Research sheds new gentle on the function of somatic mutations in temporal lobe epilepsy

Epilepsy impacts roughly 1-in-26 individuals and the most typical type, often known as temporal lobe epilepsy (TLE), usually can’t be adequately handled with anti-seizure drugs. Sufferers with this type of epilepsy might require neurosurgery to offer reduction from seizures. The situation’s origins and development usually are not effectively understood, and it has been unclear if genetic mutations might contribute to TLE. A brand new research by investigators from Mass Basic Brigham, in collaboration with colleagues at Boston Youngsters’s Hospital, sheds new gentle on the function of somatic mutations in TLE -; DNA alterations that happen after conception -; and suggests the potential of utilizing present most cancers therapies to deal with TLE that’s immune to anti-seizure drugs. Their outcomes are revealed in JAMA Neurology.

Somatic mutations are probably an underappreciated and important reason behind neurologic ailments, significantly for epilepsy. And as an epileptologist who particularly focuses on epilepsy genetics in my medical follow, my underlying assumption is that every one epilepsy is because of genetic causes till confirmed in any other case. We’re discovering increasingly new genetic pathways in epilepsy, which is essential as a result of our purpose is to supply extra particular, focused therapies for particular person sufferers and provide steerage on who would profit from one remedy versus the opposite.”

Sattar Khoshkhoo, MD, Co-First Writer, Division of Neurology at Brigham and Girls’s Hospital, founding member of the Mass Basic Brigham healthcare system

“Our outcomes present the primary strong perception into this most typical type of grownup epilepsy,” mentioned co-senior creator Christopher Walsh, MD, PhD, of Boston Youngsters’s Hospital. “It reveals that epilepsies that aren’t often inherited can nonetheless be genetic of their mechanism. And the precise genetic pathway we’ve recognized, RAS/MAPK, opens a complete new avenue of therapeutic potentialities, since anti-cancer medicine that focus on this pathway might have surprising makes use of in epilepsy.”

To uncover somatic mutations, Khoshkhoo and colleagues carried out a case-control genetic affiliation research, analyzing DNA from mind tissue samples collected from 105 sufferers with epilepsy and 30 controls between 1988 and 2019. The workforce sequenced parts of the genome coding for proteins (entire exome sequencing) and checked out particular areas within the genome (gene-panel sequencing), with every genomic area sequenced greater than 500 occasions on common.

The workforce pinpointed 11 somatic mutations that have been enriched in hippocampus, the area of the mind the place seizures sometimes originate, from 11 sufferers with treatment-resistant TLE. All however one of many 11 mutations have been linked to a selected genetic pathway often known as the RAS/MAPK pathway. This discovering is especially essential as a result of a number of anti-cancer medicine have been developed to focus on the RAS/MAPK pathway. If the research’s outcomes are confirmed and validated, such medicine may very well be examined for the remedy of TLE. Along with suggesting a possible path to remedy, the findings may be used to assist inform remedy choices for sufferers who do or don’t harbor these somatic mutations.

“This work is thrilling as a result of it identifies potential drug targets that may be modulated with repurposed, FDA-approved anti-cancer brokers. This implies the potential for a rational, precision drugs remedy for an issue that we at present deal with by eradicating a major a part of the temporal lobe with neurosurgery,” mentioned Kristopher Kahle, MD, PhD, the Nicholas T. Zervas Endowed Chair at Harvard Medical Faculty and the chief of Pediatric Neurosurgery at Massachusetts Basic Hospital, a founding member of Mass Basic Brigham. Kahle additionally holds analysis appointments in genetics/genomics and neurosurgery at Boston Youngsters’s Hospital.

The authors observe that their research contains samples solely from sufferers whose illness was extreme sufficient to require surgical procedure and is probably not generalizable to sufferers with much less extreme illness. As well as, samples from these sufferers might have extra scarring and cell dying from seizures. This might imply that the somatic mutations they detected could also be far more prevalent than the charges discovered on this research.

The investigators plan to check a bigger variety of hippocampus samples and use cell fashions to check pre-existing medicine.

“Our findings level to the potential for creating the primary disease-modifying remedy in TLE,” mentioned Khoshkhoo. “With the ability to present a genetic prognosis has implications for medical choice making and will sign a brand new day for remedy.”


Journal reference:

Khoshkhoo, S., et al. (2023) Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants within the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy. JAMA Neurology.