title: Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K+channel properties.
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 KV3.1 channels.
  
  
  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 KV3.1, increasing channel availability.
  
  
  CONCLUSIONS
  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 KV3.1 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.
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Oliver
authors.affiliation: Department of Neurophysiology, C. Besta Neurological Institute IRCCS Foundation, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Franceschetti
authors.affiliation: Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Milligan
authors.affiliation: 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.
authors.forename: Mikko
authors.initials: M
authors.lastname: Muona
authors.affiliation: 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.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Mandelstam
authors.affiliation: Department of Neurophysiology, C. Besta Neurological Institute IRCCS Foundation, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Canafoglia
authors.affiliation: Genomed Health Care Center, Genomed, Warsaw, Poland.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Boguszewska-Chachulska
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Amos D
authors.initials: AD
authors.lastname: Korczyn
authors.affiliation: IRCCS-Institute of Neurological Sciences of Bologna, Bologna, Italy.|Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bisulli
authors.affiliation: Department of Neurological Sciences, University of Rome, La Sapienza, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Di Bonaventura
authors.affiliation: Department of Pediatric Neuroscience, C. Besta Neurological Institute IRCCS Foundation, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ragona
authors.affiliation: IRCCS-Institute of Neurological Sciences of Bologna, Bologna, Italy.|Unit of Neurology, Bellaria Hospital, Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Michelucci
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Bruria
authors.initials: B
authors.lastname: Ben-Zeev
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Epilepsy Unit, Schneider Children's Medical Center of Israel, Petah Tikvah, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Straussberg
authors.affiliation: Department of Neurophysiology, C. Besta Neurological Institute IRCCS Foundation, Milan, Italy.
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Panzica
authors.affiliation: 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.
authors.forename: João
authors.initials: J
authors.lastname: Massano
authors.affiliation: Comprehensive Epilepsy Center, New York University Langone Medical Center, New York, NY.
authors.forename: Daniel
authors.initials: D
authors.lastname: Friedman
authors.affiliation: Epilepsy Unit, Gui de Chauliac Hospital, Montpellier, France.
authors.forename: Arielle
authors.initials: A
authors.lastname: Crespel
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Bernt A
authors.initials: BA
authors.lastname: Engelsen
authors.affiliation: Epilepsy Research Group, Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada.|Departments of Neurology & Neurosurgery and Paediatrics, McGill University, Montreal, Quebec, Canada.
authors.forename: Frederick
authors.initials: F
authors.lastname: Andermann
authors.affiliation: 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.
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
authors.affiliation: Genomed Health Care Center, Genomed, Warsaw, Poland.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Spodar
authors.affiliation: High School of Science, Medical University of Silesia, Department of Neurology, Upper Silesian Medical Center, Katowice, Poland.
authors.forename: Anetta
authors.initials: A
authors.lastname: Lasek-Bal
authors.affiliation: IRCCS-Institute of Neurological Sciences of Bologna, Bologna, Italy.|Unit of Neurology, Bellaria Hospital, Bologna, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Riguzzi
authors.affiliation: IRCCS-Institute of Neurological Sciences of Bologna, Bologna, Italy.|Unit of Neurology, Bellaria Hospital, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pasini
authors.affiliation: IRCCS-Institute of Neurological Sciences of Bologna, Bologna, Italy.|Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Tinuper
authors.affiliation: IRCCS-Institute of Neurological Sciences of Bologna, Bologna, Italy.|Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Licchetta
authors.affiliation: Danish Epilepsy Center, Dianalund, Denmark.|Institute for Regional Health Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Elena
authors.initials: E
authors.lastname: Gardella
authors.affiliation: Department of Neurology and Epileptology, Epilepsy Center Hamburg-Alsterdorf, Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lindenau
authors.affiliation: Department of Neurology and Epileptology, Epilepsy Center Hamburg-Alsterdorf, Hamburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Wulf
authors.affiliation: Danish Epilepsy Center, Dianalund, Denmark.|Institute for Regional Health Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.affiliation: Department of Neurology, Rabin Medical Center, Beilinson Hospital, Petah Tikvah, Israel.
authors.forename: Felix
authors.initials: F
authors.lastname: Benninger
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.affiliation: IRCCS-Institute of Neurological Sciences of Bologna, Bologna, Italy.|Danish Epilepsy Center, Filadelfia/University of Copenhagen, Dianalund, Denmark.
authors.forename: Guido
authors.initials: G
authors.lastname: Rubboli
authors.affiliation: Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reid
authors.affiliation: Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.|University of Tübingen, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Tübingen, Germany.
authors.forename: Snezana
authors.initials: S
authors.lastname: Maljevic
authors.affiliation: University of Tübingen, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Tübingen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.|Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.affiliation: Ion Channels and Disease Group, Epilepsy Division, Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.|Centre for Neural Engineering, Department of Electrical Engineering, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.affiliation: Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001259:Ataxia / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D060825:Cognitive Dysfunction / Q000209:etiology*; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D005260:Female; D057809:HEK293 Cells; D006358:Hot Temperature; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D051670:Shaw Potassium Channels / Q000235:genetics / Q000378:metabolism*; D013577:Syndrome; D055815:Young Adult
chemical_list: C489597:KCNC1 protein, human; D051670:Shaw Potassium Channels