A case report of a family with overlapping features of autosomal dominant febrile seizures and GEFS+

Familial febrile seizures occur in both generalized epilepsy with febrile seizures plus (GEFS+) and autosomal dominant febrile seizures (ADFS). The literature largely separates families with GEFS+ from those with ADFS. However, there is clinical overlap, and families with ADFS also include individuals with afebrile seizures. The phenotypic spectrum of GEFS+ is broader now than when first described, resulting in unclear boundaries between these two familial syndromes. The purpose of this report is to highlight the phenotypic similarities of GEFS+ and ADFS. A multigenerational family with febrile and afebrile seizures is described and the clinical features are compared to those of previously reported GEFS+ and ADFS families. This family meets the requirements for both ADFS and the broader definition of GEFS+. Linkage analysis has shown no clear linkage to known febrile seizure or GEFS+ loci. Despite locus heterogeneity, identified mutations in reported GEFS+ have so far all been in sodium channel or γ-aminobutyric acid (GABA)–receptor genes, with other modifier genes postulated to affect individual phenotypes. The two mutations identified in families with ADFS are in genes implicated in GEFS+, SCN1A , and GABRG2 . We conclude that it is inappropriate to separate GEFS+ and ADFS at present given the clinical and genotypic overlap.     

全面性癫(癎)伴热性惊厥附加症的临床与分子遗传学研究

目的 探讨全面性癫痫伴热性惊厥附加症（generalized epilepsy with febrile seizures plus，GEFS＋）的临床特点与分子遗传学特征。方法 收集1个GEFS＋家系所有成员的血样标本，选择3种候选基因（SCN1B、SCN1A、GABRG2）附近的11个微卫星标记物D19S414、D19S220、D19S902、D2S156、D2S142、D2S2330、D2S335、D2S364、D5s436、D5S422和D5S400，应用PCR得到扩增产物片段，根据相应产物大小的不同，得到每个样本的基因型；用连锁分析软件的MLINK程序计算每个标记的LOD值，根据两点间的LOD值判断连锁关系，探讨GEFS＋的可能致病基因与染色体19q13．1、2q24以及5q31．1-q33．1区域的连锁关系。连锁分析限定性定位后再进行GABRG2基因突变分析。结果 （1）GEFS＋家系临床特征：家系成员4代共20人。第Ⅱ～Ⅳ代中患者6例（男女各3例）；发作表型为热性惊厥（FS）1例、热性惊厥附加症（FS＋）3例、Fs＋伴失神发作1例，发作类型不详1例，未见严重发作类型。（2）GEFS＋基因连锁分析结果：①D2S335因不能进行基因分型，给予舍弃；②D19S和D2S多个LOD值小于0，在重组率为0．0时D19S220、D19s902、D2S364处的LOD值均小于-2；D19S414、D2S142、D2S156、D2S2330、D5S422处的LOD值小于0，基本可以排除连锁关系；③D5S436、D5$400处的LOD值在重组率为0．0时大于-2，但小于3，既不能排除也不能肯定其连锁关系；该家系致病基因与报道的GEFS＋定位区域19q13．1和2q24区域没有连锁关系；与5q31．1．q33．1区域的连锁关系有待于进一步明确。（3）GABRG2基因的测序结果（先证者）：显示11外显子一处同义突变（c．1420C〉T），未见GABRG2基因致病突变。结论 该GEFS＋家系呈现不同的临床表型，其疾病基因与3种候选基因SCN1A、SCN1B、GABARG2的突变无关；表明GFFS＋具有表型的异质性与遗传的异质性，其病因学有待进一步研究。     

A Case of Extended Spectrum GEFS+

Summary:  A 10-year-old boy developed febrile convulsions at age 2 years, and multiple types of nonfebrile generalized seizures over the ensuing months and years. Gestation, birth, and early development were normal, as were initial EEG and brain imaging studies. By age 5 years, he had developed behavioral difficulties, and the EEG demonstrated both interictal and ictal generalized epileptiform patterns, as well as mild background slowing. Seizures were poorly controlled with multiple medication trials. There was a strong family history of clinically benign febrile seizures in the maternal lineage. Genetic analysis revealed a novel mutation in the voltage-gated neuronal sodium channel SCN1A. This patient's relatively malignant clinical course is consistent with "extended spectrum" generalized epilepsy with febrile seizures plus (GEFS+), and along with the family history illustrates the phenotypic variability of this disease.     

Febrile Seizures: Clinical Characteristics and Initial EEG

We examined the relationship between clinical characteristics and EEG classification in all children with febrile seizures examined at the University Pediatric Clinic, Skopje, Yugoslavia between 1982 and 1984. This is the only facility in Macedonia providing EEG or neurologic consultation for children. EEGs were classified as paroxysmally abnormal if they contained spikes, sharp waves, or spike-wave complexes considered abnormal for age. In all, 22% of the 676 children had an abnormal initial EEG. The most common basis for classification as abnormal was spike-wave complexes greater than 3 Hz; the next most common basis was the presence of spikes. Birth weight, gender, accompanying illness, and family history of seizures, and whether the index seizure was single or multiple were not associated with differences in rate of abnormal EEG. Clinically focal index seizures and longer duration were associated with EEG abnormality. Number of previous febrile seizures was associated with an increasing rate of EEG abnormality, from 18% in children with no previous seizures to 63% in those with four or more previous seizures. Age at EEG was linearly related to likelihood of paroxysmal EEG abnormality, both for the total cohort and for the 376 children with no previous seizures. In the total cohort, logistic regression identified leading predictors of abnormal initial EEG to be older age, number of previous febrile seizures, preexisting motor abnormality, and focal seizures. For children with a first febrile seizure, leading predictors were focal seizure, older age, and preexisting motor abnormality.     

Seizures with Fever After Unprovoked Seizures: An Analysis in Children Followed from the Time of a First Febrile Seizure

Summary: Purpose: To determine how the onset of unprovoked seizures influences recurrence of seizures with fever in children followed from the time of a first febrile seizure.
Methods: In a prospective cohort of children (n = 428) identified at the time of a first febrile seizure, predictors of a second seizure with fever were identified. The occurrence of a first unprovoked seizure was treated as a time-dependent covariate in a Cox regression model rather than as a censoring point as it traditionally has been in the past.
Results: One hundred forty-three (33.4%) children had further seizures. Seven had further seizures with fever only after onset of unprovoked seizures. After adjustment was made for the four previously described predictors of recurrent febrile seizures (age at onset, family history, height of fever, and duration of fever), the onset of unprovoked seizures was associated with a rate ratio of 3.47 (p = 0.0015), indicating a large increase in the risk of further seizures with fever after onset of unprovoked seizures.
Conclusions: Young children who develop unprovoked seizures after a febrile seizure are at substantial risk for further seizures with fever. This may represent part of the spectrum of benign febrile seizures or it may represent the so-called "epilepsy triggered by fever" spectrum. It affects only a small proportion of children with febrile seizures; however, in some children, it may be useful information to consider when making treatment decisions.     

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.     

Neonatal Epilepsy Syndromes and GEFS+: Mechanistic Considerations

Summary:  Genetic analyses of familial epilepsies over the past decade have identified mutations in several different ion channel genes that result in neonatal or early-onset seizure disorders, including benign familial neonatal convulsions (BFNC), generalized epilepsy with febrile seizures plus (GEFS+), and severe myoclonic epilepsy of infancy (SMEI). These genes encode voltage-gated Na⁺ channel subunits ( SCN1A , SCN2A , SCN1B ), voltage-gated K⁺ channel subunits ( KCNQ2 , KCNQ3 ), and a ligand-gated neurotransmitter receptor subunit ( GABRG2 ). While the opportunity to genotype patients for mutations in these genes can have an immediate and significant impact on our ability to diagnose and provide genetic counseling to patients, the ultimate goal is to use this molecular knowledge to develop effective treatments and cures for each disorder. This will necessitate elucidation of the molecular, cellular, and network mechanisms that translate ion channel defects into specific epilepsy phenotypes. The functional analysis of epileptogenic channel mutations in vitro and in vivo has already provided a vast amount of raw biophysical data, but attempts to interpret these data to explain clinical phenotypes so far appear to raise as many questions as they answer. Nevertheless, patterns are beginning to emerge from these early studies that will help define the full scope of the challenges ahead while simultaneously providing the foundation of future efforts to overcome them. Here, I discuss some of the potential mechanisms that have been uncovered recently linking mutant ion channel genes to neonatal epilepsy syndromes and GEFS+.     

Temporal Lobe Epilepsy with Ecstatic Seizures (So-Called Dostoevsky Epilepsy)

Summary: The present report documents for the first time the polygraphic pattern of an ecstatic seizure and confirms that this kind of seizure may be an expression of a temporal lobe epilepsy.     

A novel inherited SCN1A mutation associated with GEFS+ in benign and encephalopathic epilepsy

Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant condition often caused by mutations in SCN1A that usually first manifests as childhood simple febrile seizures but may progress to a variety of afebrile generalized seizure types. Here, we describe the case of an 8-year-old boy with a novel SCN1A mutation who developed febrile seizures at 10 months of age which eventually advanced to frequent afebrile tonic-clonic seizures. His condition was unresponsive to several antiepileptic drugs and the ketogenic diet, and he experienced gradual cognitive decline. The patient’s father carries the same novel mutation, but he only experienced childhood simple febrile seizures. SCN1A mutations display incomplete penetrance and variable expressivity, and the resulting severity may depend on the location and type of mutation, whether the mutation was spontaneous or inherited, and the effect of modifying alleles. The identification of novel pathogenic SCN1A mutations may eventually advance therapeutic development and prognostic capabilities.     

全面性癫(癎)伴热性惊厥附加症一家系的临床特点及SCN2A基因分析

目的 报告一个全面性癫(癎)伴热性惊厥附加症(generlized epilepsy with febrile seizures plus,GEFS+)家系,并探讨其临床及基因特点.方法 对该家系进行全面的调查,对其临床资料进行回顾性分析;采集该家系38名成员的静脉血并抽提其基因组DNA,采用PCR-DNA直接测序和P...     

Prenatal Stress and Risk of Febrile Seizures in Children: A Nationwide Longitudinal Study in Denmark

We aimed to examine whether exposure to prenatal stress following maternal bereavement is associated with an increased risk of febrile seizures. In a longitudinal population-based cohort study, we followed 1,431,175 children born in Denmark. A total of 34,777 children were born to women who lost a close relative during pregnancy or within 1 year before the pregnancy and they were included in the exposed group. The exposed children had a risk of febrile seizures similar to that of the unexposed children (hazard ratio (HR) 1.00, 95% CI 0.94–1.06). The HRs did not differ according to the nature or timing of bereavement. Our data do not suggest any causal link between exposure to prenatal stress and febrile seizures in childhood.     

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.     

Gene Mapping in the Idiopathic Generalized Epilepsies: Juvenile Myoclonic Epilepsy, Childhood Absence Epilepsy, Epilepsy with Grand Mai Seizures, and Early Childhood Myoclonic Epilepsy

Summary: Idiopathic generalized epilepsies, i.e., juvenile myoclonic epilepsy (JME), childhood absence epilepsy, and epilepsy with grand mal [generalized tonic-clonic seizures (GTCS)], are the most common genetic epilepsies. Linkage studies using Bf, HLA serologic, and DNA markers by three independent investigators, one from Los Angeles and two from Berlin, have localized the JME locus to the short arm of chromosome 6 (6p). Because members of the same JME family have the same JME phenotype of childhood absence epilepsy, epilepsy with grand mal (GTCS) seizures, or early childhood myoclonic epilepsy (ECME), our observations give evidence for a single-locus etiology in 6p for JME and for at least some of the childhood absence seizures, epilepsy with grand mal (GTCS) seizures, and ECME. Studies should now address whether locus heterogeneity exists within childhood absence epilepsy, epilepsy with grand mal (GTCS) seizures, or ECME. Markers linked to JME (Bf, HLA serologic, and DNA markers in the DQ region) can be used to resolve etiologic heterogeneity. Using such markers, both linked and unlinked forms of phenotypes that are clinically indistinguishable may be detected and provide evidence for etiologic heterogeneity. Studies should also concentrate on narrowing the JME locus to 2 to 3 cm by screening families with recombinant events using RFLPs, candidate genes, and new expressed sequences on chromosome 6.     

Video-EEG Analysis of Drop Seizures in Myoclonic Astatic Epilepsy of Early Childhood (Doose Syndrome)

We studied 36 drop seizures in 5 patients with myoclonic astatic epilepsy of early childhood (MAEE) with simultaneous split-screen video recording and polygraph. Sixteen were falling attacks and 20 were either less severe attacks exhibiting only deep head nodding or seizures equivalent to drop attacks in terms of ictal pattern but recorded in the supine position. All seizures except those that occurred in patients in the supine position showed sudden momentary head dropping or collapse of the whole body downward. Recovery to the preictal position was observed in 0.3-1 s. As a result of carefully repeated observations, the 36 seizures were classified as myoclonic flexor type in 9, myoclonic atonic type in 2, and atonic type, with and without transient preceding symptoms in the remaining 25. The MF seizure was characterized by sudden forward flexion of the head and trunk as well as both arms, which caused the patient to fall. In the myoclonic atonic seizure, patients showed brief myoclonic flexor spasms, immediately followed by atonic falling. The AT seizure showed abrupt atonic falling, with and without transient preceding facial expression change and/or twitching of extremities. The ictal EEGs of all 36 seizures exhibited generalized bilaterally synchronous single or multiple spike(s) and wave discharges. Atonic drop attacks appear to be a common cause of ictal epileptic falling in MAEE.     

Generalized epilepsy with febrile seizures plus (GEFS+): clinical spectrum in seven Italian families unrelated to SCN1A, SCN1B, and GABRG2 gene mutations

PURPOSE: We describe seven Italian families with generalized epilepsy with febrile seizures plus (GEFS+), in which mutations of SCN1A, SCN1B, and GABRG2 genes were excluded and compare their clinical spectrum with that of previously reported GEFS+ with known mutations. METHODS: We performed a clinical study of seven families (167 individuals). The molecular study included analysis of polymerase chain reaction (PCR) fragments of SCN1A and SCN1B exons by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing of GABRG2 in all families. We excluded SCN1A, SCN1B, and GABRG2 genes with linkage analysis in a large pedigree and directly sequenced SCN2A in a family with neonatal-infantile seizures onset. We compared the epilepsy phenotypes observed in our families with those of GEFS+ families harboring mutations of SCN1A, SCN1B, and GABRG2 and estimated the percentage of mutations of these genes among GEFS+ cases by reviewing all published studies. RESULTS: Inheritance was autosomal dominant with 69% penetrance. Forty-one individuals had epilepsy: 29 had a phenotype consistent with GEFS+; seven had idiopathic generalized epilepsy (IGE); in three, the epilepsy type could not be classified; and two were considered phenocopies. Clinical phenotypes included FS+ (29.2%), FS (29.2%), IGE (18.2%), FS+ with focal seizures (13%) or absence seizures (2.6%), and FS with absence seizures (2.6%). Molecular study of SCN1A, SCN2A, SCN1B, and GABRG2 did not reveal any mutation. Results of our study and literature review indicate that mutations of SCN1A, SCN2A, SCN1B, and GABRG2 in patients with GEFS+ are rare. CONCLUSIONS: The most frequently observed phenotypes matched those reported in families with mutations of the SCN1A, SCN1B, and GABRG2 genes. IGE and GEFS+ may overlap in some families, suggesting a shared genetic mechanism. The observation that 13% of affected individuals had focal epilepsy confirms previously reported rates and should prompt a reformulation of the "GEFS+" concept to include focal epileptogenesis.     

Different degrees of loss of function between GEFS+ and SMEI Nav 1.1 missense mutants at the same residue induced by rescuable folding defects

Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) differ in their clinical severity and prognosis even though mutations of the Na(v) 1.1 sodium channel are responsible for both disorders. We compared the electrophysiologic properties of two mutant Na(v) 1.1 channels characterized by distinct amino acid substitutions at the same residue position: GEFS+ (A1685V) and SMEI (A1685D). Both the mutants showed complete loss of function when expressed alone. However, the function of A1685V can be partly rescued by the β(1) subunit, consistently with a folding defect, whereas that of A1685D was not rescued. These electrophysiologic differences are consistent with the divergence in clinical severity between GEFS+ and SMEI.