Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K+ channel properties

Karen L. Oliver, Silvana Franceschetti, Carol J. Milligan, Mikko Muona, Simone A. Mandelstam, Laura Canafoglia, Anna M. Boguszewska-Chachulska, Amos D. Korczyn, Francesca Bisulli, Carlo Di Bonaventura, Francesca Ragona, Roberto Michelucci, Bruria Ben-Zeev, Rachel Straussberg, Ferruccio Panzica, João Massano, Daniel Friedman, Arielle Crespel, Bernt A. Engelsen, Frederick AndermannEva Andermann, Krystyna Spodar, Anetta Lasek-Bal, Patrizia Riguzzi, Elena Pasini, Paolo Tinuper, Laura Licchetta, Elena Gardella, Matthias Lindenau, Annette Wulf, Rikke S. Møller, Felix Benninger, Zaid Afawi, Guido Rubboli, Christopher A. Reid, Snezana Maljevic, Holger Lerche, Anna Elina Lehesjoki, Steven Petrou, Samuel F. Berkovic

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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. 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 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.

Original languageEnglish
Pages (from-to)677-689
Number of pages13
JournalAnnals of Neurology
Volume81
Issue number5
DOIs
Publication statusPublished - May 1 2017

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ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

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., ... Berkovic, S. F. (2017). Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K+ channel properties. Annals of Neurology, 81(5), 677-689. https://doi.org/10.1002/ana.24929