Temporal lobe epilepsy (TLE), a prevalent form of epilepsy affecting approximately 1-in-26 individuals, often poses challenges in finding effective treatment with conventional anti-seizure medications.

For patients suffering from TLE, neurosurgery becomes a viable option to alleviate seizures. However, the underlying causes and progression of this condition have remained elusive, leaving uncertainties regarding the role of genetic mutations.

New Study Reveals Genetic Clues and Potential Treatment for Drug-Resistant Temporal Lobe Epilepsy

In a groundbreaking study conducted by researchers from Mass General Brigham and in collaboration with Boston Children’s Hospital, fresh insights into the impact of somatic mutations—genetic alterations occurring after conception—on TLE have emerged. Moreover, the study indicates the potential use of existing cancer therapies to address drug-resistant TLE.

The findings, offering a ray of hope for patients, are published in JAMA Neurology.

“Somatic mutations,” according to co-first author Sattar Khoshkoo, “are likely an underappreciated and significant cause of neurologic diseases, particularly for epilepsy.”

As an epileptologist, the authors working assumption is “that all epilepsy is due to genetic causes until proven otherwise.”

The findings offer “the first solid insight into this most common form of adult epilepsy,” comments co-senior author Christopher Walsh.

They demonstrate that epilepsies, typically not considered hereditary, can still have a genetic basis. Moreover, the identification of the specific genetic pathway, RAS/MAPK, presents an entirely new realm of therapeutic opportunities. Anti-cancer medications designed to target this pathway could potentially be repurposed for treating epilepsy, opening up unforeseen possibilities.

Khoshkhoo and colleagues conducted a case-control genetic association study to uncover somatic mutations. They analyzed DNA from brain tissue samples collected from 105 epilepsy patients and 30 controls between 1988 and 2019. The team utilized whole exome sequencing to sequence portions of the genome coding for proteins and gene-panel sequencing to examine specific locations in the genome. On average, each genomic region was sequenced over 500 times.

The team identified 11 somatic mutations that were enriched in the hippocampus, the brain region where seizures commonly originate, from 11 patients with treatment-resistant TLE. Most of the 11 mutations were associated with the RAS/MAPK pathway, a specific genetic pathway.

This discovery is significant because the RAS/MAPK pathway has been targeted by anti-cancer drugs. If the study’s findings are confirmed, these drugs could be tested as potential treatments for TLE. Furthermore, the study’s results may guide treatment decisions for patients with or without these somatic mutations.

The results are “exciting,” says Kristopher Kahle, MD, Ph.D., the Nicholas T. Zervas Endowed Chair at Harvard Medical School and the chief of Pediatric Neurosurgery at Massachusetts General Hospital, a founding member of Mass General Brigham, as “it identifies potential drug targets that can be modulated with repurposed, FDA-approved anti-cancer agents.

“This suggests the potential for a rational, precision medicine treatment for a problem that we currently treat by removing a significant part of the temporal lobe with neurosurgery.”

The researchers acknowledge that their study sample consists only of patients with severe forms of the disease who required surgery, which may limit the generalizability of their findings to individuals with milder cases. Moreover, the patients’ samples used in the study may exhibit more scarring and cell death resulting from seizures. Consequently, the somatic mutations identified in this study could potentially be more widespread than the observed rates suggest.

To further explore their findings, the investigators intend to expand their analysis to include a larger number of hippocampus samples and employ cellular models to evaluate the efficacy of existing drugs.

Our findings point to the potential for developing the first disease modifying treatment in TLE,” adds Khoshkhoo. “Being able to provide a genetic diagnosis has implications for clinical decision making and could signal a new day for treatment.”

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