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Myoclonus epilepsy and ataxia due toKCNC1mutation: Analysis of 20 cases and K+channel properties

Authors :
Frederick Andermann
Zaid Afawi
Krystyna Spodar
Laura Licchetta
Francesca Bisulli
Rachel Straussberg
Laura Canafoglia
Snezana Maljevic
Bernt A. Engelsen
Silvana Franceschetti
Simone Mandelstam
Samuel F. Berkovic
Rikke S. Møller
Annette Wulf
Eva Andermann
João Massano
Francesca Ragona
Elena Gardella
Carlo Di Bonaventura
Steven Petrou
Patrizia Riguzzi
Guido Rubboli
Carol J. Milligan
Anna-Elina Lehesjoki
Karen Oliver
Ferruccio Panzica
Elena Pasini
Amos D. Korczyn
Mikko Muona
Roberto Michelucci
Daniel Friedman
Anna M. Boguszewska-Chachulska
Holger Lerche
Matthias Lindenau
Felix Benninger
Christopher A. Reid
Bruria Ben-Zeev
Paolo Tinuper
Arielle Crespel
Anetta Lasek-Bal
Oliver, Karen L
Franceschetti, Silvana
Milligan, Carol J
Muona, Mikko
Mandelstam, Simone A
Canafoglia, Laura
Boguszewska-Chachulska, Anna M
Korczyn, Amo
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, Matthia
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
Source :
Oliver, K L, Franceschetti, S, Milligan, C J, Muona, M, Mandelstam, S A, Canafoglia, L, Boguszewska-Chachulska, A M, Korczyn, A D, Bisulli, F, Di Bonaventura, C, Ragona, F, Michelucci, R, Ben-Zeev, B, Straussberg, R, Panzica, F, Massano, J, Friedman, D, Crespel, A, Engelsen, B A, Andermann, F, Andermann, E, Spodar, K, Lasek-Bal, A, Riguzzi, P, Pasini, E, Tinuper, P, Licchetta, L, Gardella, E, Lindenau, M, Wulf, A, Møller, R S, Benninger, F, Afawi, Z, Rubboli, G, Reid, C A, Maljevic, S, Lerche, H, Lehesjoki, A-E, Petrou, S & Berkovic, S F 2017, ' Myoclonus epilepsy and ataxia due to KCNC1 mutation : Analysis of 20 cases and K(+) channel properties ', Annals of Neurology, vol. 81, no. 5, pp. 677-689 . https://doi.org/10.1002/ana.24929
Publication Year :
2017
Publisher :
Wiley, 2017.

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 KV 3.1 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 KV 3.1, increasing channel availability.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 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.

Details

ISSN :
03645134
Volume :
81
Database :
OpenAIRE
Journal :
Annals of Neurology
Accession number :
edsair.doi.dedup.....0e24095de7d217867a83d748eead4731
Full Text :
https://doi.org/10.1002/ana.24929