Common genetic variants linked to drug-resistant epilepsy

Certain common genetic changes might make some people with focal epilepsy less responsive to seizure medications, finds a new global study led by researchers at UCL 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 one in three 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, 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.

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.”

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

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.

“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 (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 personalized treatment strategies for many individuals who currently fall outside the scope of targeted genetic medicine.”

Certain common genetic changes might make some people with focal epilepsy less responsive to seizure medications, finds a new global study led by researchers at UCL 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 one in three 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, 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.

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.”

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

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.

“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 (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 personalized treatment strategies for many individuals who currently fall outside the scope of targeted genetic medicine.”