Elsevier

Neuroscience Research

Volume 44, Issue 1, September 2002, Pages 11-30
Neuroscience Research

Review article
Genetics of epilepsy: current status and perspectives

https://doi.org/10.1016/S0168-0102(02)00065-2Get rights and content

Abstract

Epilepsy affects more than 0.5% of the world's population and has a large genetic component. The most common human genetic epilepsies display a complex pattern of inheritance and the susceptibility genes are largely unknown. However, major advances have recently been made in our understanding of the genetic basis of monogenic inherited epilepsies. Progress has been particularly evident in familial idiopathic epilepsies and in many inherited symptomatic epilepsies, with the discovery that mutations in ion channel subunits are implicated, and direct molecular diagnosis of some phenotypes of epilepsy is now possible. This article reviews recent progress made in molecular genetics of epilepsy, focusing mostly on idiopathic epilepsy, and some types of myoclonus epilepsies. Mutations in the neuronal nicotinic acetylcholine receptor α4 and β2 subunit genes have been detected in families with autosomal dominant nocturnal frontal lobe epilepsy, and those of two K+ channel genes were identified to be responsible for underlying genetic abnormalities of benign familial neonatal convulsions. The voltage-gated Na+ -channel (α1,2 and β1 subunit), and GABA receptor (γ2 subunit) may be involved in the pathogenesis of generalized epilepsy with febrile seizure plus and severe myoclonic epilepsy in infancy. Mutations of Ca2+-channel can cause some forms of juvenile myoclonic epilepsy and idiopathic generalized epilepsy. Based upon these findings, pathogenesis of epilepsy as a channelopathy and perspectives of molecular study of epilepsy are discussed.

Introduction

Epilepsy affects more than 0.5% of the world's population and has a large genetic component (Baraister, 1990). The idea that epilepsy is not one general disorder but can be differentiated into a number of clinical subtypes provides a basis for studies investigating the genetics of idiopathic epilepsies. Strong support for a genetic role in some epilepsies comes from twin studies (Table 1) that report concordance rates consistently higher in monozygotic (MZ) than in dizygotic (DZ) twins, (Berkovic et al., 1998, Corey et al., 1991, Harveld and Hauge, 1965, Inouye, 1960, Lennox and Lennox, 1960, Sillampaa et al., 1991). Environmental influences are held to a minimum; MZ twins have identical genotypes, whereas DZ twins are no more genetically similar than any two siblings. Concordance rates ranged from 10.8% in MZ pairs with acquired brain injuries to 70% in those without these defects. In DZ twins, concordance ranged from 3 to 10%, regardless of a brain injury in the proband (Treiman and Treiman, 2001). Lennox and Lennox (1960) details of seizure type (Table 1). Here the MZ/DZ difference in concordance is striking, and recent genetic studies of epilepsy have revealed responsible genes of some phenotypes of idiopathic epilepsy and progressive myoclonus epilepsy.

The focus of research on the genetics of the epilepsies is the identification of mutations causing epilepsies, and the abnormal properties of the neuron glia system through which the mutations are expressed and result in clinical epilepsy. Once the mutated code scripts are identified in the epilepsies, it will lead to an understanding of how neurons are regulated in the face of such abnormal code scripts, and how development is affected during embryogenesis and the immediate postnatal period (Delgado-Escueta et al., 1994). Improving the classification of epilepsy genotypes will undoubtedly improve calculations of sibling risk for epilepsy, and this, in turn, improves the accuracy of risk assessments and facilitates genetic counseling. However, most idiopathic epilepsies are complex genetic diseases; they occur with a greater frequency in relatives of affected individuals (Kaneko and Wada, 1998) yet do not exhibit a simple Mendelian inheritance pattern, for it seems that multiple genes are simultaneously involved and that a diversity of ‘susceptible’ genes collaborate in determining risk (Delgado-Escueta et al., 1994). This article reviews recent progress made in molecular genetics of epilepsy and perspectives of molecular study of epilepsy.

Section snippets

Chromosomal localization of epilepsy genes and identified genes of epilepsy

Chromosomally localized epilepsies and identified mutations in the genes of some phenotypes of epilepsy have been listed in Table 2, Table 3, Table 4, Table 5.

Progressive myoclonus epilepsy

The progressive myoclonus epilepsies (PMEs) are a collection of rare disorders presenting with the triad of myoclonic seizures, tonic-clonic seizures, and progressive neurologic dysfunction that often manifests as dementia and ataxia. PMEs generally begin in late childhood to adolescence.

There is ethnic and geographic variation in the frequency of these disease syndromes, and most of PMEs are autosomal recessive in inheritance (Kaneko and Wada, 1998). Significant progress has recently been made

Febrile seizures (FS)

FS affect approximately 3% of all children under 6 years of age and are by far the most common seizure disorders. No specific gene responsible for simple FS has yet been identified but, four putative loci of FS have been mapped (FEB1: 8q; FEB2: 19p, FEB3: 2q, FEB4: 5q) (Wallace et al., 1996, Johnson et al., 1997, Peiffer et al., 1999, Nakayama et al., 2000).

Generalized epilepsy with febrile seizures plus (GEFS+)

A clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+type 1), in which many family members have seizures with

Characterization of epilepsy as channelopathies

CHRNA4 has been identified as the first gene underlying an idiopathic partial epilepsy syndrome in humans, ADNFLE (Steinlein et al., 1995, Steinlein et al., 1997b, Hirose et al., 1999, Phillips et al., 2000). The mutant receptor exhibited faster desensitization upon activation by acetylcholine and recovery from the desensitized state was much slower than in the wild type receptor suggesting that the reported mutations caused seizures via a diminution of the activity of the α4β2 neuronal

Perspectives of molecular study of epilepsy

Responsible genes for idiopathic epilepsy phenotypes so far reported all follow simple Menderian inheritance, but common phenotypes such as absence and generalized tonic–clonic convulsions do not. Multiple genes may be simultaneously involved and diversity of susceptible genes may collaborate in determining the risk of such common phenotypes of epilepsies. Although more epilepsy genes await discovery, the mode of inheritance of these phenotypes of epilepsy are not known. Therefore, the new

Conclusions

The discovery of dysfunction of ion channels in idiopathic epilepsies has led to the concept of channelopathies. At the same time, the genetic heterogeneity of epilepsies has also become apparent. Different genes and different mutations may cause the same epilepsy phenotype. Intrafamilial phenotypic heterogeneity is also clear. The expression of the mutated genes may differ among family members, causing clinical heterogeneity, or the gene may intervene in epileptogenesis at a very general

Acknowledgements

Our research was conducted as part of a comprehensive project organized by The Epilepsy Genetic Study Group, Japan (Chairperson, S.K.) and supported in part by Grants in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (09470206, 13035049, 12470174, 12559010, 14658263), The Epilepsy Research Foundation, Uehara Memorial Foundation, Heiwa Nakajima Foundation, Kobayashi Magobei Memorial Medical Foundation, Brain Science Foundation,

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