Abstract

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 KV1.1 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 KV1.1 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 KV1.1 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 KV1.1 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.

Highlights

  • Among genetic paroxysmal movement disorders, variants in ion channel coding genes constitute a major subgroup

  • Episodic ataxia type 1 (EA1) is an autosomal dominant ion channel disorder mainly caused by missense variants in the KCNA1 gene on chromosome 12 [1] encoding the α-subunit of the voltage-gated potassium channel KV1.1 (Figure 1), which are expressed in the peripheral and the central nervous system including cerebellum and mostly present as heterotetramers with KV1.2 and KV1.4 subunits [2]

  • It has been shown previously that loss-of-function (LOF) variants cause neuronal hyperexcitability due to disturbed repolarization and subsequently prolonged duration of action potentials [APs; [3]]. These biophysical changes clinically result in typical frequent and short-lasting attacks which are characterized by gait incoordination, limb ataxia, truncal instability, dysarthria, nystagmus, tremor, occasionally seizures [around 10%; [4, 5]; overview in [6]], and persistent neuromuscular symptoms like myokymia or neuromyotonia [7]

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Summary

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 KV1.1 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, and persistent neuromuscular symptoms like myokymia or neuromyotonia. It has been shown previously that loss-of-function (LOF) variants cause neuronal hyperexcitability due to disturbed repolarization and subsequently prolonged duration of action potentials [APs; [3]] These biophysical changes clinically result in typical frequent and short-lasting attacks (seconds to minutes) which are characterized by gait incoordination, limb ataxia, truncal instability, dysarthria, nystagmus, tremor, occasionally seizures [around 10%; [4, 5]; overview in [6]], and persistent neuromuscular symptoms like myokymia or neuromyotonia [7]. Brain imaging in patients with EA1 is typically unremarkable but may reveal cerebellar atrophy [around 10% of cases; [7]]

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