Progress in Mapping Human Epilepsy Genes

Summary: The chromosomal loci for seven epilepsy genes have been identified in chromosomes lq, 6p, 8q, 16p, 20q, 21q, and 22q. In 1987, the first epilepsy locus was mapped in a common benign idiopathic generalized epilepsy syndrome, juvenile myoclonic epilepsy (JME). Properdin factor or Bf, human leukocyte antigen (HLA), and DNA markers in the HLA-DQ region were genetically linked to JME and the locus, named EJM1 , was assigned to the short arm of chromosome 6. Our latest studies, as well as those by White-house et al., show that not all families with JME have their genetic locus in chromosome 6p, and that childhood absence epilepsy does not map to the same EJM1 locus. Recent results, therefore, favor genetic heterogeneity for JME and for the common idiopathic generalized epilepsies. Heterogeneity also exists in benign familial neonatal convulsions, a rare form of idiopathic generalized epilepsy. Two loci are now recognized; one in chromosome 20q (EBN1) and another in chromosome 8q. Heterogeneity also exists for the broad group of debilitating and often fatal progressive myoclonus epilepsies (PME). The gene locus (EPMI) for both the Baltic and Mediterranean types of PME or Unverricht-Lundborg disease is the same and is located in the long arm of chromosome 21. Lafora type of PME does not map to the same EPMI locus in chromosome 21. PME can be caused by the juvenile type of Gaucher's disease, which maps to chromosome lq, by the juvenile type of neuronal ceroid lipofuscinoses (CLN3), which maps to chromosome 16p, and by the "cherry-red-spot-myoclonus" syndrome of Guazzi or sialidosis type I, which has been localized to chromosome 10. A point mutation in the mitochondrial tRNA^Lys coding gene can also cause PME in children and adults (MERFF).     

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 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.     

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.     

Genetics of the Epilepsies

Summary: Recent molecular insights into the human idiopathic epilepsies have suggested the central role of ligand-gated and voltage-gated ion channels in their etiology. So far, genes coding for sodium and potassium channel subunits as well as a nicotinic cholinergic receptor subunit have been identified for mendelian idiopathic epilepsies. In vitro and in vivo studies of mutations demonstrate functional changes, allowing new insights into mechanisms underlying hyperexcitability. Similarly, spontaneous murine epilepsy models have been associated with calcium channel molecular defects. The major challenge before us in understanding the genetics of the epilepsies is to identify genes for common forms of epilepsy following complex inheritance. Once such genes are discovered, the gene–gene–environmental interactions producing specific epilepsy syndromes can be explored.     

Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy

Genetic predisposition plays a major role in the etiology of idiopathic epilepsies. The common epilepsy syndromes display a complex pattern of inheritance, with an unknown number of genes contributing to seizure susceptibility. During the last decade linkage studies have narrowed down several candidate regions for susceptibility loci of idiopathic epilepsies. Several lines of evidence point to the existence of an epilepsy susceptibility gene on chromosome 15q14. Evidence for linkage to this region has thus been reported for juvenile myoclonic epilepsy, common subtypes of idiopathic generalized epilepsy (IGE), in addition to the EEG trait 'centrotemporal spikes' in families with rolandic epilepsy. The chromosomal region 15q14 harbours several candidate genes that are involved in the regulation of neuronal excitability. One of the most promising candidate genes is the brain-expressed potassium chloride cotransporter KCC3, given that this class of ion transporter has been implicated in the regulation of neuronal chloride activity. We therefore performed a mutation analysis of KCC3 in the index patients of 23 IGE-families as well as of 16 families with rolandic epilepsy which where selected by positive evidence for linkage to D15S165. Four novel single nucleotide exchanges (SNPs) were identified, none of which change the coding sequence. These results do not support a major role for KCC3 in the etiology of rolandic epilepsy or common subtypes of IGE.     

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.     

Genetics of the epilepsies

PURPOSE OF REVIEW: This article reviews the most significant advances in the field of genetics of the epilepsies during the past year, with emphasis on newly identified genes and functional studies leading to new insights into the pathophysiology of epilepsy. RECENT FINDINGS: Mutations in the chloride channel gene CLCN2 have been associated with the most common forms of idiopathic generalized epilepsies. A mutation in the ATP1A2 sodium potassium ATPase pump gene has been described in a family in which familial hemiplegic migraine and benign familial infantile convulsions partly co-segregate. The leucine-rich, glioma-inactivated 1 gene (LGI1) (also known as epitempin) was found to be responsible for autosomal-dominant lateral temporal lobe epilepsy in additional families. The serine-threonine kinase 9 gene (STK9) was identified as the second gene associated with X-linked infantile spasms. Mutations in the Aristaless-related homeobox gene (ARX) have been recognized as a cause of X-linked infantile spasms and sporadic cryptogenic infantile spasms. A second gene underlying progressive myoclonus epilepsy of Lafora, NHLRC1, was shown to code for a putative E3 ubiquitin ligase. SUMMARY: Genes associated with idiopathic generalized epilepsies remain within the ion channel family. Mutations in non-ion channel genes are responsible for autosomal-dominant lateral temporal lobe epilepsy, a form of idiopathic focal epilepsy, malformations of cortical development, and syndromes that combine X-linked mental retardation and epilepsy. Most genetic epilepsies have a complex mode of inheritance, and genes identified so far account only for a minority of families and sporadic cases. Functional studies are leading to a better understanding of the mechanisms underlying hyperexcitability and seizures.     

Sunday July 2, 20067:30 – 9:00Hall 5BTeaching SessionEpilepsy and genetics

¹ O. Steinlein (   ¹ Institute of Human Genetics, University of Munich, Germany )
The term epilepsy describes a heterogeneous group of disorders, with a lifetime cumulative incidence of 3%. In the majority of epilepsies genes are a minor if not even the only etiological factor. There is a large subgroup of epilepsies that are suspected or proofed to be mainly genetic in origin. This group of epilepsies has been named idiopathic, and during the last decade several genes have already been identified for various idiopathic epilepsies. On the other hand there is a large group of epilepsies and disorders with epilepsy that have been termed "symptomatic" because they are due to known metabolic, neurodegenerative or structural brain damage. Many of these disorders have by now shown to be caused by clearly defined genetic factors. Seizures and myoclonus are common to many neurodegenerative and metabolic disorders, but are also a major feature in patients with structural chromosomal arrangements or neuronal migration disorders. In this talk exemplary members of both groups will be discussed to illustrate principal etiological categories of the disorder "epilepsy" and trace the various genetic pathways to epileptogenesis.     

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.     

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.     

Genetics of the epilepsies

Molecular genetic analysis of mendelian epilepsies in humans and mice has revealed a diversity of underlying genes in symptomatic epilepsies associated with disordered brain development and neuronal survival. In contrast, the idiopathic mendelian epilepsies have emerged as a new category of channelopathies. New epilepsy loci have been mapped and one new epilepsy gene isolated. Functional analysis of epilepsy genes is providing new insights into the pathways that lead from mutant gene to hyperexcitable neurones. The major challenge for the future is the analysis of genetic epilepsies with complex inheritance.     

Gene defects in idiopathic epilepsy.

Idiopathic epilepsies are mainly due to genetic factors. In most cases the mode of inheritance is either oligogenic or multifactorial. Only a few rare idiopathic epilepsies are single gene disorders. Monogenic epilepsies offer the chance to identify genes/gene families which might also be involved in the aetiology of common forms of the disease. The genetic basis of two monogenic epilepsies have recently been identified: autosomal dominant nocturnal frontal lobe epilepsy and benign familial neonatal convulsions.     

The unexpected role of copy number variations in juvenile myoclonic epilepsy

Structural genomic variants or copy number variants (CNVs) comprise submicroscopic deletions and duplications of chromosomal material, including both rearrangements at genomic hotspots as well as duplications and deletions with unique breakpoints. Copy number variants have increasingly been recognized in the Idiopathic/Genetic Generalized Epilepsies (IGE/GGE) including juvenile myoclonic epilepsy (JME). Microdeletions at 15q13.3, 15q11.2, and 16p13.11 are genetic risk factors that can be identified in 3% of patients with IGE including JME. These microdeletions, however, also represent genetic risk factors to a broad range of other neurodevelopmental disorders. Additionally, 6% of patients with GGE carry other, potentially pathogenic structural genomic variants. While family studies largely support the channelopathy concept of the idiopathic epilepsies, the results of studies investigating copy number variations suggest that JME genetically overlaps with a broad range of other neurodevelopmental disorders. In addition, the particular genetic properties of structural genomic variations as rare genetic variants highlight the complexity of the genetic architecture of human disease.This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?     

Recent Developments in the Quest for Myoclonic Epilepsy Genes

Summary:   Understanding the latest advances in the molecular genetics of the epilepsies is important, as it provides a basis for comprehending the new practice of epileptology. Epilepsies have traditionally been classified and subtyped on the basis of clinical and neurophysiologic concepts. However, the complexity and variability of phenotypes and overlapping clinical features limit the resolution of phenotype-based classification and confound epilepsy nosology. Identification of tightly linked epilepsy DNA markers and discovery of epilepsy-causing mutations provide a basis for refining the classification of epilepsies. Recent discoveries regarding the genetics surrounding certain epilepsy types (including Lafora's progressive myoclonic epilepsy, the severe myoclonic epilepsy of infancy of Dravet, and idiopathic generalized epilepsies) may be the beginning of a better understanding of how rare Mendelian epilepsy genes and their genetic architecture can explain some complexities of the common 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.     

The state of the art in the genetic analysis of the epilepsies

Genetic influences as causal factors in the epilepsies continue to be vigorously investigated, and we review several important studies of genes reported in 2006. To date, mutations in ion channel and neuroreceptor component genes have been reported in the small fraction of cases with clear Mendelian inheritance. These findings confirm that the so-called “channelopathies” are generally inherited as monogenic disorders. At the same time, the literature in common epilepsies abounds with reports of associations and reports of nonreplication of those association studies, primarily with channel genes. These contradictory reports can mostly be explained by confounding factors unique to genetic studies. The methodology of genetic studies and their common biases and confounding factors are also explained in this review. Amid the controversy, steady progress is being made on the epilepsies of complex inheritance, which represent the most common idiopathic epilepsy. Recent discoveries show that genes influencing the developmental assembly of neural circuits and neuronal metabolism may play a more prominent role in the common epilepsies than genes affecting membrane excitability and synaptic transmission.     

Different electroclinical picture of generalized epilepsy in two families with 15q13.3 microdeletion

15q.13.3 microdeletion has been described in a variety of neurodevelopmental disorders. Epilepsy appears to be a common feature and, specifically, the 15q13.3 microdeletion is found in about 1% of patients with idiopathic generalized epilepsy. Recently, absence seizures with intellectual disability (ID) have been reported in patients carrying this mutation. We describe two families in which several affected members carry a 15q13.3 microdeletion in a pattern suggestive of autosomal dominant inheritance. Their phenotype includes mainly absence epilepsy and mild ID, suggesting only similarities with genetic/idiopathic generalized epilepsies but not typical features. The importance of studying such families is crucial to broaden the phenotype and understand the long‐term outcome of patients with this condition.     

Genetic dissection of the common epilepsies

PURPOSE OF REVIEW: Only two functionally validated susceptibility genes, CACNA1H and GABRD, have so far been identified in the common epilepsies using a candidate gene approach. The difficulty with the alternative statistical approach, where none of the suggested candidates has been functionally validated, may partly be due to the posited genetic architecture of the common epilepsies, such as the idiopathic generalized epilepsies. A subset of both rare and common variants from a much larger pool of susceptibility genes may contribute to disease risk. We review methods and designs for the genetic dissection of common epilepsies. RECENT FINDINGS: Genetic association studies, though theoretically more powerful than linkage analysis, have not yet delivered validated susceptibility genes. Methodological flaws can undermine such studies but are correctable. Concerns remain, however, about the extent of underlying genetic heterogeneity in common epilepsies. Genome-wide association studies are increasingly feasible, but issues remain about their conduct and analysis. Meta-analysis may resolve conflicting association studies, facilitated by the establishment of databases of genetic association studies. Newer multi-locus and admixture mapping approaches are attractive alternatives to traditional association studies and may offer new insights into identifying epilepsy genes. SUMMARY: We conclude by emphasizing the importance of deeper endophenotyping using electroclinical, imaging, and molecular approaches to dissect the common epilepsies.