Genetics of Epilepsy - Advanced

Introduction

Epilepsy is a heterogeneous entity with great variation in etiology and clinical features. Several systems have been developed to describe epilepsies. The International League Against Epilepsy (ILAE) provides classification systems for seizure types and epilepsy syndromes. Seizures are classified as “partial”, beginning at a specific focus within the brain, or “generalized”, affecting in the entire brain at once. Partial seizures may evolve into secondarily generalized seizures. Epilepsy syndromes are categorized according to seizure type(s), age of onset, etiology, clinical course, and electroencephalographic (EEG) findings. Syndromes are classified as localization-related (focal or partial) or generalized (ILAE, 1989). According to the International Classification of Epileptic Syndromes, epilepsy syndromes are divided into three major classes according to presumed etiology. “Symptomatic” epilepsies describe those conditions resulting from injury to the central nervous system through stroke, head trauma, infection or metabolic insult. “Idiopathic” epilepsies describe those syndromes with no clear cause. Idiopathic epilepsies are believed to arise from a combination of genetic and environmental factors. “Cryptogenic” syndromes are those which lack sufficient evidence for classification. Evidence from a large study involving about 2000 families with epilepsy suggests that a genetic basis exists for both idiopathic and cryptogenic epilepsies, and that these two classes may be studied together (Ottman et al., 1997).

The extremely heterogeneous nature of epilepsy makes this condition a challenge for clinicians and researchers. Although there are several classes of anti-epileptic drugs available, it is often unclear which will be effective in a particular case, and many cases remain refractory to all treatment. Adverse drug effects can be quite serious, including the potential to worsen seizures or induce new seizure types in a patient (Guerrini et al., 1998). Major goals in clinical and basic research are aimed at improving the ability to classify seizures, eventually on a molecular basis. This knowledge will improve diagnosis, prognosis, and management. Research into basic mechanisms of epileptogenesis may also lead to the development of specific drug therapies to target particular molecular defects.

Evidence for the role of genetics in epilepsy

Studies of epilepsy in twins have consistently found a higher concordance among monozygotic compared to dizygotic twins, although the actual concordance rates vary widely (Berkovic et al., 1998; Miller et al., 1998). Using a population-based approach, Miller et al., 1998 estimated heritability (h2) for susceptibility to seizures as .69 to .85, depending on seizure type. In addition to epilepsy in general, significant heritability has been found for many, but not all, specific seizure types and syndromes (Berkovic et al., 1998; Miller et al., 1998).

In family studies, Ottman et al., 1996 and others have demonstrated an elevated risk of epilepsy in relatives of probands compared to the general population. Depending on the specific diagnosis in the proband, the relative risk of epilepsy in relatives is approximately 2- to 3-fold.

The role of genetic factors in epilepsy varies according to the syndrome. In particular, while genetic factors are important in idiopathic and cryptogenic epilepsy syndromes, they do not appear to contribute significantly to susceptibility in epilepsy following postnatal brain injury. Also, genetic influences are stronger in generalized compared to localization-related epilepsies. Finally, the strong genetic contribution to epilepsy appears limited to seizures in people under 35 years (Ottman et al., 1996; Ottman et al., 1998; Berkovic et al, 1998).

Although relatively rare, the existence of single-gene forms of epilepsy in humans and animal models demonstrates that genetic changes can underly susceptibility to seizures. Progress in identifying loci and genes in these conditions is described in detail below. The genes found thus far encode molecules involved in different aspects of the transmission of signals between neurons: ion channels, molecules involved in neurotransmitter release, and neurotransmitter receptors.

Multiple avenues of research in epilepsy have provided solid evidence for the role of genetic factors in this condition.

Complex inheritance in epilepsy

The expression of epilepsy in an individual is the result of multiple genetic and environmental factors. In symptomatic epilepsy, environmental influences, namely damage to the brain, are the major determinants. In idiopathic and cryptogenic epilepsy syndromes, there appears to be a major role for genetic influences. These, however, are complex. Incomplete penetrance suggests that there are modifying factors. Even in the cases where a single major gene has been found responsible for a syndrome, variable severity of expression suggests modifying genetic or environmental factors (Berkovic, 2000). Models to describe how multiple etiological factors interact suggest that the independent influences on epilepsy have additive rather than multiplicative effects (Miller et al., 1998; Ottman, 1997).

Further complexity in the genetic analysis of epilepsy arises from the genetic heterogeneity of epilepsy syndromes. This feature has been predicted for some time and has been confirmed by the identification of both locus and allelic heterogeneity in the single-gene epilepsy syndromes (see below). The fact that clinically similar individuals are likely to have diverse genetic etiologies for their epilepsy illustrates the challenge in genetic research of these conditions and underscores the importance of identifying clinical variables which can be used to help stratify populations.

Variable expression refers to the fact that a change on the molecular level may manifest differently in individuals as a result of modifying genetic or environmental factors. In the case of epilepsy, it appears that there are certain genetic factors which contribute to a general susceptibility to seizures and which have a variable expression depending on additional, more specific genetic factors. There is significant data supporting the existence of both general and syndrome-specific genetic factors in epilepsy.

In support of genetic influences on general seizure susceptibility, Ottman et al. (1996; 1998) and Choueiri et al. (2001) demonstrated that the elevated risk in relatives of probands with epilepsy is not only for the same type of epilepsy as the proband. Berkovic et al. (1998) found incomplete concordance for specific syndrome in monozygotic twins concordant for epilepsy. These studies also suggested the existence of syndrome-specific genetic factors. Ottman et al. (1998) found that in probands with localization-related epilepsy, there was a greater risk for localization-related epilepsy compared to generalized epilepsy. Also, among twin pairs concordant for epilepsy, the frequency of monozygotic twins with the same syndrome (94%) is significantly greater than the frequency of dizygotic twins with the same syndrome (71%) (Berkovic et al., 1998).

There have been many reports of a maternal effect in the inheritance of epilepsy. The risk of epilepsy has consistently been found to be more than twice as high in the offspring of women than men with epilepsy. Offspring of both groups have a higher risk of epilepsy than the general population. Ottman et al., 1988 found a correlation of exposure to seizures in utero with increased risk to offspring. However, these cases explained only a minority of maternal effect. Significant contribution from prenatal exposure to anti-convulsants, increased perinatal complications in women with epilepsy, or greater fertility among women compared to men with epilepsy have also been ruled out. Possible mechanisms for the maternal effect in the inheritance of epilepsy include the involvement of mitochondrial genes, imprinting, or selective expansion of repeat sequences.

In 1997, Ottman et al. published the results of segregation analysis on almost 2000 families with idiopathic/cryptogenic epilepsy. Although the initial results suggested an autosomal dominant mode of inheritance with reduced penetrance, attempts to validate these findings demonstrated an unusual pattern of inheritance. Significantly, the risk to offspring was greater than the risk to siblings of the probands. The risk to siblings was best explained by an autosomal recessive model, while the risk to offspring was best explained by an autosomal dominant model. In fact, all models tested underestimated the risk to offspring. This phenomenon appeared to be restricted to families in which the proband had localization-related epilepsy. (Families in which the proband had generalized epilepsy seemed to fit an autosomal dominant model, although the sample size was small). The finding of significantly greater risk to offspring than to siblings cannot be explained by conventional genetic mechanisms, but it is suggestive of genetic anticipation. This intriguing result merits further study.

Progress in the genetics of epilepsy

Significant progress has also been made in unraveling the genetics of symptomatic epilepsies, including the progressive myoclonic epilepsies (PME), the neuronal ceroid lipofuscinoses, and myoclonic epilepsy with ragged red fibres (MERRF) (Robinson and Gardiner, 2000). Because seizures in those syndromes are secondary to metabolic brain damage, the findings are less likely to be generalizable to the common idiopathic epilepsies.

Multifactorial epilepsies are more common than those caused by mutations in single genes. As described above, these conditions are much more complicated to study. Nonetheless, some progress has been made in identifying major loci in these conditions, although no specific genes have been implicated thus far. The findings to date for some major syndromes are described below.

Childhood absence epilepsy: The onset of this condition, which comprises about 10-15% of childhood epilepsies, is between 2-12 years. It consists of brief “staring spells,” during which the individual is unaware. The characteristic EEG shows bilateral, synchronous, symmetrical discharges of 2.5-4 Hz spike wave or polyspike wave on a normal background. There is evidence for autosomal dominant transmission of an EEG pattern with bilaterally symmetrical 3 Hz spike and slow wave complexes. The seizures themselves are not inherited in a Mendelian pattern. Identification of a locus for childhood absence epilepsy is focused on the long arm of chromosome 8 at 8q24. In addition, multiple mouse models for exist for this syndrome. They include “stargazer,” caused by a mutation in a voltage-gated calcium channel subunit; “slow wave epilepsy mutant,” due to a mutation in a Na/H exchanger; and “mocha,” arising from mutations in the adapter related d subunit gene.

Juvenile absence epilepsy: This syndrome has an onset between 12 and 26 years. It shows familial clustering with juvenile absence with childhood absence, childhood absence, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures on awakening. Association of this condition has been found with an allele of a glutamate receptor gene (GRIK1).

Juvenile myoclonic epilepsy: This condition accounts for about 5-10% of epilepsy. Besides myoclonic seizures, many affected individuals have typical absence seizures and generalized tonic-clonic seizures. There is a proposed locus, EJM1, on chromosome 6p. In addition, linkage has been found to 15q14, the location of CHRNA7, the a 7 subunit of the neuronal nicotinic acetylcholine receptor. Researchers are currently looking for mutations in this gene.

Febrile convulsions: Although not an epilepsy, because seizures are not unprovoked, susceptibilty to febrile convulsions shares a genetic basis with epilepsy. This condition has a multifactorial form as well as an autosomal dominant form. Linkage has been found to 8q13-21 and to19p13.3.

Understanding of the molecular basis for many epilepsy syndromes is moving forward at a rapid pace. In addition to the syndromes described here, there is evidence for genetic contributions in a number of other multifactorial epilepsy syndromes, including benign epilepsy with centrotemporal spikes (BECTS), unspecified idiopathic generalized epilepsy, absence epilepsy evolving into myoclonic epilepsy, benign myoclonic epilepsy in infancy, epilepsy with generalized tonic-clonic seizures on awakening, and multifactorial forms of benign neonatal convulsions. Progress in the genetics of these syndromes can be expected in the near future.

Future directions in studying the genetics of epilepsy

The genetics of epilepsy are currently an area of intense research activity and progress. The foundation has been laid to pose and, hopefully, answer many key questions in this field. For example, large family registries and increasing genomic information are facilitating identification of loci and genes involved in single-gene and multifactorial epilepsy syndromes. These molecular studies should also address the features of maternal effect and of possible anticipation in the inheritance of epilepsy. Some other critical areas which are still poorly understood are described below.

Because of the study design of many previous epidemiological studies, there has been a bias towards ascertainment of epilepsy syndromes which persist into adulthood. The genetic epidemiology of childhood epilepsy remains under-studied. Cowan et al., (1989) demonstrated that ascertainment of childhood epilepsy cases varies considerably depending on the source and advocated using diverse resources to maximize ascertainment. In particular, EEG requisitions and hospital outpatient records covered the greatest number and types of cases.

Appropriate drug treatment is a major problem in epilepsy management. As many as 20% of chronic epilepsy cases are refractory to current medical treatment (Shorvon, 1996). Further complications arise from adverse drug effects (Guerrini et al, 1998). In past genetic epidemiological studies, the patterns of anti-epileptic drug use and response have not been examined. This information could contribute significantly to genetic research and, eventually, to medical management. The diversity in response to anti-epileptic drugs is likely a direct or indirect reflection of underlying diversity in molecular and cellular physiology, which is essentially genetically determined. Thus, families or individuals who appear to have the same epilepsy syndrome may be distinguishable by detailed clinical data about the efficacy and/or adverse reactions to medication. This information will facilitate the stratification of populations for epidemiologic and molecular research. In turn, molecular research will eventually allow clinicians to provide specifically targeted drug treatment to each patient.

There is a growing body of evidence for a shared genetic susceptibility of epilepsy with other neurological conditions. Future investigations of families with a history of epilepsy should investigate these associations further. Migraines have been reported to cluster with epilepsy in families (Baier and Doose, 1985; Saka and Saygi, 2000). Data from Ottman et al., 1996 suggest a shared susceptibility of idiopathic/cryptogenic epilepsy with cerebral palsy or mental retardation present from birth, as well as with seizures related to alcohol consumption and to fever (febrile convulsions). Comorbidity with psychiatric conditions, particularly depression, is another concern (Hermann et al., 2000). Other studies have demonstrated an increase in EEG abnormalities among family members of probands with epilepsy (Doose et al., 1995). Berkovic (2000) has suggested that clinical manifestations of genetic susceptibility may be as subtle as déja vu or a mild impairment of awareness. While these questions are intriguing, Berkovic also raised some ethical considerations particular to this aspect of genetic research in epilepsy. He cautioned that the suggestion that subtle and diverse conditions may have a common genetic etiology may lead to stigmatization, guilt, or blame.

Epilepsy is a heterogeneous entity and has thus defied effective classification and investigation for many decades. Recently, progress in epidemiology and genetics has facilitated major advances in the understanding of this condition. These advances will serve as a critical basis for further research in this area.

Note: Human genetics is an extremely complex topic. This website is meant only as an introduction and overview. If you are concerned about how genetics may affect your health, please consult a health care professional.