Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/19500
Title: Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K+ channel properties.
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
Citation: 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: http://ahro.austin.org.au/austinjspui/handle/1/19500
DOI: 10.1002/ana.24929
ORCID: 0000-0003-4580-841X
PubMed URL: 28380698
Type: Journal Article
Appears in Collections:Journal articles

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