KCNA1 – Episodic Ataxia Type 1

Episodic Ataxia Type 1 (EA1) is an autosomal dominant channelopathy caused by heterozygous variants in the KCNA1 gene, encoding the voltage-gated potassium channel Kv1.1. A spectrum of missense and loss-of-function mutations disrupts cerebellar and peripheral nerve excitability, leading to brief, stress-triggered attacks of ataxia and persistent myokymia. Established since 1994, over 50 families and probands have been described worldwide, with both inherited and de novo mutations defining EA1 as a definitive gene–disease relationship (PMID:31586945).

Genetic evidence includes more than 50 unrelated probands from over 15 families with clear segregation of KCNA1 variants and EA1 phenotypes. Recurrent and de novo missense mutations cluster throughout the channel, notably c.1025G>T (p.Ser342Ile) segregates in a multigenerational pedigree lacking myokymia but presenting ataxia episodes (AD inheritance; PMID:15532032). Other variants include truncating alleles and inframe deletions, reinforcing the allelic heterogeneity in EA1.

Segregation analysis demonstrates high penetrance in affected relatives, with reported cosegregation in up to 6–7 members per pedigree. De novo events and parental mosaicism broaden the genetic spectrum and underscore the need for family screening and genetic counseling (PMID:31586945).

Functional studies in heterologous systems show that EA1-linked Kv1.1 variants cause dominant-negative or haploinsufficient effects. Patch-clamp analysis of F184C and V408A channels in mammalian cells reveals reduced current amplitude, slowed activation, and accelerated inactivation consistent with EA1 pathophysiology (PMID:10383630). Kcna1-mutant rat models exhibit myokymia, neuromyotonia, and spontaneous seizures, confirming in vivo relevance (PMID:22206926).

Mechanistically, impaired Kv1.1 function enhances neuronal excitability in cerebellar Purkinje cells and peripheral motor axons, explaining episodic ataxia and neuromyotonia. Concordance between human and animal data, along with successful pharmacological modulation of mutant channels, supports Kv1.1 as a precision-medicine target.

Key Take-home: Genetic testing for KCNA1 variants is critical for diagnosing EA1, guiding family counseling, and tailoring treatments—such as acetazolamide or sodium channel blockers—that ameliorate aberrant Kv1.1 channel function.

References

• Journal of medical genetics • 2020 • Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia. PMID:31586945
• Human Mutation • 2004 • A novel mutation in KCNA1 causes episodic ataxia without myokymia. PMID:15532032
• The European Journal of Neuroscience • 1999 • Expression in mammalian cells and electrophysiological characterization of two mutant Kv1.1 channels causing episodic ataxia type 1 (EA-1). PMID:10383630
• Brain Research • 2012 • Kcna1-mutant rats dominantly display myokymia, neuromyotonia and spontaneous epileptic seizures. PMID:22206926

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