Genetic epilepsy with febrile seizures plus

Eleni Panagiotakaki MD PhD (Dr. Panagiotakaki of University Hospitals of Lyon has no relevant financial relationships to disclose.)
Petra Grdjan MD (Dr. Grdjan of the University Hospital Centre, Zagreb, Croatia, has no relevant financial relationships to disclose.)
Adriana Ulate-Campos MD (Dr. Ulate-Campos of National Childrens Hospital, San Jose, Costa Rica, has no relevant financial relationships to disclose.)
Alexis Arzimanoglou MD (Dr. Arzimanoglou, Director of the Pediatric Epilepsy Department of the University Hospitals of Lyon (HCL), has no relevant financial relationships to disclose.)
Jerome Engel Jr MD PhD, editor. (Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, has no relevant financial relationships to disclose.)
Originally released September 2, 2004; last updated November 9, 2016; expires November 9, 2019

This article includes discussion of genetic epilepsy with febrile seizures plus, GEFS+, and generalized epilepsy with febrile seizures plus. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Genetic epilepsy with febrile seizures plus (GEFS+) is an epileptic condition characterized by childhood febrile seizures and later development of epilepsy. This disorder seems to have autosomal dominant inheritance with incomplete penetrance. The definition of GEFS+ applies to families with multiple members that present febrile seizures or various types of (mostly) generalized epilepsies. The development of epilepsy typically presents as afebrile generalized tonic-clonic seizures that extend into late childhood. The predominant presence of this seizure type initially gave rise to the term "generalized epilepsy with febrile seizures plus"; however, the term “genetic epilepsy” is now preferred due to the presence of partial as well as generalized seizures in some patients. Other seizure types include myoclonic attacks, myoclonic-astatic seizures, absences, and status epilepticus. Mutations associated with GEFS+ have been identified in genes that encode for sodium channel subunits (SCN1A, SCN2A, SCN1B) and ligand-gated gamma aminobutyric acid receptor A gamma2 and delta subunits (GABRG2, GABRD).

Key points

 

• Genetic epilepsy with febrile seizures plus (GEFS+) is an epileptic condition characterized by childhood febrile seizures and later development of epilepsy; the disorder is associated with autosomal dominant inheritance with incomplete penetrance.

 

• Seizures typically extend into late childhood as afebrile generalized tonic-clonic seizures as well as other seizure types, including myoclonic attacks, myoclonic-astatic seizures, absences and episodes of status epilepticus.

 

• Epilepsy could be generalized or partial.

 

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

 

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

Historical note and terminology

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 (Aicardi 1994). On the basis of clinical symptoms and course, a possible syndrome of childhood epilepsy with generalized tonic-clonic seizures (GTCS) was suggested.

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, febrile seizures, often of unusual duration or severity, and afebrile generalized seizures of various types appeared to be transmitted as a dominant genetic character. Simple febrile seizures constituted the most common manifestation. However, these often tended to occur beyond the usual upper limit of 4 to 5 years, and the term "febrile seizures plus" (FS+) was proposed. Afebrile seizures were mainly GTCS; however, myoclonic attacks, myoclonic-astatic seizures, absences, or even episodes of status epilepticus also occurred in some pedigree members. The pattern of inheritance was autosomal dominant. 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." Subsequently, some authors reported that patients within the GEFS+ spectrum also presented with partial seizures, including patients with temporal lobe epilepsy (Abou-Khalil et al 2001) that was sometimes associated with hippocampal sclerosis or even frontal lobe epilepsy (Scheffer et al 2005).

In accordance with Scheffer and Berkovic, GEFS+ is now more appropriately referred to as "genetic epilepsy with febrile seizures plus" because both partial and generalized seizures occur in such families (Scheffer and Berkovic 2008). Furthermore, GEFS+ is not a syndromic entity in the sense given to the term "syndrome" by the ILAE classification because diagnosis is based on familial occurrence rather than an association of signs and symptoms in an individual patient (signs and symptoms may vary extensively between patients). In the new sense of the definition, GEFS+ is, thus, a "genetic syndrome" characterized by phenotypic heterogeneity and autosomal dominant inheritance with incomplete penetrance. Linkage studies have identified genes that are mutated among such families; however, it is clear that like the characteristic phenotypic heterogeneity, there is also extensive genetic heterogeneity within this group.

The initial study of the Anglo-Australian family included 25 affected persons over 4 generations (Scheffer and Berkovic 1997). Twenty-three family members had a history of febrile convulsions that were often prolonged. 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. The proband had myoclonic-astatic epilepsy; 4 had infrequent absence seizures in addition to febrile seizures plus (FS+), and 1 man had atonic attacks that were mostly in the form of head falls. 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). Other similar pedigrees were later reported (Moulard et al 1999; Singh et al 1999; Bonanni et al 2004), and linkage to chromosome 2q (2q24) was demonstrated (Baulac et al 1999). This linkage was later associated with mutations in the alpha subunit of the sodium channel SCN1A gene (patients are referred to as GEFS+2) (Escayg et al 2001; Wallace et al 2001b). Other associated sodium channel genes include the alpha2 subunit gene (SCN2A) (Sugawara et al 2001) and alpha9 subunit gene (SCN9A) (Singh et al 2009). In addition, mutations in ligand-gated gamma aminobutyric acid (GABA) receptor A subunits have also been identified in patients with GEFS+. These include the gamma2 subunit (GABRG2; locus 5q34) and delta subunit (GABRD; 1p36.3) (patients are referred to as GEFS+3 and GEFS+5, respectively) (see Table 1).

Linkage studies have further identified 7 other loci in patients with features of GEFS+: at 2p24 (GEFS+ 4) (Audenaert et al 2005), 8p23-p21 (GEFS+ 6) (Baulac et al 2008), 21q22 (Hedera et al 2006), 2q23-q24 (Peiffer et al 1999), 5q14-q15 (Nakayama et al 2000), 6q16.3-22.31 (Poduri et al 2009), and 12p13.33 (Morar et al 2011). Another 7 loci have been identified in patients with predominantly familial febrile seizures: at 8q13-q21 (Wallace et al 1996), 6q22-q24 (Nabbout et al 2002), 19p13 (Johnson et al 1998), 3q26.2-26.33 (Dai et al 2008), 3p and 18p (Nabbout et al 2007) and 18p11 (Nakayama et al 2004). For the latter, Nakayama and colleagues identified a putative susceptibility gene for febrile seizures (Nakayama et al 2004)--the IMPA2 gene, which encodes for myo-inositol monophosphatase (IMPase) 2; however, this was shown not to be the case in a Caucasian population (Blair et al 2007). The identity of important genes associated with these linkage studies is thus far unknown (see Table 1); however, a susceptibility gene for febrile seizures has been identified as the seizure-related SEZ6 gene (Yu et al 2007; Mulley et al 2011). Duplications in 17q12 are the first reported inherited copy number variation that causes GEFS+/FS; however, this is a rare cause, with a frequency of only 1 out of 222 (0,45%). It can present with intellectual disability, but some family members could present only with epilepsy (Hardies et al 2013). Belhedi and colleagues found a new locus 22q13.31, with an autosomal recessive mode of inheritance, in a Tunisian consanguineous family with a GEFS+ phenotype, but they were not able to identify a mutation in the last exons of the TBC1D22A gene located in this region so further studies are needed in order to confirm this finding. This is the first description of GEFS+ family with a possible autosomal recessive mode of inheritance (Belhedi et al 2013).

Table 1. Genetic Loci and Known Genes Associated with Dravet Syndrome, GEFS+, and Febrile Seizures

Locus

Gene

Dravet

GEFS+

FS

19q13.1
2q24 (FEB3A)
5q34 (FEB8)
2q24.3
2q24.3-31.1 (FEB3B)
2q22-23
Xq22
2p24
1p36.2
8p23-21
21q22 (FEB7)
2q23-24 (FEB3)
5q14-15 (FEB4)
6q16.3-22.31
12p13.33
8q13-21 (FEB1)
6q22-24 (FEB5)
19p13.3 (FEB2)
3p24.2-23 (FEB9)
18p
17q12 duplication
22q13.31 (confirmation needed)

SCN1B
SCN1A
GABRG2
SCN2A
SCN9A
CACNB4
PCDH19
GABRD
SEZ6

+
+ (high frequency)
+
+
+
+
+ (females)*

+ (GEFS+1)
+ (GEFS+2)
+ (GEFS+3)
+
+ (GEFS+7)
+ (females)
+ (GEFS+4)
+ (GEFS+5)
+ (GEFS+6)
+
+
+
+
+
+
+

+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+

* Dravet-like features predominantly associated with febrile seizures (Depienne et al 2011).

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