Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment

Symonds, J. D., Zuberi, S. M. and Johnson, M. R. (2017) Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment. Current Opinion in Neurology, 30(2), pp. 193-199. (doi: 10.1097/WCO.0000000000000433) (PMID:28212175)

Abstract

Purpose of review: Epilepsy genetics is shifting from the academic pursuit of gene discovery to a clinical discipline based on molecular diagnosis and stratified medicine. We consider the latest developments in epilepsy genetics and review how gene discovery in epilepsy is influencing the clinical classification of epilepsy and informing new therapeutic approaches and drug discovery. Recent findings: Recent studies highlighting the importance of mutation in GABA receptors, NMDA receptors, potassium channels, G-protein coupled receptors, mammalian target of rapamycin pathway and chromatin remodeling are discussed. Examples of precision medicine in epilepsy targeting gain-of-function mutations in KCNT1, GRIN2A, GRIN2D and SCN8A are presented. Potential reasons for the paucity of examples of precision medicine for loss-of-function mutations or in non-ion channel epilepsy genes are explored. We highlight how systems genetics and gene network analyses have suggested that pathways disrupted in epilepsy overlap with those of other neurodevelopmental traits including human cognition. We review how network-based computational approaches are now being applied to epilepsy drug discovery. Summary: We are living in an unparalleled era of epilepsy gene discovery. Advances in clinical care from this progress are already materializing through improved clinical diagnosis and stratified medicine. The application of targeted drug repurposing based on single gene defects has shown promise for epilepsy arising from gain-of-function mutations in ion-channel subunit genes, but important barriers remain to translating these approaches to non-ion channel epilepsy genes and loss-of-function mutations. Gene network analysis offers opportunities to discover new pathways for epilepsy, to decipher epilepsy’s relationship to other neurodevelopmental traits and to frame a new approach to epilepsy drug discovery

• Item Type: Articles
• Additional Information: J.D.S. is funded for a PhD in epilepsy genetics by the Glasgow Children’s Hospital Charity (Scottish Charity Number SCO 007856). S.M.Z. receives research funding from Epilepsy Research UK, Dravet Syndrome UK, UCB Pharma and Glasgow Childrens Hospital Charity. He is Editor-in-Chief of the European Journal of Paediatric Neurology for which he receives an honorarium. M.J.R. receives funding from Imperial College NIHR Biomedical Research Centre (BRC) Scheme, UCB Pharma, and the Medical Research Council.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Zuberi, Dr Sameer
• Authors: Symonds, J. D., Zuberi, S. M., and Johnson, M. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Current Opinion in Neurology
• Publisher: Lippincott, Williams & Wilkins
• ISSN: 1350-7540
• ISSN (Online): 1473-6551
• Published Online: 15 February 2017