Genetic epilepsy with febrile seizures plus

Eleni Panagiotakaki MD PhD (

Dr. Panagiotakaki of University Hospitals of Lyon has no relevant financial relationships to disclose.

Maria Papadopoulou MD (

Dr. Papadopoulou of ‘Papageorgiou’ University Hospital of Thessaloniki, Greece, has no relevant financial relationships to disclose.

Alexis Arzimanoglou MD (

Dr. Arzimanoglou of University Hospitals of Lyon received honorariums from Eisai, GW, Sanofi, Takeda, and UCB as an advisory board member.

Jerome Engel Jr MD PhD, editor. (

Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, received honorariums from Cerebel for advisory committee membership.

Originally released September 2, 2004; last updated January 18, 2021; expires January 18, 2024


Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epileptic syndrome characterized by occurrence of seizures in multiple family members with important phenotypical heterogeneity. The phenotypical spectrum usually includes febrile seizures or febrile seizures plus but various types of seizures/epileptic syndromes could be observed in at least 2 family members. The initial description included development of epilepsy as afebrile generalized tonic-clonic seizures that extend into late childhood following febrile seizures. The syndrome was thus referred to as “generalized epilepsy with febrile seizures plus”; however, the term “genetic epilepsy” is now preferred due to the presence of focal as well as generalized seizures in some patients. Other seizure types include myoclonic attacks, myoclonic-astatic seizures, absences, and focal seizures. At the severe end of the spectrum lie epileptic encephalopathies, such as Dravet syndrome and myoclonic-atonic epilepsy. EEG patterns and drug responsiveness depend on seizure type and clinical phenotype. The inheritance follows a complex pattern that was initially considered as autosomal dominant with incomplete penetrance; subsequent data also suggest polygenic, recessive inheritance and de novo mutations that encode in the majority of cases of ion channel subunits. Neurodevelopment, apart from severe cases of epileptic encephalopathies, is usually normal.

Key points


• Genetic epilepsy with febrile seizures plus (GEFS+) is an epileptic condition characterized by the occurrence of febrile seizures and a variety of other seizures types (febrile seizures, febrile seizures plus, other generalized or focal) in at least 2 members of the same family.


• The clinical presentation of patients with GEFS+ is diverse, and the clinical spectrum extends from familial febrile seizures (least severe cases) to myoclonic-astatic epilepsy or Dravet syndrome (most severe cases).


• Inheritance is mainly autosomal dominant with incomplete penetrance but other inheritance patterns (recessive, copy number variations, de novo, etc.) have been described.


• Mutations associated with GEFS+ have been identified in genes that encode for sodium channel subunits (SCN1A, SCN2A, SCN1B, SCN9A) and ligand-gated gamma aminobutyric acid receptor A gamma2 and delta subunits (GABRG2, GABRD) and in several other genes implicated in epileptogenesis.


• Management depends on seizure type, which can be either generalized of focal, or on epileptic syndrome phenotype (ie, stiripentol for Dravet syndrome). In the majority of cases neuroimaging and neurodevelopment are normal.

Historical note and terminology

In 1994, Aicardi initially recognized a subgroup of patients with febrile convulsions followed by infrequent generalized seizures that often remitted definitively by 9 to 12 years of age, suggesting a possible syndrome of childhood epilepsy with generalized tonic-clonic seizures (GTCS) (Aicardi 1994).

The term "generalized epilepsy with febrile seizures plus" (GEFS+) was first used by Scheffer and Berkovic to describe "a genetic disorder with heterogeneous clinical phenotypes" (Scheffer and Berkovic 1997). The description was based on the recognition that in a large Anglo-Australian extended family of 25 members studied over 4 generations, febrile seizures, and afebrile generalized seizures of various types appeared to be transmitted as a dominant genetic character.

Twenty-three family members had a history of febrile convulsions that were often prolonged in duration and extended over the age of 5 years (FS+). Later, 9 individuals had afebrile seizures of variable severity and a repetition rate that started at a median age of 2.2 years and remitted by 11.7 years (range 6 to 25 years). All had normal intellect, and EEGs were normal at last examination. Other seizure types were also present; 1 proband had myoclonic-astatic epilepsy; 4 had infrequent absence seizures in addition to FS+, and 1 man had atonic attacks that were mostly in the form of head falls, and even episodes of status epilepticus occurred in some pedigree members. In this family, linkage of the condition to chromosome 19q (19q13.1) was demonstrated (Wallace et al 1998), and the gene in question was later identified as the beta subunit of the sodium channel SCN1B gene (patients are referred to as GEFS+1). Based on the fact that members of this family presented with various forms of generalized seizures, the authors suggested that "the insights afforded by this family have major implications for clinical and molecular genetic strategies for the generalized epilepsies."

Other similar pedigrees were soon reported (Moulard et al 1999; Singh et al 1999; Bonanni et al 2004); their linkage to chromosome 2q (2q24) (Baulac et al 1999) and mutations in the alpha subunit of the sodium channel SCN1A gave rise to GEFS+2 patient group (Escayg et al 2001; Wallace et al 2001b). At the same time, other ion-channel associated genes were soon described; patients with mutation in the gamma2 subunit (GABRG2; locus 5q34) and delta subunit (GABRD; 1p36.3) were respectively referred to as GEFS+3 and GEFS+5 (Wallace et al 2001a).

Linkage studies that further identified several genetic loci in patients with features of genetic epilepsy with febrile seizures plus have led so far to the description of 10 GEFS+ subgroups, delineated by their causative gene (see Table 1). The above categorization, targeting to correlate genetic and clinical variability, has over the years been pushed aside by the increasing number of genetic loci, complex inheritance genes, and copy number variations described. However, it could still be used in clinical practice and worth mentioning.

Reports that patients within genetic epilepsy with febrile seizures plus families could also present with focal seizures as temporal lobe epilepsy (Abou-Khalil et al 2001) or frontal lobe epilepsy (Scheffer et al 2005) came to light in the early 2000s. Scheffer and Berkovic, along with many other experts, thus proposed that GEFS+ should more appropriately referred to as "genetic epilepsy with febrile seizures plus" because both focal and generalized seizures occur in such families (Scheffer and Berkovic 2008; Zhang et al 2017; Bisulli et al 2019).

Genetic epilepsy with febrile seizures plus is a difficult to diagnose entity in the sense that the term "syndrome" in this case is used to describe a familial occurrence rather than an association of signs and symptoms in an individual patient (signs and symptoms may vary extensively between patients of the same family). In a report the ILAE Genetics Commission adopted the term “GEFS+ spectrum” for this “genetic syndrome” characterized by phenotypic along with continuously enriched genetic heterogeneity (Myers et al 2018). In their articles, experts from China adopted the term “fever-associated seizures or epilepsy” (FASE) in order to refer to all different phenotypes associated with the disorder (Deng et al 2018; Ding et al 2019).

Table 1. Genetic Loci and Most Commonly Known Genes Associated with GEFS+






GEFS+1 (Wallace et al 1998)



GEFS+2 (Escayg et al 2001)



GEFS+3 (Wallace et al 2001a)



GEFS+4 (Audenaert et al 2005)



GEFS+5 (Wallace et al 2001a)



GEFS+6 (Baulac et al 2008)



GEFS+7 (Singh et al 2009)



GEFS+8 (Poduri et al 2009)



GEFS+9 (Schubert et al 2014)



GEFS+10 (Marini et al 2018)

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