Generalized Epilepsy with Febrile Seizures

Generalized epilepsy with febrile seizures, GEFSP, Generalized epilepsy with febrile seizures plus; GEFSP, GEFS+, Familial febrile seizures, FEB

Autosomal dominant

Epilepsy (generalized) with febrile seizures is a complex autosomal dominant disorder characterized by generalized febrile convulsions. Febrile seizures are the most common convulsive event occurring in 2-6% of the population ¹. The lifetime prevalence of febrile seizures is estimated at 3-4% of all children in Europe and North America and is even higher in Japan and Scandinavia ^{2, 3}. About 40% of children with a first febrile seizure will have a recurrence, with one third of patients with only febrile seizures and two thirds with a variety of epilepsy syndromes, both focal and generalized. Febrile seizures most commonly present at the age of 18 months with about 80% of incident febrile seizures occurring between 1 and 3 years of age ^{1, 2}.

Epidemiologic studies have led to the division of febrile seizures into 3 groups, as follows:

• Simple febrile seizures
• Complex febrile seizures
• Symptomatic febrile seizures

Children with simple febrile seizures are neurologically and developmentally healthy before and after the seizure. In the absence of fever they do not experience a seizure. The seizure is described as either a generalized clonic or a generalized tonic-clonic seizure. Simple febrile seizure activity usually lasts for 15 minutes or less, although a postictal period of sleepiness or confusion can extend beyond these 15 minutes. Simple febrile seizures often occur with the initial temperature elevation at the onset of illness and they could be the first indication of the disease. Symptomatic febrile seizures are accompanied by the preexisting neurologic abnormality or acute illness.

Febrile seizures are considered a genetic disorder, most commonly reported with an autosomal dominant mode of inheritance. Several genes, which encode sodium or GABA receptor subunits, have been associated with febrile seizures phenotypes (see table):

• Idiopathic generalized epilepsy 10, generalized epilepsy with febrile seizures plus type 5 and juvenile myoclonic epilepsy 7 can be conferred by variations in the GABRD gene on chromosome 1p36.3, encoding GABA receptor subunit delta. Three heterozygous missense pathogenic variants have been reported in this gene so far: p.E177A, p.R220C, and p.R220H, all associated with generalized epilepsy with febrile seizures ⁴ (HGMD® Professional 2017.1).
• The GABRG2 gene encodes additional GABA receptor protein, and mutations in this gene have primarily been associated with generalized epilepsy with febrile seizures (7/26). Mutations in GABRG2 have also been associated with Rolandic epilepsy (2/26), childhood absence epilepsy (2/26), generalized epilepsy (2/26), and others (HGMD® Professional 2017.1).
• The SCN1A gene encodes the alpha subunit of the neuronal voltage-gated sodium channel. SCN1A-related seizure disorders are channelopathies characterized by seizures as their primary manifestation. The molecular abnormality causes neuronal dysfunction and hyperexcitability at the level of the cortical network, which is a morphological substrate for seizure disorders. More than 1300 pathogenic variants have been reported in SCN1A, primarily associated with Dravet syndrome (597/1378) (HGMD® Professional 2017.1), myoclonic epilepsy of infancy (407/1378), generalized epilepsy with febrile seizures plus (63/1378), and other seizure-related phenotypes. Generalized epilepsy with febrile seizures plus (GEFS+) is mostly associated with missense SCN1A pathogenic variants ⁵. Almost half the pathogenic variants associated with the severe myoclonic epilepsy in infancy and Dravet syndrome are truncating variants of SCN1A and the remainder includes missense SCN1A variants (39%-43%), splice site variants (7%), and deletions (3%) ⁶.
• Generalized epilepsy with febrile seizures plus-1 (GEFSP1) is caused by heterozygous mutations in the SCN1B gene on chromosome 19q13. The SCN1B gene encodes a beta-1 subunit of voltage-gated sodium channels that regulates generation and propagation of action potentials in nerve and muscle. Mutations in SCN1B have been associated with Brugada syndrome (5/20), generalized epilepsy with febrile seizures (5/20), atrial fibrillation (2/20), idiopathic and generalized epilepsy (2/20), and other conditions associated with neuronal membrane activity (HGMD® Professional 2017.1).
• Benign familial neonatal-infantile seizures-3 (BFIS3) is caused by heterozygous mutation in the SCN2A gene on chromosome 2q24. SCN2A encodes a subunit of sodium channel and similar to SCN1B regulates formation and propagation of action potential in neuronal and muscle cells. More than 160 pathogenic variants have been reported in this gene so far (HGMD® Professional 2017.1) and these have been assigned to autistic spectrum disorders (32/162), epileptic encephalopathy (20/162), neonatal-infantile seizures (18/162), benign infantile seizures (7/162), and other epilepsy-related phenotypes.
• Generalized epilepsy with febrile seizures plus, type 7 (GEFSP7) and familial febrile seizures-3B (FEB3B) are both caused by heterozygous mutations in the SCN9A gene on chromosome 2q24, encoding a subunit of sodium channel. More than 100 pathogenic variants in the SCN9A gene have been reported (HGMD® Professional 2017.1), associated with congenital insensitivity to pain (28/1049, erythromelalgia (12/104), febrile seizures (7/104), Dravet syndrome (17/104), and other phenotypes.