Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Epilepsy: HELP
Articles by Christopher Alan Reid
Based on 32 articles published since 2010
(Why 32 articles?)
||||

Between 2010 and 2020, C. A. Reid wrote the following 32 articles about Epilepsy.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Spectrum of GABAA receptor variants in epilepsy. 2019

Maljevic, Snezana / Møller, Rikke S / Reid, Christopher A / Pérez-Palma, Eduardo / Lal, Dennis / May, Patrick / Lerche, Holger. ·The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Melbourne, Australia. · The Danish Epilepsy Centre, Dianalund, Denmark. · Cologne Centre for Genomics, University of Cologne, Cologne, Germany. · Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. · Epilepsy Center, Neurological Institute. · Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA. · Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg. · Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany. ·Curr Opin Neurol · Pubmed #30664068.

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.

2 Review Can mutation-mediated effects occurring early in development cause long-term seizure susceptibility in genetic generalized epilepsies? 2018

Reid, Christopher Alan / Rollo, Ben / Petrou, Steven / Berkovic, Samuel F. ·The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia. · Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia. ·Epilepsia · Pubmed #29658992.

ABSTRACT: Epilepsy has a strong genetic component, with an ever-increasing number of disease-causing genes being discovered. Most epilepsy-causing mutations are germ line and thus present from conception. These mutations are therefore well positioned to have a deleterious impact during early development. Here we review studies that investigate the role of genetic lesions within the early developmental window, specifically focusing on genetic generalized epilepsy (GGE). Literature on the potential pathogenic role of sub-mesoscopic structural changes in GGE is also reviewed. Evidence from rodent models of genetic epilepsy support the idea that functional and structural changes can occur in early development, leading to altered seizure susceptibility into adulthood. Both animal and human studies suggest that sub-mesoscopic structural changes occur in GGE. The existence of sub-mesoscopic structural changes prior to seizure onset may act as biomarkers of excitability in genetic epilepsies. We also propose that presymptomatic treatment may be essential for limiting the long-term consequences of disease-causing mutations in genetic epilepsies.

3 Review Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies. 2018

Oyrer, Julia / Maljevic, Snezana / Scheffer, Ingrid E / Berkovic, Samuel F / Petrou, Steven / Reid, Christopher A. ·The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Melbourne, Australia (J.O., S.M., I.E.S., S.P., C.A.R.); Department of Medicine, Austin Health, University of Melbourne, Heidelberg West, Melbourne, Australia (I.E.S., S.F.B.); and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia (I.E.S.). · The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Melbourne, Australia (J.O., S.M., I.E.S., S.P., C.A.R.); Department of Medicine, Austin Health, University of Melbourne, Heidelberg West, Melbourne, Australia (I.E.S., S.F.B.); and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia (I.E.S.) christopher.reid@florey.edu.au. ·Pharmacol Rev · Pubmed #29263209.

ABSTRACT: Epilepsy is a common and serious neurologic disease with a strong genetic component. Genetic studies have identified an increasing collection of disease-causing genes. The impact of these genetic discoveries is wide reaching-from precise diagnosis and classification of syndromes to the discovery and validation of new drug targets and the development of disease-targeted therapeutic strategies. About 25% of genes identified in epilepsy encode ion channels. Much of our understanding of disease mechanisms comes from work focused on this class of protein. In this study, we review the genetic, molecular, and physiologic evidence supporting the pathogenic role of a number of different voltage- and ligand-activated ion channels in genetic epilepsy. We also review proposed disease mechanisms for each ion channel and highlight targeted therapeutic strategies.

4 Review Models for discovery of targeted therapy in genetic epileptic encephalopathies. 2017

Maljevic, Snezana / Reid, Christopher A / Petrou, Steven. ·The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia. · University of Melbourne, Melbourne, Australia. ·J Neurochem · Pubmed #28742937.

ABSTRACT: Epileptic encephalopathies are severe disorders emerging in the first days to years of life that commonly include refractory seizures, various types of movement disorders, and different levels of developmental delay. In recent years, many de novo occurring variants have been identified in individuals with these devastating disorders. To unravel disease mechanisms, the functional impact of detected variants associated with epileptic encephalopathies is investigated in a range of cellular and animal models. This review addresses efforts to advance and use such models to identify specific molecular and cellular targets for the development of novel therapies. We focus on ion channels as the best-studied group of epilepsy genes. Given the clinical and genetic heterogeneity of epileptic encephalopathy disorders, experimental models that can reflect this complexity are critical for the development of disease mechanisms-based targeted therapy. The convergence of technological advances in gene sequencing, stem cell biology, genome editing, and high throughput functional screening together with massive unmet clinical needs provides unprecedented opportunities and imperatives for precision medicine in epileptic encephalopathies.

5 Review Epilepsy, energy deficiency and new therapeutic approaches including diet. 2014

Reid, Christopher A / Mullen, Saul / Kim, Tae Hwan / Petrou, Steven. ·Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia. Electronic address: careid@unimelb.edu.au. · Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia. · Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia; Centre for Neural Engineering, The University of Melbourne, Parkville, Melbourne, Australia; Department of Electrical Engineering, The University of Melbourne, Parkville, Melbourne, Australia. ·Pharmacol Ther · Pubmed #24924701.

ABSTRACT: Metabolic dysfunction leading to epilepsy is well recognised. Dietary therapy, in particular the ketogenic diet, is now considered an effective option. Recent genetic studies have highlighted the central role that metabolism can play in setting seizure susceptibility. Here we discuss various metabolic disorders implicated in epilepsy focusing on energy deficiency due to genetic and environmental causes. We argue that low, uncompensated brain glucose levels can precipitate seizures. We will also explore mechanisms of disease and therapy in an attempt to identify common metabolic pathways involved in modulating seizure susceptibility. Finally, newer therapeutic approaches based on diet manipulation in the context of energy deficiency are discussed.

6 Review HCN channelopathies: pathophysiology in genetic epilepsy and therapeutic implications. 2012

Reid, Christopher A / Phillips, A Marie / Petrou, Steven. ·Florey Neuroscience Institute and The Centre for Neuroscience, The University of Melbourne, Parkville, Victoria, Australia. careid@unimelb.edu.au ·Br J Pharmacol · Pubmed #21615728.

ABSTRACT: Hyperpolarization-activated cyclic nucleotide-gated channels (HCN) can act as pacemakers in the brain making them strong candidates for driving aberrant hypersynchronous network activity seen in epilepsy. Transcriptional changes in HCN channels occur in several animal models of epilepsy. However, only recently have genetic studies demonstrated sequence variation in HCN1 and HCN2 genes associated with human epilepsy. These include a triple proline deletion in HCN2 that increases channel function and occurs more often in patients with febrile seizure syndromes. Other HCNx gene variants have been described in idiopathic generalized epilepsy although the functional consequence of these remains unclear. In this review we explore potential cellular and network mechanisms involving HCN channels in the genetic epilepsies. We suggest how new genetic sequencing technology, medium-throughput functional assays and the ability to develop syndrome-specific animal models will provide a more comprehensive understanding of how I(h) contributes to pathogenic mechanisms underlying human genetic epilepsy. We also discuss what is known about the pharmacological manipulation of HCN channels in the context of epilepsy and how this may help future efforts in developing HCN-channel-based therapy.

7 Review New therapeutic opportunities in epilepsy: a genetic perspective. 2010

Reid, Christopher A / Jackson, Graeme D / Berkovic, Samuel F / Petrou, Steven. ·Florey Neuroscience Institutes, The University of Melbourne, Parkville, Melbourne, Australia. ·Pharmacol Ther · Pubmed #20705092.

ABSTRACT: Epilepsy is a common and serious neurological disorder. Despite recent advances in drug therapy, treatment for epilepsy is still largely empirical and rational prescribing based on the mechanism of action in an individual patient is generally not possible. Genetic studies have identified an increasing collection of disease-causing genes providing a fundamental molecular foundation on which to build this understanding, at least for some forms of epilepsy. The impact of these genetic discoveries is likely to be wide reaching-from the discovery and validation of new drug targets to the potential to enable rational prescribing based on genetic makeup and even further through animal experimentation to tease out molecular and cellular mechanisms that lead to hyperexcitable neuronal networks causing epilepsy. Here we discuss how we can use knowledge of genetic mechanisms to improve treatment strategies now and into the future.

8 Review Axon initial segment dysfunction in epilepsy. 2010

Wimmer, Verena C / Reid, Christopher A / So, Eva Y-W / Berkovic, Samuel F / Petrou, Steven. ·Florey Neuroscience Institutes, University of Melbourne, Parkville 3010, Victoria, Australia. ·J Physiol · Pubmed #20375142.

ABSTRACT: The axon initial segment (AIS) contains the site of action potential initiation and plays a major role in neuronal excitability. AIS function relies on high concentrations of different ion channels and complex regulatory mechanisms that orchestrate molecular microarchitecture. We review recent evidence that a large number of ion channels associated with epilepsy are enriched at the AIS, making it a 'hotspot' for epileptogenesis. Furthermore, we present novel data on the clustering of GABRgamma2 receptors in the AIS of cortical and hippocampal neurons in a knock in mouse model of a human genetic epilepsy. This article highlights the molecular coincidence of epilepsy mutations at the AIS and reviews pathogenic mechanisms converging at the AIS.

9 Article Selective Na 2018

Richards, Kay L / Milligan, Carol J / Richardson, Robert J / Jancovski, Nikola / Grunnet, Morten / Jacobson, Laura H / Undheim, Eivind A B / Mobli, Mehdi / Chow, Chun Yuen / Herzig, Volker / Csoti, Agota / Panyi, Gyorgy / Reid, Christopher A / King, Glenn F / Petrou, Steven. ·Ion Channels and Disease Group, Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia. · Neuroscience Drug Discovery, H. Lundbeck A/S, DK-2500 Valby, Denmark. · Department of Drug Design and Pharmacology, Copenhagen University, DK-2100 Copenhagen, Denmark. · Sleep and Cognition Group, Epilepsy Division, Florey Insitute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia. · Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, VIC 3010, Australia. · Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD 4072, Australia. · Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. · Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary. · Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia. · Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; glenn.king@imb.uq.edu.au spetrou@unimelb.edu.au. · Ion Channels and Disease Group, Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia; glenn.king@imb.uq.edu.au spetrou@unimelb.edu.au. ·Proc Natl Acad Sci U S A · Pubmed #30076230.

ABSTRACT: Dravet syndrome is a catastrophic, pharmacoresistant epileptic encephalopathy. Disease onset occurs in the first year of life, followed by developmental delay with cognitive and behavioral dysfunction and substantially elevated risk of premature death. The majority of affected individuals harbor a loss-of-function mutation in one allele of

10 Article Rare coding variants in genes encoding GABA 2018

May, Patrick / Girard, Simon / Harrer, Merle / Bobbili, Dheeraj R / Schubert, Julian / Wolking, Stefan / Becker, Felicitas / Lachance-Touchette, Pamela / Meloche, Caroline / Gravel, Micheline / Niturad, Cristina E / Knaus, Julia / De Kovel, Carolien / Toliat, Mohamad / Polvi, Anne / Iacomino, Michele / Guerrero-López, Rosa / Baulac, Stéphanie / Marini, Carla / Thiele, Holger / Altmüller, Janine / Jabbari, Kamel / Ruppert, Ann-Kathrin / Jurkowski, Wiktor / Lal, Dennis / Rusconi, Raffaella / Cestèle, Sandrine / Terragni, Benedetta / Coombs, Ian D / Reid, Christopher A / Striano, Pasquale / Caglayan, Hande / Siren, Auli / Everett, Kate / Møller, Rikke S / Hjalgrim, Helle / Muhle, Hiltrud / Helbig, Ingo / Kunz, Wolfram S / Weber, Yvonne G / Weckhuysen, Sarah / Jonghe, Peter De / Sisodiya, Sanjay M / Nabbout, Rima / Franceschetti, Silvana / Coppola, Antonietta / Vari, Maria S / Kasteleijn-Nolst Trenité, Dorothée / Baykan, Betul / Ozbek, Ugur / Bebek, Nerses / Klein, Karl M / Rosenow, Felix / Nguyen, Dang K / Dubeau, François / Carmant, Lionel / Lortie, Anne / Desbiens, Richard / Clément, Jean-François / Cieuta-Walti, Cécile / Sills, Graeme J / Auce, Pauls / Francis, Ben / Johnson, Michael R / Marson, Anthony G / Berghuis, Bianca / Sander, Josemir W / Avbersek, Andreja / McCormack, Mark / Cavalleri, Gianpiero L / Delanty, Norman / Depondt, Chantal / Krenn, Martin / Zimprich, Fritz / Peter, Sarah / Nikanorova, Marina / Kraaij, Robert / van Rooij, Jeroen / Balling, Rudi / Ikram, M Arfan / Uitterlinden, André G / Avanzini, Giuliano / Schorge, Stephanie / Petrou, Steven / Mantegazza, Massimo / Sander, Thomas / LeGuern, Eric / Serratosa, Jose M / Koeleman, Bobby P C / Palotie, Aarno / Lehesjoki, Anna-Elina / Nothnagel, Michael / Nürnberg, Peter / Maljevic, Snezana / Zara, Federico / Cossette, Patrick / Krause, Roland / Lerche, Holger / Anonymous5240955 / Anonymous5250955 / Anonymous5260955. · ·Lancet Neurol · Pubmed #30033060.

ABSTRACT: BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABA FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABA INTERPRETATION: Functionally relevant variants in genes encoding GABA FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).

11 Article Gain-of-function HCN2 variants in genetic epilepsy. 2018

Li, Melody / Maljevic, Snezana / Phillips, A Marie / Petrovski, Slave / Hildebrand, Michael S / Burgess, Rosemary / Mount, Therese / Zara, Federico / Striano, Pasquale / Schubert, Julian / Thiele, Holger / Nürnberg, Peter / Wong, Michael / Weisenberg, Judith L / Thio, Liu Lin / Lerche, Holger / Scheffer, Ingrid E / Berkovic, Samuel F / Petrou, Steven / Reid, Christopher A. ·Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia. · School of Biosciences, The University of Melbourne, Parkville, Victoria, Australia. · Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia. · Laboratory of Neurogenetics, Department of Neuroscience, Institute "G. Gaslini", Genoa, Italy. · Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Institute "G. Gaslini", Genoa, Italy. · University of Tübingen, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Tübingen, Germany. · Cologne Centre for Genomics, University of Cologne, Cologne, Germany. · Department of Neurology, Washington University School of Medicine and St. Louis Children's Hospital, St Louis, Missouri. ·Hum Mutat · Pubmed #29064616.

ABSTRACT: Genetic generalized epilepsy (GGE) is a common epilepsy syndrome that encompasses seizure disorders characterized by spike-and-wave discharges (SWDs). Pacemaker hyperpolarization-activated cyclic nucleotide-gated channels (HCN) are considered integral to SWD genesis, making them an ideal gene candidate for GGE. We identified HCN2 missense variants from a large cohort of 585 GGE patients, recruited by the Epilepsy Phenome-Genome Project (EPGP), and performed functional analysis using two-electrode voltage clamp recordings from Xenopus oocytes. The p.S632W variant was identified in a patient with idiopathic photosensitive occipital epilepsy and segregated in the family. This variant was also independently identified in an unrelated patient with childhood absence seizures from a European cohort of 238 familial GGE cases. The p.V246M variant was identified in a patient with photo-sensitive GGE and his father diagnosed with juvenile myoclonic epilepsy. Functional studies revealed that both p.S632W and p.V246M had an identical functional impact including a depolarizing shift in the voltage dependence of activation that is consistent with a gain-of-function. In contrast, no biophysical changes resulted from the introduction of common population variants, p.E280K and p.A705T, and the p.R756C variant from EPGP that did not segregate with disease. Our data suggest that HCN2 variants can confer susceptibility to GGE via a gain-of-function mechanism.

12 Article Functional variants in 2017

Becker, Felicitas / Reid, Christopher A / Hallmann, Kerstin / Tae, Han-Shen / Phillips, A Marie / Teodorescu, Georgeta / Weber, Yvonne G / Kleefuss-Lie, Ailing / Elger, Christian / Perez-Reyes, Edward / Petrou, Steven / Kunz, Wolfram S / Lerche, Holger / Maljevic, Snezana. ·Department of Neurology and Epileptology Hertie-Institute for Clinical Brain-Research University of Tübingen Tübingen Germany. · RKU-University Neurology Clinic of Ulm Ulm Germany. · The Florey Institute of Neuroscience and Mental Health Melbourne Victoria Australia. · Department of Neurology and Epileptology University of Bonn Medical Center Bonn Germany. · Present address: Illawarra Health and Medical Research Institute (IHMRI) University of Wollongong Wollongong New South Wales Australia. · School of Biosciences The University of Melbourne Melbourne Victoria Australia. · Department of Pharmacology University of Virginia Charlottesville Virginia U.S.A. ·Epilepsia Open · Pubmed #29588962.

ABSTRACT: Objective: Genetic generalized epilepsy (GGE) encompasses seizure disorders characterized by spike-and-wave discharges (SWD) originating within thalamo-cortical circuits. Hyperpolarization-activated (HCN) and T-type Ca Methods: Targeted gene sequencing was performed in 20 unrelated familial cases with different subtypes of GGE, and the results confirmed in 230 ethnically matching controls. Selected variants in Results: We discovered a novel Significance: Our results are consistent with a model suggesting cumulative contributions of subtle functional variations in ion channels to seizure susceptibility and GGE.

13 Article Gabapentin Modulates HCN4 Channel Voltage-Dependence. 2017

Tae, Han-Shen / Smith, Kelly M / Phillips, A Marie / Boyle, Kieran A / Li, Melody / Forster, Ian C / Hatch, Robert J / Richardson, Robert / Hughes, David I / Graham, Brett A / Petrou, Steven / Reid, Christopher A. ·Florey Institute of Neuroscience and Mental Health, The University of Melbourne, ParkvilleVIC, Australia. · School of Biomedical Sciences and Pharmacy, University of Newcastle, CallaghanNSW, Australia. · Hunter Medical Research Institute, New Lambton HeightsNSW, Australia. · School of BioSciences, The University of Melbourne, ParkvilleVIC, Australia. · Institute of Neuroscience and Psychology, University of GlasgowGlasgow, United Kingdom. ·Front Pharmacol · Pubmed #28871229.

ABSTRACT: Gabapentin (GBP) is widely used to treat epilepsy and neuropathic pain. There is evidence that GBP can act on hyperpolarization-activated cation (HCN) channel-mediated

14 Article Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K 2017

Oliver, Karen L / Franceschetti, Silvana / Milligan, Carol J / Muona, Mikko / Mandelstam, Simone A / Canafoglia, Laura / Boguszewska-Chachulska, Anna M / Korczyn, Amos D / Bisulli, Francesca / Di Bonaventura, Carlo / Ragona, Francesca / Michelucci, Roberto / Ben-Zeev, Bruria / Straussberg, Rachel / Panzica, Ferruccio / Massano, João / Friedman, Daniel / Crespel, Arielle / Engelsen, Bernt A / Andermann, Frederick / Andermann, Eva / Spodar, Krystyna / Lasek-Bal, Anetta / Riguzzi, Patrizia / Pasini, Elena / Tinuper, Paolo / Licchetta, Laura / Gardella, Elena / Lindenau, Matthias / Wulf, Annette / Møller, Rikke S / Benninger, Felix / Afawi, Zaid / Rubboli, Guido / Reid, Christopher A / Maljevic, Snezana / Lerche, Holger / Lehesjoki, Anna-Elina / Petrou, Steven / Berkovic, Samuel F. ·Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia. · Department of Neurophysiology, C. Besta Neurological Institute IRCCS Foundation, Milan, Italy. · Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia. · Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. · Folkhälsan Institute of Genetics, Helsinki, Finland. · Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. · Neuroscience Center, University of Helsinki, Helsinki, Finland. · Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia. · Departments of Paediatrics and Radiology, University of Melbourne, Melbourne, Victoria, Australia. · Department of Medical Imaging, Royal Children's Hospital, Melbourne, Victoria, Australia. · Genomed Health Care Center, Genomed, Warsaw, Poland. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · IRCCS-Institute of Neurological Sciences of Bologna, Bologna, Italy. · Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. · Department of Neurological Sciences, University of Rome, La Sapienza, Rome, Italy. · Department of Pediatric Neuroscience, C. Besta Neurological Institute IRCCS Foundation, Milan, Italy. · Unit of Neurology, Bellaria Hospital, Bologna, Italy. · Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel. · Epilepsy Unit, Schneider Children's Medical Center of Israel, Petah Tikvah, Israel. · Department of Neurology, Hospital Pedro Hispano/ULS Matosinhos, Senhora da Hora, Portugal. · Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, Porto, Portugal. · Comprehensive Epilepsy Center, New York University Langone Medical Center, New York, NY. · Epilepsy Unit, Gui de Chauliac Hospital, Montpellier, France. · Department of Clinical Medicine, University of Bergen, Bergen, Norway. · Epilepsy Research Group, Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada. · Departments of Neurology & Neurosurgery and Paediatrics, McGill University, Montreal, Quebec, Canada. · Neurogenetics Unit and Epilepsy Research Group, Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada. · Departments of Neurology & Neurosurgery and Human Genetics, McGill University, Montreal, Quebec, Canada. · High School of Science, Medical University of Silesia, Department of Neurology, Upper Silesian Medical Center, Katowice, Poland. · Danish Epilepsy Center, Dianalund, Denmark. · Institute for Regional Health Research, University of Southern Denmark, Odense, Denmark. · Department of Neurology and Epileptology, Epilepsy Center Hamburg-Alsterdorf, Hamburg, Germany. · Department of Neurology, Rabin Medical Center, Beilinson Hospital, Petah Tikvah, Israel. · Danish Epilepsy Center, Filadelfia/University of Copenhagen, Dianalund, Denmark. · University of Tübingen, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Tübingen, Germany. · Centre for Neural Engineering, Department of Electrical Engineering, University of Melbourne, Parkville, Victoria, Australia. ·Ann Neurol · Pubmed #28380698.

ABSTRACT: OBJECTIVE: To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever. METHODS: We analyzed clinical, electroclinical, and neuroimaging data for 20 patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch-clamp to explore biophysical properties of wild-type and mutant K RESULTS: Symptoms began at between 3 and 15 years of age (median = 9.5), with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early, but quickly became overshadowed by myoclonus; 10 patients were wheelchair-bound by their late teenage years. Mild cognitive decline occurred in half. Early death was not observed. Electroencephalogram (EEG) showed generalized spike and polyspike wave discharges, with documented photosensitivity in most. Polygraphic EEG-electromyographic studies demonstrated a cortical origin for myoclonus and striking coactivation of agonist and antagonist muscles. Magnetic resonance imaging revealed symmetrical cerebellar atrophy, which appeared progressive, and a prominent corpus callosum. Unexpectedly, transient clinical improvement with fever was noted in 6 patients. To explore this, we performed high-temperature in vitro recordings. At elevated temperatures, there was a robust leftward shift in activation of wild-type K INTERPRETATION: MEAK has a relatively homogeneous presentation, resembling Unverricht-Lundborg disease, despite the genetic and biological basis being quite different. A remarkable improvement with fever may be explained by the temperature-dependent leftward shift in activation of wild-type K

15 Article A targeted resequencing gene panel for focal epilepsy. 2016

Hildebrand, Michael S / Myers, Candace T / Carvill, Gemma L / Regan, Brigid M / Damiano, John A / Mullen, Saul A / Newton, Mark R / Nair, Umesh / Gazina, Elena V / Milligan, Carol J / Reid, Christopher A / Petrou, Steven / Scheffer, Ingrid E / Berkovic, Samuel F / Mefford, Heather C. ·From the Epilepsy Research Centre (M.S.H., B.M.R., J.A.D., S.A.M., M.R.N., I.E.S., S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia · Division of Genetic Medicine (C.T.M., G.L.C., H.C.M.), Department of Pediatrics, University of Washington, Seattle, WA · Florey Institute for Neuroscience and Mental Health (U.N., E.V.G., C.J.M., C.A.R., S.P., I.E.S.), University of Melbourne, Melbourne, Victoria, Australia · Department of Neurology (I.E.S.), Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia · and Department of Pediatrics (I.E.S.), University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia. ·Neurology · Pubmed #27029629.

ABSTRACT: OBJECTIVES: We report development of a targeted resequencing gene panel for focal epilepsy, the most prevalent phenotypic group of the epilepsies. METHODS: The targeted resequencing gene panel was designed using molecular inversion probe (MIP) capture technology and sequenced using massively parallel Illumina sequencing. RESULTS: We demonstrated proof of principle that mutations can be detected in 4 previously genotyped focal epilepsy cases. We searched for both germline and somatic mutations in 251 patients with unsolved sporadic or familial focal epilepsy and identified 11 novel or very rare missense variants in 5 different genes: CHRNA4, GRIN2B, KCNT1, PCDH19, and SCN1A. Of these, 2 were predicted to be pathogenic or likely pathogenic, explaining ∼0.8% of the cohort, and 8 were of uncertain significance based on available data. CONCLUSIONS: We have developed and validated a targeted resequencing panel for focal epilepsies, the most important clinical class of epilepsies, accounting for about 60% of all cases. Our application of MIP technology is an innovative approach that will be advantageous in the clinical setting because it is highly sensitive, efficient, and cost-effective for screening large patient cohorts. Our findings indicate that mutations in known genes likely explain only a small proportion of focal epilepsy cases. This is not surprising given the established clinical and genetic heterogeneity of these disorders and underscores the importance of further gene discovery studies in this complex syndrome.

16 Article PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy. 2015

Hildebrand, Michael S / Tankard, Rick / Gazina, Elena V / Damiano, John A / Lawrence, Kate M / Dahl, Hans-Henrik M / Regan, Brigid M / Shearer, Aiden Eliot / Smith, Richard J H / Marini, Carla / Guerrini, Renzo / Labate, Angelo / Gambardella, Antonio / Tinuper, Paolo / Lichetta, Laura / Baldassari, Sara / Bisulli, Francesca / Pippucci, Tommaso / Scheffer, Ingrid E / Reid, Christopher A / Petrou, Steven / Bahlo, Melanie / Berkovic, Samuel F. ·Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbogurne Melbourne, Victoria, Australia. · Bioinformatics Division, The Walter and Eliza Hall Institute Melbourne, Victoria, Australia. · The Florey Institute for Neuroscience and Mental Health, The University of Melbourne Melbourne, Victoria, Australia. · Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics Iowa City, Iowa. · Pediatric Neurology and Neurogenetics Unit and Laboratories, A. Meyer Children's Hospital-University of Florence Florence, Italy. · Institute of Neurology, University Magna Græcia Catanzaro, Italy ; Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR) Germaneto, CZ, Italy. · Medical Genetics Unit, Polyclinic Sant'Orsola-Malpighi and Department of Medical and Surgical Sciences, University of Bologna Bologna, Italy. · Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbogurne Melbourne, Victoria, Australia ; Department of Paediatrics, Royal Children's Hospital, University of Melbourne Melbourne, Victoria, Australia. ·Ann Clin Transl Neurol · Pubmed #26339676.

ABSTRACT: OBJECTIVE: Nocturnal frontal lobe epilepsy (NFLE) can be sporadic or autosomal dominant; some families have nicotinic acetylcholine receptor subunit mutations. We report a novel autosomal recessive phenotype in a single family and identify the causative gene. METHODS: Whole exome sequencing data was used to map the family, thereby narrowing exome search space, and then to identify the mutation. RESULTS: Linkage analysis using exome sequence data from two affected and two unaffected subjects showed homozygous linkage peaks on chromosomes 7, 8, 13, and 14 with maximum LOD scores between 1.5 and 1.93. Exome variant filtering under these peaks revealed that the affected siblings were homozygous for a novel splice site mutation (c.93+2T>C) in the PRIMA1 gene on chromosome 14. No additional PRIMA1 mutations were found in 300 other NFLE cases. The c.93+2T>C mutation was shown to lead to skipping of the first coding exon of the PRIMA1 mRNA using a minigene system. INTERPRETATION: PRIMA1 is a transmembrane protein that anchors acetylcholinesterase (AChE), an enzyme hydrolyzing acetycholine, to membrane rafts of neurons. PRiMA knockout mice have reduction of AChE and accumulation of acetylcholine at the synapse; our minigene analysis suggests that the c.93+2T>C mutation leads to knockout of PRIMA1. Mutations with gain of function effects in acetylcholine receptor subunits cause autosomal dominant NFLE. Thus, enhanced cholinergic responses are the likely cause of the severe NFLE and intellectual disability segregating in this family, representing the first recessive case to be reported and the first PRIMA1 mutation implicated in disease.

17 Article Oxcarbazepine and its active metabolite, (S)-licarbazepine, exacerbate seizures in a mouse model of genetic generalized epilepsy. 2015

Kim, Tae Hwan / Reid, Christopher A / Petrou, Steven. ·Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Melbourne, Australia. ·Epilepsia · Pubmed #25489632.

ABSTRACT: Oxcarbazepine (OXC), widely used to treat focal epilepsy, is reported to exacerbate seizures in patients with generalized epilepsy. OXC is metabolized to monohydroxy derivatives in two enantiomeric forms: (R)-licarbazepine and (S)-licarbazepine. Eslicarbazepine acetate is a recently approved antiepileptic drug that is rapidly metabolized to (S)-licarbazepine. It is not known whether (S)-licarbazepine exacerbates seizures. Here, we test whether OXC or either of its enantiomers exacerbates the number of spike-and-wave discharges (SWDs) in mice harboring the human γ-aminobutyric acid A receptor (GABAA)γ2(R43Q) mutation. OXC (20 mg/kg), (S)-licarbazepine (20 mg/kg), and (R)-licarbazepine (20 mg/kg) all significantly increased the number of SWDs, while their duration was unaffected. The potential for (S)-licarbazepine to exacerbate SWDs suggests that eslicarbazepine acetate should be used with caution in generalized epilepsy. Furthermore, generalized seizure exacerbation for first-, second-, and third-generation carbamazepine-based compounds is likely to occur through a common mechanism.

18 Article Reduced dendritic arborization and hyperexcitability of pyramidal neurons in a Scn1b-based model of Dravet syndrome. 2014

Reid, Christopher A / Leaw, Bryan / Richards, Kay L / Richardson, Robert / Wimmer, Verena / Yu, Christiaan / Hill-Yardin, Elisa L / Lerche, Holger / Scheffer, Ingrid E / Berkovic, Samuel F / Petrou, Steven. ·1 Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, 3010, Australia. · 2 Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Germany3 Neurological Clinic and Institute of Applied Physiology, University of Ulm, D-89081 Germany. · 1 Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, 3010, Australia4 Department of Medicine, Austin Health, The University of Melbourne, Heidelberg West, Melbourne, 3081, Australia5 Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Melbourne, 3010, Australia. · 4 Department of Medicine, Austin Health, The University of Melbourne, Heidelberg West, Melbourne, 3081, Australia. · 1 Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, 3010, Australia6 Centre for Neural Engineering, The University of Melbourne, Parkville, Melbourne, 3010, Australia7 Department of Anatomy and Neuroscience. The University of Melbourne, Parkville, Melbourne, 3010, Australia spetrou@unimelb.edu.au. ·Brain · Pubmed #24747835.

ABSTRACT: Epileptic encephalopathies, including Dravet syndrome, are severe treatment-resistant epilepsies with developmental regression. We examined a mouse model based on a human β1 sodium channel subunit (Scn1b) mutation. Homozygous mutant mice shared phenotypic features and pharmaco-sensitivity with Dravet syndrome. Patch-clamp analysis showed that mutant subicular and layer 2/3 pyramidal neurons had increased action potential firing rates, presumably as a consequence of their increased input resistance. These changes were not seen in L5 or CA1 pyramidal neurons. This raised the concept of a regional seizure mechanism that was supported by data showing increased spontaneous synaptic activity in the subiculum but not CA1. Importantly, no changes in firing or synaptic properties of gamma-aminobutyric acidergic interneurons from mutant mice were observed, which is in contrast with Scn1a-based models of Dravet syndrome. Morphological analysis of subicular pyramidal neurons revealed reduced dendritic arborization. The antiepileptic drug retigabine, a K+ channel opener that reduces input resistance, dampened action potential firing and protected mutant mice from thermal seizures. These results suggest a novel mechanism of disease genesis in genetic epilepsy and demonstrate an effective mechanism-based treatment of the disease.

19 Article Enhanced in vitro CA1 network activity in a sodium channel β1(C121W) subunit model of genetic epilepsy. 2014

Hatch, Robert J / Reid, Christopher A / Petrou, Steven. ·The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia. ·Epilepsia · Pubmed #24605816.

ABSTRACT: OBJECTIVE: A NaV β1(C121W) mouse model of human genetic epilepsy has enhanced neuronal excitability and temperature sensitivity attributed to a decreased threshold for action potential firing in the axon initial segment. To investigate the network consequences of this neuronal dysfunction and to establish a genetic disease state model we developed an in vitro assay to investigate CA1 network properties and antiepileptic drug sensitivity. METHODS: CA1 network oscillations were induced by tetanic stimulation and average number of spikes, interspike interval (ISI), duration, and latency were measured in slices from control and NaV β1(C121W) heterozygous mice in the presence and absence of retigabine or carbamazepine. Retigabine was also tested in a thermogenic seizure model. RESULTS: Oscillations were reliably induced by tetanic stimulation and were maintained after severing connections between CA3 and CA1, suggesting a local recurrent circuit. Blocking α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), γ-aminobutyric acid receptor A (GABAA ), Ih , and T-type Ca(2+) channels/receptors reduced the number of spikes. Slices from NaV β1(C121W) heterozygous mice displayed several hallmarks of increased network excitability including increases in duration of the oscillation, the number and frequency of spikes and a decrease in their onset latency. The effect of genotype on network excitability was temperature sensitive, as it was seen only at elevated temperatures. Carbamazepine and retigabine were more effective in reducing network excitability in slices from NaV β1(C121W) heterozygous mice. Retigabine appeared to be more effective in suppressing time to thermogenic seizures in NaV β1(C121W) heterozygous mice compared to wild-type (WT) controls. SIGNIFICANCE: Hippocampal networks of the NaV β1(C121W) heterozygous mouse model of genetic epilepsy show enhanced excitability consistent with earlier single neuron studies bridging important scales of brain complexity relevant to seizure genesis. Altered pharmacosensitivity further suggests that genetic epilepsy models may be useful in the development of novel antiepileptic drugs that target disease state pathology. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

20 Article HCN channelopathy and cardiac electrophysiologic dysfunction in genetic and acquired rat epilepsy models. 2014

Powell, Kim L / Jones, Nigel C / Kennard, Jeremy T / Ng, Caroline / Urmaliya, Vijay / Lau, Shannen / Tran, Adora / Zheng, Thomas / Ozturk, Ezgi / Dezsi, Gabi / Megatia, Ika / Delbridge, Lea M / Pinault, Didier / Reid, Christopher A / White, Paul J / O'Brien, Terence J. ·Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia. ·Epilepsia · Pubmed #24592881.

ABSTRACT: OBJECTIVE: Evidence from animal and human studies indicates that epilepsy can affect cardiac function, although the molecular basis of this remains poorly understood. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels generate pacemaker activity and modulate cellular excitability in the brain and heart, with altered expression and function associated with epilepsy and cardiomyopathies. Whether HCN expression is altered in the heart in association with epilepsy has not been investigated previously. We studied cardiac electrophysiologic properties and HCN channel subunit expression in rat models of genetic generalized epilepsy (Genetic Absence Epilepsy Rats from Strasbourg, GAERS) and acquired temporal lobe epilepsy (post-status epilepticus SE). We hypothesized that the development of epilepsy is associated with altered cardiac electrophysiologic function and altered cardiac HCN channel expression. METHODS: Electrocardiography studies were recorded in vivo in rats and in vitro in isolated hearts. Cardiac HCN channel messenger RNA (mRNA) and protein expression were measured using quantitative PCR and Western blotting respectively. RESULTS: Cardiac electrophysiology was significantly altered in adult GAERS, with slower heart rate, shorter QRS duration, longer QTc interval, and greater standard deviation of RR intervals compared to control rats. In the post-SE model, we observed similar interictal changes in several of these parameters, and we also observed consistent and striking bradycardia associated with the onset of ictal activity. Molecular analysis demonstrated significant reductions in cardiac HCN2 mRNA and protein expression in both models, providing a molecular correlate of these electrophysiologic abnormalities. SIGNIFICANCE: These results demonstrate that ion channelopathies and cardiac dysfunction can develop as a secondary consequence of chronic epilepsy, which may have relevance for the pathophysiology of cardiac dysfunction in patients with epilepsy.

21 Article Spike-and-wave discharge mediated reduction in hippocampal HCN1 channel function associates with learning deficits in a genetic mouse model of epilepsy. 2014

Phillips, A Marie / Kim, Taehwan / Vargas, Ernesto / Petrou, Steven / Reid, Christopher A. ·Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville 3010, Australia; Department of Genetics, University of Melbourne, Parkville 3010, Australia. Electronic address: m.phillips@unimelb.edu.au. · Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville 3010, Australia; Centre for Neural Engineering, The University of Melbourne, Parkville 3010, Melbourne, Australia. Electronic address: kaarkim@gmail.com. · Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville 3010, Australia. Electronic address: e.vargas@commercial.unimelb.edu.au. · Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville 3010, Australia; Centre for Neural Engineering, The University of Melbourne, Parkville 3010, Melbourne, Australia; Department of Anatomy and Neuroscience, The University of Melbourne, Parkville 3010, Melbourne, Australia. Electronic address: steven.petrou@florey.edu.au. · Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville 3010, Australia. Electronic address: careid@unimelb.edu.au. ·Neurobiol Dis · Pubmed #24368169.

ABSTRACT: The GABAAγ2(R43Q) mouse is an established model of absence epilepsy displaying spontaneous spike-and-wave discharges (SWD) and associated behavioral arrest. Absence epilepsy typically results from cortico-thalamic networks. Nevertheless, there is increasing evidence for changes in hippocampal metabolism and electrical behavior, consistent with a link between absence seizures and hippocampus-related co-morbidities. Hyperpolarization-activated-cyclic-nucleotide-gated (HCN) channels are known to be transcriptionally regulated in a number of seizure models. Here we investigate the expression and function of these channels in the hippocampus of the genetic epilepsy model. A reduction in HCN1, but not HCN2 transcript, was observed in GABAAγ2(R43Q) mice relative to their littermate controls. In contrast, no change in HCN1 transcript was noted at an age prior to seizure expression or in a SWD-free model in which the R43Q mutation has been crossed into a seizure-resistant genetic background. Whole-cell recordings from CA1 pyramidal neurons confirm a reduction in Ih in the GABAAγ2(R43Q) mouse. Further, a left-shift in half-activation of the Ih conductance-voltage relationship is consistent with a reduction in HCN1 with no change in HCN2 channel expression. Behavioral analysis using the Morris water maze indicates that GABAAγ2(R43Q) mice are unable to learn as effectively as their wildtype littermates suggesting a deficit in hippocampal-based learning. SWD-free mice harboring the R43Q mutation had no learning deficit. We conclude that SWDs reduce hippocampal HCN1 expression and function, and that the reduction associates with a spatial learning deficit.

22 Article Low glycaemic index diet reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy. 2014

Kim, Tae Hwan / Petrou, Steven / Reid, Christopher A. ·Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia; Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Melbourne, Australia. · Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia; Centre for Neural Engineering, The University of Melbourne, Parkville, Melbourne, Australia; Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Melbourne, Australia. · Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia. Electronic address: careid@unimelb.edu.au. ·Epilepsy Res · Pubmed #24246146.

ABSTRACT: PURPOSE: Clinical evidence suggests that low glycaemic index diets are effective at reducing seizure frequency potentially through the stabilization of blood glucose levels. Here we investigate if diets containing carbohydrates with varying glycaemic index (GI) can modulate seizure susceptibility in a mouse model of generalized epilepsy. METHODS: Electrocortical recordings were made from mice harboring the GABAAγ2 (R43Q) epilepsy mutation after three weeks on a low-or high-GI diet. Standard rodent diet was used as a control. Occurrence and durations of spike-wave-discharges (SWDs) were measured. An insulin injection was used to reduce blood glucose to levels known to precipitate SWDs in the GABAAγ2 (R43Q) mouse on the low and high-GI diets. KEY FINDINGS: SWD occurrence was reduced by approximately 35% in mice on the low-GI compared to high-GI diet. SWD occurrence was not different between high-GI diet and a standard diet suggesting that low-GI diet is protective. Weight gain of mice for all diet groups was identical suggesting that they were equally well tolerated. Under low blood glucose conditions SWD occurrence increased in the low and high-GI diets. Importantly, under low glucose conditions the low-GI diet no longer conferred protection against SWDs. SIGNIFICANCE: SWDs were reduced in mice on a low GI-diet suggesting it may be an effective and well tolerated therapy for generalized epilepsy. The lack of effect of low-GI diet when glucose levels are reduced suggests that seizure protection in the GABAAγ2 (R43Q) mouse model may be due to the diets ability to stabilize blood glucose levels.

23 Article Hippocampal volume and cell density changes in a mouse model of human genetic epilepsy. 2013

Richards, Kay L / Kurniawan, Nyoman D / Yang, Zhengyi / Kim, Tae Hwan / Keller, Marianne D / Low, Jun / Ullmann, Jeremy F P / Cole, Stacey / Foong, Samuel / Galloway, Graham J / Reid, Christopher A / Paxinos, George / Reutens, David C / Petrou, Steven. ·Australian Mouse Brain Mapping Consortium, The University of Queensland, Brisbane, Queensland. ·Neurology · Pubmed #23468543.

ABSTRACT: OBJECTIVE: The human γ-aminobutyric acid type A (GABAA)γ2R43Q (R43Q) mutation is associated with genetic epilepsy with febrile seizures. R43Q mice in the C57Bl/6J background do not display spontaneous seizures, but are significantly more susceptible to hyperthermic seizures, providing a model with enhanced seizure susceptibility without the confounding influence of ongoing epileptic activity. Because of GABA's role in brain development, we sought to determine whether the R43Q mutation alters brain structure before the appearance of seizures. METHODS: We used 16.4-tesla, high-field MRI to determine the volumes of hippocampal subregions. Histologic analysis of the same brains allowed stereology-based estimates of neuron counts to be obtained in CA1-3 and the dentate gyrus. RESULTS: Morphologic changes were evident in seizure-naive hippocampi of susceptible mice. Dentate granule cell MRI determined that volume was 5% greater in R43Q mice compared with controls (0.628 mm(3), 95% confidence interval [CI] 0.611-0.645 vs 0.595 mm(3), 95% CI 0.571-0.619). The dentate granule cell density was 30% higher in R43Q compared with control mice (553 × 10(3) cells/mm(3), 95% CI 489-616 vs 427 × 10(3) cells/mm(3), 95% CI 362-491). CONCLUSIONS: In a genetic epilepsy model that is both seizure-naive and carries an allele for febrile seizure susceptibility, we have determined hippocampal structural changes that may be applied as a biomarker for seizure susceptibility.

24 Article Multiple molecular mechanisms for a single GABAA mutation in epilepsy. 2013

Reid, Christopher A / Kim, Taehwan / Phillips, A Marie / Low, Jun / Berkovic, Samuel F / Luscher, Bernhard / Petrou, Steven. ·Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia. careid@unimelb.edu.au ·Neurology · Pubmed #23408872.

ABSTRACT: OBJECTIVE: To understand the molecular basis and differential penetrance of febrile seizures and absence seizures in patients with the γ2(R43Q) GABA receptor mutation. METHODS: Spike-and-wave discharges and thermal seizure susceptibility were measured in heterozygous GABA γ2 knock-out and GABA γ2(R43Q) knock-in mice models crossed to different mouse strains. RESULTS: By comparing the GABA γ2 knock-out with the GABA γ2(R43Q) knock-in mouse model we show that haploinsufficiency underlies the genesis of absence seizures but cannot account for the thermal seizure susceptibility. Additionally, while the expression of the absence seizure phenotype was very sensitive to mouse background genetics, the thermal seizure phenotype was not. CONCLUSIONS: Our results show that a single gene mutation can cause distinct seizure phenotypes through independent molecular mechanisms. A lack of effect of genetic background on thermal seizure susceptibility is consistent with the higher penetrance of febrile seizures compared to absence seizures seen in family members with the mutation. These mouse studies help to provide a conceptual framework within which clinical heterogeneity seen in genetic epilepsy can be explained.

25 Article Triheptanoin reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy. 2013

Kim, Tae Hwan / Borges, Karin / Petrou, Steven / Reid, Christopher A. ·The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia. ·Epilepsy Res · Pubmed #23196212.

ABSTRACT: Triheptanoin is a triglyceride containing heptanoate, an odd-chained medium fatty acid that is metabolized to produce propionyl-CoA and subsequently C4 intermediates of the citric acid cycle and therefore capable of anaplerosis. These metabolic products are believed to underlie triheptanoin's anticonvulsant effects in rodent seizure models. Here we investigate the anticonvulsive effects of oral triheptanoin in a syndrome-specific genetic mouse model of generalized epilepsy based on the GABA(A)γ2(R43Q) mutation. Mice were fed a diet supplemented with triheptanoin from weaning for three weeks prior to electrocortical recordings. Occurrence and durations of spike and wave discharges (SWDs) were measured. Triheptanoin did not alter body weight or basal blood glucose levels suggesting that it was well tolerated. Triheptanoin supplementation halved the time spent in seizures due to a reduction in both SWD occurrence and duration. An injection of insulin was used to reduce blood glucose, a metabolic stress known to precipitate seizures in the GABA(A)γ2(R43Q) mouse. The reduction in seizure count was also evident following insulin induced hypoglycemia with the triheptanoin treated group having significantly less SWDs than control animals under similar low blood glucose conditions. In summary, triheptanoin may be an effective and well tolerated dietary therapy for generalized epilepsy.

Next