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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.

التفاصيل البيبلوغرافية
العنوان: Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1 -Associated Episodic Ataxia and a Comprehensive Review of the Literature.
المؤلفون: Lauxmann S; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; Institute of Neurobiology, University of Tübingen, Tübingen, Germany., Sonnenberg L; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; Institute of Neurobiology, University of Tübingen, Tübingen, Germany.; Bernstein Center for Computational Neuroscience Tübingen, Tübingen, Germany., Koch NA; Institute of Neurobiology, University of Tübingen, Tübingen, Germany.; Bernstein Center for Computational Neuroscience Tübingen, Tübingen, Germany., Bosselmann C; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany., Winter N; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany., Schwarz N; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany., Wuttke TV; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.; Department of Neurosurgery, University of Tübingen, Tübingen, Germany., Hedrich UBS; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany., Liu Y; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany., Lerche H; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany., Benda J; Institute of Neurobiology, University of Tübingen, Tübingen, Germany.; Bernstein Center for Computational Neuroscience Tübingen, Tübingen, Germany., Kegele J; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
المصدر: Frontiers in neurology [Front Neurol] 2021 Sep 09; Vol. 12, pp. 703970. Date of Electronic Publication: 2021 Sep 09 (Print Publication: 2021).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Frontiers Research Foundation Country of Publication: Switzerland NLM ID: 101546899 Publication Model: eCollection Cited Medium: Print ISSN: 1664-2295 (Print) Linking ISSN: 16642295 NLM ISO Abbreviation: Front Neurol Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: [Lausanne : Frontiers Research Foundation, 2010]-
مستخلص: 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.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Lauxmann, Sonnenberg, Koch, Bosselmann, Winter, Schwarz, Wuttke, Hedrich, Liu, Lerche, Benda and Kegele.)
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فهرسة مساهمة: Keywords: KCNA1; KV1.1; conduction-based model; episodic ataxia; precision medicine; riluzole; sodium channel blockers; voltage-gated potassium channels
تواريخ الأحداث: Date Created: 20210927 Latest Revision: 20240407
رمز التحديث: 20240407
مُعرف محوري في PubMed: PMC8459024
DOI: 10.3389/fneur.2021.703970
PMID: 34566847
قاعدة البيانات: MEDLINE
الوصف
تدمد:1664-2295
DOI:10.3389/fneur.2021.703970