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Myoclonus epilepsy and ataxia due toKCNC1mutation: Analysis of 20 cases and K+channel properties
- 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.
- Subjects :
- Male
0301 basic medicine
Pathology
Hot Temperature
Epilepsies, Myoclonic
Corpus callosum
Epilepsy
0302 clinical medicine
Age of Onset
Cognitive decline
Electroencephalography
Syndrome
Middle Aged
Magnetic Resonance Imaging
Pedigree
3. Good health
Unverricht–Lundborg disease
Shaw Potassium Channels
Neurology
Spinocerebellar ataxia
Female
medicine.symptom
Psychology
Adult
congenital, hereditary, and neonatal diseases and abnormalities
medicine.medical_specialty
Ataxia
Adolescent
KCNC1 mutation
Progressive myoclonus epilepsy
progressive myoclonus epilepsy
Young Adult
k+ channel
03 medical and health sciences
Journal Article
medicine
Humans
Cognitive Dysfunction
myoclonu
ataxia
medicine.disease
HEK293 Cells
030104 developmental biology
Mutation
epilepsy
Neurology (clinical)
Myoclonus
Neuroscience
030217 neurology & neurosurgery
Subjects
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