Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

Purpose: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome‐wide linkage meta‐analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type–related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. Methods: Meta‐analysis of three genome‐wide linkage datasets was carried out in 379 GGE‐multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type–related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type–related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE‐multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. Key Findings: For the entire set of 379 GGE‐multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome‐wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). Significance: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype– genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.     

No evidence for a susceptibility locus for idiopathic generalized epilepsy on chromosome 5 in families with typical absence seizures

A recent genome-wide scan revealed suggestive evidence for two susceptibility loci for idiopathic generalized epilepsy (IGE) in the chromosomal regions 5p15 and 5q14-q22 in families with typical absence seizures. The present replication study tested the validity of the tentative IGE loci on chromosome 5. Our study included 99 multiplex families in which at least one family member had typical absence seizures. Parametric and non-parametric multipoint linkage analyses were carried out between the IGE trait and 23 microsatellite polymorphisms covering the entire region of chromosome 5. Multipoint parametric heterogeneity lod scores < -2 were obtained along chromosome 5 when a proportion of linked families greater than 50% was assumed under recessive inheritance and > 60% under dominant inheritance. Furthermore, non-parametric multipoint linkage analyses revealed no hint of linkage throughout the candidate region (P > 0.05). Accordingly, we failed to support previous evidence for common IGE loci on chromosome 5. If there is a susceptibility locus for IGE on chromosome 5 then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.     

Genetic architecture of idiopathic generalized epilepsy: clinical genetic analysis of 55 multiplex families

PURPOSE: In families with idiopathic generalized epilepsy (IGE), multiple IGE subsyndromes may occur. We performed a genetic study of IGE families to clarify the genetic relation of the IGE subsyndromes and to improve understanding of the mode(s) of inheritance. METHODS: Clinical and genealogic data were obtained on probands with IGE and family members with a history of seizures. Families were grouped according to the probands' IGE subsyndrome: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with tonic-clonic seizures only (IGE-TCS). The subsyndromes in the relatives were analyzed. Mutations in genes encoding alpha1 and gamma 2 gamma-aminobutyric acid (GABA)-receptor subunits, alpha1 and beta1 sodium channel subunits, and the chloride channel CLC-2 were sought. RESULTS: Fifty-five families were studied. 122 (13%) of 937 first- and second-degree relatives had seizures. Phenotypic concordance within families of CAE and JME probands was 28 and 27%, respectively. JAE and IGE-TCS families had a much lower concordance (10 and 13%), and in the JAE group, 31% of relatives had CAE. JME was rare among affected relatives of CAE and JAE probands and vice versa. Mothers were more frequently affected than fathers. No GABA-receptor or sodium or chloride channel gene mutations were identified. CONCLUSIONS: The clinical genetic analysis of this set of families suggests that CAE and JAE share a close genetic relation, whereas JME is a more distinct entity. Febrile seizures and epilepsy with unclassified tonic-clonic seizures were frequent in affected relatives of all IGE individuals, perhaps representing a nonspecific susceptibility to seizures. A maternal effect also was seen. Our findings are consistent with an oligogenic model of inheritance.     

Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy

BACKGROUND: Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy (IGE) with complex inheritance. Previous studies have suggested maternal inheritance and female excess in IGEs but have not been specific for JME. We investigated evidence for maternal inheritance, female excess and patterns of familial seizure risk in a well-characterized sample of JME families. METHODS: We ascertained 89 families through a JME proband and 50 families through a non-JME IGE proband. JME families were divided into those with and without evidence of linkage to the EJM1 susceptibility locus on chromosome 6. We analyzed transmission in 43 multigenerational families, calculated the adjusted sex ratio for JME, and looked for evidence of seizure specific risk in 806 family members. RESULTS: We found evidence for preferential maternal transmission in both EJM1-linked and unlinked families (2.7:1), evidence even more marked when potential selection factors were excluded. The adjusted female: male risk ratio was very high in JME (RR=12.5; 95% CI: 1.9-83.7). Absence seizures in JME probands increased the overall risk of seizures in first degree relatives (15.8% vs. 7.0%, P=0.011), as well as first-degree relatives' specific risk of absence seizures (6% vs. 1.6%, P=0.01), but not myoclonic seizures. CONCLUSIONS: We have confirmed the finding of maternal inheritance in JME, which is not restricted to JME families linked to the EJM1 locus. The striking female excess in JME may relate to anatomical and/or endocrine sexual dimorphism in the brain. Evidence for independent inheritance of absence and myoclonic seizures in JME families reinforces a model in which combinations of loci confer susceptibility to the component seizure types of IGE.     

A locus for generalized tonic-clonic seizure susceptibility maps to chromosome 10q25-q26

Inheritance patterns in twins and multiplex families led us to hypothesize that two loci were segregating in subjects with juvenile myoclonic epilepsy (JME), one predisposing to generalized tonic-clonic seizures (GTCS) and a second to myoclonic seizures. We tested this hypothesis by performing genome-wide scan of a large family (Family 01) and used the results to guide analyses of additional families. A locus was identified in Family 01 that was linked to GTCS (10q25-q26). Model-based multipoint analysis of the 10q25-q26 locus showed a logarithm of odds (LOD) score of 2.85; similar results were obtained with model-free analyses (maximum nonparametric linkage [NPL] of 2.71; p = 0.0019). Analyses of the 10q25-q26 locus in 10 additional families assuming heterogeneity revealed evidence for linkage in four families; model-based and model-free analyses showed a heterogeneity LOD (HLOD) of 2.01 (alpha = 0.41) and maximum NPL of 2.56 (p = 0.0027), respectively, when all subjects with GTCS were designated to be affected. Combined analyses of all 11 families showed an HLOD of 4.04 (alpha = 0.51) and maximum NPL score of 4.20 (p = 0.000065). Fine mapping of the locus defined an interval of 4.45Mb. These findings identify a novel locus for GTCS on 10q25-q26 and support the idea that distinct loci underlie distinct seizure types within an epilepsy syndrome such as JME.     

The Seizure Prognosis of Juvenile Myoclonic Epilepsy

Abstract: Thirty-two patients with juvenile myoclonic epilepsy (JME) were studied to evaluate the seizure prognosis. The response to antiepileptic drugs ww excellent in 68%, but the patients, who had much more focal discharges on EEG and were sensitive to neuropsychological EEG activations at the beginning of treatment, had an unfavorable outcome. A combination of absence seizure alone resulted in the excellent prognosis for both absence and myoclonic seizures, and a combination of generalized tonic-clonic seizure on awakening related to rare myoclonic seizures. These findings suggest that the outcome of JME would be predicted by the EEG abnormality and the combination of the other types of seizures, which are probably determined by the pathophysiology at the beginning of treatment.     

Benign familial infantile convulsions: linkage to chromosome 16p12-q12 in 14 families

PURPOSE: Benign familial infantile convulsions (BFIC) is a form of idiopathic epilepsy. It is characterized by clusters of afebrile seizures occurring around the sixth month of life. The disease has a benign course with a normal development and rare seizures in adulthood. Previous linkage analyses defined three susceptibility loci on chromosomes 19q12-q13.11, 16p12-q12, and 2q23-31. However, a responsible gene has not been identified. We studied linkage in 16 further BFIC families. METHODS: We collected 16 BFIC families, without an additional paroxysmal movement disorder, of German, Turkish, or Japanese origin with two to eight affected individuals. Standard two-point linkage analysis was performed. RESULTS: The clinical picture included a large variety of seizure semiologies ranging from paleness and cyanosis with altered consciousness to generalized tonic-clonic seizures. Interictal EEGs showed focal epileptiform discharges in six patients, and three ictal EEGs in three distinct patients revealed a focal seizure onset in different brain regions. In all analyzed families, we found no evidence for linkage to the BFIC loci on chromosomes 19q and 2q, as well as to the known loci for benign familial neonatal convulsions on chromosomes 8q and 20q. In 14 of the families, the chromosome 16 locus could be confirmed with a cumulative maximum two-point lod score of 6.1 at marker D16S411, and the known region for BFIC could be narrowed to 22.5 Mbp between markers D16S690 and D16S3136. CONCLUSIONS: Our data confirm the importance of the chromosome 16 locus for BFIC and may narrow the relevant interval.     

Genetic localization of the familial adult myoclonic epilepsy (FAME) gene to chromosome 8q24.

OBJECTIVE: To identify the genetic locus for the familial adult myoclonic epilepsy (FAME) gene. BACKGROUND: Idiopathic generalized epilepsy (IGE) represents a collection of disorders in which affected individuals present with recurring seizures that have diffuse onset on EEG. These individuals have no known structural cerebral lesions or other identifiable etiology. IGE accounts for approximately 40% of all epilepsies. FAME is a type of IGE characterized by autosomal dominant inheritance, adult onset, varying degrees of myoclonus in the limbs, rare tonic-clonic seizures, and a benign course. METHODS: We investigated four previously reported Japanese kindreds and performed a genome-wide screen with genetic linkage analysis. RESULTS: Clinical characterization and sampling of 30 individuals in four families revealed that 21 had the FAME phenotype. We defined a 4.6-cM region on chromosome 8q24 (maximum lod score of 4.86 at theta = 0) that contains the FAME gene. CONCLUSIONS: The identification and characterization of the FAME gene allows us to better understand the molecular basis of FAME. Such knowledge may provide clues to understanding the molecular basis of the clinically similar, and more common, juvenile myoclonic epilepsies, and other generalized seizure disorders that have thus far eluded genetic approaches.     

Genome scan of idiopathic generalized epilepsy: evidence for major susceptibility gene and modifying genes influencing the seizure type

Idiopathic generalized epilepsy (IGE) is a common, complex disease with an almost exclusively genetic etiology but with variable phenotypes. Clinically, IGE can be divided into different syndromes. Varying lines of evidence point to the involvement of several interacting genes in the etiology of IGE. We performed a genome scan in 91 families ascertained through a proband with adolescent-onset IGE. The IGEs included juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and epilepsy with generalized tonic clonic seizures (EGTCS). Our linkage results support an oligogenic model for IGE, with strong evidence for a locus common to most IGEs on chromosome 18 (lod score 4.4/5.2 multipoint/two-point) and other loci that may influence specific seizure phenotypes for different IGEs: a previously identified locus on chromosome 6 for JME (lod score 2.5/4.2), a locus on chromosome 8 influencing non-JME forms of IGE (lod score 3.8/2.5), and, more tentatively, two newly discovered loci for absence seizures on chromosome 5 (lod scores 3.8/2.8 and 3.4/1.9). Our data also suggest that the genetic classification of different forms of IGE is likely to cut across the clinical classification of these subforms of IGE. We hypothesize that interactions of different combinations of these loci produce the related heterogeneous phenotypes seen in IGE families.     

Adult-onset idiopathic generalized epilepsy: clinical and behavioral features

PURPOSE: To identify and define clinical and behavioral features of patients with adult-onset idiopathic generalized epilepsy (IGE). METHODS: We reviewed the charts of 313 IGE patients at the NYU Comprehensive Epilepsy Center over the past 5 years to identify patients with adult onset (18 years old or older). We excluded patients with childhood or adolescent symptoms that suggested absence, myoclonic, or tonic-clonic seizures, as well as those with a history of significant head injury or other known causes of localization-related epilepsy. RESULTS: Forty-two (13.4%) patients had a clear onset of IGE in adulthood; average age of onset was early 20s (mean, 23.8 years; range, 18-55 years). Twenty-one patients had adult myoclonic epilepsy (AME, 50%), and three had generalized tonic-clonic seizures on awakening (GTCS-A, 7%). More than two thirds (n=30) are well controlled with current antiepileptic drugs (AEDs), and almost 90% are currently employed (n=37). One third were diagnosed and treated for mental disorders, including depression (n=12), anxiety (n=7), obsessive-compulsive personality disorder (n=2), and postictal psychosis (n=1). CONCLUSIONS: Adult-onset IGE is associated with a good prognosis. An association may exist between psychological disorders, psychotropic medication, and level of seizure control in adults with IGE.     

Idiopathic generalized epilepsies with typical absences

Idiopathic generalized epilepsy (IGE) comprises several subsyndromes. These are principally: benign neonatal familial convulsions, benign neonatal convulsions, benign myoclonic epilepsy in infancy, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, epilepsy with generalised tonic-clonic seizures on awakening. In addition, there are less well-recognized syndromes, such as eyelid myoclonia with absences. The pathophysiology of the IGE syndromes is not fully understood; it is evident that typical absences are the result of abnormal oscillations between the thalamus and cerebral cortex. Genetic studies are in progress to elucidate the biochemical defects underlying the conditions. The clinical and electroencephalographic features of the individual subsyndromes are distinct, but some patients may be difficult to classify into a particular subgroup. A correct syndromic diagnosis is important, as treatment strategies differ for patients with the different forms of IGE, and it is necessary for genetic research. Received: 4 February 1997     

Chronic management of seizures in the syndromes of idiopathic generalized epilepsy

As a group, idiopathic generalized epilepsies (IGEs) have the highest rates of complete seizure control with medication. However, there are little evidence-based data to guide drug choice for treatment. Examples of IGE include absence epilepsy, generalized tonic-clonic epilepsy, and juvenile myoclonic epilepsy. Generalized epilepsies seem to be particularly vulnerable to seizure aggravation, and medications that are primarily effective against partial seizures are more commonly involved in seizure aggravation than other medications. A review of current research has shown that only a few medications can control IGE without potentially causing seizure aggravation. Broad-spectrum antiepileptic drugs such as valproate (VPA), lamotrigine, and topiramate are extremely effective at controlling a variety of seizures without causing excessive seizure aggravation. Among these drugs, VPA has the longest clinical experience history and the largest body of published data.     

Linkage analysis between idiopathic generalized epilepsies and the GABAA receptor α5, β3 and γ3 subunit gene cluster on chromosome 15

Introduction - We tested the hypothesis that genetic variants within the GABA_Aα₅, β₃ and γ₃ subunit gene cluster on chromosome 15q11-q13 confer genetic susceptibility to common subtypes of idiopathic generalized epilepsy (IGE). Material and methods - Ninety-four families were selected from IGE patients with either juvenile myoclonic epilepsy (JME), juvenile (JAE) or childhood absence epilepsy (CAE). Cosegregation was tested between dinucleotide polymorphisms associated with the human GABA_Aα₅, β₃ and γ₃ subunit gene cluster and three different IGE trait models. Results - Evidence against linkage to the GABA_Aα₅, β₃ and γ₃ subunit gene cluster was found in the entire family set and subsets selected from either CAE or JAE. In 61 families of JME patients, a maximum lod score (Z_max=1.40 at θ_max=0.00) was obtained for a broad IGE spectrum ("idiopathic" generalized seizure or generalized spike and wave discharges in the electroencephalogram) assuming genetic heterogeneity (α=0.37; P =0.06) and an autosomal recessive mode of inheritance. Conclusion - The possible hint of linkage in families of JME patients emphasizes the need for further studies to determine whether a recessively inherited gene variant within the GABA_Aα₅, β₃ and γ₃ subunit gene cluster contributes to the pathogenesis of "idiopathic" generalized seizures and associated EEG abnormalities in a proportion of families.     

Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy

Genetic predisposition plays a major role in the etiology of idiopathic epilepsies. The common epilepsy syndromes display a complex pattern of inheritance, with an unknown number of genes contributing to seizure susceptibility. During the last decade linkage studies have narrowed down several candidate regions for susceptibility loci of idiopathic epilepsies. Several lines of evidence point to the existence of an epilepsy susceptibility gene on chromosome 15q14. Evidence for linkage to this region has thus been reported for juvenile myoclonic epilepsy, common subtypes of idiopathic generalized epilepsy (IGE), in addition to the EEG trait 'centrotemporal spikes' in families with rolandic epilepsy. The chromosomal region 15q14 harbours several candidate genes that are involved in the regulation of neuronal excitability. One of the most promising candidate genes is the brain-expressed potassium chloride cotransporter KCC3, given that this class of ion transporter has been implicated in the regulation of neuronal chloride activity. We therefore performed a mutation analysis of KCC3 in the index patients of 23 IGE-families as well as of 16 families with rolandic epilepsy which where selected by positive evidence for linkage to D15S165. Four novel single nucleotide exchanges (SNPs) were identified, none of which change the coding sequence. These results do not support a major role for KCC3 in the etiology of rolandic epilepsy or common subtypes of IGE.     

Replication Analysis of a Putative Susceptibility Locus (EGI) for Idiopathic Generalized Epilepsy on Chromosome 8q24

Summary: Purpose: The present replication study was designed to test the validity of a previously mapped susceptibility locus (EGI) for common subtypes of idiopathic generalized epilepsy (IGE) in chromosomal region 8q24. Methods: Thirty-eight multiplex families of probands with common IGE syndromes were included in the present study. Parametric and nonparametric multipoint linkage analyses were conducted between the IGE trait (either “idiopathic” generalized seizure or generalized spike-wave EEG discharges) and three microsatellite polymorphisms (D8S256, D8S284, 0881128) encompassing the putative EGI locus. Results: Parametric and nonparametric multipoint linkage analysis provided no evidence for linkage between the IGE trait and the markers encompassing the putative EGI locus. Moreover, we noted no indication favoring linkage to this chromosomal region in two distinct subsets of families subdivided by the absence (n = 18) or presence (n = 20) of family members with juvenile myoclonic epilepsy (JME). Conclusions: We failed to replicate evidence of a major locus (EGI) for common familial IGE in chromosome region 8q24. On the contrary, our present parametric linkage results provide evidence against linkage across the region under a broad range of genetic models. If there is a susceptibility locus for IGE in this region, the effect size or the proportion of linked families is too small to detect linkage in these families. Taking into account the problems in replicating initial linkage claims in oligogenic traits, further linkage studies in additional family sets are necessary to evaluate the validity of the previous linkage finding.     

Eight years follow-up of a generalized epilepsy patient with eating-induced late-onset epileptic spasms and atypical absence with myoclonic jerks

PurposeEating epilepsy was previously known as a kind of focal reflex epilepsy. However, the development of eating-induced multiple generalized seizures and the associated EEG changes were rarely reported. Herein, we present a 13-year-old generalized epilepsy patient with eating-induced generalized seizures since the age of 5.Case presentationThe 13-year-old male patient had suffered from late-onset eating-induced epileptic spasms during the meal since the age of 5. Meanwhile, he also experienced spontaneous epileptic spasms during the period of sleep. The seizure frequency and type gradually increased from 7 years of age. In addition to epileptic spasms, he started experiencing atypical absence with myoclonic jerks during the meal. Ictal EEG presented as the appearance of an irregular slow-wave mixed with generalized polyspike wave with the intake of food, and gradually evolved to bursts of generalized polyspike wave complexes. At the end of the meal, the EEG returned to normal. Nevertheless, at the age of 13, his seizure frequency increased and appeared new seizure type, and besides epileptic spasm and atypical absence, he began to experience myoclonic seizure during sleep and awaking-generalized tonic-clonic seizure in the morning. In this period he started taking valproic acid, topiramate and clonazepam, and his seizure frequency was reduced.ConclusionIn conclusion, this case demonstrated the variability of eating induced multiple generalized seizure types, and eight years follow-up also indicates that generalized epilepsy progressed with age. The EEG and clinical changes of our patient contribute to a better understanding of the electro-clinical features of eating-induced multiple generalized seizures and the course of generalized epilepsy with such seizures.     

Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (Na+)-channel alpha 1 subunit gene, SCN1A

Evidence that febrile seizures have a strong genetic predisposition has been well documented. In families of probands with multiple febrile convulsions, an autosomal dominant inheritance with reduced penetrance is suspected. Four candidate loci for febrile seizures have been suggested to date; FEB1 on 8q13-q21, FEB2 on 19p, FEB3 on 2q23-q24, and FEB4 on 5q14-15. A missense mutation was identified in the voltage-gated sodium (Na(+))-channel beta 1 subunit gene, SCN1B at chromosome 19p13.1 in generalized epilepsy with the febrile seizures plus type 1 (GEFS+1) family. Several missense mutations of the (Na(+))-channel alpha 1 subunit (Nav1.1) gene, SCN1A were also identified in GEFS+2 families at chromosome 2q23-q24.3. The aim of this report is precisely to describe the phenotypes of Japanese patients with novel SCN1A mutations and to reevaluate the entity of GEFS+. Four family members over three generations and one isolated (phenotypically sporadic) case with SCN1A mutations were clinically investigated. The common seizure type in these patients was febrile and afebrile generalized tonic-clonic seizures (FS+). In addition to FS+, partial epilepsy phenotypes were suspected in all affected family members and electroencephalographically confirmed in three patients of two families. GEFS+ is genetically and clinically heterogeneous, and associated with generalized epilepsy and partial epilepsy as well. The spectrum of GEFS+ should be expanded to include partial epilepsies and better to be termed autosomal dominant epilepsy with febrile seizures plus (ADEFS+).     

How to diagnose and classify idiopathic (genetic) generalized epilepsies

Idiopathic or genetic generalized epilepsies (IGE) constitute an electroclinically well‐defined group that accounts for almost one third of all people with epilepsy. They consist of four well‐established syndromes and some other rarer phenotypes. The main four IGEs are juvenile myoclonic epilepsy, childhood absence epilepsy, juvenile absence epilepsy and IGE with generalized tonic‐clonic seizures alone. There are three main seizure types in IGE, namely generalized tonic‐clonic seizures, typical absences and myoclonic seizures, occurring either alone or in any combination. Diagnosing IGEs requires a multidimensional approach. The diagnostic process begins with a thorough medical history with a specific focus on seizure types, age at onset, timing and triggers. Comorbidities and family history should be questioned comprehensively. The EEG can provide valuable information for the diagnosis, including specific IGE syndromes, and therefore contribute to their optimal pharmacological treatment and management.     

Generalized epilepsy with febrile seizures plus: further heterogeneity in a large family

BACKGROUND: Generalized epilepsy with febrile seizures plus (GEFS(+)) is a recently described benign childhood-onset epileptic syndrome with autosomal dominant inheritance. The most common phenotypes are febrile seizures (FS) often with accessory afebrile generalized tonic-clonic seizures (GTCS, FS(+)). In about one third, additional seizure types occur, such as absences, myoclonic, or atonic seizures. So far, three mutations within genes encoding subunits of neuronal voltage-gated Na(+) channels have been found in GEFS(+) families, one in SCN1B (beta(1)-subunit) and two in SCN1A (alpha-subunit). METHODS: The authors examined the phenotypic variability of GEFS(+) in a five-generation German family with 18 affected individuals. Genetic linkage analysis was performed to exclude candidate loci. RESULTS: Inheritance was autosomal dominant with a penetrance of about 80%. A variety of epilepsy phenotypes occurred predominantly during childhood. Only four individuals showed the FS or FS(+) phenotype. The others presented with different combinations of GTCS, tonic seizures, atonic seizures, and absences, only in part associated with fever. The age at onset was 2.8 +/- 1.3 years. Interictal EEG recordings showed rare, 1- to 2-second-long generalized, irregular spike-and-wave discharges of 2.5 to 5 Hz in eight cases and additional focal parietal discharges in one case. Linkage analysis excluded the previously described loci on chromosomes 2q21-33 and 19q13. All other chromosomal regions containing known genes encoding neuronal Na(+) channel subunits on chromosomes 3p21-24, 11q23, and 12q13 and described loci for febrile convulsions on chromosomes 5q14-15, 8q13-21, and 19p13.3 were also excluded. CONCLUSION: These results indicate further clinical and genetic heterogeneity in GEFS(+).