Neonatal Epilepsy Syndromes and Generalized Epilepsy with Febrile Seizures Plus (GEFS+)

The molecular revolution during the past decade has had a major impact on our understanding of the genetics of the epilepsies. Molecular discoveries have been particularly important for two groups of epilepsy syndromes: the autosomal-dominant seizure syndromes of the first year of life, and the “genetic epilepsy syndrome”, generalized epilepsy with febrile seizures plus (GEFS+). Indeed, the neonatal syndrome benign familial neonatal seizures (BFNS) is the only autosomal-dominant epilepsy syndrome where the molecular basis has essentially been solved with the vast majority of families having mutations of the potassium channel subunit genes KCNQ2 or KCNQ3. GEFS+ is characterized by phenotypic heterogeneity and is associated with mutations in four genes, although mutation-positive cases only account for a minority of GEFS+ patients overall. The most severe end of the phenotypic GEFS+ spectrum is severe myoclonic epilepsy of infancy (SMEI), or Dravet syndrome, and closely related phenotypic variations. In SMEI, molecular genetics has elucidated much of the etiology of this devastating disorder with about 80% of SMEI patients carrying mutations of the sodium channel alpha 1 subunit gene, SCN1A. This has already impacted on clinical diagnosis and management of patients with SMEI. There are three seizure syndromes that begin in the first year of life, follow autosomal-dominant inheritance, and have very similar clinical characteristics. These syndromes are largely distinguished by their average ages of onset and associated gene defects. The earliest onset syndrome is BFNS, also known as benign familial neonatal convulsions; the later onset syndrome is benign familial infantile seizures (BFIS); and more recently, an intermediate subgroup benign familial neonatal-infantile seizures (BFNIS) with intermediate age of onset and molecular specificity have gained prominence. These three syndromes arise in previously well and developmentally normal neonates or infants who present with clusters of convulsive seizures over a few days. Although BFNS and BFIS were included in the 1989 International League Against Epilepsy (ILAE) classification as “generalized” syndromes (1), the seizures often have focal clinical and electroencephalogram (EEG) features. These disorders share a good outcome with affected babies having normal development and only a minority having later febrile seizures or epilepsy. Rett and Teubel first recognized BFNS in 1964 (2). BFNS is an autosomal-dominant disorder where previously well newborn infants develop seizures on day 2 or 3 of life in 80% of cases (3). If the neonate is premature, seizure onset may be delayed until the baby is chronologically at term (4). Seizures usually start in the first week; the vast majority have onset within the first month with rare cases reported with later onset (5). Seizures have a variety of manifestations including tonic attacks, apnoea, clonic, focal, and autonomic features. Attacks are often stereotyped with hypertonia that may be diffuse or show varying lateralization and apnoea, followed by motor manifestations involving the oculofacial region and clonic activity, which may involve the limbs symmetrically or asymmetrically (3,6). The babies remain relatively well between seizures such that they can feed normally; transient hypotonia may occur (3). Interictal EEG is normal or may have focal or multifocal abnormalities (3). Ictal studies show diffuse flattening evolving to focal or generalized spikes (7). Seizures typically remit by 4 months but may continue until 18 months (8). Later, febrile seizures occur in 5% of individuals and epilepsy in 11% of individuals (3). Focal epilepsy may develop later including rolandic epilepsy (5,9,10). Poor outcome with refractory epilepsy and mental retardation is rare (11,12); one family had later onset of myokymia (13). Mutations in potassium channel subunits KCNQ2 and KCNQ3 were discovered in BFNS in 1998 (14–16). Most families with BFNS have mutations in KCNQ2 with only three mutations reported in KCNQ3 (5,8,10,17–20). The penetrance of BFNS mutations is about 85%. De novo mutations in KCNQ2 have been reported in sporadic neonatal seizures (21). KCNQ2 and KCNQ3 form a heteromeric potassium channel responsible for the M-current, which has a key role in the stabilization of membrane potential and thus neuronal excitability (22–24). In vitro studies of mutant potassium channel subunits show variable loss of function. Effects include decreased potassium current, reduced cell surface channel expression, altered channel gating kinetics, and altered voltage dependence of activation (11,13,14,17,23,25). Some mutations exert a dominant negative effect (5,12,26). Fukuyama recognized benign infantile convulsions in 1963 and the autosomal-dominant inheritance pattern seen in some families was brought to the fore by Vigevano and colleagues in 1992 (27,28). Seizures typically begin between 4 and 7 months of age. The seizures typically comprise slow head and eye deviation, which may alternate in different seizures. They may have unilateral clonic or bilateral features sometimes with hypertonia. The seizures may occur singly, but often present as a cluster over a few days, raising concern about a more serious condition. Interictal EEG studies are usually normal; ictal recordings show a focal onset, often parieto-occipital, and there may be parietal spikes and slowing between seizures during a cluster (29,30). There is a related and overlapping syndrome called infantile convulsions and choreoathetosis (ICCA) (31). These families have infantile convulsions indistinguishable from BFIS and a paroxysmal movement disorder that often begins later. Not all individuals in a family experience both types of attacks. The choreoathetosis begins at any time from infancy to adolescence and may have prominent dystonic and kinesigenic features; it is often triggered by rest, exertion, or anxiety (30,31). A molecular locus for ICCA, as well as for some families with BFIS alone, has been mapped to the pericentromeric region of chromosome 16 (31–33). Despite considerable effort, there has been no success in finding BFIS genes in this region, which is complicated by chromosomal duplication. Two other BFIS loci map to chromosomes 1 and 19 although both localizations require replication (34). A mutation in ATP1A2 on chromosome 1q23 has been found in a single family with familial hemiplegic migraine and infantile convulsions (35). ATP1A2 is a sodium-potassium, ATPase transporter and is likely to be important in familial hemiplegic migraine although its role in BFIS requires confirmation. BFNIS was reported in a large North American family in 1983 (36). No further families were recognized until 2002 when two families were described with a mean seizure onset of around 3 months, falling in between the average onset of seizures for BFNS (day 2 or 3) and BFIS (6 months). Both families had mutations of SCN2A, the gene encoding the alpha-2 subunit of the sodium channel (37). There are now a total of eight families reported with mutations of SCN2A including one recurrent mutation found in three unrelated Italian families (38). Included in these eight families is the “BFIS” family of Malacarne et al. (2001) that was mapped to 2q24 and prompted mutation screening of the SCN1A-SCN2A-SCN3A gene cluster in the same chromosomal region (39). SCN2A has been studied in over 100 cases of other early childhood epilepsies, including GEFS+, and no mutations were found (38). The absolute specificity of SCN2A mutations for BFNIS was questioned by a single small Japanese family with a SCN2A mutation with phenotypes of febrile and afebrile seizures, where it was difficult to apply a clear syndromal classification (40). Given the recent SCN2A data, it is possible that BFNIS is more important than previously appreciated and accounts for some families formerly regarded as having BFIS. The familial epilepsy syndrome GEFS+ is characterized by heterogeneous epilepsy phenotypes or subsyndromes within families (41) (Fig. 1). Recognition of GEFS+ as a syndrome came from careful clinical evaluation of large autosomal-dominant kindreds where penetrance of seizure disorders was around 50–60% (42). After validation of GEFS+ as a specific syndrome, confirmed by segregation of a single pathogenic mutation in some families (43–46), it has been recognized that GEFS+ occurs more frequently in smaller families and even sporadic cases may have specific GEFS+ phenotypes. GEFS+ and the classical idiopathic generalized epilepsies (IGEs) are subgroups of the broad category of idiopathic generalized epilepsy with GEFS+ tending to occur in families separately from the classical IGEs such as childhood absence epilepsy (CAE) and juvenile myoclonic epilepsy, although overlap may occasionally be seen (47,48). The phenotypes within GEFS+ usually have seizure onset within the first decade of life and the vast majority begin with febrile seizures, although this is not universal (42). Spectrum of phenotypes within GEFS+. The most common phenotypes or subsyndromes within GEFS+ are febrile seizures (FS) and febrile seizures plus (FS+) (41,42,48). FS are convulsions (generalized tonic–clonic seizures [GTCS]) with fever over 38°C between 3 months and 6 years of age. FS+ may have a number of different presentations. The most straightforward presentation is where the febrile seizures continue beyond the defined age range of FS of 3 months to 6 years. In this situation, the child may have febrile seizures that continue into late childhood or adolescence. A second type of presentation of FS+ is where afebrile GTCS occur in addition to FS. These afebrile GTCS may occur only within the typical time frame of febrile seizures (3 months to 6 years), or alternatively, they may occur after the febrile seizures remit. Sometimes, there may even be a relative break of several years without seizures before the afebrile GTCS occur (41,42). In rare instances, family members with afebrile GTCS alone, for example, occurring in late childhood, carry the same GEFS+ mutation as other family members with typical GEFS+ phenotypes (44). It is difficult to accept these individuals as having FS+ as they have never had a febrile seizure. Thus, Afebrile GTCS (AGTCS) is a GEFS+ phenotype in which FS do not occur. Both FS and FS+ may be associated with other seizure types. It is more common for generalized seizures to be associated with GEFS+ although focal seizures may occur and have been associated with the same mutations. In terms of generalized seizure types, absence seizures can be seen although they often differ from classical CAE as they are often relatively infrequent yet quite definite attacks. Myoclonic or atonic seizures are also well recognized (41,42). Focal epilepsies in individuals with GEFS+ phenotypes include temporal lobe epilepsy and frontal lobe epilepsy. Temporal lobe epilepsy may occur following FS or FS+ and can be associated with hippocampal sclerosis (42,49,50). Interestingly, temporal lobe epilepsy may also occur without preceding FS suggesting that temporal lobe epilepsy alone may be a phenotype of GEFS+ in its own right albeit rare (51). Frontal lobe epilepsy has been described in French GEFS+ families with hemiclonic seizures and orofacial motor seizures (52). The GEFS+ spectrum includes more severe phenotypes such as the epileptic encephalopathies Myoclonic-astatic epilepsy (MAE), and SMEI and related phenotypes. These syndromes are discussed below. Doose first described MAE and recognized that it had a genetic etiology (53). MAE begins with febrile seizures in one-third of cases and afebrile GTCS in other cases. The child then develops a number of generalized seizure types including the key seizure type of myoclonic-astatic seizures as well as a combination of myoclonic, atonic, absence, and GTCS (54). Onset occurs between 1 and 5 years and boys are more commonly affected than girls. MAE has a variable course with intellectual disability being common but by no means universal. Tonic seizures and episodes of nonconvulsive status epilepticus are associated with a poorer prognosis. The EEG shows fast generalized spike wave activity (55,56). Affected family members of MAE probands studied by Doose most commonly had febrile and afebrile GTCS beginning before 5 years (57), akin to FS and FS+ in GEFS+. Doose's family study was consistent with complex inheritance of MAE (54). To date, only a few patients with MAE have been found to carry mutations of GEFS+ genes including mutations of sodium channel subunit genes, SCN1A and SCN1B, and a GABAA receptor subunit gene GABRG2 (see below) (43,44,47,58,59). Even in these patients with a familial mutation, it is likely that additional unidentified modifier genes contribute to the more severe MAE phenotype. Despite the description of many large families with GEFS+ where there is clinical and molecular genetic evidence of a major gene of dominant effect, the majority of individuals have complex inheritance of GEFS+ phenotypes and thus have no family history or only a small family history of seizure disorders. Clues suggestive of polygenic inheritance include the finding of a bilineal family history of seizure disorders (43). In disorders with complex inheritance, such as the classical IGEs, the recurrence risk to siblings is relatively low. Formal epidemiological studies of GEFS+ are necessary to establish the true recurrence risks in the general population. Genes encoding both voltage-gated and ligand-gated ion channel subunits have been implicated in GEFS+, specifically, sodium channels and GABAA receptors are involved. These findings are not surprising given the key role of ion channels in the pathophysiology of seizure disorders. The neuronal sodium channel is made up of an alpha pore-forming subunit comprising four transmembrane domains, flanked by two beta subunits that regulate channel-gating kinetics. The beta subunit has an extracellular immunoglobulin-like fold considered critical for its regulatory function. The alpha-1 subunit gene, SCN1A, is the most important GEFS+ gene to date and a number of missense mutations scattered throughout the gene have been reported in GEFS+ families (60). The beta-1 subunit gene, SCN1B, has been associated with four different mutations in GEFS+, all localized to the extra cellular immunoglobulin-like fold (43,50,61). The recurrent C121W mutation disrupts a putative disulphide bridge within the extracellular immunoglobulin-like fold. A deletion mutation has also been reported in a single family (62). The GABAA receptor is a heteropentamer with the most common configuration in human brain comprising two alpha, two beta, and a gamma subunit. The GABAA receptor is a ligand-gated chloride channel that has a major role in inhibition in the brain. Four mutations have been described in the gamma-2 subunit gene, GABRG2, three occurring in families with GEFS+ phenotypes (46,58,63). GABRG2 is involved in both GEFS+ and IGE phenotypes as two families with mutations have classical CAE as a central phenotype; this differs considerably from most GEFS+ pedigrees (47,58,64). Importantly, one of the GEFS+-associated GABRG2 mutations occurs in a family where the proband has SMEI (63). GABAA receptors are composed of different combinations of subunits that confer specific functional characteristics to the receptor. For example, a GABAA receptor comprising two alpha, two beta, and a gamma subunit is mostly subsynaptic in location, rapidly desensitizing, and mediates basic inhibition. GABRD encodes the delta subunit of the GABAA receptor, which usually takes the place of the gamma subunit in combining with two alpha and two beta subunits. This configuration of GABAA receptor lies either in the perisynaptic or extrasynaptic region and is a relatively nondesensitizing channel with a role in tonic inhibition. We recently reported a mutation in a small GEFS+ family in GABRD and suggested that GABRD could represent a susceptibility gene for GEFS+ and IGE (65). The E177A GABRD mutation was found in a family with siblings with FS+ and FS and in their unaffected mother. Electrophysiological in vitro studies of the E177A mutation in recombinant GABAA receptors expressed in human embryonic kidney cells showed that the mutant receptors had markedly reduced currents compared with the wild-type receptors when exposed to a saturating concentration of GABA (65). This finding illustrates the functional effect of the mutation and suggests that it may have a significant role in the GEFS+ phenotype and be one of several or many genes contributing to GEFS+ phenotypes in this family. Charlotte Dravet described SMEI in 1978 and it has been suggested that the syndrome be renamed Dravet syndrome (66). SMEI is a distinctive epilepsy syndrome: a previously well and developmentally normal infant develops febrile seizures at around 6 months of age, often presenting with hemiclonic or generalized febrile status epilepticus. One or two months later, they present with a hemiclonic seizure on the alternate side or further generalized seizures and they may have frequent episodes of febrile status epilepticus. Between 1 and 4 years, other seizure types develop including myoclonic seizures in most, but not all, children. Partial seizures are frequent and atonic and atypical absence seizures may also occur. These children are often prone to seizures with fever or in warm water such as bathing. Development is normal in the first year of life with psychomotor slowing thereafter. Ataxia and pyramidal signs may evolve. Intellectual outcome is usually poor and seizures remain refractory. SMEI is often associated with de novo mutations of SCN1A, the gene encoding the alpha-1 subunit of the sodium channel (67). Many groups have described SCN1A mutations in SMEI cases, with the reported frequency varying from 33% to 100% of cases; this variation may depend on the screening procedure used and the mode of ascertainment and diagnosis of cases (68–75). With current optimal detection techniques, approximately 80% of classical SMEI cases have mutations. Over 100 mutations are now described and most commonly comprise truncation mutations, although splice site, deletion, and missense mutations are also reported (60). SCN1A missense mutations in SMEI have a predilection for the S5–6 transmembrane segments of each domain and the linker between them, which together form the ion channel pore. A high proportion of mutations occur in the C-terminus, important in localizing the channel to the axonal membrane, as well as the N-terminus. The majority of more than 100 SCN1A mutations so far characterized are novel with current estimates suggesting around 95% (76/80) arise de novo (60). Familial mutations in SMEI most commonly involve SCN1A mutations; for example, 3 of 33 cases of SMEI had familial mutations in a large French-Italian study (73). To date, there are only two familial GABRG2 mutations reported in individuals with SMEI (63,71). Interestingly, in the rare familial mutation families, usually only one individual has SMEI, with milder phenotypes in other affected family members. Despite the fact that 95% of SCN1A mutations arise de novo in SMEI, many probands have a family history of seizures (76). Specific study of the family history has determined that family members have seizure disorders consistent with the GEFS+ spectrum (77,78). This led to the concept that SMEI is the most severe phenotype within the GEFS+ spectrum. The high proportion of SMEI individuals with de novo SCN1A mutations does not explain the relatively high rate of a family history of seizures, which suggests the potential involvement of other genes and remains an intriguing puzzle to unravel (79). Severe myoclonic epilepsy of infancy is a phenotype where individuals have but not all, of the key features of SMEI. 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Although there are a number of with known on sodium channels or GABA they do not have specific with a known molecular Thus, their at present is not In terms of understanding the of the classical IGEs and GEFS+, both can be associated with preceding febrile seizures, which occur in of children. The sodium channel subunit genes, SCN1A and SCN1B, are associated with GEFS+, with SCN1A having a critical role in SMEI. There is some overlap between GEFS+ and the classical although this is not and both may be associated with GABAA receptor subunit genes, GABRG2 and There is considerable to be to the many combinations and of genes likely to be to GEFS+, and classical IGE and their each specific genetic to a specific epilepsy