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Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature

Introduction: Among genetic paroxysmal movement disorders, variants in ion channel coding genes constitute a major subgroup. Loss-of-function (LOF) variants in KCNA1, the gene coding for K(V)1.1 channels, are associated with episodic ataxia type 1 (EA1), characterized by seconds to minutes-lasting a...

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Autores principales: Lauxmann, Stephan, Sonnenberg, Lukas, Koch, Nils A., Bosselmann, Christian, Winter, Natalie, Schwarz, Niklas, Wuttke, Thomas V., Hedrich, Ulrike B. S., Liu, Yuanyuan, Lerche, Holger, Benda, Jan, Kegele, Josua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459024/
https://www.ncbi.nlm.nih.gov/pubmed/34566847
http://dx.doi.org/10.3389/fneur.2021.703970
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author Lauxmann, Stephan
Sonnenberg, Lukas
Koch, Nils A.
Bosselmann, Christian
Winter, Natalie
Schwarz, Niklas
Wuttke, Thomas V.
Hedrich, Ulrike B. S.
Liu, Yuanyuan
Lerche, Holger
Benda, Jan
Kegele, Josua
author_facet Lauxmann, Stephan
Sonnenberg, Lukas
Koch, Nils A.
Bosselmann, Christian
Winter, Natalie
Schwarz, Niklas
Wuttke, Thomas V.
Hedrich, Ulrike B. S.
Liu, Yuanyuan
Lerche, Holger
Benda, Jan
Kegele, Josua
author_sort Lauxmann, Stephan
collection PubMed
description Introduction: Among genetic paroxysmal movement disorders, variants in ion channel coding genes constitute a major subgroup. Loss-of-function (LOF) variants in KCNA1, the gene coding for K(V)1.1 channels, are associated with episodic ataxia type 1 (EA1), characterized by seconds to minutes-lasting attacks including gait incoordination, limb ataxia, truncal instability, dysarthria, nystagmus, tremor, and occasionally seizures, but also persistent neuromuscular symptoms like myokymia or neuromyotonia. Standard treatment has not yet been developed, and different treatment efforts need to be systematically evaluated. Objective and Methods: Personalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome limitations in therapy. Toward this aim, we (i) reviewed all available clinical reports on treatment response and functional consequences of KCNA1 variants causing EA1, (ii) examined the potential effects on neuronal excitability of all variants using a single compartment conductance-based model and set out to assess the potential of two sodium channel blockers (SCBs: carbamazepine and riluzole) to restore the identified underlying pathophysiological effects of K(V)1.1 channels, and (iii) provide a comprehensive review of the literature considering all types of episodic ataxia. Results: Reviewing the treatment efforts of EA1 patients revealed moderate response to acetazolamide and exhibited the strength of SCBs, especially carbamazepine, in the treatment of EA1 patients. Biophysical dysfunction of K(V)1.1 channels is typically based on depolarizing shifts of steady-state activation, leading to an LOF of KCNA1 variant channels. Our model predicts a lowered rheobase and an increase of the firing rate on a neuronal level. The estimated concentration dependent effects of carbamazepine and riluzole could partially restore the altered gating properties of dysfunctional variant channels. Conclusion: These data strengthen the potential of SCBs to contribute to functional compensation of dysfunctional K(V)1.1 channels. We propose riluzole as a new drug repurposing candidate and highlight the role of personalized approaches to develop standard care for EA1 patients. These results could have implications for clinical practice in future and highlight the need for the development of individualized and targeted therapies for episodic ataxia and genetic paroxysmal disorders in general.
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spelling pubmed-84590242021-09-24 Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature Lauxmann, Stephan Sonnenberg, Lukas Koch, Nils A. Bosselmann, Christian Winter, Natalie Schwarz, Niklas Wuttke, Thomas V. Hedrich, Ulrike B. S. Liu, Yuanyuan Lerche, Holger Benda, Jan Kegele, Josua Front Neurol Neurology Introduction: Among genetic paroxysmal movement disorders, variants in ion channel coding genes constitute a major subgroup. Loss-of-function (LOF) variants in KCNA1, the gene coding for K(V)1.1 channels, are associated with episodic ataxia type 1 (EA1), characterized by seconds to minutes-lasting attacks including gait incoordination, limb ataxia, truncal instability, dysarthria, nystagmus, tremor, and occasionally seizures, but also persistent neuromuscular symptoms like myokymia or neuromyotonia. Standard treatment has not yet been developed, and different treatment efforts need to be systematically evaluated. Objective and Methods: Personalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome limitations in therapy. Toward this aim, we (i) reviewed all available clinical reports on treatment response and functional consequences of KCNA1 variants causing EA1, (ii) examined the potential effects on neuronal excitability of all variants using a single compartment conductance-based model and set out to assess the potential of two sodium channel blockers (SCBs: carbamazepine and riluzole) to restore the identified underlying pathophysiological effects of K(V)1.1 channels, and (iii) provide a comprehensive review of the literature considering all types of episodic ataxia. Results: Reviewing the treatment efforts of EA1 patients revealed moderate response to acetazolamide and exhibited the strength of SCBs, especially carbamazepine, in the treatment of EA1 patients. Biophysical dysfunction of K(V)1.1 channels is typically based on depolarizing shifts of steady-state activation, leading to an LOF of KCNA1 variant channels. Our model predicts a lowered rheobase and an increase of the firing rate on a neuronal level. The estimated concentration dependent effects of carbamazepine and riluzole could partially restore the altered gating properties of dysfunctional variant channels. Conclusion: These data strengthen the potential of SCBs to contribute to functional compensation of dysfunctional K(V)1.1 channels. We propose riluzole as a new drug repurposing candidate and highlight the role of personalized approaches to develop standard care for EA1 patients. These results could have implications for clinical practice in future and highlight the need for the development of individualized and targeted therapies for episodic ataxia and genetic paroxysmal disorders in general. Frontiers Media S.A. 2021-09-09 /pmc/articles/PMC8459024/ /pubmed/34566847 http://dx.doi.org/10.3389/fneur.2021.703970 Text en Copyright © 2021 Lauxmann, Sonnenberg, Koch, Bosselmann, Winter, Schwarz, Wuttke, Hedrich, Liu, Lerche, Benda and Kegele. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Lauxmann, Stephan
Sonnenberg, Lukas
Koch, Nils A.
Bosselmann, Christian
Winter, Natalie
Schwarz, Niklas
Wuttke, Thomas V.
Hedrich, Ulrike B. S.
Liu, Yuanyuan
Lerche, Holger
Benda, Jan
Kegele, Josua
Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature
title Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature
title_full Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature
title_fullStr Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature
title_full_unstemmed Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature
title_short Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature
title_sort therapeutic potential of sodium channel blockers as a targeted therapy approach in kcna1-associated episodic ataxia and a comprehensive review of the literature
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459024/
https://www.ncbi.nlm.nih.gov/pubmed/34566847
http://dx.doi.org/10.3389/fneur.2021.703970
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