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Title: | Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K+ channel properties. | Austin Authors: | 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 | Affiliation: | Centre for Neural Engineering, Department of Electrical Engineering, University of Melbourne, Parkville, Victoria, Australia 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 Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, 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 |
Issue Date: | May-2017 | Publication information: | Annals of neurology 2017; 81(5): 677-689 | Abstract: | 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. 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 KV 3.1 channels. 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 KV 3.1, increasing channel availability. 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 KV 3.1 subunit-containing channels, which would counter the loss of function observed for mutant channels, highlighting KCNC1 as a potential target for precision therapeutics. Ann Neurol 2017;81:677-689. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/19500 | DOI: | 10.1002/ana.24929 | ORCID: | 0000-0003-4580-841X | Journal: | Annals of neurology | PubMed URL: | 28380698 | Type: | Journal Article |
Appears in Collections: | Journal articles |
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