Clinical and electrophysiological features ofSCN8Avariants causing episodic or chronic ataxia
Authors: Lyu Hang , Boßelmann Christian M , Johannesen Katrine M , Koko Mahmoud , Ortigoza-Escobar Juan Dario , Aguilera-Albesa Sergio , Núñez Deyanira Garcia-Navas , Linnankivi Tarja , Gaily Eija , van Ruiten Henriette JA , Richardson Ruth , Betzler Cornelia , Horvath Gabriella , Brilstra Eva , Geerdink Niels , Orsucci Daniele , Tessa Alessandra , Gardella Elena , Fleszar Zofia , Schöls Ludger , Lerche Holger , Møller Rikke S , Liu Yuanyuan 
Published: April 2023

AbstractObjectiveVariants inSCN8Aare associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom ofSCN8Avariation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations ofSCN8A-related ataxia.MethodsWe collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novelSCN8Avariants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons.ResultsVariants 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.InterpretationWe identified episodic or chronic ataxia as new phenotypes caused by variants inSCN8A. Genotype-phenotype correlations revealed a more pronounced LOF effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions.Summary for Social MediaTwitter handles@cmbosselmann, @FiladelfiaGene1, @Katrine92658231, @ElegardellaWhat is the current knowledge on the topic?Variants inSCN8A, 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 whetherSCN8Avariants 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 withSCN8Adysfunction. Genotype-phenotype correlations help to differentiate between chronic and episodic ataxia.How might this potentially impact on the practice of neurology?Loss-of-functionSCN8Avariants 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.