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Epilepsy Genetics Group

Epilepsies represent one of the most common neurological disorders with a life-time prevalence of 3%. Idiopathic generalized epilepsies (IGEs) affect about 0.2% of the general population and account for 30% of all epilepsies (Jallon and Latour, 2005). The IGE syndromes are characterized by the age-related occurrence of recurrent unprovoked generalized seizures in the absence of detectable brain lesions or metabolic abnormalities (International League Against Epilepsy, 1989). The most common subtypes are childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME) and epilepsy with generalized tonic-clonic seizures (EGTCS) (Sander, 1996; Nordli, 2005). The electroencephalographic signature of IGE seizures is marked by generalized spike-wave discharges (GSW-EEG), which reflect a synchronized hyperexcitability state of thalamocortical circuits (Blumenfeld, 2005).

IGE syndromes have a predominant genetic etiology (λsiblings ≈ 10-20 depending on the IGE subtype), but in the vast majority of IGE patients the complex pattern of inheritance suggests epistatic effects of several susceptibility genes (Ottman, 2005). The genetic architecture of common IGE syndromes likely represents a biological continuum, in which a small fraction follows monogenic inheritance, whereas the majority of IGE patients presumably display a polygenic predisposition (Mulley et al., 2005). Twin and family studies indicate an overlapping genetic component that is shared across the common IGE syndromes, but also provide evidence that different genetic configurations determine the phenotypic expression of certain seizure types, such as absence and myoclonic seizures (Marini et al., 2004). Considering the strong impact of genetic factors, molecular genetic studies offer a promising approach to identify the responsible susceptibility genes and to elucidate their molecular pathways in epileptogenes

Molecular genetic approaches have identified causative gene mutations in rare monogenic forms of idiopathic epilepsies (Gardiner, 2005). Most of the currently known genes for human idiopathic epilepsies encode voltage-gated or ligand-gated ion channels (Turnbull et al., 2005). Several attempts to map susceptibility loci for genetically complex IGE syndromes have revealed inconsistent results (Mulley, 2005; Hempelmann et al., 2006). For most implicated regions, replication studies have failed to establish unequivocal linkage relationships, probably due to the confounding effects of phenotypic variability, complex inheritance, genetic heterogeneity and differences in study protocols (Tan et al., 2005). Overall, the discordant linkage findings reported so far contradict the optimistic view that a few common major susceptibility genes account for a substantial fraction of the overall genetic variance of IGE syndromes.

Progress in four research activities will strongly improve the prospects of molecular genetic approaches to elucidate molecular key sites of epileptogenesis. First, large multicenter collaborations using standardized protocols for assessing IGE phenotypes are imperative to achieve sufficient power to disentangle the complex genetic basis of common IGE traits (see EPICURE guidelines for phenotyping and sampling procedures). Second, clinical genetics need to delineate suitable endophenotypes (e.g. photosensitivity, age-at-onset, certain seizure types) and to specify phenotype-genotype-relationships that are closer to the effect of a small set of susceptibility genes. Third, emerging genome resources (Human Genome Project, HapMap Project, large scale comparative gene sequencing) and the application of innovative technologies will accelerate progress in the systematic identification of genes underlying these complex traits. Fourth, statistic approaches have to take into account gene interactions.

The Epilepsy Genetics Group is an integrated part of the Cologne Center for Genomics (CCG), which offers excellent facilities for high-throughput genotyping of microsatellite (STRs) and single-nucleotide polymorphisms (SNPs). Our research activities are focused on functional genomic approaches to dissect the complex genetic architecture of common epilepsy syndromes and to identify major susceptibility genes. The functional characterization of the underlying molecular pathways will provide important insights into epileptogenesis and may have equally significant therapeutic implications. Our research group has an outstanding expertise and long track record in molecular genetic analyses of common IGE syndromes, febrile seizures and photoparoxysmal response. The present research projects are funded by the Deutsche Forschungsgemeinschaft (DFG, Sa434/4-1), the Federal Ministry of Education, Research and Technology (BMBF, NGFN2, NeuroNet, 01GS0479) and currently by the European Integrated Project EPICURE (http://www.epicureproject.eu/) which is dedicated to Functional Genomics and Neurobiology of Epilepsy: a basis for new therapeutic strategies (EU FP6 Integrated Project EPICURE, grant: LSH-2005-2.1.3-2). This comprehensive research program will join the resources and expertise of 29 European research groups to accelerate progress in epilepsy research and to translate basic sciences into therapeutic applications. To map and identify major epilepsy genes we will conduct genome-wide linkage and association studies in the largest study samples of IGE patients and families reported so far (EPICURE Subproject 1). A major goal will be to establish a molecular genetic platform for international collaborative projects on epilepsy genetics.



Blumenfeld, H., 2005. Cellular and network mechanisms of spike-wave seizures. Epilepsia 46 Suppl 9, 21-33.

Gardiner, M., 2005. Genetics of idiopathic generalized epilepsies. Epilepsia 46 Suppl 9, 15-20.

Hempelmann, A., Taylor, K.P., Heils, A., Lorenz, S., Prud'homme, J.F., Nabbout, R., Dulac, O., Rudolf, G., Zara, F., Bianchi, A., Robinson, R., Gardiner, R.M., Covanis, A., Lindhout, D., Stephani, U., Elger, C.E., Weber, Y.G., Lerche, H., Nurnberg, P., Kron, K.L., Scheffer, I.E., Mulley, J.C., Berkovic, S.F., Sander, T., 2006. Exploration of the genetic architecture of idiopathic generalized epilepsies. Epilepsia 47, 1682-1690.

International League Against Epilepsy, 1989. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 30, 389-399.

Jallon, P., Latour, P., 2005. Epidemiology of idiopathic generalized epilepsies. Epilepsia 46 Suppl 9, 10-14.

Marini, C., Scheffer, I.E., Crossland, K.M., Grinton, B.E., Phillips, F.L., McMahon, J.M., Turner, S.J., Dean, J.T., Kivity, S., Mazarib, A., Neufeld, M.Y., Korczyn, A.D., Harkin, L.A., Dibbens, L.M., Wallace, R.H., Mulley, J.C., Berkovic, S.F., 2004. Genetic architecture of idiopathic generalized epilepsy: clinical genetic analysis of 55 multiplex families. Epilepsia 45:467-78.

Mulley, J.C., Scheffer, I.E., Harkin, L.A., Berkovic, S.F., Dibbens, L.M., 2005. Susceptibility genes for complex epilepsy. Hum Mol Genet 14(2), R243-249. Review

Nordli, D.R., Jr., 2005. Idiopathic generalized epilepsies recognized by the International League Against Epilepsy. Epilepsia 46 Suppl 9, 48-56.

Ottman, R., 2005. Analysis of genetically complex epilepsies. Epilepsia 46 Suppl 10, 7-14.

Sander, T., 1996. The genetics of idiopathic generalized epilepsy: implications for the understanding of its aetiology. Mol Med Today 2, 173-180.

Tan, N.C., Mulley, J.C., Berkovic, S.F., 2004. Genetic association studies in epilepsy: "the truth is out there". Epilepsia 45, 1429-1442.

Turnbull, J., Lohi, H., Kearney, J.A., Rouleau, G.A., Delgado-Escueta, A.V., Meisler, M.H., Cossette, P., Minassian, B.A., 2005. Sacred Disease Secrets Revealed: The Genetics of Human Epilepsy. Hum Mol Genet 14, 2491-2500.