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Jornal de Pediatria

Print version ISSN 0021-7557On-line version ISSN 1678-4782

J. Pediatr. (Rio J.) vol.84 no.4 suppl.0 Porto Alegre Aug. 2008 



The genetics of epilepsies



Iscia Lopes–Cendes

Associate professor, School of Medical Sciences, Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil





OBJECTIVES: To discuss some of the clinical and molecular genetic aspects of new discoveries in the field of the genetics of the epilepsies and relate these with relevant clues for a better understanding of the mechanisms underlying some of the monogenic epilepsy syndromes.
SOURCES: Many study designs have been performed over the years and these include family–based studies, genetic–epidemiology surveys. More recently, molecular genetics studies and gene discovery strategies have been used to unravel the molecular and cell mechanisms involved in several Mendelian epilepsy syndromes.
SUMMARY OF THE FINDINGS: The importance of genetic factors in the epilepsies has been recognized since the time of Hippocrates.
CONCLUSIONS: In the modern era, many studies have demonstrated the existence of an inherited component in the generalized and focal epilepsies and in the last 2 decades a number of families segregating different types of monogenic epilepsy have been described leading to progresses in the characterization of the molecular defects in these families.

Keywords: Monogenic disorders, channelopathies, seizures.




Epilepsies are one of the most common neurological conditions with a prevalence of approximately 1–1.5% in the general population and, therefore, are considered a public health problem. The molecular genetics revolution provided new insights into the human idiopathic epilepsies and, more recently, a major role has been suggested for the ligand–gated and voltage–gated ion channels in the etiology of many epilepsy syndromes.1 To date, genes encoding for sodium and potassium channel subunits as well as nicotinic cholinergic receptor subunits have been identified for Mendelian idiopathic epilepsies.2 In vitro and in vivo studies of mutations demonstrate functional changes, allowing new insights into mechanisms underlying hyperexcitability.3 Progress in this area has been so intense that researchers are now trying to identify genes for the more common forms of epilepsy following complex inheritance.4 We believe that once such genes are discovered, the more complex interactions between genes and environment will be better understood making it easier to assess the mechanisms producing specific epilepsy syndromes, as well as determining clinical variability among different patients.

In the 1950's the pioneer studies by Lennox5 and Metrakos6 were the first to propose scientific evidence for the genetic predisposition to idiopathic generalized epilepsies (IGE). These initial studies reported that the risk of developing epilepsy was 1.5 to 5 times higher in the relatives of patients with epilepsy than that observed in the general population.5,6 In addition, the risk for relatives of patients with IGE was twice that observed for patients with focal epilepsy.7,8 These results were confirmed by twin studies in which the concordance rates for monozygotic (MZ) twins were higher as compared to dizygotic (DZ) twins.9 By contrast, until recently focal epilepsies were widely believed to be nongenetic. This view probably resulted from the recognition that epilepsy following environmental insults is usually partial; and that a greater proportion of partial than generalized epilepsies are environmental in origin. However, the importance of the genetic contributions to the focal epilepsies is now well established. Evidence for this genetic contribution has come from different study designs, such as a) familial aggregation studies; b) twin studies; c) clinical description of families; and d) the identification of specific genes.10

Familial aggregation studies, which use an epidemiological approach to assess the degree of increased risk in relatives of individuals with partial epilepsy, as compared to other groups (generalized epilepsy or normal controls), are consistent in showing an increased risk of epilepsy in the relatives of patients with partial epilepsies.11,12 However, this contribution is in a lower magnitude than that of the generalized epilepsies.12,13 Early studies also provided evidence for a genetic contribution to epilepsy with complex partial seizures (most of which was probably temporal lobe epilepsy).12 Two recent studies further elucidated the familial aggregation of partial epilepsies. Standardized morbidity ratios (SMR) for unprovoked seizures, a measure of the risk of unprovoked seizures, were determined for a large North American population.13 The SMR were very similar for offspring of patients with generalized (SMR = 3.3) and partial epilepsy (SMR = 3.2). However, risk was increased in the offspring of parents with absence seizures (SMR = 9.2), suggesting that the greater genetic contribution to generalized epilepsy may be restricted to specific syndromes.8 Another study examined the risk, calculating the relative risk (RR) of epilepsy in first degree relatives of 1,498 patients with cryptogenic epilepsy.8 Risk was significantly elevated in both groups, focal and generalized epilepsy, when compared to the controls. In parents and siblings, the RR was lower if the probands epilepsy was focal (RR =2.4 for focal epilepsy and RR = 4.7 for generalized epilepsy). By contrast, in offspring, the risk was actually greater if the probands epilepsy was focal (RR = 4.2 for focal epilepsy and RR = 1.6).10

However, clustering of disease within families can sometimes result from shared exposure to environmental factors or shared behavioral patterns, rather than from genetic susceptibility.14 One of the best strategies to confirm that familial aggregation is indeed caused by shared genetic predisposition is twin studies. These have consistently found higher concordance rates of epilepsy in MZ than DZ twins, providing strong evidence for genetic contributions to epilepsy.15–17 However, very few of these studies have examined focal epilepsies specifically, or compared focal and generalized epilepsies. Berkovic et al.8 studied the concordance rates for specific epilepsy syndromes in 253 twin pairs in which one or both twins had epilepsy or febrile convulsions. Concordance rates were significantly higher in MZ than in DZ pairs in both generalized (MZ = 82% vs. DZ = 26%) and focal epilepsies (MZ = 36% vs. DZ = 5%). Interestingly, all of the evidence for a genetic effect in the focal epilepsies came from 30 pairs with cryptogenic epilepsy, in whom the concordance in MZ and DZ pairs was 55% and 0. In the 10 pairs with idiopathic partial epilepsies, most of whom had benign rolandic epilepsy; concordance rates did not differ between MZ and DZ pairs. In addition, none of the 25 pairs with symptomatic focal epilepsy was concordant, excluding the possibility of a major genetic determinant for these types of focal epilepsy.15

Several studies have described the clinical manifestations of epilepsy in single families, or sets of families. These studies are interesting because they show the full spectrum of symptoms different patients within single families can have, giving a very accurate idea of the clinical variability of specific syndromes. However, prove of the genetic contribution to epileptogenesis is only achieved when the causative genes are localized. To date, familial aggregation has been documented in many epilepsy syndromes. A partial list of these types of epilepsy is presented in Tables 1 to 4. It is important to note that any listing of this type becomes out of date in a short period of time, since new syndromes, loci or genes are identified continuously. In many cases in which the genes have been identified they are voltage–gated or receptor genes, except in familial temporal epilepsy with auditory symptoms, in which the leucine–rich, glioma–inactivated 1 gene (LGI1) has been implicated.18 The exact functional properties of the LGI1 gene remain unknown.18 This gene was cloned from the breakpoints of a glioblastoma cell line and its expression is reduced or absent in many high–grade gliomas. This evidence indicates a possible function related to cellular proliferation and tumor suppression.18 Furthermore, this gene is characterized by a central leucine–rich repeat region, which is involved in regulation of cell growth, adhesion, and migration.18,19 The exact relationship of the LGI1 gene mutation with epilepsy is still unclear. Gu et al.17 demonstrated the presence of hlgi1 protein in the human brain, particularly in neurons from the frontal and temporal lobes, but no definite pathogenic mechanism was found which could correlate mutations in this gene and epileptogenesis.

As discussed above, in only a small proportion of epilepsy syndromes a causative gene has been identified. This comprises a very small proportion of all partial epilepsies described.72 However, they hold great promise for elucidating the basic mechanisms of epileptogenesis, and in particular the genetic basis for pathology expression in localized brain regions. It is very interesting to note that despite the widespread assumption of a greater genetic effect on generalized epilepsies, more progress has been made to date in localizing genes for focal epilepsies than for generalized epilepsies.8

In summary, significant progress has been made in recent years in understanding the genetics of the epilepsies. Research in this area is moving rapidly, and genes that raise risk for new syndromes will undoubtedly be discovered soon. This information will be crucial for elucidating pathogenesis, and also for clarifying definition of syndromes with a major genetic contribution.



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Iscia Lopes–Cendes
Department of Medical Genetics, Unicamp
Cidade Universitária Zeferino Vaz
Distrito de Barão Geraldo
CEP 13084–971 – Campinas, SP – Brazil
Tel.: +55 (19) 3521.8907
Tel.: +55 (19) 3521.8909



No conflicts of interest declared concerning the publication of this article.



Suggested citation: Lopes–Cendes I. The genetics of epilepsies. J Pediatr (Rio J). 2008;84(4 Suppl):S33–39.

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