Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia

Abstract

BackgroundSince 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events.MethodsA patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings.ResultsWES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures.ConclusionThis newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.

Kv1.1 deficiency alters repetitive and social behaviors in mice and rescues autistic‐like behaviors due to Scn2a haploinsufficiency

“…At least 34 of the 62 genes implicated in EE have also been associated with ASD, including sodium (e.g., SCN1A and SCN2A ) and potassium channel genes (e.g., KCNQ2 and KCNQ3 ), and several EE genes have ASD prevalence rates as high as 70%–100% (Srivastava & Sahin, 2017). Whole exome sequencing has now identified KCNA1 mutations as the cause of EE in 5 child patients (Rogers et al., 2018; Verdura et al., 2019). In one patient with infantile EE, a de novo single‐nucleotide variant in KCNA1 was found in the highly conserved Pro‐Val‐Pro motif of Kv1.1 that is essential for channel gating (Paulhus et al., 2020; Rogers et al., 2018).…”

Clinical Spectrum of KCNA1 Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity

“…Interestingly, mutation of the valine in the PVP motif (V404I) is associated with EA1 without epilepsy and only mild intellectual disability, suggesting alteration of the prolines may cause higher risk for the development of epileptic encephalopathy or epilepsy with intellectual disability [44]. The only other clinical case of KCNA1 epileptic encephalopathy was caused by a V368L mutation [42]. While not in the PVP motif, this mutation sits behind the selectivity filter of the pore, helping to support its structure [86].…”

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

“…In the Kv channel, the Kv1 subfamily leads to differences in susceptibility to epilepsy in the brain (Pena and Coimbra, 2015). In fact, many of the symptoms of hyperexcitability, including epilepsy, are caused by mutations or downregulation of the Kv1 channel (Glasscock, 2019;Verdura et al, 2019). Studies have shown that the convulsive agent pentylenetetrazol can significantly reduce the Kv1.3 currents (Madeja et al, 1997), indicating that Kv1.3 may be associated with epileptogenesis (Figure 2).…”