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  • Updated 01.18.2021
  • Released 09.02.2004
  • Expires For CME 01.18.2024

Genetic epilepsy with febrile seizures plus

Introduction

Overview

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) (02).

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" (120). 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 (150), 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 (98; 136; 16); their linkage to chromosome 2q (2q24) (12) and mutations in the alpha subunit of the sodium channel SCN1A gave rise to GEFS+2 patient group (47; 148). 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 (147).

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 (01) or frontal lobe epilepsy (122) 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 (121; 156; 15).

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 (102). 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 (32; 42).

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

Locus

Gene

GEFS+

19q13.1

SCN1B

GEFS+1 (150)

2q24.3

SCN1A

GEFS+2 (47)

5q34

GABRG2

GEFS+3 (147)

2p24

GEFS+4 (07)

1p36.2

GABRD

GEFS+5 (147)

8p23-21

GEFS+6 (10)

2q24.3-31.1

SCN9A

GEFS+7 (134)

6q16.3-q22.31

GEFS+8 (114)

16p11.2

STX1B

GEFS+9 (127)

5p12

HCN1

GEFS+10 (90)

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