Snezana Maljevic1, Rikke S Møller2, Christopher A Reid1, Eduardo Pérez-Palma3, Dennis Lal3,4,5,6, Patrick May7, Holger Lerche8. 1. The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Melbourne, Australia. 2. The Danish Epilepsy Centre, Dianalund, Denmark. 3. Cologne Centre for Genomics, University of Cologne, Cologne, Germany. 4. Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 5. Epilepsy Center, Neurological Institute. 6. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA. 7. Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg. 8. Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Abstract
PURPOSE OF REVIEW: Recent publications point to an increasingly important role of variants in genes encoding GABAA receptor subunits associated with both common and rare forms of epilepsies. The aim of this review is to give an overview of the current clinical phenotypes, genetic findings and pathophysiological mechanisms related to GABAA receptor variants. RECENT FINDINGS: Early work showed that inherited variants in GABRG2 and GABRA1 cause relatively mild forms of monogenic epilepsies in large families. More recent studies have revealed that de novo variants in several GABAA receptor genes cause severe developmental and epileptic encephalopathies, inherited variants cause remarkably variable phenotypes within the same pedigrees ranging from asymptomatic carriers to developmental and epileptic encephalopathies, and variants in all GABAA receptor genes are enriched in common forms of epilepsy, namely rolandic epilepsy and genetic generalized epilepsy. Analyses from cellular expression systems and mouse models suggest that all variants cause a loss of GABAA receptor function resulting in GABAergic disinhibition. SUMMARY: Genetic studies have revealed a crucial role of the GABAergic system in the underlying pathogenesis of various forms of common and rare epilepsies. Our understanding of functional consequences of GABAA receptor variants provide an opportunity to develop precision-based therapeutic strategies that are hopefully free from the side-effect burden seen with currently available GABAergic drugs.
PURPOSE OF REVIEW: Recent publications point to an increasingly important role of variants in genes encoding GABAA receptor subunits associated with both common and rare forms of epilepsies. The aim of this review is to give an overview of the current clinical phenotypes, genetic findings and pathophysiological mechanisms related to GABAA receptor variants. RECENT FINDINGS: Early work showed that inherited variants in GABRG2 and GABRA1 cause relatively mild forms of monogenic epilepsies in large families. More recent studies have revealed that de novo variants in several GABAA receptor genes cause severe developmental and epilepticencephalopathies, inherited variants cause remarkably variable phenotypes within the same pedigrees ranging from asymptomatic carriers to developmental and epilepticencephalopathies, and variants in all GABAA receptor genes are enriched in common forms of epilepsy, namely rolandic epilepsy and genetic generalized epilepsy. Analyses from cellular expression systems and mouse models suggest that all variants cause a loss of GABAA receptor function resulting in GABAergic disinhibition. SUMMARY: Genetic studies have revealed a crucial role of the GABAergic system in the underlying pathogenesis of various forms of common and rare epilepsies. Our understanding of functional consequences of GABAA receptor variants provide an opportunity to develop precision-based therapeutic strategies that are hopefully free from the side-effect burden seen with currently available GABAergic drugs.
Authors: Saad Hannan; Aida H B Affandi; Marielle Minere; Charlotte Jones; Pollyanna Goh; Gary Warnes; Bernt Popp; Regina Trollmann; Dean Nizetic; Trevor G Smart Journal: J Neurosci Date: 2020-06-08 Impact factor: 6.167
Authors: Sarah E Heron; Brigid M Regan; Rebekah V Harris; Alison E Gardner; Matthew J Coleman; Mark F Bennett; Bronwyn E Grinton; Katherine L Helbig; Michael R Sperling; Sheryl Haut; Eric B Geller; Peter Widdess-Walsh; James T Pelekanos; Melanie Bahlo; Slavé Petrovski; Erin L Heinzen; Michael S Hildebrand; Mark A Corbett; Ingrid E Scheffer; Jozef Gécz; Samuel F Berkovic Journal: Neurology Date: 2021-03-23 Impact factor: 9.910
Authors: Christelle M El Achkar; Merle Harrer; Lacey Smith; McKenna Kelly; Sumaiya Iqbal; Snezana Maljevic; Cristina E Niturad; Lisenka E L M Vissers; Annapurna Poduri; Edward Yang; Dennis Lal; Holger Lerche; Rikke S Møller; Heather E Olson Journal: Ann Neurol Date: 2020-12-24 Impact factor: 11.274
Authors: Nathan L Absalom; Vivian W Y Liao; Kavitha Kothur; Dinesh C Indurthi; Bruce Bennetts; Christopher Troedson; Shekeeb S Mohammad; Sachin Gupta; Iain S McGregor; Michael T Bowen; Damien Lederer; Sandrine Mary; Liesbeth De Waele; Katrien Jansen; Deepak Gill; Manju A Kurian; Amy McTague; Rikke S Møller; Philip K Ahring; Russell C Dale; Mary Chebib Journal: Brain Commun Date: 2020-10-01