Genetic abnormalities underlying familial epilepsy syndromes

doi:10.1016/S0387-7604(02)00056-6

Brain and Development

Volume 24, Issue 4, June 2002, Pages 211-222

https://doi.org/10.1016/S0387-7604(02)00056-6 Get rights and content

Abstract

Genetic defects have been recently identified in certain inherited epilepsy syndromes in which the phenotypes are similar to common idiopathic 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. Both receptors are components of neuronal acetylcholine receptor, a ligand-gated ion channel in the brain. Furthermore, mutations of two K⁺-channel genes were also identified as the underlying genetic abnormalities of benign familial neonatal convulsions. Mutations in the voltage-gated Na⁺-channel α1, 2 and β1 and the gamma aminobutyric acid (GABA_A) receptor γ2 subunit genes were found as a cause of generalized epilepsy with febrile seizures plus, a clinical subset of febrile convulsions. Na⁺-channels, GABA_A receptor and their auxiliaries may be involved in the pathogenesis of this subtype and even in simple febrile convulsions. Mutation of a voltage-gated K⁺-channel gene can cause partial seizures associated with periodic ataxia type 1 and some forms of juvenile myoclonic epilepsy and idiopathic generalized epilepsy can result from mutations of a Ca²⁺-channel. This line of evidence suggests the involvement of channels expressed in the brain in the pathogenesis of certain types of epilepsy. Our working hypothesis is to view certain idiopathic epilepsies as disorders of ion channels, i.e. ‘channelopathies’. Such hypothesis should provide a new insight to our understanding of the genetic background of epilepsy.

Introduction

Familial epilepsy syndrome generally refers to epilepsies with identifiable inheritance but without neurodegenerative aspects such as mental retardation and cerebellar ataxia, which are often seen in progressive myoclonus epilepsy syndrome. Exploiting their inheritance with high penetrance, genetic defects have been recently identified in some familial epilepsies (Table 1). We provide in this review a detailed description of the genetic abnormalities identified in familial epilepsies. Only specific genes identified as causally related to familial epilepsies will be discussed, although loci for other familial epilepsies have been mapped to various chromosomal regions.

Section snippets

Autosomal dominant nocturnal frontal lobe epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was first reported in 1994 and has since been recognized as a new clinical entity of epilepsy. This partial epilepsy is characterized by clusters of a brief seizure during light sleep, and is often misdiagnosed as nightmare or parasomnia [1], [2]. The predominant seizure pattern has frontal lobe semiology with clusters of brief nocturnal motor attacks occurring during non-rapid eye movement (NREM) sleep. Onset usually occurs in

Benign familial neonatal convulsions

Benign familial neonatal convulsions (BFNC) is monogenic epilepsy inherited via an autosomal dominant trait with high penetrance and characterized by clusters of generalized and partial seizures afflicting exclusively, if any, neonates, and remits spontaneously. Thus, in most affected cases, seizures develop 2–3 days after birth. BFNC is classified as idiopathic generalized epilepsy according to International league against epilepsy (ILAE) classification [21]. Seizure types are

Generalized epilepsy with febrile seizures plus (GEFS+)

Febrile seizures (FS) are the most common provoked seizures afflicting infants and young children. No specific gene responsible for simple FS has yet been identified but four loci have been reported for FS; FEB1 at chromosome 8q13–q21; FEB2, 19p; FEB3, 2q23–24; FEB4, 5q14–q15 [48], [49], [50], [51]. A small proportion of patients with FS develop afebrile seizures later in life. This clinical subset of FS includes a clinical entity referred to as generalized epilepsy with febrile seizures plus

Others

Other genetic abnormalities have been identified in individuals with epilepsy, albeit such epilepsies are often associated with a known syndrome or found in small pedigrees. A missense mutation in KCNA1, a voltage gated K⁺-channel gene, causes periodic ataxia type 1, EA1 (MIM 160120) and can sometimes lead to partial seizures [79]. This provides supporting evidence that not only KCNQ K⁺-channels, which are involved in M-current formation, but also other K⁺-channels expressed in the brain may be

Conclusions

All identified causative genes of human familial epilepsy syndromes encode ion channels or their auxiliary subunits expressed in the brain. Although such familial epilepsies are distinguished from idiopathic epilepsy by dominant inheritance with high penetrance, the similarities in symptomatology between dominant disorders and certain types of idiopathic epilepsy syndromes suggest that at least some forms of idiopathic epilepsies as well as FS could be explained by defects in ion channels. Such

Electronic database information

Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/omim/.

Acknowledgments

We are indebted to our patients with epilepsy and their families for their helpful cooperation and encouragement in our research. We thank Ms Minako Yonetani and Miyuki Yamashita for their technical assistance, Ms Mayumi Sakai for preparation of the figures and Ms Yumiko Oka for typing and formatting the manuscript. 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 for Scientific

References (84)

I.E. Scheffer et al.
Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder
Lancet
(1994)
S.F. Berkovic et al.
Epilepsies with single gene inheritance
Brain Dev
(1997)
H.A. Phillips et al.
Autosomal dominant nocturnal frontal-lobe epilepsy: genetic heterogeneity and evidence for a second locus at 15q24
Am J Hum Genet
(1998)
S. Weiland et al.
An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics
FEBS Lett
(1996)
N. Matsushima et al.
Mutation (Ser284Leu) of neuronal nicotinic acetylcholine receptor α4 subunit associated with frontal lobe epilepsy causes faster desensitization of the rat receptor expressed in oocytes
Epilepsy Res
(2002)
H.A. Phillips et al.
CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy
Am J Hum Genet
(2001)
W.P. Yang et al.
Functional expression of two KvLQT1-related potassium channels responsible for an inherited idiopathic epilepsy
J Biol Chem
(1998)
M. Schwake et al.
Surface expression and single channel properties of KCNQ2/KCNQ3, M-type K⁺ channels involved in epilepsy
J Biol Chem
(2000)
B.C. Schroeder et al.
KCNQ5, a novel potassium channel broadly expressed in brain, mediates M-type currents
J Biol Chem
(2000)
C. Lerche et al.
Molecular cloning and functional expression of KCNQ5, a potassium channel subunit that may contribute to neuronal M-current diversity
J Biol Chem
(2000)

S. Baulac et al.

A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21–q33

Am J Hum Genet

(1999)

B. Moulard et al.

Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+) on chromosome 2q24–q33

Am J Hum Genet

(1999)

M. Ito et al.

Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (Na⁺)-channel α1 subunit gene, SCN1A

Epilepsy Res

(2002)

R.H. Wallace et al.

Neuronal sodium-channel α1-subunit mutations in generalized epilepsy with febrile seizures plus

Am J Hum Genet

(2001)

A. Escayg et al.

A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus-and prevalence of variants in patients with epilepsy

Am J Hum Genet

(2001)

A.L. Goldin et al.

Nomenclature of voltage-gated sodium channels

Neuron

(2000)

I. Lopes-Cendes et al.

A new locus for generalized epilepsy with febrile seizures plus maps to chromosome 2

Am J Hum Genet

(2000)

J.A. Kearney et al.

A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities

Neuroscience

(2001)

K. Ganguly et al.

GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition

Cell

(2001)

M. Lilly et al.

Developmental analysis of the smellblind mutants: evidence for the role of sodium channels in Drosophila development

Dev Biol

(1994)

A.R. Cantrell et al.

Muscarinic modulation of sodium current by activation of protein kinase C in rat hippocampal neurons

Neuron

(1996)

M. Fukuda et al.

The effect of GABAergic system activity on hyperthermia-induced seizures in rats

Brain Res Dev Brain Res

(1997)

M. Munakata et al.

Temperature-dependent effect of zolpidem on the GABA_A receptor-mediated response at recombinant human GABA_A receptor subtypes

Brain Res

(1998)

J.S. Rhee et al.

Developmental changes of GABA_A receptor-chloride channels in rat Meynert neurons

Brain Res

(1998)

A. Escayg et al.

Coding and noncoding variation of the human calcium-channel β₄-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia

Am J Hum Genet

(2000)

L. Claes et al.

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

Am J Hum Genet

(2001)

S. Hirose et al.

Are some idiopathic epilepsies disorders of ion channels?: A working hypothesis

Epilepsy Res

(2000)

I.E. Scheffer et al.

Autosomal dominant nocturnal frontal lobe epilepsy. A distinctive clinical disorder

Brain

(1995)

H.A. Phillips et al.

Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13.2

Nat Genet

(1995)

A. Gambardella et al.

A new locus for autosomal dominant nocturnal frontal lobe epilepsy maps to chromosome 1

Neurology

(2000)

O.K. Steinlein et al.

A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy

Nat Genet

(1995)

O.K. Steinlein et al.

An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy

Hum Mol Genet

(1997)

S. Hirose et al.

A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy

Neurology

(1999)

M. Ito et al.

Electroclinical picture of autosomal dominant nocturnal frontal lobe epilepsy in a Japanese family

Epilepsia

(2000)

A. Kuryatov et al.

Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca²⁺ permeability, conductance, and gating of human α4β2 nicotinic acetylcholine receptors

J Neurosci

(1997)

N. Unwin

Acetylcholine receptor channel imaged in the open state

Nature

(1995)

O.K. Steinlein

New insights into the molecular and genetic mechanisms underlying idiopathic epilepsies

Clin Genet

(1998)

M. De Fusco et al.

The nicotinic receptor β2 subunit is mutant in nocturnal frontal lobe epilepsy

Nat Genet

(2000)

L.M. Marubio et al.

Reduced antinociception in mice lacking neuronal nicotinic receptor subunits

Nature

(1999)

S.A. Forman et al.

Alternative mechanism for pathogenesis of an inherited epilepsy by a nicotinic AChR mutation

Nat Genet

(1996)

H.A. Phillips et al.

A de novo mutation in sporadic nocturnal frontal lobe epilepsy

Ann Neurol

(2000)

ILAE classification of epilepsies: its applicability and practical value of different diagnostic categories....

Cited by (45)

Application of induced pluripotent stem cells in epilepsy
2020, Molecular and Cellular Neuroscience
Citation Excerpt :
Genetic abnormalities, mainly dominant de novo mutations, are being rapidly identified for DEEs. > 80 genes are associated with DEEs (Hirose et al., 2000; Hirose et al., 2002a; Hirose et al., 2002b; Hirose et al., 2003; Hirose et al., 2005). It is suggested that when a genetic mutation with a major effect is identified, the term “DEE” may be replaced with the name of the underlying condition, such as CDKL5 encephalopathy or STXBP1 encephalopathy.
Epilepsy is among the most common neurological disorders, affecting approximately 50 million people worldwide. Importantly, epilepsy is genetically and etiologically heterogenous, but several epilepsy types exhibit similar clinical presentations. Epilepsy-associated genes are being identified. However, the molecular pathomechanisms remain largely unknown. Approximately one-third of epilepsy is refractory to multiple conventional anti-epileptic drugs (AEDs). Induced pluripotent stem cells (iPSCs) provide an excellent tool to study the pathomechanisms underlying epilepsy and to develop novel treatments. Indeed, disease-specific iPSCs have been established for several genetic epilepsies. In particular, the molecular mechanisms underlying certain developmental and epileptic encephalopathies, such as Dravet syndrome, have been revealed. Modeling epilepsy with iPSCs enables new drug development based on the elucidated pathomechanisms. This can also be used to evaluate conventional AEDs and drug repurposing. Furthermore, transplanting neuronal cells derived from iPSCs into the brain has great potential to treat refractory epilepsies. Recent advances in iPSC technology have enabled the generation of neuronal organoids, or “mini brains.” These organoids demonstrate electrophysiological activities similar to those of the brain and have the potential for extensive epilepsy research opportunities. Thus, the application of iPSCs in epilepsy provides insight into novel treatments based on the molecular pathomechanisms of epilepsy. In this review, we comprehensively discuss the studies conducted on iPSCs established for genetic epilepsy or epilepsies without major structural dysmorphic features.
Mutant GABA<inf>A</inf> receptor subunits in genetic (idiopathic) epilepsy
2014, Progress in Brain Research
Citation Excerpt :
Recent experiments on neurons derived from patient iPS cells have confirmed the pathomechanism in human neurons (Higurashi et al., 2013). Mutations of neural acetylcholine receptors cause autosomal dominant frontal epilepsy characterized by seizures occurring exclusively during sleep (Hirose et al., 1999, 2000, 2002a,b, 2003, 2005; Kurahashi and Hirose, 1993). A study on transgenic rats harboring one of these mutations revealed the impaired GABAergic inhibitory transmission was most evident during sleep and preceded the seizures during sleep (Zhu et al., 2008).
The γ-aminobutyric acid receptor type A (GABA_A receptor) is a ligand-gated chloride channel that mediates major inhibitory functions in the central nervous system. GABA_A receptors function mainly as pentamers containing α, β, and either γ or δ subunits. A number of antiepileptic drugs have agonistic effects on GABA_A receptors. Hence, dysfunctions of GABA_A receptors have been postulated to play important roles in the etiology of epilepsy. In fact, mutations or genetic variations of the genes encoding the α1, α6, β2, β3, γ2, or δ subunits (GABRA1, GABRA6, GABRB2, GABRB3, GABRG2, and GABRD, respectively) have been associated with human epilepsy, both with and without febrile seizures. Epilepsy resulting from mutations is commonly one of following, genetic (idiopathic) generalized epilepsy (e.g., juvenile myoclonic epilepsy), childhood absence epilepsy, genetic epilepsy with febrile seizures, or Dravet syndrome. Recently, mutations of GABRA1, GABRB2, and GABRB3 were associated with infantile spasms and Lennox–Gastaut syndrome. These mutations compromise hyperpolarization through GABA_A receptors, which is believed to cause seizures. Interestingly, most of the insufficiencies are not caused by receptor gating abnormalities, but by complex mechanisms, including endoplasmic reticulum (ER)-associated degradation, nonsense-mediated mRNA decay, intracellular trafficking defects, and ER stress. Thus, GABA_A receptor subunit mutations are now thought to participate in the pathomechanisms of epilepsy, and an improved understanding of these mutations should facilitate our understanding of epilepsy and the development of new therapies.
Computational models of epilepsy
2012, Seizure
Approximately 30% of epilepsy patients suffer from medically refractory epilepsy, in which seizures can not controlled by the use of anti-epileptic drugs (AEDs). Understanding the mechanisms underlying these forms of drug-resistant epileptic seizures and the development of alternative effective treatment strategies are fundamental challenges for modern epilepsy research. In this context, computational modeling has gained prominence as an important tool for tackling the complexity of the epileptic phenomenon. In this review article, we present a survey of computational models of epilepsy from the point of view that epilepsy is a dynamical brain disease that is primarily characterized by unprovoked spontaneous epileptic seizures.
We introduce key concepts from the mathematical theory of dynamical systems, such as multi-stability and bifurcations, and explain how these concepts aid in our understanding of the brain mechanisms involved in the emergence of epileptic seizures.
We present a literature survey of the different computational modeling approaches that are used in the study of epilepsy. Special emphasis is placed on highlighting the fine balance between the degree of model simplification and the extent of biological realism that modelers seek in order to address relevant questions. In this context, we discuss three specific examples from published literature, which exemplify different approaches used for developing computational models of epilepsy. We further explore the potential of recently developed optogenetics tools to provide novel avenue for seizure control.
We conclude with a discussion on the utility of computational models for the development of new epilepsy treatment protocols.
KCNQ2 abnormality in BECTS: Benign childhood epilepsy with centrotemporal spikes following benign neonatal seizures resulting from a mutation of KCNQ2
2012, Epilepsy Research
Citation Excerpt :
Interestingly, the majority of such genetic abnormalities were detected in genes encoding ion channels expressed in the brain (Hirose et al., 2000a, 2002). Benign familial neonatal convulsion (BFNC) is one such rare epilepsy syndrome, characterized by a cluster of seizures occurring during neonatal life but ceases spontaneously later in life, with obvious autosomal dominant inheritance (Hirose et al., 2000a, 2002). BFNC can result from mutations of either of two genes encoding subunits of K+ channel (Kv7.2 and Kv7.3), namely KCNQ2 and KCNQ3 (Charlier et al., 1998; Hirose et al., 2000b; Singh et al., 1998).
The molecular pathogenesis of benign childhood epilepsy with centrotemporal spikes (BECTS) remains unclear whereas mutations of the KCNQ2 and KCNQ3 genes have been identified as causes of benign familial neonatal convulsions. We report here a girl with benign neonatal convulsions followed by BECTS, for whom a mutation of KCNQ2 was identified. This case may provide the clue to the understanding of the molecular pathogenesis of BECTS.
Positive association between benign familial infantile convulsions and LGI4
2010, Brain and Development
Purpose: LGI4 is located in 19q13.11, where the locus of benign familial infantile convulsions (BFIC) has been mapped. LGI4 belongs to a family of proteins with the epilepsy-associated repeat (EAR) domain and is associated with various epilepsies. We investigated whether LGI4 is a candidate gene for BFIC. Methods: Fifteen patients with BFIC were examined for mutations and/or polymorphisms of LGI4 by using a direct sequencing method. Results: Several frequent polymorphisms were identified. The genotype frequency distribution of c.1722G/A polymorphism was significantly different between patients with BFIC and control subjects (p < 0.05). Logistic regression analysis showed that the G allele of c.1722G/A polymorphism had significant recessive effects on the increased relative risk for BFIC (p < 0.05). There was no association between c.1722G/A polymorphism and benign familial neonatal convulsion, an epilepsy phenotype similar to BFIC but genetically distinguished from BFIC. Discussion: The positive genotypic association between BFIC and c.1722G/A polymorphism suggests that LGI4 might contribute to the susceptibility to BFIC.
A de novo KCNQ2 mutation detected in non-familial benign neonatal convulsions
2009, Brain and Development
Background: The underlying genetic abnormalities of rare familial idiopathic epilepsy have been identified, such as mutation in KCNQ2, a K⁺ channel gene. Yet, few genetic abnormalities have been reported for commoner epilepsy, i.e., sporadic idiopathic epilepsy, which share a phenotype similar to those of familial epilepsy. Objective: To search for the genetic cause of seizures in a girl with the diagnosis of non-familial benign neonatal convulsions, and define the consequence of the genetic abnormality identified. Methods: Genetic abnormality was explored within candidate genes for benign familial neonatal and infantile convulsions, such as KCNQ2, 3, 5, KCNE2, SCN1A and SCN2A. The electrophysiological properties of the channels harboring the identified mutation were examined. Western blotting and immunostaining were employed to characterize the expression and intracellular localization of the mutant channel molecules. Results: A novel heterozygous mutation (c.910-2delTTC or TTT, Phe304del) of KCNQ2 was identified in the patient. The mutation was de novo verified by parentage analysis. The mutation was associated with impaired functions of KCNQ K⁺ channel. The mutant channels were expressed on the cell surface. Conclusion: The mutant Phe304del of KCNQ2 leads to null function of the KCNQ K⁺ channel but the mutation does not alter proper channel sorting onto the cell membrane. Our findings indicate that the genes responsible for rare inherited forms of idiopathic epilepsy could be also involved in sporadic forms of idiopathic epilepsy and expand our notion of the involvement of molecular mechanisms in the more common forms of idiopathic epilepsy.

View all citing articles on Scopus

View full text

Review articleGenetic abnormalities underlying familial epilepsy syndromes

Abstract

Introduction

Section snippets

Autosomal dominant nocturnal frontal lobe epilepsy

Benign familial neonatal convulsions

Generalized epilepsy with febrile seizures plus (GEFS+)

Others

Conclusions

Electronic database information

Acknowledgments

Lancet

Brain Dev

Am J Hum Genet

FEBS Lett

Epilepsy Res

Am J Hum Genet

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Am J Hum Genet

Am J Hum Genet

Epilepsy Res

Am J Hum Genet

Am J Hum Genet

Neuron

Am J Hum Genet

Neuroscience

Cell

Dev Biol

Neuron

Brain Res Dev Brain Res

Brain Res

Brain Res

Am J Hum Genet

Am J Hum Genet

Epilepsy Res

Autosomal dominant nocturnal frontal lobe epilepsy. A distinctive clinical disorder

Brain

Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13.2

Nat Genet

A new locus for autosomal dominant nocturnal frontal lobe epilepsy maps to chromosome 1

Neurology

A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy

Nat Genet

An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy

Hum Mol Genet

A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy

Neurology

Electroclinical picture of autosomal dominant nocturnal frontal lobe epilepsy in a Japanese family

Epilepsia

Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca2+ permeability, conductance, and gating of human α4β2 nicotinic acetylcholine receptors

J Neurosci

Acetylcholine receptor channel imaged in the open state

Nature

New insights into the molecular and genetic mechanisms underlying idiopathic epilepsies

Clin Genet

The nicotinic receptor β2 subunit is mutant in nocturnal frontal lobe epilepsy

Nat Genet

Reduced antinociception in mice lacking neuronal nicotinic receptor subunits

Nature

Alternative mechanism for pathogenesis of an inherited epilepsy by a nicotinic AChR mutation

Nat Genet

A de novo mutation in sporadic nocturnal frontal lobe epilepsy

Ann Neurol

Review article
Genetic abnormalities underlying familial epilepsy syndromes

Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca²⁺ permeability, conductance, and gating of human α4β2 nicotinic acetylcholine receptors