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