New study shows how our genes could help explain drug resistance in epilepsy

The Epilepsy Society has welcomed the findings of an international study that throws new light on why some people with focal epilepsy do not respond to anti-seizure medications. It is the first research to provide evidence that common genetic variants significantly contribute to drug resistance in epilepsy.

One in three people with epilepsy have drug resistance, meaning their seizures cannot be controlled with current treatment options. Focal epilepsy, which begins in one part of the brain, is the most common form of epilepsy.

Now the study led by researchers at UCL and UT-Health Houston has shown that certain common genetic variants may contribute to drug resistance. This means that, in the future, it may be possible to predict from the point of diagnosis which individuals are likely to be drug resistant. 

This could avoid the prescribing of medications which ultimately prove ineffective and result in unpleasant side effects. And it could lead to the development of newer, more effective medications.

Hope for people with uncontrolled seizures

Clare Pelham, Chief Executive at the Epilepsy Society said: “This offers real hope to the 200,000 people across the UK whose lives are dominated by uncontrolled seizures. This is such an important area of research as seizure control really is the key to quality of life for people with epilepsy and their family and friends.

“If a person’s seizures can be controlled their education is less likely to be interrupted, they will have greater employment opportunities and they will be able to drive. Most importantly, their risk of Sudden Unexpected Death in Epilepsy(SUDEP) is reduced. It is obviously early days but identifying the genetic cause of drug resistance feels like there is a glimmer of light at the end of the tunnel.”

International research data

The global study looked across the genomes of 6,826 people with epilepsy. Researchers  compared information from 4,208 people who had drug-resistant epilepsy with 2,618 whose seizures were successfully controlled with antiseizure medications. 

Data was drawn from EpiPGX, an international  research project on epilepsy pharmacogenetics, and Epi25, the largest sequencing study in epilepsy.

Researchers found that common genetic variants in two  genes – CNIH3 and WDR26 - were linked to a higher risk of drug resistance in focal epilepsy. CNIH3 helps control the function of specific brain receptors, while WDR26 is important for various cell processes.

Professor Sanjay Sisodiya, Director of Genomics at the Epilepsy Society and Professor of Neurology at UCL, is the senior author of the study and leads EpiPGX. He said: “The findings of our study offer new insights about why some people have seizures that are resistant to existing antiseizure medications. Further work may enable doctors to use this information to help predict who may turn out to have drug-resistant epilepsy and may help doctors develop newer treatments for the condition.

The study illustrates what can be achieved through international collaboration.”

Call to expand genetic testing

First author, Assistant Professor Costin Leu (previously UCL Queen Square Institute of Neurology and now UTHealth Houston) said this was the first study to provide evidence that common genetic variants significantly contribute to drug resistance in epilepsy.

He said it was important to recognise the significant role these genes play in epilepsy and treatment outcome and that the study underlined  the importance of expanding genetic testing as part of the diagnostic process. 

“Polygenic epilepsy (a type of epilepsy that is influenced by multiple genes) represents the vast majority of all genetic epilepsy cases, and addressing it through genetics-informed approaches could substantially enhance personalised treatment strategies for many individuals who currently fall outside the scope of targeted genetic medicine.”

Find out more

You can read the full study here.