Primer Part 1—The building blocks of epilepsy genetics

This is the first of a two‐part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy. In Part 1, we cover the foundations of epilepsy genetics including genetic epidemiology and the range of genetic variants that can affect the risk for developing epilepsy. We discuss various epidemiologic study designs that have been applied to the genetics of the epilepsies including population studies, which provide compelling evidence for a strong genetic contribution in many epilepsies. We discuss genetic risk factors varying in size, frequency, inheritance pattern, effect size, and phenotypic specificity, and provide examples of how genetic risk factors within the various categories increase the risk for epilepsy. We end by highlighting trends in epilepsy genetics including the increasing use of massive parallel sequencing technologies.     

Genetics and epilepsy

The term "epilepsy" describes a heterogeneous group of disorders, most of them caused by interactions between several or even many genes and environmental factors. Much rarer are the genetic epilepsies that are due to single-gene mutations or defined structural chromosomal aberrations, such as microdeletions. The discovery of several of the genes underlying these rare genetic epilepsies has already considerably contributed to our understanding of the basic mechanisms in epileptogenesis. The progress made in the last 15 years in the genetics of epilepsy is providing new possibilities for diagnosis and therapy. Here, different genetic epilepsies are reviewed as examples, to demonstrate the various pathways that can lead from genes to seizures.     

The impact of genetics on the classification of epilepsy syndromes

Recent progress in the genetics of epilepsies may potentially provide important insights into biologic processes underlying epileptogenesis. However, the genetic etiology underlying epilepsy remains largely unknown, and the impact of available genetic data on the nosology of epilepsy is still limited. Therefore, at present, classification of epileptic disorders should be mainly based on electroclinical features. In the future, it is likely that the investigation of familial traits will lead to the definition of novel syndromes and that genotype–phenotype correlations in inherited conditions will shed light on the variable expressivity of epileptic disorders. Moreover, the discovery of new epilepsy genes may allow assessment of whether different phenotypes are etiologically linked.     

Obtaining genetic testing in pediatric epilepsy

The steps from patient evaluation to genetic diagnosis remain complicated. We discuss some of the genetic testing methods available along with their general advantages and disadvantages. We briefly review common pediatric epilepsy syndromes with strong genetic association and provide a potentially useful algorithm for genetic testing in drug‐resistant epilepsy. We performed an extensive literature review of available information as it pertains to genetic testing and genetics in pediatric epilepsy. If a genetic disorder is suspected as the cause of epilepsy, based on drug resistance, family history, or clinical phenotype, timely diagnosis may reduce overall cost, limit the diagnostic odyssey that can bring much anxiety to families, improve prognostic accuracy, and lead to targeted therapy. Interpretation of complicated results should be performed only in collaboration with geneticists and genetic counselors, unless the ordering neurologist has a strong background in and understanding of genetics. Genetic testing can play an important role in the care provided to patients with epilepsy.     

Genetics of cognition in epilepsy

With the completion of the Human Genome Project and the advent of more advanced sequencing platforms capable of high throughput genotyping at reduced cost, research on the genetics/genomics of cognition has expanded rapidly over the past several decades. This has been facilitated even further by global consortia including HapMap, 1000 Genomes Project, ENCODE, and others, which have made information regarding genetic variation and genomic functional elements readily available to all researchers. Thus, the goal of this Targeted Review is not to provide an exhaustive review of the existing literature on the role of genetic factors in cognition. Rather, we will highlight some of the most consistent findings in this field, review the research in epilepsy to date, and provide a background within which to set forth unique opportunities epilepsy may provide to further elucidate the role of genetics in cognition.     

Mapping genes in juvenile myoclonic epilepsy

The genetics of the various forms of epilepsy can be best understood by knowing where the affected gene is located. Genetic methodologies used to explore the genetics of epilepsy now include segregation analysis, linkage analysis and recombinant DNA technology. Juvenile myoclonic epilepsy (JME), a form of idiopathic epilepsy with a strong genetic component, provides informative pedigrees for linkage studies. Preliminary results demonstrate the heterogenous nature of the JME syndrome.     

Generalized epilepsy with febrile seizures plus: A common childhood-onset genetic epilepsy syndrome

We examined the phenotypic variation and clinical genetics in nine families with generalized epilepsy with febrile seizures plus (GEFS⁺). This genetic epilepsy syndrome with heterogeneous phenotypes was hitherto described in only one family. We obtained genealogical information on 799 individuals and conducted detailed evaluation of 272 individuals. Ninety-one individuals had a history of seizures and 63 had epilepsy consistent with the GEFS⁺ syndrome. Epilepsy phenotypes were febrile seizures (FS) in 31, febrile seizures plus (FS⁺) in 15, FS⁺ with other seizure types (atonic, myoclonic, absence, or complex partial) in 8, and myoclonic–astatic epilepsy in 9 individuals. Inheritance was autosomal dominant with approximately 60% penetrance. This study confirms and expands the spectrum of GEFS⁺ and provides new insights into the phenotypic relationships and genetics of FS and the generalized epilepsies of childhood. Moreover, the ability to identify large families with this newly recognized common, childhood-onset, generalized genetic epilepsy syndrome suggests that it should be a prime target for attempts to identify genes relevant to FS and generalized epilepsy. Ann Neurol 1999;45:75–81     

Genetics of epilepsy

Understanding the molecular biology of epilepsy is a challenge for modern science. Epilepsy results from alternations in fundamental mechanisms of brain and membrane function. Although an understanding of the mode of inheritance and the etiology of genetic epilepsy syndromes forms the basis for genetic counseling, the development of specific therapies will come from knowing the basic mechanisms of epilepsy. Defining the genes causing epilepsy requires an unambiguous definition of seizure phenotype, along with the stability of that trait, an unremitting clinical course, and an abundance of clinical material. This article reviews the task of defining the genetics of epilepsy and discusses genetic methodology, idiopathic generalized and localization-related partial epilepsies, neuronal migration disorders, progressive myoclonus epilepsies, molecular biology of epileptogenesis, and future research.     

Ethical, legal, and social dimensions of epilepsy genetics

PURPOSE: Emerging genetic information and the availability of genetic testing has the potential to increase understanding of the disease and improve clinical management of some types of epilepsy. However, genetic testing is also likely to raise significant ethical, legal, and social issues for people with epilepsy, their family members, and their health care providers. We review the genetic and social dimensions of epilepsy relevant to understanding the complex questions raised by epilepsy genetics. METHODS: We reviewed two literatures: (a) research on the genetics of epilepsy, and (b) social science research on the social experience and social consequences of epilepsy. For each, we note key empiric findings and discuss their implications with regard to the consequences of emerging genetic information about epilepsy. We also briefly review available principles and guidelines from professional and advocacy groups that might help to direct efforts to ascertain and address the ethical, legal, and social dimensions of genetic testing for epilepsy. RESULTS: Genetic information about epilepsy may pose significant challenges for people with epilepsy and their family members. Although some general resources are available for navigating this complex new terrain, no guidelines specific to epilepsy have yet been developed to assist people with epilepsy, their family members, or their health care providers. CONCLUSIONS: Research is needed on the ethical, legal, and social concerns raised by genetic research on epilepsy and the advent of genetic testing. This research should include the perspectives of people with epilepsy and their family members, as well as those of health care professionals, policymakers, and bioethicists.     

The role of genetics and ethnicity in epilepsy management

Recent exciting developments in epilepsy genetics have led to significant insights into the mechanisms underlying seizure disorders. Success in epilepsy genetics research to date has resulted from identification of genes responsible for rare monogenic disorders, the majority encoding either voltage- or ligand-gated ion channels. For some conditions, such as benign familial neonatal seizures, an understanding of the underlying genetics is helpful in predicting prognosis. However, for other disorders, such as autosomal dominant nocturnal frontal lobe epilepsy, phenotypic severity is determined by factors other than the major dominant nicotinic subunit mutation found in some families. Further complexity arises when single-gene mutations give rise to heterogeneous phenotypes, as typically occur with generalized epilepsy with febrile seizures plus. Another area of increasing genetic endeavour, pharmacogenetics will allow tailoring of antiepileptic medication for each patient. Pharmacogenetics explores genetic polymorphisms in genes coding for drug-metabolizing enzymes, receptors and transporters. Polymorphisms have been identified that result in marked ethnic and interindividual differences in response to treatment. With further understanding of the impact of these differences, pharmacogenetic screening is likely to guide the management of epilepsy in the future.     

Familial occurrence of febrile seizures and epilepsy in severe myoclonic epilepsy of infancy (SMEI) patients with SCN1A mutations

PURPOSE: The role of the familial background in severe myoclonic epilepsy of infancy (SMEI) has been traditionally emphasized in literature, with 25-70% of the patients having a family history of febrile seizures (FS) or epilepsy. We explored the genetic background of SMEI patients carrying SCN1A mutations to further shed light on the genetics of this disorder. METHODS: We analyzed the occurrence of FS and epilepsy among first- and second-degree relatives (N = 867) of 74 SMEI probands with SCN1A mutations (70 de novo, four inherited) and compared data with age-matched and ethnically matched control families. Familial clustering and syndromic concordance within the affected relatives in both groups were investigated. RESULTS: The frequency of FS or epilepsy in relatives of SMEI patients did not significantly differ from that in controls (FS: 13 of 867 vs. 12 of 674, p = 0.66; epilepsy: 15 of 867 vs. six of 674, p = 0.16). Different forms of epilepsy were identified in both relatives of SMEI probands and controls. Twenty-eight relatives with FS and epilepsy were distributed in 20 (27%) of 74 SMEI families; among the controls, 18 affected relatives were clustered in 13 (18.5%) of 70 families. No pedigree showed several affected members, including the four with inherited mutations. CONCLUSIONS: A substantial epileptic family background is not present in our SMEI patients with SCN1A mutations. These data do not confirm previous observations and would not support polygenic inheritance in SMEI. The investigation of the family background in additional series of SMEI patients will further shed light on the genetics of this syndrome.     

Genetics of temporal lobe epilepsy

The most common partial epilepsy, temporal lobe epilepsy (TLE) consists of a heterogeneous group of seizure disorders originating in the temporal lobe. TLE had been thought to develop as a result of acquired structural problems in the temporal lobe. During the past two decades, there has been growing evidence of the important influence of genetic factors, and familial and non-lesional TLE have been increasingly described. Here, we focus on the genetics of TLE and review related genes which have been studied recently. Although its molecular mechanisms are still poorly understood, TLE genetics is a fertile field, awaiting more research.     

Molecular typing of familial temporal lobe epilepsy

The pathogenesis of temporal lobe epilepsy (TLE) was originally considered to be acquired. However, some reports showed that TLE was clustered in some families, indicating a genetic etiology. With the popularity of genetic testing technology, eleven different types of familial TLE (FTLE), including ETL1-ETL11, have been reported, of which ETL9-ETL11 had not yet been included in the OMIM database. These types of FTLE were caused by different genes/Loci and had distinct characteristics. ETL1, ETL7 and ETL10 were characterized by auditory, visual and aphasia seizures, leading to the diagnosis of familial lateral TLE. ETL2, ETL3 and ETL6 showed prominent autonomic symptom and automatism with or without hippocampal abnormalities, indicating a mesial temporal origin. Febrile seizures were common in FTLEs such as ETL2, ETL5, ETL6 and ETL11. ETL4 was diagnosed as occipitotemporal lobe epilepsy with a high incidence of migraine and visual aura. Considering the diversity and complexity of the symptoms of TLE, neurologists enquiring about the family history of epilepsy should ask whether the relatives of the proband had experienced unnoticeable seizures and whether there is a family history of other neurological diseases carefully. Most FTLE patients had a good prognosis with or without anti-seizure medication treatment, with the exception of patients with heterozygous mutations of the CPA6 gene. The pathogenic mechanism was diverse among these genes and spans disturbances of neuron development, differentiation and synaptic signaling. In this article, we describe the research progress on eleven different types of FTLE. The precise molecular typing of FTLE would facilitate the diagnosis and treatment of FTLE and genetic counseling for this disorder.     

Genetic aspects of epilepsy: current knowledge and perspectives

Rapidly advancing knowledge concerning the genetic aspects of epilepsy have led us to complete a recent article on the subject published in the journal. A contrasting picture is emerging, particularly between symptomatic and idiopathic epilepsy. For symptomatic epilepsy, divers gene products implicated in brain development and neuron survival have been identified. Inversely, for idiopathic epilepsy, the latest discoveries confirm their canalopathic nature. In addition, rapid progress in the field of mendelian inherited epilepsy has pointed out the lack of notable progress concerning common epilepsy with a complex hereditary pattern. These forms are one of the major challenges for genetic analysis of epilepsy.     

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.     

Current controversies in the relationships between autism and epilepsy

The controversies that have arisen in endeavoring to establish the nature of the relationships between autism and epilepsy might be summarized in a few simple questions, most of which do not yet have clear, complete answers. Does epilepsy cause autism? Does autism cause epilepsy? Are there underlying brain mechanisms that predispose to both conditions? What is the role of genetics in this regard? What is the importance of prenatal, perinatal, and postnatal environmental factors? Do any of the proposed relationships between autism and epilepsy provide insight into useful management or treatment? Is the prognosis of either autism or epilepsy different when the other condition is also present? What is the role of additional comorbidities, such as intellectual impairment or attention deficit hyperactivity disorder, in the relationship between the two conditions and in influencing treatment choices? From the evidence currently available, it would appear that epilepsy can rarely be the cause of autistic features but is not the cause of autism in most cases. There is currently no credible mechanism for suggesting that autism might cause epilepsy. There is strong evidence for an underlying predisposition for both conditions, particularly arising from genetic investigations. However, many issues remain unresolved. Considering the amount of research that has been published in this area, it is surprising that so few definitive answers have been established. The papers in this issue’s special section provide additional insights into the relationships between autism and epilepsy; while they do not provide answers to all the questions, they represent considerable progress in this area and, at the very least, give some strong indication of what research might, in the future, provide such answers.     

Novel approaches to epilepsy treatment

The aim of epilepsy treatment is to achieve complete seizure freedom. Nonetheless, numerous side effects and seizure resistance to antiepileptic drugs (AEDs) affecting about 30–40% of all patients are main unmet needs in today’s epileptology. For this reason, novel approaches to treat epilepsy are highly needed. Herein, we highlight recent progress in stem‐cell–based and gene transfer–based therapies in epilepsy according to findings in animal models and address their potential clinical application. Multiple therapeutic targets are described, including neuropeptides, neurotrophic factors, and inhibitory neurotransmitters. We also address new molecular‐genetic approaches utilizing optogenetic technology. The therapeutic strategies presented herein are predominately aimed toward treatment of partial/focal epilepsies, but could also be envisaged for targeting key seizure propagation areas in the brain. These novel strategies provide proof‐of‐principle for developing effective treatments for refractory epilepsy in the foreseeable future.     

The concept of symptomatic epilepsy and the complexities of assigning cause in epilepsy

The concept of symptomatic epilepsy and the difficulties in assigning cause in epilepsy are described. A historical review is given, emphasizing aspects of the history which are relevant today. The historical review is divided into three approximately semicentenial periods (1860–1910, 1910–1960, 1960–present). A definition of symptomatic epilepsy and this is followed by listing of causes of symptomatic epilepsy. The fact that not all the causes of idiopathic epilepsy are genetic is discussed. A category of provoked epilepsy is proposed. The complexities in assigning cause include the following: the multifactorial nature of epilepsy, the distinction between remote and proximate causes, the role of nongenetic factors in idiopathic epilepsy, the role of investigation in determining the range of causes, the fact that not all symptomatic epilepsy is acquired, the nosological position of provoked epilepsy and the view of epilepsy as a process, and the differentiation of new-onset and established epilepsy. The newly proposed ILAE classification of epilepsy and its changes in terminologies and the difficulties in the concept of acute symptomatic epilepsy are discussed, including the inconsistencies and gray areas and the distinction between idiopathic, symptomatic, and provoked epilepsies. Points to be considered in future work are listed.