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

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.

Clinical and Functional Study of a De Novo Variant in the PVP Motif of Kv1.1 Channel Associated with Epilepsy, Developmental Delay and Ataxia

“…Cannabidiol was unsuccessful in our patient and was rapidly discontinued, as well as ketogenic diet. Overall, the comparison of the treatment regimens of patients carrying a KCNA1 mutation confirms the need of a patient-centric approach and supports the use of sodium channel blockers, such as carbamazepine, lacosamide, lamotrigine, to improve the course of the disease [ 34 , 38 ]. Caution must be taken when using sodium valproate in children due to possible seizure aggravation and clonazepam and oxcarbazepine due to motor coordination disturbances [ 39 ].…”

“…Acetazolamide, a carbonic anhydrase inhibitor, is often used to treat ataxia, with moderate benefit in most patients, including the girl described here. Sodium channel blockers proved effective to restore brain excitability in both EA1 and epilepsy [ 18 , 34 , 35 ] ( Table S1 ). In severe epilepsy cases, however, seizures may remain intractable or poorly improve after trials with combinations of AEDs, including phenobarbital, clobazam, valproate, lamotrigine, carbamazepine and phenytoin.…”

kcna1a mutant zebrafish as a model of episodic ataxia type 1 and epilepsy

“…Although a range of symptoms are caused by variants in KCNA1, over 50% of all variants result in a diagnosis of EA1 and the remaining 50% associated with additional comorbidities, including EA1 with epilepsy, epilepsy alone, myokymia, hyperthermia and hypomagnesemia (26,40,41). Predictably, patients with distinct KCNA1 variants have differential responses to drug treatments, confirmed by a recent report that compiled the available clinical findings of 15 patients with 36 treatment efforts using 12 different drugs (9). The authors found that two sodium channel blockers were promising, with carbamazepine showing the most therapeutic benefits and phenytoin leading to substantial clinical improvement.…”

“…Phenytoin, a blocker of voltage-gated sodium channels is also effective in EA1 patients; however, its ability to induce permanent cerebellar dysfunction and atrophy has raised concerns against its long-term usage (5). Another sodium channel blocker, carbamazepine, can partially relieve ataxia and seizures in a patient subpopulation (7)(8)(9). Combined, current medications fail to provide effective treatment of the ataxia and seizures, making animal models necessary to provide further insights into the cellular and molecular mechanisms of the disorder as well as for drug screening to develop improved therapies.…”

Case report: A novel loss-of-function pathogenic variant in the KCNA1 cytoplasmic N-terminus causing carbamazepine-responsive type 1 episodic ataxia

“…Episodic ataxia symptoms include recurring episodes of poor coordination and balance, and in addition can comprise blurred vision, slurred speech, vertigo, nausea and emesis, migraines, tinnitus, muscle weakness, hemiplegia, seizures, and myokymia (predominantly in the interictal interval in EA1) ( 9 , 10 ). EA1 and EA2 are typically treated with anticonvulsant/antiseizure medications such as carbamazepine, valproic acid and acetazolamide, although the latter is generally more effective at treating EA2 ( 11 , 12 ).…”