Genetic approach to the pathogeneses of epilepsy]

Recently, genetic causes have been identified in certain epilepsy syndromes in which the phenotypes are similar to common idiopathic epilepsies. Interestingly, almost all such genetic abnormalities were detected in genes encoding ion channels expressed in the brain. Thus such epilepsy syndromes are disorders of ion channels, i.e., "channelopathies". The list of ion channel abnormalities that are associated with childhood epilepsy is expanding and includes the followings. Mutations of the genes encoding two subunits of the neuronal nicotinic acetylcholine receptor, a ligand-gated ion channel, were found in autosomal dominant nocturnal frontal lobe epilepsy. Mutations of two KCNQ K+-channel genes were identified in benign familial neonatal convulsions. Mutations of the genes encoding several subunits of the voltage-gated Na+-channel and GABA(A) receptor, a ligand-gated ion channel, were also identified as underlying causes of various epilepsy syndromes, such as autosomal dominant epilepsy with febrile seizures plus or generalized epilepsy with febrile seizures plus, benign familial neonatal infantile seizures and autosomal dominant juvenile myoclonic epilepsy. Mutations within the same gene can result in different epilepsy phenotypes. Abnormalities of Na+-channel alpha1 subunit were also associated with severe myoclonic epilepsy in infancy. Epilepsy syndromes mentioned above, except for severe myoclonic epilepsy in infancy, were familial epilepsy syndromes showing dominant inheritance with high penetrance while common idiopathic epilepsies do not show obvious inheritance. However, the similarities in symptomatology between such familial epilepsies and common idiopathic epilepsy may provide us with clues to the genetics of common idiopathic epilepsies.     

Genetic mechanisms in idiopathic epilepsies

Idiopathic epilepsies are considered to be genetically determined. The inheritance can be monogenic and the detected mutation considered sufficient to cause the phenotype. In contrast, when the inheritance is complex, the epileptic phenotype is determined by several minor genetic defects that are much more difficult to discover. In recent years, an increasing number of mutations, mainly associated with rare monogenic idiopathic epilepsy syndromes, have been identified in genes encoding subunits of voltage- or ligand-gated ion channels. A few mutations have also been found in the frequent classical forms of idiopathic generalized epilepsies which are thought to follow a complex genetic trait, for example, in absence or juvenile myoclonic epilepsies. Functional studies characterizing the molecular defects of the mutant channels point to an important role of GABAergic synaptic inhibition in the pathophysiology of idiopathic epilepsies. As a result of genetic and functional investigations, not only will the pathophysiology of epilepsy be better understood, but newly discovered genes and pathophysiological pathways may also determine novel targets for pharmacotherapy, as has been shown for the anticonvulsant drug retigabine, which enhances the activity of neuronal KCNQ potassium channels.     

KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy

In 1998, the discovery of two novel genes KCNQ2 and KCNQ3, mutated in a rare inherited form of epilepsy known as benign familial neonatal convulsions, for the first time enabled insight into the molecular etiology of a human idiopathic generalized epilepsy syndrome. These disease genes encode subunits of neuronal M-type K+ channels, key regulators of brain excitability. Analogies between benign familial neonatal convulsions and other channelopathies of skeletal and cardiac muscle, including periodic paralysis, myotonia and the long QT syndrome, provide clues about the nature of epilepsy-susceptibility genes and about the fundamental basis of epilepsy as an episodic disorder. It now appears that the KCNQ2/KCNQ3 K+ channels that are mutated in benign familial neonatal convulsions represent an important new target for anti-epileptic drugs. In the future, the identification of ion channel defects as predisposing factors in the common epilepsies could herald a new era of genotype-specific therapies.     

Ion channels and the genetic contribution to epilepsy

Recent application of genetic analysis to rare, hereditary epilepsies has resulted in the identification of mutations in genes encoding ion channels or functionally related proteins in several human and animal syndromes. Reviewed here are selected human and murine epilepsies that result from ion channel mutations. In humans, three autosomal-dominant disorders--benign familial neonatal convulsions, nocturnal frontal lobe epilepsy, and "generalized epilepsy with febrile seizures plus"--result from mutations affecting voltage-sensitive potassium channels, a central nicotinic acetylcholine receptor, and a voltage-sensitive sodium channel, respectively. In mice, four genetically distinct, autosomal-recessive models of absence epilepsy are caused by mutations in genes encoding three types of calcium channel subunits and a sodium-hydrogen ion exchanger. These findings suggest that variation in genes encoding ion channels could determine susceptibility to common human epilepsies.     

Channelopathies in idiopathic epilepsy

Approximately 70% of all patients with epilepsy lack an obvious extraneous cause and are presumed to have a predominantly genetic basis. Both familial and de novo mutations in neuronal voltage-gated and ligand-gated ion channel subunit genes have been identificd in autosomal dominant epilepsies. However, patients with dominant familial mutations are rare and the majority of idiopathic epilepsy is likely to be the result of polygenic susceptibility alleles (complex epilepsy). Data on the identity of the genes involved in complex epilepsy is currently sparse but again points to neuronal ion channels. The number of genes and gene families associated with epilepsy is rapidly increasing and this increase is likely to escalate over the coming years with advances in mutation detection technologics. The genetic heterogeneity underlying idiopathic epilepsy presents challenges for the rational selection of therapics targeting particular ion channels. Too little is currently known about the genetic architecture of the epilepsies, and genetic testing for the known epilepsy genes remains costly. Pharmacogenetic studies have yet to explain why 30% of patients do not respond to the usual anticpileptic drugs. Despite this, the recognition that the idiopathic epilepsies are a group of channelopathies has, to a limited extent, explained the therapeutic action of the common anticpileptic drugs and has assisted clinical diagnosis of some epilepsy syndromes.     

Characterization of a 6p21 translocation breakpoint in a family with idiopathic generalized epilepsy

The idiopathic generalized epilepsies (IGE), for which a genetic cause is widely accepted, account for 20-30% of all epilepsies. Mapping these epilepsies is difficult, but progress in the positional cloning of idiopathic epilepsy genes responsible for monogenic forms provide emerging evidence that many idiopathic epilepsies are caused by mutations in genes coding for ion channels. Here, we show the characterization of a balanced translocation present in three members of a nuclear family, two of them affected with IGE. The translocation involved chromosome 6p21 [t(4;6) (q35;p21)], a region in which a susceptibility locus for IGE (EJM1) has been reported. Fluorescence in situ hybridization analysis with YACs and PACs resulted in the identification of a PAC clone that included the 6p21 translocation breakpoint. The genomic sequence of this PAC clone contains two 2-pore potassium channel genes, TALK-1 and TALK-2. We characterized the genomic organization of both genes, including three different isoforms of TALK-1, and investigated them in IGE patients, finding some polymorphisms in the coding sequence of TALK-1A.     

Impact of our understanding of the genetic aetiology of epilepsy

A genetic contribution to aetiology is estimated to be present in up to 40% of patients with epilepsy. It is useful to categorise genetic epilepsies according to the mechanisms of inheritance into Mendelian disorders, non-mendelian or ‘complex’ disorders, and chromosomal disorders. Over 200 Mendelian diseases include epilepsy as part of the phenotype, and the genes for a number of these have been identified recently. These include autosomal recessive progressive myoclonic epilepsies such as Unverricht-Lundborg disease, Lafora disease and the neuronal ceroid lipofuscinoses, and three autosomal dominant idiopathic epilepsies. The last named have been shown to arise from mutations in ion channel genes. Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in CHRNA4, benign familial neonatal convulsions by mutations in KCNQ2 and KCNQ3, and generalised epilepsy with febrile seizures plus by mutations in SCN1B. ‘Complex’, familial epilepsies are more difficult to analyse, but evidence has been obtained for loci predisposing to juvenile myoclonic epilepsy on chromosome 6p and 15q. Lastly, the genes underlying several spike-wave epilepsies in mice have been cloned, and three of these encode sub-units of voltage-gated calcium channels. Received: 29 September 1999/Accepted: 7 December 1999     

Genetic basis of the human epilepsies.

Genetic factors contribute to aetiology in up to 40% of patients with epilepsy. Over 100 single gene Mendelian disorders include epilepsy as one component of what is usually a complex neurological phenotype, but the majority of idiopathic or primary epilepsies display a 'complex' non-Mendelian pattern of inheritance. There have been significant recent advances in understanding the genetic basis of inherited epilepsies at a molecular level. Epilepsy genes fall into several distinct categories including those in which mutations cause abnormal brain development, progressive neurodegeneration, disturbed energy metabolism and abnormal function of ion channels. Ion channel genes involved include those encoding neuronal nicotinic acetylcholine receptor subunits and voltage-gated potassium and sodium channels.     

Genetic background of epilepsies

In this article we review epilepsies with monogenic inheritance. Most of these diseases are caused by abnormal function of ligand- and voltage gated ion channels caused by a genetic defect, therefore belonging to the channelopathies. From the inherited epilepsies the genetics of the autosomal dominant partial epilepsies is clarified the best. Mutations of the nicotinic acetylcholine receptor subunits are found in familial nocturnal frontal lobe epilepsy, while defects in the voltage gated potassium channels (KCNQ2 and KCNQ3) have been identified in benign familial neonatal convulsions. Familial temporolateral epilepsy was associated with mutations of a tumor suppressor gene. From the generalized epilepsies, the syndrome of generalized epilepsy with febrile seizures plus (GEFS+) can be caused by mutations of the sodium channel subunits and of the GABAA receptor subunits. These important results would probably lead to new findings in the genetics of the more common forms of idiopathic generalized epilepsies, which have presumed polygenic origin. Although without definite conclusions, sodium channel and GABA receptor dysfunction is presumed. The accumulated knowledge about channelopathies enables insight to the cellular mechanism of epileptogenesis as well.     

Advances in Epilepsy Genetics and Genomics

Current and emerging technologies for mutation identification are changing the landscape of genetics and accelerating the pace of discovery. Application of high throughput genomic analysis to epilepsy will advance our understanding of the genetic contribution to common forms of epilepsy and suggest novel therapeutic strategies for improved treatment.Epilepsy is a common neurological disease that exhibits a high degree of heritability based on familial aggregation and twin studies (1–6). It is estimated that there is an underlying genetic predisposition for epilepsy in approximately half of individuals, with monogenic epilepsies accounting for less than 1 percent. The vast majority of genetic generalized epilepsies (GGE) and nonacquired focal epilepsies (NAFE) have a strong genetic basis with a complex inheritance pattern in which multiple genetic and environmental factors contribute to epilepsy risk (6–8). Considerable progress has been made in the last 15 years in identifying genes that contribute to monogenic forms of epilepsy. The genes identified are components of neuronal signaling, including voltage-gated ion channels, neurotransmitter receptors, ion channel–associated proteins and synaptic proteins (7, 9, 10). These genes have provided useful insights into the molecular basis of epileptogenesis. However, population-based studies in more common forms of epilepsy have not identified significant risk associated with those monogenic epilepsy genes. Thus, it is likely that there are many more epilepsy genes yet to be discovered. Identification of genes for more common forms of epilepsy will likely come from unbiased genome-wide surveys in large study populations.     

Potassium Channels: How Genetic Studies of Epileptic Syndromes Open Paths to New Therapeutic Targets and Drugs

Summary: How can epilepsy gene hunting lead to better care for patients with epilepsy? Lessons may be learned from the progress made by identifying the mutated genes that cause Benign Familial Neonatal Convulsions (BFNC). In 1998, a decade of clinical and laboratory-based genetics work resulted in the cloning of the KCNQ2 potassium channel gene at the BFNC locus on chromosome 20. Subsequently, computer "mining" of public DNA databases allowed the rapid identification of three more brain KCNQ genes. Mutations in each of these additional genes were implicated as causes of human hereditary diseases: epilepsy (KCNQ3), deafness (KCNQ4), and, possibily, retinal degeneration (KCNQ5). Physiologists discovered that the KCNQ genes encoded subunits of the "M-channel," a type of potassium channel known to control repetitive neuronal discharges. Finally, pharmacologists discovered that retigabine, a novel anticonvulsant with a broad but distinctive efficacy profile in animal studies, was a potent KCNQ channel opener. These studies suggest that KCNQ channels may be an important new class of targets for anticonvulsant therapies. The efficacy of retigabine is currently being tested in multicenter clinical trials; identification of its molecular targets will allow it to be more efficiently exploited as a "lead compound." Cloned human KCNQ channels can now be expressed in cultured cells for "high-throughput" screening of drug candidates. Ongoing studies of the KCNQ channels in humans and animal models will refine our understanding of how M-channels control excitability at the cellular, network, and behavioral levels, and may reveal additional targets for therapeutic manipulation.     

Genetic polymorphisms and idiopathic generalized epilepsies

In recent years, progress in understanding the genetic basis of idiopathic generalized epilepsies has proven challenging because of their complex inheritance patterns and genetic heterogeneity. Genetic polymorphisms offer a convenient avenue for a better understanding of the genetic basis of idiopathic generalized epilepsy by providing evidence for the involvement of a given gene in these disorders, and by clarifying its pathogenetic mechanisms. Many of these genes encode for some important central nervous system ion channels (KCNJ10, KCNJ3, KCNQ2/KCNQ3, CLCN2, GABRG2, GABRA1, SCN1B, and SCN1A), while many others encode for ubiquitary enzymes that play crucial roles in various metabolic pathways (HP, ACP1, ME2, LGI4, OPRM1, GRIK1, BRD2, EFHC1, and EFHC2). We review the main genetic polymorphisms reported in idiopathic generalized epilepsy, and discusses their possible functional significance in the pathogenesis of seizures.     

离子通道变异与癫痫病

离子通道是神经系统和其它可兴奋组织(肌肉和腺体)产生兴奋和行使功能活动的核心基本物质之一。因编码离子通道基因的突变所导致的各类先天性疾病被称之为通道病因学。临床上常见的先天性癫痫综合征多属于通道病。先天性癫痫占癫痫人群的40％，常见的有以下几种：由N型乙酰胆碱受体CHRNA4或CHRNB亚基突变所致的常染色体显性夜间额叶癫痫：因电压门控钾通道KCNQ2和KCNQ3缺陷所致的良性家族性新生儿惊厥；因电压门控钠通道SCN1B．SCN1A和SCN2A亚基以及GABA受体GABRG2亚基突变诱发的高热抽搐全身型癫痫叠加综合征：南电压门控氯通道(C1C2突变)和GABAA受体或亚基突变所致的几种特发性全身性癫痫：此外，近来还发现了与电压门控钾通道KCNA1有关的另一种与1型共济失调伴发的局限性癫痫。研究分析先天性癫痫家系基因遗传谱及其突变通道的电生理特性，有利于更深入地认识和了解先天性癫痫的通道突变发病机制．制定新的抗癫痫策略，开发针对性抗癫痫新药。本文将对先天性癫痫的通道病因学研究进展作一简要梳理。     

Genetics of Idiopathic Generalized Epilepsies

Summary:  The idiopathic generalized epilepsies (IGEs) are considered to be primarily genetic in origin. They encompass a number of rare mendelian or monogenic epilepsies and more common forms which are familial but manifest as complex, non-mendelian traits. Recent advances have demonstrated that many monogenic IGEs are ion channelopathies. These include benign familial neonatal convulsions due to mutations in KCNQ2 or KCNQ3 , generalized epilepsy with febrile seizures plus due to mutations in SCN1A , SCN2A , SCN1B , and GABRG2 , autosomal-dominant juvenile myoclonic epilepsy (JME) due to a mutation in GABRA1 and mutations in CLCN2 associated with several IGE sub-types. There has also been progress in understanding the non-mendelian IGEs. A haplotype in the Malic Enzyme 2 gene, ME2 , increases the risk for IGE in the homozygous state. Five missense mutations have been identified in EFHC1 in 6 of 44 families with JME. Rare sequence variants have been identified in CACNA1H in sporadic patients with childhood absence epilepsy in the Chinese Han population. These advances should lead to new approaches to diagnosis and treatment.     

M-channels: neurological diseases,neuromodulation, and drug development

Efforts in basic neuroscience and studies of rare hereditary neurological diseases are partly motivated by the hope that such work can lead to better understanding of and treatments for the common neurological disorders. An example is the progress that has resulted from identification of the genes that cause benign familial neonatal convulsions (BFNCs). Benign familial neonatal convulsions is a rare idiopathic, generalized epilepsy syndrome. In 1998, geneticists discovered that BFNC is caused by mutations in a novel potassium channel subunit, KCNQ2. Further work quickly revealed the sequences of 3 related brain channel genes KCNQ3, KCNQ4, and KCNQ5. Mutations in 2 of these genes were shown to cause BFNC (KCNQ3) and hereditary deafness (KCNQ4). Physiologists soon discovered that the KCNQ genes encoded subunits of the M-channel, a widely expressed potassium channel that mediates effects of modulatory neurotransmitters and controls repetitive neuronal discharges. Finally, pharmacologists discovered that the biological activities of 3 classes of compounds in development as treatments for Alzheimer disease, epilepsy, and stroke were mediated in part by effects on brain KCNQ channels. Cloned human KCNQ channels can now be used for high-throughput screening of additional drug candidates. Ongoing studies in humans and animal models will refine our understanding of KCNQ channel function and may reveal additional targets for therapeutic manipulation.     

No evidence for association between the KCNQ3 gene and susceptibility to idiopathic generalized epilepsy

Idiopathic generalized epilepsy (IGE) comprises a heterogeneous group of disorders, in which a high genetic predisposition and a complex mode of inheritance have been suggested. Recent identification of ion channel gene mutations in Mendelian epileptic disorders suggests genetically driven neuronal hyperexcitability as one important factor in epileptogenesis. Mutations in two neuronal voltage-gated potassium channel genes (KCNQ2 and KCNQ3) have already been shown to cause epilepsy (BFNC), and we now tested the hypothesis that genetic variation in the KCNQ3 gene confers liability to common IGE subtypes. Length variation of two intragenic polymorphic markers (D8S558 and D8S1835) were therefore assessed in 71 nuclear families ascertained for an affected child. However, the transmission-disequilibrium-test did not show significant differences between the transmitted and non-transmitted parental alleles. Thus, our findings do not provide evidence that genetic variation in the KCNQ3 gene exerts a relevant effect in the etiology of common IGE subtypes.     

Monogenic idiopathic epilepsies

Major advances have recently been made in our understanding of the genetic bases of monogenic inherited epilepsies. Direct molecular diagnosis is now possible in numerous inherited symptomatic epilepsies. Progress has also been spectacular with respect to several idiopathic epilepsies that are caused by mutations in genes encoding subunits of ion channels or neurotransmitter receptors. Although these findings concern only a few families and sporadic cases, their potential importance is great, because these genes are implicated in a wide range of more common epileptic disorders and seizure types as well as some rare syndromes. Functional studies of these mutations, while leading to further progress in the neurobiology of the epilepsies, will help to refine genotype-phenotype relations and increase our understanding of responses to antiepileptic drugs. In this article, we review the clinical and genetic data on most of the idiopathic human epilepsies and epileptic contexts in which the association of epilepsy and febrile convulsions is genetically determined.     

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

Epilepsy is a common neurological disease and encompasses a variety of disorders with paroxysms. Although there is a genetic component in the pathogenesis of epilepsy, the molecular mechanisms of this syndrome remains poorly understood. Linkage analysis and positional cloning have not been sufficient tools for determining the pathogenic mechanisms of common idiopathic epilepsies, and hence, novel approaches, based on the etiology of epilepsy, are necessary. Recently, many paroxysmal disorders, including, epilepsy, have been considered to be due to ion channel abnormalities or channelopathies. Results of recent studies employing gene analysis in animal models of epilepsy and human familial epilepsies support the hypothesis that at least some of the so called idiopathic epilepsies, i.e. epilepsies currently, classified as idiopathic could be considered as a channelopathy. This hypothesis is consistent with the putative prerequisites for genes responsible for the majority of idiopathic epilepsies that can adequately explain the following characteristics of epilepsy. Neuronal hyperexcitability, dominant inheritance with various penetrance, pharmacological role of some conventional antiepileptic drugs, age dependency in the onset of epilepsy, and the involvement of genetic factors in the pathogenesis of post-traumatic epilepsy. Search for mutations in ion channels expressed in the central nervous system may help in finding defects underlying some of idiopathic epilepsies, thereby enhancing, our understanding of the molecular pathogenesis of epilepsy. A working hypothesis to view certain idiopathic epilepsies as disorders of ion channels should provide a new insight to our understanding of epilepsy and allow the design of novel therapies.     

Advances in the pathophysiology of developmental epilepsies

Pediatric epilepsies display unique characteristics that differ significantly from epilepsy in adults. The immature brain exhibits a decreased seizure threshold and an age-specific response to seizure-induced brain injury. Many idiopathic epilepsy syndromes and symptomatic epilepsies commonly present during childhood. This review highlights recent advances in the pathophysiology of developmental epilepsies. Cortical development involves maturational regulation of multiple cellular and molecular processes, such as neurogenesis, neuronal migration, synaptogenesis, and expression of neurotransmitter receptors and ion channels. These normal developmental changes of the immature brain also contribute to the increased risk for seizures and unique responses to seizure-induced brain injury in pediatric epilepsies. Recent technological advances, especially in genetics and imaging, have yielded exciting discoveries about the pathophysiology of specific pediatric epilepsy syndromes, such as the emergence of channelopathies as the cause of many idiopathic epilepsies and identification of malformations of cortical development as a major source of symptomatic epilepsies in children.     

Sodium and potassium channel dysfunctions in rare and common idiopathic epilepsy syndromes

Mutations in the SCN1A gene are found in up to 80% of individuals with severe myoclonic epilepsy of infancy (SMEI), and mutations in KCNQ2 and KCNQ3 were identified in benign familial neonatal convulsions (BFNC) as well as in single families with Rolandic epilepsy (RE) and idiopathic generalized epilepsies (IGE). This paper summarizes recent findings concerning sodium (SCN1A) and potassium channel (KCNQ2 and KCNQ3) dysfunctions in the pathogenesis of rare and common idiopathic epilepsies (IE). SMEI, severe idiopathic generalized epilepsy of infancy (SIGEI), and myoclonic–astatic epilepsy (MAE) are rare IE. Because of some semeiologic overlap, a comparative analysis of the SCN1A gene performed in 20 patients with MAE and in 18 with SIGEI. This revealed mutations in three subjects with SIGEI only. Since BFNC are over-represented in families with RE, a mutational analysis was performed in 58 families with RE with and without BNFC. This revealed functionally relevant mutations in two index cases with BNFC, and three missense mutations (one resulting in a significantly reduced potassium current amplitude) in three patients with RE, but without BNFC. One KCNQ3 missense variant was also detected in eight out of 455 IGE patients but not in 454 controls, and a silent KCNQ2-SNP was found over-represented in both epilepsy samples. These findings confirm that mutations in the SCN1A gene are mainly involved in the pathogenesis of SMEI, rarely in that of SIGEI, and are commonly not found in patients with MAE. They also demonstrate that sequence variations of the KCNQ2 and KCNQ3 genes may contribute to the etiology of common IE syndromes.