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

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Title: Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment
Authors: Symonds, JD
Zuberi, SM
Johnson, MR
Item Type: Journal Article
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.
Issue Date: 1-Apr-2017
Date of Acceptance: 1-Apr-2017
URI: http://hdl.handle.net/10044/1/47913
DOI: https://dx.doi.org/10.1097/WCO.0000000000000433
ISSN: 1350-7540
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Start Page: 193
End Page: 199
Journal / Book Title: CURRENT OPINION IN NEUROLOGY
Volume: 30
Issue: 2
Copyright Statement: © 2017 Wolters Kluwer Health, Inc. All rights resereved. This is a non-final version of an article published in final form in Current Opinion in Neurology Issue: Volume 30(2), April 2017, p 193–199, DOI: 10.1097/WCO.0000000000000433 available at: https://dx.doi.org/10.1097/WCO.0000000000000433
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: RDA03
Keywords: Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Neurosciences & Neurology
drug discovery
epilepsy
genetics
networks
next-generation sequencing
precision medicine
systems genetics
FOCAL CORTICAL DYSPLASIA
SEVERE DEVELOPMENTAL DELAY
OF-FUNCTION MUTATIONS
DE-NOVO MUTATIONS
PHENOTYPIC SPECTRUM
SOMATIC MUTATIONS
MAMMALIAN TARGET
GRIN2A MUTATIONS
ILAE COMMISSION
ENCEPHALOPATHY
Neurology & Neurosurgery
1103 Clinical Sciences
1109 Neurosciences
1702 Cognitive Science
Publication Status: Published
Appears in Collections:Department of Medicine (up to 2019)