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 Andermann; Eva 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

doi:10.1002/ana.24929

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^*

^*Corresponding author for this work

Department of Clinical Medicine

29 Citations (Scopus)

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 K_V3.1 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 K_V3.1, 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 K_V3.1 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 language	English
Journal	Annals of Neurology
Volume	81
Issue number	5
Pages (from-to)	677-689
ISSN	0364-5134
DOIs	https://doi.org/10.1002/ana.24929
Publication status	Published - May 2017

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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

Oliver, KL, Franceschetti, S, Milligan, CJ, Muona, M, Mandelstam, SA, Canafoglia, L, Boguszewska-Chachulska, AM, Korczyn, AD, Bisulli, F, Di Bonaventura, C, Ragona, F, Michelucci, R, Ben-Zeev, B, Straussberg, R, Panzica, F, Massano, J, Friedman, D, Crespel, A, Engelsen, BA, Andermann, F, Andermann, E, Spodar, K, Lasek-Bal, A, Riguzzi, P, Pasini, E, Tinuper, P, Licchetta, L, Gardella, E, Lindenau, M, Wulf, A, Møller, RS, Benninger, F, Afawi, Z, Rubboli, G, Reid, CA, Maljevic, S, Lerche, H, Lehesjoki, AE, Petrou, S & Berkovic, SF 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

@article{b222f97db4dd4d27a8aab86f75552d3d,

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. 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.",

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

year = "2017",

month = may,

doi = "10.1002/ana.24929",

language = "English",

volume = "81",

pages = "677--689",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "JohnWiley & Sons, Inc.",

number = "5",

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TY - JOUR

T1 - Myoclonus epilepsy and ataxia due to KCNC1 mutation

T2 - Analysis of 20 cases and K+ channel properties

AU - Oliver, Karen L.

AU - Franceschetti, Silvana

AU - Milligan, Carol J.

AU - Muona, Mikko

AU - Mandelstam, Simone A.

AU - Canafoglia, Laura

AU - Boguszewska-Chachulska, Anna M.

AU - Korczyn, Amos D.

AU - Bisulli, Francesca

AU - Di Bonaventura, Carlo

AU - Ragona, Francesca

AU - Michelucci, Roberto

AU - Ben-Zeev, Bruria

AU - Straussberg, Rachel

AU - Panzica, Ferruccio

AU - Massano, João

AU - Friedman, Daniel

AU - Crespel, Arielle

AU - Engelsen, Bernt A.

AU - Andermann, Frederick

AU - Andermann, Eva

AU - Spodar, Krystyna

AU - Lasek-Bal, Anetta

AU - Riguzzi, Patrizia

AU - Pasini, Elena

AU - Tinuper, Paolo

AU - Licchetta, Laura

AU - Gardella, Elena

AU - Lindenau, Matthias

AU - Wulf, Annette

AU - Møller, Rikke S.

AU - Benninger, Felix

AU - Afawi, Zaid

AU - Rubboli, Guido

AU - Reid, Christopher A.

AU - Maljevic, Snezana

AU - Lerche, Holger

AU - Lehesjoki, Anna Elina

AU - Petrou, Steven

AU - Berkovic, Samuel F.

PY - 2017/5

Y1 - 2017/5

N2 - 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.

AB - 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.

U2 - 10.1002/ana.24929

DO - 10.1002/ana.24929

M3 - Journal article

C2 - 28380698

AN - SCOPUS:85019947788

SN - 0364-5134

VL - 81

SP - 677

EP - 689

JO - Annals of Neurology

JF - Annals of Neurology

IS - 5

ER -

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

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