Myoclonus epilepsy and ataxia due to <scp>KCNC</scp>1 mutation: Analysis of 20 cases and <scp>K</scp>+ channel properties

Oliver, Karen; Franceschetti, Silvana; Milligan, Carol J.; Muona, Mikko; Mandelstam, Simone; Canafoglia, Laura; Boguszewska-Chachulska, Anna M.; Korczyn, Amos D.; Bisulli, Francesca; Bonaventura, Carlo Di; Ragona, Francesca; Michelucci, Roberto; Ben‐Zeev, Bruria; Straussberg, Rachel; Panzica, Ferruccio; Massano, João; Friedman, Daniel; Crespel, Arielle; Engelsen, Bernt A.; Andermann, Frédérick; Andermann, Eva; Spodar, Krystyna; Lasek–Bal, Anetta; Riguzzi, P.; 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.

doi:10.1002/ana.24929

Cited by 65 publications

(83 citation statements)

References 47 publications

(102 reference statements)

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“…Patient 1 (Cys208Tyr) exhibited nonprogressive, relatively mild, action‐induced myoclonus (or irregular tremor) as the only clinical sign without any cerebellar, epileptic, or cognitive symptoms. In contrast, MEAK patients (Arg320His) had a more severe and progressive action‐induced myoclonus, epilepsy, and ataxia leading to wheelchair dependency in 11 of 22 published patients by the age of approximately 17 years . The phenotype of patient 2 (Thr399Met), who showed ID and dysmorphic features, is more similar to the family reported by Poirier et al .…”

Section: Discussionsupporting

confidence: 68%

“…To date, only one recurrent de novo missense variant in KCNC1 (c.959G > A, p.Arg320His) has been reported as a cause of progressive myoclonus epilepsy and ataxia (MEAK; OMIM #616187). The respective phenotype is similar to Unverricht‐Lundborg disease . Subsequently, one nonsense variant (c.1015C > T, p.Arg339*) has been identified in three affected members of single family with ID without seizures .…”

Section: Introductionmentioning

confidence: 85%

“…Their effect on GABA neurotransmitters, enhancing the inhibitory effect on neurons might have played a critical role in reducing the patients' seizure frequencies. Also Oliver et al described that clonazepam beside valproate was most effective in MEAK patients . Another more specific therapeutic strategy might be to directly activate mutant heterotetrameric K V 3 channels.…”

Section: Discussionmentioning

confidence: 99%

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KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

Park

Koko

Hedrich

et al. 2019

Ann Clin Transl Neurol

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A recurrent de novo missense variant in KCNC1, encoding a voltage‐gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic‐clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant‐negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

Park

Koko

Hedrich

et al. 2019

Ann Clin Transl Neurol

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“…I to current characteristics, nonetheless, are less sensitive to R S and current amplitude as compared to I Na : when R S is equal to 5 MΩ (in orange), alteration in the shape of the recordings is significant only when current amplitude is 10-fold higher than Na + currents (in red). When R S reaches 15 MΩ and current amplitude is equal to several tens of nA, conditions routinely observed in automated patch-clamp with stable cell lines (Oliver et al, 2017;Ranjan et al, 2019), the model predicts major modification of the activation curve and apparition of a delayed inactivation ( Figure 5B, bottom right). When R S is not null, increasing peak current amplitude range up to 100 nA leads to major shift in voltage-dependence of activation as the following: for a peak current of 100 nA, R S of 5 and 15 MΩ induces a −9 mV and −18 mV shift of the half activation potential, respectively.…”

Section: Resultsmentioning

confidence: 77%

Computer modeling of whole-cell voltage-clamp analyses to delineate guidelines for good practice of manual and automated patch-clamp

Montnach

Lorenzini

Lesage

et al. 2020

Preprint

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The patch-clamp technique has contributed to major advances in the characterization of ion channels. The recent development of high throughput patch-clamp provides a new momentum to the field. However, whole-cell voltage-clamp technique presents certain limits that need to be considered for robust data generation. One major caveat is that current amplitude profoundly impacts the precision of the analyzed characteristics of the ion current under study. For voltagegated channels, the higher the current amplitude is, the less precise the characteristics of voltagedependence are. Similarly, in ion channel pharmacology, the characteristics of dose-response curves are hindered by high current amplitudes. In addition, the recent development of high throughput patch-clamp technique is often associated with the generation of stable cell lines demonstrating high current amplitudes. It is therefore critical to set the limits for current amplitude recordings to avoid inaccuracy in the characterization of channel properties or drug actions, such limits being different from one channel to another. In the present study, we use kinetic models of a voltage-gated sodium channel and a voltage-gated potassium channel to edict simple guidelines for good practice of whole-cell voltage-clamp recordings. words

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“…Recently, a role of Kv 3.1 in causing a distinct form of progressive myoclonus epilepsy called myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK) has been described [46]. Specifically, loss of Kv 3.1 function in inhibitory GABAergic interneurons and cerebellar neurons due to genetic mutation was found to lead to myoclonus and seizures accompanied by ataxia and tremor [46-48]. Positive modulators of Kv 3.1 channels are envisioned as potential therapeutic agents in the treatment of epilepsy, hearing disorders, schizophrenia and cognitive impairments [49].…”

Section: Discussionmentioning

confidence: 99%

A Potassium-Selective Current Affected by Micromolar Concentrations of Anion Transport Inhibitors

Costa

Civello

Bernardinelli

et al. 2018

Cell Physiol Biochem

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Background/Aims: In the human genome, more than 400 genes encode ion channels, which are ubiquitously expressed and often coexist and participate in almost all physiological processes. Therefore, ion channel blockers represent fundamental tools in discriminating the contribution of individual channel types to a physiological phenomenon. However, unspecific effects of these compounds may represent a confounding factor. Three commonly used chloride channel inhibitors, i.e. 4,4′-diisothiocyano-2,2′-stilbene-disulfonic acid (DIDS), 5-nitro-2-[(3-phenylpropyl) amino]benzoic acid (NPPB) and the anti-inflammatory drug niflumic acid were tested to identify the lowest concentration effective on Cl^- channels and ineffective on K⁺ channels. Methods: The activity of the above mentioned compounds was tested by whole cell patch-clamp on the swelling-activated Cl^- current ICl,swell and on the endogenous voltage-dependent, outwardly rectifying K⁺ selective current in human kidney cell lines (HEK 293/HEK 293 Phoenix). Results: Micromolar (1-10 µM) concentrations of DIDS and NPPB could not discriminate between the Cl^- and K⁺ selective currents. Specifically, 1 µM DIDS only affected the K⁺ current and 10 µM NPPB equally affected the Cl^- and K⁺ currents. Only relatively high (0.1-1 mM) concentrations of DIDS and prolonged (5 minutes) exposure to 0.1-1 mM NPPB preferentially suppressed the Cl^- current. Niflumic acid preferentially inhibited the Cl^- current, but also significantly affected the K⁺ current. The endogenous voltage-dependent, outwardly rectifying K⁺ selective current in HEK 293/HEK 293 Phoenix cells was shown to arise from the Kv 3.1 channel, which is extensively expressed in brain and is involved in neurological diseases. Conclusion: The results of the present study underscore that sensitivity of a given physiological phenomenon to the Cl^- channel inhibitors NPPB, DIDS and niflumic acid may actually arise from an inhibition of Cl^- channels but can also result from an inhibition of voltage-dependent K⁺ channels, including the Kv 3.1 channel. The use of niflumic acid as anti-inflammatory drug in patients with concomitant Kv 3.1 dysfunction may result contraindicated.

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

Cited by 65 publications

References 47 publications

KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

Computer modeling of whole-cell voltage-clamp analyses to delineate guidelines for good practice of manual and automated patch-clamp

A Potassium-Selective Current Affected by Micromolar Concentrations of Anion Transport Inhibitors

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

Cited by 65 publications

References 47 publications

KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

Computer modeling of whole-cell voltage-clamp analyses to delineate guidelines for good practice of manual and automated patch-clamp

A Potassium-Selective Current Affected by Micromolar Concentrations of Anion Transport Inhibitors

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