Common genetic variants linked to drug-resistant epilepsy, according to research by UTHealth Houston and ULC

Certain common genetic changes might make some people with focal epilepsy less responsive to seizure medications, according to a new global study led by researchers from UCL in London and UTHealth Houston.

Focal epilepsy is a condition where seizures start in one part of the brain. It is the most common type of epilepsy.

Antiseizure medication is usually prescribed for people with the condition. However, for 1 in 3 people with epilepsy (around 20 million individuals worldwide), current antiseizure medications are ineffective. This means that people will continue to have seizures despite taking medication — a condition called drug resistance.

Drug resistance is associated with additional significant health risks in epilepsy, including a higher risk of sudden unexpected death in epilepsy, alongside substantially higher health care costs.

However, until now, there has been little understanding about why antiseizure medications fail to work for some people.

The new international study, published in eBioMedicine, part of The Lancet, found strong evidence that certain common genetic factors may contribute to drug resistance in epilepsy.

The researchers used data from EpiPGX, an international multicenter research project on epilepsy pharmacogenetics, and Epi25, the largest sequencing study in epilepsy, to examine genetic variation across the entire genome (the complete set of genetic instructions found in an organism’s DNA) in 6,826 people with epilepsy.

The team compared the genomes of those who had drug-resistant epilepsy (4,208 individuals) with those whose seizures were successfully controlled with antiseizure medications (2,618 individuals).

They found that the presence of some specific common genetic variants in two genes — CNIH3, which helps control how certain brain receptors function, and WDR26, which is involved in various cell processes — was associated with a higher risk of having drug resistance in focal epilepsy and may influence a person’s response to antiseizure medications.

“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,” said senior author Sanjay Sisodiya, MBBS, PhD, professor of neurology at UCL Queen Square Institute of Neurology.

The findings are particularly important as these genetic signatures can be determined at the onset of epilepsy, rather than after several antiseizure medications have been tried without success.

This could eventually help predict which individuals with epilepsy are likely to develop drug resistance and avoid unnecessary exposure to ineffective medications and their associated side effects.

“Our study provides the first evidence that common genetic variants — usually not addressed in clinical genetic testing — significantly contribute to drug resistance in epilepsy,” said first author Costin Leu, PhD, assistant professor of neurology at McGovern Medical School at UTHealth Houston. “Recognizing these genetic variants, which are frequent in the general population yet strongly influence treatment outcomes, underscores the need to expand genetic testing and future therapies to address polygenic epilepsy.”

Polygenic epilepsy, a type of epilepsy that is influenced by multiple genes, represents the vast majority of all genetic epilepsy cases, Leu said.

“Addressing it through genetics-informed approaches could substantially enhance personalized treatment strategies for many individuals who currently fall outside the scope of targeted genetic medicine,” Leu said.

This work is part of the European Union’s Seventh Framework Programme and the Centers for Common Disease Genomics, funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute, part of the National Institutes of Health.

The study authors are grateful to all the people with epilepsy and their doctors who helped enable this important research.

--Adapted from original news release by UCL