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Epilepsy affects approximately 1-in-26 people and the most common form, known as temporal lobe epilepsy (TLE), often cannot be adequately treated with anti-seizure medications. Patients with this form of epilepsy may require neurosurgery to provide relief from seizures.
The condition’s origins and progression are not well understood, and it has been unclear if genetic mutations may contribute to TLE.
A new study by Harvard Medical School investigators at Brigham and Women’s and Massachusetts General hospitals, in collaboration with colleagues at Boston Children’s Hospital, sheds new light on the role of somatic mutations in TLE — DNA alterations that occur after conception — and suggests the potential of using existing cancer therapies to treat TLE that is resistant to anti-seizure medications. The results are published in JAMA Neurology.
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“Somatic mutations are likely an underappreciated and significant cause of neurologic diseases, particularly for epilepsy,” said co-first author Sattar Khoshkhoo, HMS instructor in neurology at Brigham and Women’s Hospital.
“And as an epileptologist who specifically focuses on epilepsy genetics in my clinical practice, my underlying assumption is that all epilepsy is due to genetic causes until proven otherwise. We are discovering more and more new genetic pathways in epilepsy, which is important because our goal is to offer more specific, targeted treatments for individual patients and offer guidance on who would benefit from one treatment versus the other,” he said.
“Our results provide the first solid insight into this most common form of adult epilepsy,” said co-senior author Christopher A. Walsh,the Bullard Professor of Pediatrics and Neurology at Boston Children’s Hospital.
“It shows that epilepsies that are not usually inherited can still be genetic in their mechanism. And the specific genetic pathway we have identified, RAS/MAPK, opens a whole new avenue of therapeutic possibilities, since anti-cancer drugs that target this pathway may have unexpected uses in epilepsy,” Walsh said.
Uncovering somatic mutations
To uncover somatic mutations, Khoshkhoo and colleagues performed a case-control genetic association study, analyzing DNA from brain tissue samples collected from 105 patients with epilepsy and 30 controls between 1988 and 2019.
The team sequenced portions of the genome coding for proteins (whole exome sequencing) and looked at specific locations in the genome (gene-panel sequencing), with each genomic region sequenced more than 500 times on average.
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