Review article
Progress in searching for the febrile seizure susceptibility genes

https://doi.org/10.1016/j.braindev.2008.11.014Get rights and content

Abstract

Febrile seizures (FS) represent the most common form of childhood seizures. They affect 2–5% of infants in the Caucasian population and are even more common in the Japanese population, affecting 6–9% of infants. Some familial FS are associated with a wide variety of afebrile seizures. Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a spectrum of phenotypes including FS, atypical FS (FS+) and afebrile seizures. A significant genetic component exists for susceptibility to FS and GEFS+: extensive genetic studies have shown that at least nine loci are responsible for FS. Furthermore, mutations in the voltage-gated sodium channel subunit genes (SCN1A, SCN2A and SCN1B) and the GABAA receptor subunit genes (GABRG2 and GABRD) have been identified in GEFS+. However, the causative genes have not been identified in most patients with FS or GEFS+. Common forms of FS are genetically complex disorders believed to be influenced by variations in several susceptibility genes. Recently, several association studies on FS have been reported, but the results vary among different groups and no consistent or convincing FS susceptibility gene has emerged. Herein, we review the genetic data reported in FS, including the linkage analysis, association studies, and genetic abnormalities found in the FS-related disorders such as GEFS+ and severe myoclonic epilepsy in infancy.

Introduction

Febrile seizures (FS) are relatively common and represent the majority of childhood seizures. Studies in developed nations indicate that 2–5% of all children will experience a FS before 5 years of age [1]. FS are not thought of as a true epileptic disease but rather as a special syndrome characterized by its provoking factor (fever) and a typical range of 6 months to 6 years. The prognosis is generally very good, but people who have had FS have a higher risk of developing spontaneous afebrile seizures, which defines epilepsy when they recur [2].

The disease is complex and heterogeneous, and genetic factors contribute significantly to the etiology of FS. Family studies have shown that relatives of patients with FS are at increased risk compared to the general population [3], [4]. Twin studies have also indicated that genetic factors play an important role in susceptibility to FS [5]. Segregation patterns in families with FS suggest different modes of inheritance. Most studies have supported a polygenic or multifactorial model, with a large heritable component [6], [7], [8]. However, in families of probands with multiple FS, the incidence pattern was consistent with a single-major-locus model that best fit autosomal dominant with reduced penetrance [6], [8]. Although specific genes that affect the majority of FS cases have not yet been identified, several genetic loci for FS have been reported recently.

In this article, we review recent progress in the genetics of FS, including the linkage analysis, association studies, and the genetic abnormalities found in the FS-related epilepsy syndromes such as generalized epilepsy with FS plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI).

Section snippets

Linkage studies of febrile seizures

Extensive genetic linkage analyses have been performed in FS families, and nine genetic loci have been mapped in the Online Mendelian Inheritance in Man (OMIM) database thus far (Table 1). FEB2, FEB5 and FEB8 have been reported as the loci for pure FS [9], [10], [11]. Although the majority of affected individuals with other FS loci experienced FS only, a few individuals later developed afebrile seizures or epilepsy [12], [13], [14], [15], [16], [17]. Thus, it is possible that these FS loci

Association studies of febrile seizures

Genetic association studies offer a powerful alternative for identifying common variants of a complex disease [40]. Association studies compare the frequency of specific alleles in affected cases against those in unaffected controls. An allele is said to be associated with the disease if its frequency differs between cases and controls more than would be predicted by chance [41], provided the controls are representative of the test population in all aspects other than disease affection status.

GEFS+

GEFS+ was first described by Scheffer and Berkovic as an autosomal dominant epilepsy syndrome characterized by a variety of mainly generalized epilepsy phenotypes occurring within the same family [18]. The most common phenotypes include FS and FS+, in which FS persist beyond 6 years of age or are associated with afebrile, mostly generalized or more rarely partial, seizures. More severe epilepsy phenotypes such as myoclonic–atonic epilepsy or SMEI have also been described within GEFS+ families.

Conclusion

During the past decade, molecular genetic studies have contributed a great deal to the identification of genetic factors involved in FS and related disorders. The identification of the mutations of the SCN1A gene in SMEI has been the most noteworthy discovery. This short review illustrates the progress in FS and related disorders but also draws attention to the still-existing frustration that in the large majority of FS, no specific genetic influences have been discovered yet. FS families with

Acknowledgment

This work was supported by a grant from Scientific Research from Japan Society for the Promotion of Sciences (19591212).

References (73)

  • J. Nakayama et al.

    Failure to find evidence for association between voltage-gated sodium channel gene SCN2A variants and febrile seizures in humans

    Neurosci Lett

    (2002)
  • J. Nakayama et al.

    Failure to find causal mutations in the GABA(A)-receptor gamma2 subunit (GABRG2) gene in Japanese febrile seizure patients

    Neurosci Lett

    (2003)
  • R. Kira et al.

    Genetic susceptibility to simple febrile seizures: interleukin-1beta promoter polymorphisms are associated with sporadic cases

    Neurosci Lett

    (2005)
  • N. Tilgen et al.

    Association analysis between the human interleukin 1beta (−511) gene polymorphism and susceptibility to febrile convulsions

    Neurosci Lett

    (2002)
  • M. Matsuo et al.

    Increased IL-1beta production from dsRNA-stimulated leukocytes in febrile seizures

    Pediatr Neurol

    (2006)
  • M.A. Kauffman et al.

    Association study between interleukin 1 beta gene and epileptic disorders: a HuGe review and meta-analysis

    Genet Med

    (2008)
  • L. Claes et al.

    De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy

    Am J Hum Genet

    (2001)
  • I. Ohmori et al.

    Significant correlation of the SCN1A mutations and severe myoclonic epilepsy in infancy

    Biochem Biophys Res Commun

    (2002)
  • F. Madia et al.

    No evidence of GABRG2 mutations in severe myoclonic epilepsy of infancy

    Epilepsy Res

    (2003)
  • T. Tsuboi

    Genetic aspects of febrile convulsions

    Hum Genet

    (1977)
  • Y. Fukuyama et al.

    A genetic study of febrile convulsions

    Eur Neurol

    (1979)
  • T. Tsuboi et al.

    Genetic studies of febrile convulsions: analysis of twin and family data

    Epilepsy Res Suppl

    (1991)
  • S.S. Rich et al.

    Complex segregation analysis of febrile convulsions

    Am J Hum Genet

    (1987)
  • T. Tsuboi

    Genetic analysis of febrile convulsions: twin and family studies

    Hum Genet

    (1987)
  • W.G. Johnson et al.

    Pedigree analysis in families with febrile seizures

    Am J Med Genet

    (1996)
  • E.W. Johnson et al.

    Evidence for a novel gene for familial febrile convulsions, FEB2, linked to chromosome 19p in an extended family from the Midwest

    Hum Mol Genet

    (1998)
  • R. Nabbout et al.

    A locus for simple pure febrile seizures maps to chromosome 6q22-q24

    Brain

    (2002)
  • D. Audenaert et al.

    A novel GABRG2 mutation associated with febrile seizures

    Neurology

    (2006)
  • R.H. Wallace et al.

    Suggestion of a major gene for familial febrile convulsions mapping to 8q13-21

    J Med Genet

    (1996)
  • A. Peiffer et al.

    A locus for febrile seizures (FEB3) maps to chromosome 2q23-24

    Ann Neurol

    (1999)
  • P. Hedera et al.

    Identification of a novel locus for febrile seizures and epilepsy on chromosome 21q22

    Epilepsia

    (2006)
  • R. Nabbout et al.

    New locus for febrile seizures with absence epilepsy on 3p and a possible modifier gene on 18p

    Neurology

    (2007)
  • J. Nakayama et al.

    Significant evidence for linkage of febrile seizures to chromosome 5q14-q15

    Hum Mol Genet

    (2000)
  • J. Nakayama et al.

    Linkage and association of febrile seizures to the IMPA2 gene on human chromosome 18

    Neurology

    (2004)
  • I.E. Scheffer et al.

    Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes

    Brain

    (1997)
  • S.L. Kugler et al.

    Hereditary febrile seizures: phenotype and evidence for a chromosome 19p locus

    Am J Med Genet

    (1998)

    • Cited by (0)

    View full text
    Copyright © 2009 Elsevier B.V. All rights reserved.