Generalized Epilepsy With Febrile Seizures Plus, Type 2

A number sign (#) is used with this entry because generalized epilepsy with febrile seizures plus, type 2 (GEFSP2) and familial febrile seizures-3A (FEB3A) are both caused by heterozygous mutation in the SCN1A gene (182389) on chromosome 2q24.

See also GEFS+, type 7 (613863) and FEB3B (613863), which are both caused by mutation in the SCN9A gene (603415) on chromosome 2q24.

Description

Mutations in the SCN1A gene cause a spectrum of seizure disorders, ranging from early-onset isolated febrile seizures to generalized epilepsy with febrile seizures plus, type 2, which represents a more severe phenotype. Patients with isolated febrile seizures usually have onset between ages 6 months and 4 years and show spontaneous remission by age 6 years (summary by Mantegazza et al., 2005), whereas patients with GEFS+ continue to have various types of febrile and afebrile seizures later in life (summary by Singh et al., 2009). Dravet syndrome (607208), or severe myoclonic epilepsy of infancy, is the most severe phenotype associated with SCN1A mutations.

Mutations in certain genes can cause a phenotypic spectrum of overlap between the isolated febrile phenotype and the GEFS+ phenotype. For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233. For a phenotypic description and a discussion of genetic heterogeneity of familial febrile seizures, see 121210.

Clinical Features

GEFS+ Type 2

Baulac et al. (1999) studied a family in which affected individuals in 3 successive generations presented clinical similarities with families with GEFS+. Patients expressed a variable phenotype combining febrile seizures, generalized seizures often precipitated by fever at age greater than 6 years, myoclonic seizures, absence seizures, hemiclonic seizures, and partial seizures, with a variable degree of severity.

Moulard et al. (1999) reported a family in which 6 individuals had isolated typical febrile seizures, and 5 had typical febrile seizures associated with generalized epilepsy. Afebrile seizures occurred in childhood until the teenage years.

Familial Febrile Seizures 3A

Mantegazza et al. (2005) reported a large Italian family in which at least 12 members spanning 4 generations had simple febrile seizures. The age at onset ranged from 5 months to 4 years, and none had seizures beyond age 6 years. Most seizures were brief, lasting 1 to 5 minutes, although 1 patient had seizures lasting up to 15 minutes. Three affected individuals developed afebrile partial seizures of mesial temporal lobe origin with vegetative or experiential phenomena at the ages of 10, 13, and 11 years. Very rare partial complex seizures or nocturnal secondary generalized tonic-clonic seizures also occurred in all 3 of them. Two of these patients had MRI evidence of unilateral mesial temporal sclerosis. Mantegazza et al. (2005) noted that febrile convulsions had been identified as a risk factor for temporal lobe epilepsy with hippocampal sclerosis (Briellmann et al., 2001). Mantegazza et al. (2005) concluded that the phenotype was distinct from GEFS+ and was most consistent with simple febrile seizures.

Mapping

By genomewide linkage analysis of a family with GEFS+ using semiautomated fluorescent genotyping, Baulac et al. (1999) identified a GEFS+ locus on chromosome 2q21-q33. The maximum pairwise lod score was 3.00 with a recombination fraction 0.0 for marker D2S2330. Haplotype reconstruction defined a 22-cM candidate interval flanked by markers D2S156 and D2S2314.

Moulard et al. (1999) also found linkage of GEFS+ to chromosome 2q24-q33.

By linkage analysis of an Italian family with simple febrile seizures, Mantegazza et al. (2005) found linkage to the FEB3 locus on chromosome 2q24 (see Peiffer et al. (1999) and NOMENCLATURE).

Molecular Genetics

Escayg et al. (2000) demonstrated that the 2 GEFS+ families reported by Baulac et al. (1999) and Moulard et al. (1999) each carried a different heterozygous mutation in the SCN1A gene (R1648H, 182389.0001 and T875M, 182389.0002, respectively).

In 2 unrelated Japanese families with GEFS+2 associated with development of partial epilepsy, Sugawara et al. (2001) identified 2 novel mutations in the SCN1A gene. One of these mutations, val1428-to-ala (182389.0011), was a missense mutation in the pore-forming region of the sodium channel, which the authors hypothesized may affect ion selectivity.

Orrico et al. (2009) identified 21 mutations, including 14 novel mutations, in the SCN1A gene in 22 (14.66%) of 150 Italian pediatric probands with epilepsy. SCN1A mutations were found in 21.2% of patients with GEFS+ and in 75% of patients with Dravet syndrome (607208) from the overall patient cohort.

Familial Febrile Seizures 3A

In 12 affected members of an Italian family with simple febrile seizures mapping to 2q24, Mantegazza et al. (2005) identified a heterozygous mutation in the SCN1A gene (182389.0015). This disorder is designated FEB3A.

In a 2-stage case-control study including a total of 234 patients with febrile seizures, Schlachter et al. (2009) found a significant association between the major A allele of SNP rs3812718 in the SCN1A gene (182389.0016) and febrile seizures (first stage p value of 0.000017; replication p value of 0.00069). The data suggested that homozygosity for the A allele confers a 3-fold increased relative risk of febrile seizures and may account for a population attributable risk factor of up to 50%. The data were consistent with the hypothesis that low-risk variants with a high population frequency contribute to the risk of common and genetically complex diseases such as epilepsy.

Cytogenetics

Suls et al. (2010) reported a 4-generation Bulgarian family with epilepsy transmitting a heterozygous 400-kb deletion on chromosome 2q24 encompassing the SCN1A and TTC21B (612014) genes. The phenotype was variable, but all had onset of generalized tonic-clonic seizures around the first year of life (range, 8 to 14 months), and some had myoclonic or absence seizures. Three of 4 patients had febrile seizures in infancy. One patient had mild mental retardation, 1 had psychomotor slowing, and 1 had mental retardation from early infancy; all had reduced seizures on medication. The fourth patient died of status epilepticus at age 13 months. Thus, 2 patients had a phenotype reminiscent of Dravet syndrome, whereas the phenotype in the other 2 was more consistent with GEFS+2. The unaffected father in the first generation was found to be somatic mosaic for the deletion. Suls et al. (2010) noted that deletions involving SCN1A usually result in the much more severe Dravet syndrome, in which affected individuals cannot raise a family and thus do not transmit the mutation. The report of this family with a deletion of SCN1A in which 2 affected individuals were able to raise a family suggested the presence of genetic modifiers and showed intrafamilial variability.

Nomenclature

Two different genes, SCN1A (182389) and SCN9A (603415), map to the FEB3 locus on chromosome 2q24, first identified by Peiffer et al. (1999) in a large Utah family with febrile seizures. This family was later found by Singh et al. (2009) to have GEFS+7 (613863) caused by mutation in the SCN9A gene (603415).

In an Italian family with isolated febrile seizures, Mantegazza et al. (2005) found linkage to the FEB3 locus and identified a pathogenic mutation in the SCN1A gene; this form of febrile seizures is designated FEB3A.

In 2 unrelated probands with isolated febrile seizures, Singh et al. (2009) identified pathogenic mutations in the SCN9A (603415) gene on chromosome 2q24; this form of febrile seizures is designated FEB3B (see 613863).