Epileptic drug resistance associated with genetic mutants

People with local epilepsy who are resistant to available drugs may be carriers of common genetic variants that affect the efficacy of these drugs.

Local epilepsy, starting in a specific area of ​​the brain, is the most common form of neurological condition (61% of cases), affecting approximately 4 people per 1,000 people. Antiseizure drugs are available, but only work in two-thirds of people with this type of epilepsy.

“Although previous studies are inconclusive, they suggested the involvement of common genetic variation in drug responses and the potential components of hereditary nature for drug resistance in epilepsy,” wrote Sanjay Sisodiya, a professor at the University of London, and her colleague Sanjay Sisodiya. Ebiomedysin.

“This study provides evidence of common genetic variation associated with drug responses in local epilepsy and confirms these previous suggestions.”

Using European ancestors, the researchers conducted genome-wide association studies in two epileptic cohorts, EPIPGX and EPI25. Overall, the group had 4,208 drug-resistant patients and 2,618 drug-responsive patients.

They found that seven single nucleotide polymorphisms in the region of chromosome 1, including the genes CNIH4, WDR26, and CNIH3 are associated with protection against drug resistance. Furthermore, overexpression of the genes CNIH3 and WDR26 was seen in individuals with drug-resistant epilepsy compared to individuals who responded to treatment.

“Pathogenic mutants of WDR26 cause a drug-responsive seizure phenotype consistent with the protective effects observed in meta-analyses, and have been shown to be consistent with higher expression levels in drug-resistant cases suggested by transcriptome-wide association studies,” the authors write. “CNIH3 functions as a supplementary subunit that regulates AMPA receptor gating and human trafficking, and abnormal AMPA receptor trafficking may contribute to seizure activity,” they added.

Researchers need to further examine the findings before they can be used in patients, but they believe they will help identify people who may develop drug resistance to epileptic medications early and will also help develop new medications for these patients.

“Our study provides the first evidence that common genetic variants (usually not addressed by clinical genetic testing) contribute significantly to epilepsy drug resistance,” Dr. Costin Leu, a researcher at Uthealth Houston, the first author of the study, said at a press conference.

“Recognizing these genetic variations that are frequently found in the general population but strongly affect treatment outcomes underscore the need to expand genetic testing and future treatments to address polygenic epilepsy, a type of epilepsy that is affected by multiple genes.”

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