Epilepsy with febrile seizures plus (GEFS+)

GEFS+ is a familial epilepsy syndrome defined at the family rather than individual level. Within a single pedigree, affected relatives display markedly variable expressivity, with phenotypes spanning from simple febrile seizures at the mild end through febrile seizures plus (FS+) and generalised, myoclonic, absence or focal epilepsies in the intermediate range, to intractable generalised epilepsy or Dravet syndrome at the severe end. Febrile seizures typically begin before the first year of life and, in FS+, persist beyond the age of six years, may show unusual severity including status epilepticus, and are accompanied by unprovoked seizures. Subsequent afebrile tonic, clonic, myoclonic or absence seizures generally respond to medication and remit by late childhood or early adolescence. Onset of the first seizure in the context of immunisation appears to be more frequent than in unrelated febrile seizures.

Due to insufficient data, no reliable statement on prevalence can currently be made.

GEFS+ is genetically heterogeneous; heterozygous germline pathogenic variants in at least seven genes have been associated with the syndrome. The most commonly implicated genes are SCN1A (the most frequently identified gene), SCN1B (the first GEFS+ gene reported), GABRG2, GABRA1 and GABRD. These variants affect voltage-gated sodium channel subunits (SCN1A, SCN1B), GABA-A receptor subunits (GABRG2, GABRA1, GABRD) or the SNARE-complex protein syntaxin-1B (STX1B), perturbing the balance between neuronal excitation and inhibition and predisposing to fever-triggered and unprovoked generalised seizures.

GEFS+ is inherited in an autosomal dominant manner. The recurrence risk for each child of an affected individual is 50%. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

There are no established clinical diagnostic criteria for GEFS+; the diagnosis is suspected on the basis of the characteristic familial pattern of febrile and afebrile seizures and is confirmed by molecular genetic testing. Brain MRI is typically normal early in the course; nonspecific changes such as cortical or cerebellar atrophy, hippocampal sclerosis or white-matter hyperintensities may evolve over time, particularly in more severe phenotypes.

Main differential diagnoses include:

• : severe end of the SCN1A spectrum; onset 1-18 months, prolonged hyperthermia-triggered seizures, intractable course, mostly de novo; SCN1A
• PCDH19-related epilepsy: X-linked, predominantly female; clustered fever-induced seizures, usually onset ≥12 months; PCDH19
• : treatable mimic; low CSF glucose, responds to ketogenic diet; SLC2A1

• Establishing a molecular genetic diagnosis confirms the clinical suspicion and ends the diagnostic odyssey for the affected individual and their family.
• Identification of the underlying genetic cause is a prerequisite for individualised clinical management, with treatment decisions tailored by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is known, targeted predictive testing of at-risk relatives becomes possible, supporting informed reproductive and clinical decision-making.

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• Pavone P, Pappalardo XG, Parano E, Falsaperla R, Marino SD, Fink JK, et al. Fever-Associated Seizures or Epilepsy: An Overview of Old and Recent Literature Acquisitions. Frontiers in pediatrics. 2022;10:858945. doi: 10.3389/fped.2022.858945. PMID: . PMCID: PMC9070101.
• Cornejo-Sanchez DM, Acharya A, Bharadwaj T, Marin-Gomez L, Pereira-Gomez P, Nouel-Saied LM, et al. SCN1A Variants as the Underlying Cause of Genetic Epilepsy with Febrile Seizures Plus in Two Multi-Generational Colombian Families. Genes. 2022;13(5). doi: 10.3390/genes13050754. PMID: . PMCID: PMC9140479.