A new global study has found genetic changes that may make individuals with focal epilepsy less responsive to seizure medications
Focal epilepsy is a condition where seizures start in one part of the brain and is the most common type of epilepsy. During a focal-aware seizure, patients will stay fully aware of what’s happening around them, even if they cannot move or respond.
Typically, antiseizure medicine is prescribed for this condition; however, for one in three people with focal epilepsy, current medications are ineffective, resulting in a condition called ‘drug resistance’.
Researchers at UCL and UTHealth Houston explored the impact of common genetic factors on drug resistance in focal epilepsy and published their findings in eBioMedicine.
Drug resistance causes additional health risks
Drug resistance is associated with a higher risk of sudden unexpected death in focal epilepsy and higher healthcare costs. Until recently, there has been little understanding about why antiseizure medications fail to work for some people.
The researchers used data from EpiPGX, an international multicentre research project on epilepsy pharmacogenetics, and Epi25, the most extensive 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.
They 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).
Specific genetic variants are associated with drug-resistant focal epilepsy
The researchers found that the presence of some specific common genetic variants in two genes, CNIH3, which helps control how specific 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 highlight that these genetic variants can be determined at the onset of focal epilepsy, rather than after several antiseizure medications have not worked. This could eventually lead to predicting which individuals with focal epilepsy are likely to develop drug resistance.
Senior author, Professor Sanjay Sisodiya (UCL Queen Square Institute of Neurology) 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.”
First author, Assistant Professor Costin Leu (previously UCL Queen Square Institute of Neurology and now UTHealth Houston) said: “Our study provides the first evidence that common genetic variants — usually not addressed in clinical genetic testing — significantly contribute to drug resistance in epilepsy.
“Recognising 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 (a type of epilepsy that is influenced by multiple genes).
“Polygenic epilepsy 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.”
