Novel variants in GABAA receptor subunits: A possible association with benzodiazepine resistance in patients with drug-resistant epilepsy.

Benzodiazepines (BDZ) such as diazepam and lorazepam are popular as first-line treatment for acute seizures due to their rapid action and high efficacy. However, long-term usage of BDZ leads to benzodiazepine resistance, a phenomenon whose underlying mechanisms are still being investigated. One of the hypothesised mechanisms contributing to BDZ resistance is the presence of mutations in benzodiazepine-sensitive receptors. While a few genetic variants have been reported previously, knowledge of relevant pathogenic variants is still scarce. We used Sanger Sequencing to detect variants in the ligand-binding domain of BDZ-sensitive GABAA receptor subunits α1-3 and 5 expressed in resected brain tissues of drug-resistant epilepsy (DRE) patients with a history of BDZ resistance and found two previously unreported predicted pathogenic frameshifting variants - NM_000807.4(GABRA2):c.367_368insG and NM_000810.4(GABRA5):c.410del - significantly enriched in these patients. The findings were further explored in resected DRE brain tissues through cellular electrophysiological experiments.

Recent advances in Epilepsy Research in India.

There are more than 10 million persons with epilepsy (PWE) in India. Despite availability of antiepileptic drugs (AEDs), there is a large treatment gap varying from 50 to 70% among PWE. For treatable epilepsy, this gap can be attributed to poor education, poverty, cultural beliefs, stigma, and poor healthcare infrastructure; whereas for chronic epilepsy, this gap can be attributed to lack of proper diagnosis and treatment. To prevent, treat, and cure epilepsy, researchers worldwide have made exciting advances across all areas of epilepsy research. Studies carried out in India have also shown substantial progress; however, most of them are focused on the epidemiological aspects of epilepsy, genetic associations, identification, and validation of new AEDs in animal models of epilepsy.Very few studies are reported on understanding the process of epileptogenesis, a dynamic process by which neurons begin to display abnormal firing patterns that cause epileptic seizures. Animal epilepsy models can be used for in depth studies; however, studies conducted on resected brain tissues from epilepsy patients are clinically relevant. Finally, more funding support from government and collaborations among basic research institutes, medical institutes, as well as industries is required to raise the standards of epilepsy research in India.This review focuses on the evaluation of the current status of epilepsy research in India and the need to identify potential anti-epileptogenic interventions.