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

2017-05

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

Journal Article

0000-0003-4580-841X

10.1002/ana.24929

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.

link

Annals of neurology 2017; 81(5): 677-689

Annals of neurology