Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia

Objective Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A -related ataxia. Methods We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons. Results Variants associated with chronic progressive ataxia either significantly decreased Na+ current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter), i.e. strong loss-of-function (LOF) effects. Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing LOF by decreasing Na+ current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain-and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms. Interpretation We identified episodic or chronic ataxia as new phenotypes caused by variants in SCN8A . Genotype-phenotype correlations revealed a more pronounced LOF effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions. Twitter handles @cmbosselmann, @FiladelfiaGene1, @Katrine92658231, @Elegardella What is the current knowledge on the topic? Variants in SCN8A , a gene encoding the voltage-gated sodium channel NaV1.6, are associated with neurodevelopmental disorders, including epilepsy, intellectual disability, and autism spectrum disorder. What question did this study address? This study investigated whether SCN8A variants can cause predominant episodic or chronic ataxia, as well as the cellular and molecular mechanisms underlying these variants. What does this study add to our knowledge? Episodic or chronic ataxia as a sole or predominant symptom caused by NaV1.6 channel loss-of-function comprise new phenotypes in the broad spectrum associated with SCN8A dysfunction. Genotype-phenotype correlations help to differentiate between chronic and episodic ataxia. How might this potentially impact on the practice of neurology? Loss-of-function SCN8A variants may represent an underdiagnosed etiology in hereditary ataxia. Treatment with sodium channel blockers, commonly prescribed in other types of episodic ataxia, may harm these individuals, and should be avoided. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Federal Ministry for Education and Research (Treat-ION, 01GM1907A and 01GM2210A to YL, LS, and HoL), the German Research Foundation (Research Unit FOR-2715, Le1030/15-2 and /16-2 to HoL), and the Italian Ministry of Health (RC5X1000 to AT). CMB was supported by intramural funding of the Medical Faculty, University of Tuebingen (PATE F.1315137.1). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee of the Faculty of Medicine, University of Tuebingen gave ethical approval for this work (IRB-ID 198/2010BO1). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data not published within this article will be made available upon reasonable request from any qualified investigator.