Clinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations

Abstract

Mutations in the KCNA1 gene are known to cause episodic ataxia/myokymia syndrome type 1 (EA1). Here, we describe two families with unique presentations who were enrolled in an IRB-approved study, extensively phenotyped, and whole exome sequencing (WES) performed. Family 1 had a diagnosis of isolated cataplexy triggered by sudden physical exertion in multiple affected individuals with heterogeneous neurological findings. All enrolled affected members carried a KCNA1 c.941T>C (p.I314T) mutation. Family 2 had an 8-year-old patient with muscle spasms with rigidity for whom WES revealed a previously reported heterozygous missense mutation in KCNA1 c.677C>G (p.T226R), confirming the diagnosis of EA1 without ataxia. WES identified variants in KCNA1 that explain both phenotypes expanding the phenotypic spectrum of diseases associated with mutations of this gene. KCNA1 mutations should be considered in patients of all ages with episodic neurological phenotypes, even when ataxia is not present. This is an example of the power of genomic approaches to identify pathogenic mutations in unsuspected genes responsible for heterogeneous diseases.

Episodic Ataxia Type 1 (K‐channelopathy) Manifesting as Paroxysmal Nonkinesogenic Dyskinesia: Expanding the Phenotype

“…Some affected individuals may also display delayed motor development, choreoathetosis, carpal spasm, cognitive dysfunctions, expressive language delay, and inability to learn a motor task. A short‐sleep phenotype and cataplexy have also recently been reported …”

“…EA1 may have a broad spectrum of symptoms like ataxia and myokymia. During attacks, additional symptoms may be reported, including vertigo, blurred vision, diplopia, nausea, headache, diaphoresis, body stiffening, and difficulty breathing …”

A de novo <b><i>KCNA1</i></b> Mutation in a Patient with Tetany and Hypomagnesemia

“…The latter is also observed in our study. The phenotype of EA1 patients is highly heterogeneous and may include myokymia, cataplexy, epilepsy, neuromyotonia, paroxysmal dyspnea, and also skeletal defects [13, 15-20]. Of note, episodic ataxia is not present in all patients.…”

Retained Myogenic Potency of Human Satellite Cells from Torn Rotator Cuff Muscles Despite Fatty Infiltration

“…We also found that KCNA1 and HOXA11 levels were downregulated in disused muscle. HOXA11 negatively regulates the myogenic differentiation expression of the transcription factor myoblast determination protein in muscle precursors (Yamamoto et al 2003), and KCNA1, a gene responsible for myokymia (Brownstein et al 2016), suppresses myogenic contraction. These results suggest a myogenic shift of gene expression in satellite cells derived from disused muscle compared with the intact muscle.…”