Generalized Epilepsy With Febrile Seizures Plus, Type 7

A number sign (#) is used with this entry because generalized epilepsy with febrile seizures plus, type 7 (GEFSP7) and familial febrile seizures-3B (FEB3B) are both caused by heterozygous mutation in the SCN9A gene (603415) on chromosome 2q24.

See also GEFS+, type 2 and FEB3A (604403), which are both caused by mutation in the SCN1A gene (182389) on chromosome 2q24.

Description

Mutations in the SCN9A gene cause a spectrum of seizure disorders, ranging from early-onset isolated febrile seizures to generalized epilepsy with febrile seizures plus, type 7, which represents a more severe phenotype. Patients with isolated febrile seizures usually have onset between ages 5 months to 4 years and show spontaneous remission by age 6 years (summary by Singh et al., 2009), whereas patients with GEFS+ continue to have various types of febrile and afebrile seizures later in life (summary by Singh et al., 1999).

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

Singh et al. (2009) studied a large Utah family with autosomal dominant GEFS+. The family was originally reported by Peiffer et al. (1999) as having predominantly febrile seizures, which was mapped to a locus on chromosome 2q24 designated 'FEB3.' However, Moulard et al. (2000) and Scheffer et al. (2000) both concluded that the phenotype reported in the family by Peiffer et al. (1999) was most consistent with GEFS+, since afebrile seizures continued beyond childhood in several affected individuals. The follow-up report by Singh et al. (2009) stated that this family showed a broad spectrum of seizure manifestations. Eleven individuals experienced only febrile seizures before age 6 years, whereas 10 additional individuals developed later afebrile seizures. In 8 of the 10, seizures remitted by age 16 years. The remaining 2 affected individuals developed intractable epilepsy: 1 had complex-partial seizures associated with left mesial temporal sclerosis, and the other had afebrile generalized convulsive seizures requiring the placement of a vagal nerve stimulator. This phenotype is designated GEFS+, type 7.

Singh et al. (2009) also reported 2 unrelated patients with simple febrile seizures and 2 different heterozygous mutations in the SCN9A gene (I62V; 603415.0020 and P149Q; 603415.0021, respectively). This phenotype is designated FEB3B.

Mapping

Peiffer et al. (1999) first mapped this locus, which they designated FEB3, to chromosome 2q23-q24 by linkage analysis of a large Utah family with febrile seizures (lod score of 8.08 at D2S2330). Haplotype analysis identified a critical 10-cM interval between D2S141 and D2S2345.

Molecular Genetics

In affected members of a large Utah family with generalized epilepsy with febrile seizures plus, type 7, originally reported by (Peiffer et al., 1999), Singh et al. (2009) identified a heterozygous mutation in the SCN9A gene (N641Y; 603415.0018) on 2q24.

In 2 unrelated probands with isolated febrile seizures (FEB3B), Singh et al. (2009) identified 2 different heterozygous mutations in the SCN9A gene (I62V, 603415.0020 and P149Q, 603415.0021, respectively).

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 to have GEFS+7 caused by mutation in the SCN9A gene by Singh et al. (2009).

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 (182389); 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 gene on chromosome 2q24; this form of febrile seizures is designated FEB3B.