Generalized Epilepsy With Febrile Seizures Plus, Type 1

A number sign (#) is used with this entry because generalized epilepsy with febrile seizures plus-1 (GEFSP1) is caused by heterozygous mutation in the SCN1B gene (600235) on chromosome 19q13.

Description

Scheffer and Berkovic (1997) and Singh et al. (1999) described a clinical subset of febrile seizures, termed 'generalized epilepsy with febrile seizures plus' (GEFS+). Classic febrile seizures (see, e.g., FEB1, 121210) affect approximately 3% of children under 6 years of age and are by far the most common seizure disorder; classic febrile seizures typically spontaneously remit by age 6 years. GEFS+ occurs in a small proportion of children with febrile seizures who either have febrile seizures extending beyond age 6 years or develop epilepsy with afebrile seizures. Patients with GEFS+ express a highly variable phenotype combining febrile seizures, generalized seizures often precipitated by fever at age 6 years or more, absence seizures, partial seizures, myoclonic seizures, or atonic seizures, with a variable degree of severity (summary by Wallace et al., 1998).

Deprez et al. (2009) reviewed the genetics of epilepsy syndromes starting in the first year of life, and included a diagnostic algorithm.

Genetic Heterogeneity of GEFS+

GEFS+ is a genetically heterogeneous disorder. See also GEFS+2 (604403), caused by mutation in the SCN1A gene (182389) on chromosome 2q24; GEFS+3 (see 607681), caused by mutation in the GABRG2 gene (137164) on 5q34; GEFS+5 (613060), associated with variation in the GABRD (137163) gene on 1p36; GEFS+7 (613863), caused by mutation in the SCN9A gene (603415) on 2q24; GEFS+9 (616172), caused by mutation in the STX1B gene (601485) on chromosome 16p11; and GEFS+10 (618482), caused by mutation in the HCN1 gene (602780) on chromosome 5p12.

Several putative loci have also been identified. See GEFS+4 (609800), which maps to chromosome 2p24; GEFS+6 (612279), which maps to chromosome 8p23-p21; and GEFS+8 (613828), which maps to chromosome 6q16.3-q22.31.

Also see Associations Pending Confirmation under MOLECULAR GENETICS.

Clinical Features

Scheffer and Berkovic (1997) reported a large multigenerational family from Tasmania with early childhood onset of febrile seizures as well as febrile seizures occurring beyond age 6 years and development of afebrile seizures, including generalized tonic-clonic seizures (GTCS), absence seizures, myoclonic seizures, and atonic seizures. There was wide phenotypic severity. Most had onset in the first year of life and many had remittance of the seizures in the first or second decades, although some had seizures into adulthood. All patients had normal intellectual development, except 1 patient with myoclonic-astatic epilepsy who had moderate intellectual disability.

Wallace et al. (1998) reported a large 6-generation Australian family in which 42 individuals had a history of seizures. Extensive clinical study showed that 26 had epilepsy consistent with the GEFS+ syndrome, 3 had other forms of epilepsy, and 4 obligate carriers had unclassified seizures. Further clinical details were not provided.

Wallace et al. (2002) reported another large Australian family with GEFS+ type 1. The proband developed fever-associated generalized tonic-clonic seizures at age 18 months. These continued until he was 3 years old, at which time he developed afebrile seizures, including absence seizures. He later noted sensory aura preceding complex partial seizures or GTCS. At age 14 years, neurologic examination and brain MRI was normal, whereas EEG showed generalized spike wave activity and, on one occasion, right temporal epileptiform activity. His phenotype was designated FS+, followed by partial epilepsy of the temporal lobe type. Family history showed 19 individuals with seizures, including GEFS+ and febrile seizures.

Audenaert et al. (2003) reported a family with GEFS+ type 1. The phenotype was unusual in that the proband presented with afebrile absence seizures at age 17 months and never had febrile seizures. However, her older brother had classic febrile seizures. Her mother was unaffected, but 2 maternal uncles and a first cousin had febrile seizures which remitted by age 7 years. Genetic analysis identified a heterozygous splice site mutation in the SCN1B gene (600235.0002). The penetrance of the disorder was estimated to be 63%.

Molecular Genetics

Wallace et al. (1998) found linkage to 19q13.1 in a large GEFS+ family and identified a heterozygous mutation in the voltage-gated sodium channel beta-1 subunit gene, SCN1B (C121W; 600235.0001). Their observations developed further the theme that idiopathic epilepsies are a family of channelopathies and raised the possibility of involvement of other sodium-channel subunit genes in febrile convulsions and general epilepsies with complex inheritance patterns.

Wallace et al. (2002) identified a heterozygous C121W mutation in another Australian family with GEFS+. Four unaffected individuals carried the mutation, indicating reduced penetrance.

Associations Pending Confirmation

Dibbens et al. (2010) identified a variant in the HCN2 gene (602781) that resulted in a 9-bp deletion (2156delCGCCGCCGC) removing 3 proline residues at 719 to 721 (delPPP) from a 7-proline repeat close to the cyclic nucleotide-binding domain. The deletion was present in only 3 (0.2%) of 772 controls, but in 3 (2.5%) of 61 patients with febrile seizure (121210) and in 3 (2.3%) of 65 patients with GEFS+. In vitro functional expression studies in Xenopus oocytes showed that the delPPP variant had a 35% increase in current size in response to hyperpolarization compared to wildtype. This current increase would depolarize the membrane potential, taking the neuron closer to the firing potential, and thus could enhance neuronal excitability. The HCN2 delPPP variant was not observed in patients with idiopathic generalized epilepsy (EIG; 600669), who do not have febrile seizures. The findings suggested an association between variation in the HCN2 gene and predisposition to febrile seizures.