The genetic basis of epilepsy

Rolandic epilepsy is the most common type of childhood epilepsy, manifesting with seizures and a characteristic electroencephalographic (EEG) signature. Additionally, children with epilepsy often present with a reading disability and inability to perceive speech sounds. Accumulating evidence strongly indicates that there is a genetic component to rolandic epilepsy associated with each of the aforementioned clinical phenotypes.

Scientists on the EU-funded 'Translational research in human epilepsies' (TRHE) project wished to further explore the genetic cause of rolandic epilepsy. Using a number of volunteer families, they employed genetic methods to narrow down the causative gene variants that cause epilepsy and link this information with clinical data.

They found that the EEG trait is associated with variants at the ELP4 gene that maps on the human chromosome 11. The speech sound disability was found to be due to defects in the timing of voice onset and vowel duration.

With respect to reading disability, researchers performed a genome-wide linkage analysis with known dyslexia loci. Although no association was found with these loci, a novel linkage was found between genes located at chromosomes 1 and 7 and the emergence of rolandic epilepsy. Familial genetic studies showed that the siblings of individuals with epilepsy also had an increased chance of developing language and attention deficit, clearly underscoring the genetic component of the disease.

The work of the TRHE study extended to other idiopathic focal epilepsies and led to the identification of mutations in the glutamate NMDA receptor in patients with epilepsy. This was an interesting observation given the role of NMDA in sleep-dependent memory consolidation and therefore associative learning. Combined with the observation that children with rolandic epilepsy sleep 30 minutes less than their healthy counterparts, this mutation provided a strong causative cue for the impaired learning phenotype in epilepsy.

Overall, the genetic mutations and copy number variations identified during the TRHE project will drive future research towards understanding how key molecular pathways are implicated in epilepsy. Most importantly, these findings will help design future targeted therapeutic interventions.