Grant round winners 2011

Epileptic disorders can be described as focal (meaning that seizures originate in a specific part of the brain) or generalised (meaning that seizures involve most or all of the brain). They are also either symptomatic (the cause is known), idiopathic (the cause is not clear), or cryptogenic (a cause is suspected but not confirmed).

Idiopathic generalised epilepsy (IGE) is a group of epileptic disorders that are believed to have a strong genetic basis. They include epilepsy with myoclonic-astatic seizures (EMAS), childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME) and juvenile absence epilepsy. Symptomatic generalised epilepsies (SGEs) include West Syndrome and Lennox-Gastaut Syndrome, and there is also some overlap between the two groups (for example EMAS can be either symptomatic or idiopathic).

Evidence suggests that if two different forms of epilepsy produce the same type of seizure, they could share the same underlying pathology. This has encouraged researchers to investigate the genetics of distinct seizure types rather than epilepsy syndromes as a whole.

Absence seizures occur in both IGE and SGE and are associated with a defect in GABA function (GABA is the major inhibitory neurotransmitter in the brain). However, although a GABA receptor gene mutation has been linked to CAE, very little is known about absence seizures and how they originate.

In a recent study, Dr Seokyung Chung and colleagues, at Swansea University, analysed the DNA of 504 people with different forms of IGE. Based on previous work they focused on the variations in the genes involved in GABA synthesis and transport. The team discovered 12 different variations across four genes in 20 of the people with IGE. All of these people suffered from absence seizures.

Dr Chung has now been awarded £198,520, over 36 months, for a fellowship entitled Pathophysiological analysis of GABAergic gene variants in childhood epilepsies, in which she will examine these 12 gene variations more closely, in order to confirm whether they actually cause absence seizures.

Firstly, Dr Chung and her colleagues will analyse the DNA of 300 more people with IGE, all of whom have absence seizures. They will be looking to see how regularly the variations feature in this population, and whether there are others present. The group will also compare the DNA of people who have IGE and experience absence seizures with the DNA of those with no prior evidence of epilepsy or seizures. If one of the variations is present in the latter group, it will be excluded.

In the second stage of the study the team will characterise the ‘valid’ gene variants in terms of their function and contribution to absence epilepsy. They will do this by introducing the individual variants into bacteria and assessing the consequences, in preparation for work with animal models. The team predicts that most of the variants are responsible for absence seizures in some IGE cases.

Dr Chung is hopeful that this research will provide a better understanding of the mechanisms of absence seizures and highlight genetic targets for the development of new treatments.