提供病史),发现受累者80例,其中74例符合GEFS+临床发作谱,2例为特发性全面性癫痫,4例不能明确分类。其中有两个家系较为特殊(家系I和家系H),2个家系受累者绝大部分仅表现为热性惊厥(febrile seizure,FS),每个家系仅有先症者1人表现为热性惊厥附加症(febrile seizure plus,FS+)。此外还发现3例FS+伴局灶性发作,2例为FS+伴儿童良性癫痫伴中央颞部棘波,1例为FS+伴颞叶癫痫。结论GEFS+是一种常见的、儿童时期起病的遗传性癫痫综合征,GEFS+最常见的表型为FS和FS+,其次是FS+伴局灶性发作、FS伴IGE、FS+伴失神发作以及FS+伴肌阵挛发作,我们的10个GEFS+家系中未发现FS+伴失张力发作、肌阵挛站立不能性癫痫和婴儿严重肌阵挛癫痫,说明这些表型为临床少见表型;此外我们还发现了GEFS+合并IGE以及在FS遗传背景上仅个别患者为FS+的较特殊家系,这些将进一步扩展GEFS+的概念。     

Autism in several members of a family with generalized epilepsy with febrile seizures plus

The neurobiologic basis for autism is not well understood. In contrast, there have been several recent discoveries into the genetics of generalized epilepsy with febrile seizures plus, a group of epilepsy syndromes characterized by multiple seizure phenotypes. Here we describe a family with generalized epilepsy with febrile seizures plus and variably expressed autism spectrum disorder that does not show linkage to any of the four known generalized epilepsy with febrile seizures plus loci. A relationship between these two disorders has not previously been described.     

Genetic screening of Scandinavian families with febrile seizures and epilepsy or GEFS+

Background –  Mutations in the three genes SCN1A , SCN1B and GABRG2 , all encoding subunits of ion channels, have been known to cause generalized epilepsy with febrile seizures plus (GEFS+) in families of different origin.
Objective –  To study the occurrence of mutations in these genes in families with GEFS+ or a GEFS+ resembling phenotype of Scandinavian origin.
Material and methods –  We performed linkage analysis in 19 Scandinavian families with a history of febrile seizures (FS) and epilepsy or GEFS+. Where linkage could not be excluded, the genes of interest were sequenced.
Results –  We identified only one mutation in SCN1A , which seems to be a rare variant with no functional consequence.
Conclusion –  This suggests that mutations in these three genes are not a prevalent cause of familial cases of FS and epilepsy or GEFS+ in Scandinavia.     

一个全面性癫痫伴热性惊厥附加症家系的临床表型及SCN1A基因突变筛查

目的观察全面性癫痫伴热性惊厥附加症家系(GEFS+)的临床表型,并分析有无钠通道α1亚单位基因(SCN1A)突变。方法收集先证者及家系成员临床资料及外周血,提取基因组DNA,设计引物,进行PCR扩增,琼脂糖凝胶电泳,选取符合条件的PCR产物进行双向测序。结果该家系临床表型包括热性惊厥(FS)、热性惊厥附加症(FS+)伴失神发作,通过PCR对所有SCN1A的所有外显子进行扩增,所有患者和50例正常对照的测序结果与基因组序列相对比,均未发现碱基改变。结论全面性癫痫伴热性惊厥附加症是一种复杂综合征,具有表型异质性,在本家系中未发现SCN1A基因的突变,表明GEFS+具有遗传异质性。     

Phenotypes and genotypes in epilepsy with febrile seizures plus

In the last several years, mutations of sodium channel genes, SCN1A, SCN2A, and SCN1B, and GABA(A) receptor gene, GABRG2 were identified as causes of some febrile seizures related epilepsies. In 19 unrelated Japanese families whose probands had febrile seizures plus or epilepsy following febrile seizures plus, we identified 2 missense mutations of SCN1A to be responsible for the seizure phenotypes in two FS+ families and another mutation of SCN2A in one family. The combined frequency of SCN1A, SCN2A, SCN1B, SCN2B, and GABRG2 mutations in Japanese patients with FS+ was 15.8%. One family, which had R188W mutation in SCN2A, showed digenic inheritance, and another modifier gene was thought to take part in the seizure phenotype. The phenotypes of probands were FS+ in 5, FS+ and partial epilepsy in 10, FS+ and generalized epilepsy in 3, and FS+ and unclassified epilepsy in 1. We proposed the term epilepsy with febrile seizures plus (EFS+), because autosomal-dominant inheritance in EFS+ might be rare, and most of EFS+ display a complex pattern of inheritance, even when it appears to be an autosomal-dominant inheritance. There is a possibility of simultaneous involvement of multiple genes for seizure phenotypes.     

部分性癫(癎)伴热性惊厥附加症家系中的SCN1A基因嵌合突变

目的 筛查一个部分性癫伴热性惊厥附加症(partial epilepsy with febrile seizures plus,PEFS+)家系中的钠通道α1基因(voltage-gated sodium channel α1-subunit,SCN1A)及其遗传特性.方法 总结一个PEFS+家系中2例患者及其父亲的临床特点,应用变性高效液相色谱(denaturing high performance liquid chromtography,DHPLC)技术筛查SCN1A全部26个外显子,发现有异常洗脱峰者进行直接测序,对直接测序未能证实突变的再进行焦磷酸测序.结果 先证者及其同父异母姐姐均为PEPS+患者,他们在SCN1A基因第26号外显子发现有相同的杂合突变A5768G,并导致编码的氨基酸改变Q1923R,其父亲儿时频繁出现热性惊厥(febrile seizures,FS),后自然痊愈,直接测序未发现异常,进一步用焦磷酸测序则发现该位点存在嵌合突变(突变量为25%).结论 SCN1A基因突变可导致部分性癫.PEFS+可遗传,而携带致病基因者可因体内发生嵌合突变,致病基因含量偏低导致临床症状轻微.     

A family of generalized epilepsy with febrile seizures plus type 2-a new missense mutation of SCN1A found in the pedigree of several patients with complex febrile seizures

We report a family with complex febrile seizures (FS). The proband is a 15-year-old boy with seizures that persisted beyond 6 years of age. His father, aunt, and cousin also have the histories of FS until 8, 9, and 8 years old, respectively. A base substitution 5569G-->T of voltage-gated sodium channel alpha-1 subunit gene was found in DNA derived from the affected members of this family.