Identification and Treatment of Somatic Mutations in Mesial Temporal Lobe Epilepsy (MTLE)

Background

Epilepsy is a chronic neurological condition that affects over 50 million people worldwide. Mesial temporal lobe epilepsy (MTLE), the most common focal epilepsy, is characterized by recurrent focal seizures, memory issues, risk of injury due to recurrent seizures, and a generally low quality of life. MTLE is resistant to common drug treatments in roughly one-third of all patients, resulting in significant neurologic and psychiatric morbidity. The only other treatment option is temporal lobectomy, a surgery which can cost up to 100K USD per patient. Despite being common, MTLE is still relatively poorly understood. It has long been thought to not have a genetic component and with a few exceptions, researchers have been unable to successfully identify genetic determinants of focal epilepsies such as MTLE. Therefore, improved methods for characterizing and treating patients with MTLE are urgently required, and the development of alternative drug therapies is estimated to have a potential market size of 5-20 billion USD.

Technology Overview

A team of researchers at Boston Children’s Hospital has devised new methods or identifying and/or treating MTLE. Researchers performed whole-exome sequencing to identify rare somatic mutations in the hippocampus tissues of patients suffering from MTLE and who are resistant to drug treatments. The team identified several pathogenic somatic Ras-MAPK variants, such as PTPN11 and FGFR1, as present in >30% of patient hippocampal tissue from drug-resistant TLE cases. This approach allows the identification of many factors involved in MTLE that were previously uncharacterized. This analysis opens the field for targeting all these factors by using new small-molecule drugs or testing off-label drugs already well characterized.

Benefits

• Identification of new targets for possible therapeutic interventions
• Possible treatment by off-label drug already commercialized or in development
• May reduce the need for invasive surgical interventions and their associated risks

Applications

• Treatments of mesial temporal lobe epilepsy
• Targeted genetic testing for epilepsy disorders

Publications

Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy. Khoshkhoo et al. JAMA Neurol. 2023;80(6):578-587. doi:10.1001/jamaneurol.2023.0473