Epilepsy impacts roughly 1-in-26 folks 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 could require neurosurgery to supply reduction from seizures. The situation’s origins and development are usually not properly understood, and it has been unclear if genetic mutations could contribute to TLE. A brand new research by investigators from Mass Common Brigham, in collaboration with colleagues at Boston Youngsters’s Hospital, sheds new gentle on the position 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 proof against anti-seizure drugs. Their outcomes are printed in JAMA Neurology.
Somatic mutations are seemingly an underappreciated and important reason behind neurologic ailments, notably for epilepsy. And as an epileptologist who particularly focuses on epilepsy genetics in my scientific observe, my underlying assumption is that each one epilepsy is because of genetic causes till confirmed in any other case. We’re discovering an increasing number of new genetic pathways in epilepsy, which is essential as a result of our aim is to supply extra particular, focused remedies for particular person sufferers and provide steerage on who would profit from one therapy versus the opposite.”
Sattar Khoshkhoo, MD, Co-First Creator, Division of Neurology at Brigham and Ladies’s Hospital, founding member of the Mass Common Brigham healthcare system
“Our outcomes present the primary strong perception into this commonest type of grownup epilepsy,” stated co-senior creator Christopher Walsh, MD, PhD, of Boston Youngsters’s Hospital. “It reveals that epilepsies that aren’t normally inherited can nonetheless be genetic of their mechanism. And the particular genetic pathway now we have recognized, RAS/MAPK, opens a complete new avenue of therapeutic prospects, since anti-cancer medication that concentrate on this pathway could 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 instances on common.
The workforce pinpointed 11 somatic mutations that have been enriched within the hippocampus, the area of the mind the place seizures usually originate, from 11 sufferers with treatment-resistant TLE. All however one of many 11 mutations have been linked to a particular genetic pathway often known as the RAS/MAPK pathway. This discovering is especially essential as a result of a number of anti-cancer medication have been developed to focus on the RAS/MAPK pathway. If the research’s outcomes are confirmed and validated, such medication could possibly be examined for the therapy of TLE. Along with suggesting a possible path to therapy, the findings may be used to assist inform therapy 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 medication therapy for an issue that we presently deal with by eradicating a big a part of the temporal lobe with neurosurgery,” stated Kristopher Kahle, MD, PhD, the Nicholas T. Zervas Endowed Chair at Harvard Medical College and the chief of Pediatric Neurosurgery at Massachusetts Common Hospital, a founding member of Mass Common Brigham. Kahle additionally holds analysis appointments in genetics/genomics and neurosurgery at Boston Youngsters’s Hospital.
The authors notice that their research contains samples solely from sufferers whose illness was extreme sufficient to require surgical procedure and will not be generalizable to sufferers with much less extreme illness. As well as, samples from these sufferers could have extra scarring and cell loss of life from seizures. This might imply that the somatic mutations they detected could also be way 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 medication.
“Our findings level to the potential for creating the primary disease-modifying therapy in TLE,” stated Khoshkhoo. “Having the ability to present a genetic analysis has implications for scientific determination making and will sign a brand new day for therapy.”
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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. doi.org/10.1001/jamaneurol.2023.0473.
