Study to investigate endophenotypes in epilepsy.

The cause of epilepsy is complicated and probably involves many genes working together. Currently our understanding of the genetics of epilepsy is limited.
There are certain characteristics called ‘endophenotypes‘ which may be present in individuals who carry genes that cause a disease, but who do not show symptoms of the disease. Identification of these characteristics has revolutionised genetic studies in other diseases, but the potential for endophenotypes to cast light on the genetics of epilepsy has not yet been explored
Endophenotypes can only be detected with special tests. We plan to study families with epilepsy to try to identify endophenotypes using a number of methods. One method, EEG, measures electrical activity of the brain. A second method, transcranial magnetic stimulation, measures brain activity using special magnets. We will also use brain scanning methods (magnetic resonance imaging and spectroscopy) to obtain images of the brain and to measure chemical levels in the brain. We hope to identify abnormalities with these tests in apparently unaffected relatives of patients with epilepsy.
If successful, the identification of endophenotypes will contribute to the identification of genes that cause epilepsy, and by understanding better the genetic causes of epilepsy, we can move towards developing new treatments.

Background: Idiopathic generalised epilepsies (IGE) fit a model of complex inheritance. Characterising the genetic basis of epilepsy would provide novel approaches to developing new treatments. Clarifying the basis of complex genetic diseases has been revolutionised by the approach of identifying endophenotypes, heritable characteristics associated with a disease, which may have a simpler genetic basis. Endophenotypes can assist in the identification of individuals for genetic linkage studies. This approach has already shown promise in epilepsy in studies using EEG. Specific transcranial magnetic stimulation (TMS), MRI and magnetic resonance spectroscopy (MRS) abnormalities are found in patients with epilepsy. Expanding this approach by the identification of new endophenotypes using these techniques could help increase the power of future genetic linkage studies
Aims and objectives: In this study I plan to 1) identify and characterise endophenotypes in IGE using EEG, TMS, MRI and MRS, 2) to explore whether these endophenotypes can be used to improve the power of linkage studies.
Methodology: I will recruit subjects in each of the following groups: affected individuals with IGE (n=40); ‘unaffected‘ relatives of patients with IGE (n=40); healthy volunteers (n=40). Each subject will have detailed clinical assessment to determine seizure history, family history and classification of seizure type/syndrome. All subjects will undergo resting EEG recording, and where specific consent is obtained activation procedures will be performed. TMS will be carried out on all subjects to obtain resting/active motor threshold, cortical silent period threshold and intracortical inhibition/ facilitation. MRI will be performed to acquire data for voxel-based morphometry. Proton MRS will be used for single voxel acquisition of glutamate and NAA/Ch measurements in the frontal lobes and thalamus. Analysis will be performed to establish group differences in TMS, MRI and MRS between controls, affected subjects and ‘asymptomatic‘ family members. Promising endophenotypes will be used to reclassify individuals in large pedigrees with borderline power for linkage, and linkage studies carried out on pedigrees which have sufficient power following reclassification.
Medical and scientific opportunities: This project will investigate endophenotypes in epilepsy with the aim of increasing power of linkage studies. This will provide greater insight into the genetic mechanisms and pathogenesis of IGE and may have implications for the development of new treatment strategies.