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Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy.

ABSTRACT: The recurrent variant KCNC1-p.Arg320His causes progressive myoclonus epilepsy (EPM) type 7, defined by progressive myoclonus, epilepsy, and ataxia, and is without effective treatment. KCNC1 encodes the voltage-gated potassium channel subunit Kv3.1, specifically expressed in high-frequency-firing neurons. Variant subunits act via loss of function; hence, EPM7 pathogenesis may involve impaired excitability of Kv3.1-expressing neurons, while enhancing Kv3 activity could represent a viable therapeutic strategy. We generate a mouse model, Kcnc1-p.Arg320His/+, which recapitulates the core features of EPM7, including progressive ataxia and seizure susceptibility. Kv3.1-expressing cerebellar granule cells and neocortical parvalbumin-positive GABAergic interneurons exhibit abnormalities consistent with Kv3 channel dysfunction. A Kv3-specific positive modulator (AUT00206) selectively enhances the firing frequency of Kv3.1-expressing neurons and improves motor function and seizure susceptibility in Kcnc1-Arg320His/+ mice. This work identifies a cellular and circuit basis of dysfunction in EPM7 and demonstrates that Kv3 positive modulators such as AUT00206 have therapeutic potential for the treatment of EPM7.

SUBMITTER: Feng H

PROVIDER: S-EPMC10897515 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy.

Feng Huijie H Clatot Jerome J Kaneko Keisuke K Flores-Mendez Marco M Wengert Eric R ER Koutcher Carly C Hoddeson Emily E Lopez Emily E Lee Demetrius D Arias Leroy L Liang Qiansheng Q Zhang Xiaohong X Somarowthu Ala A Covarrubias Manuel M Gunthorpe Martin J MJ Large Charles H CH Akizu Naiara N Goldberg Ethan M EM

Cell reports. Medicine 20240123 2

The recurrent variant KCNC1-p.Arg320His causes progressive myoclonus epilepsy (EPM) type 7, defined by progressive myoclonus, epilepsy, and ataxia, and is without effective treatment. KCNC1 encodes the voltage-gated potassium channel subunit Kv3.1, specifically expressed in high-frequency-firing neurons. Variant subunits act via loss of function; hence, EPM7 pathogenesis may involve impaired excitability of Kv3.1-expressing neurons, while enhancing Kv3 activity could represent a viable therapeut ...[more]

PMID: 38266642

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Project description:BackgroundThe clinical demarcation of the syndrome progressive myoclonus ataxia is unclear, leading to a lack of recognition and difficult differentiation from other neurological syndromes.ObjectivesThe objective of this study was to apply a refined definition of progressive myoclonus ataxia and describe the clinical characteristics in patients with progressive myoclonus ataxia and with isolated cortical myoclonus.MethodsA retro- and prospective analysis was performed in our tertiary referral center between 1994 and 2014. Inclusion criteria for progressive myoclonus ataxia patients were the presence of myoclonus and ataxia with or without infrequent (all types, treatment responsive) epileptic seizures. Inclusion criteria for isolated cortical myoclonus was the presence of isolated cortical myoclonus. Clinical and electrophysiological characteristics data were systematically scored.ResultsA total of 14 progressive myoclonus ataxia patients (males, 7; females, 7), median age 14.5 years, and 8 isolated cortical myoclonus patients (males, 2; females, 6), median age 23.5 years, were identified. In 93% of the progressive myoclonus ataxia patients, ataxia started first (median 2 years) followed by myoclonus (4 years) and finally infrequent epilepsy (9.3 years), with a progressive course in 93%. In 64% of the progressive myoclonus ataxia patients, a genetic underlying etiology was identified, including 3 not earlier reported causative progressive myoclonus ataxia genes. In isolated cortical myoclonus patients, myoclonus started at (median) 12 years with progression over time in 63% and a single epileptic seizure in 1 patient. No genetic causes were identified.ConclusionUsing a refined definition, we could create a rather homogenous progressive myoclonus ataxia group. Patients with isolated cortical myoclonus have a different course and do not appear to evolve in progressive myoclonus ataxia. The refined progressive myoclonus ataxia definition is a successful first step toward creating a separate syndrome for both clinical practice and future genetic research. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Dataset Information

Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy.

Publications

Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy.

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