CACNA1A c.5610del in a three-generation family: epilepsy with ataxia/migraine
Abstract
OBJECTIVE: CACNA1A encodes the Cav2.1 (P/Q-type) channel whose spectrum extends from FHM1/EA2/SCA6 to epilepsy and vertigo, but penetrance-especially sex differences-remains unclear. We report a three-generation family with CACNA1A c.5610del, detail electroclinical features, assess sex-stratified penetrance, and discuss individualised therapy.
METHODS: We retrospectively reviewed histories, neurological exams, EEG, treatments, and follow-up. Trio whole-exome sequencing across 13 relatives was Sanger-confirmed and interpreted per ACMG; gnomAD/ClinVar were queried. Sex-stratified penetrance was summarised with exact binomial 95% CIs.
RESULTS: The female proband developed clinically focal seizures with preserved awareness in 2019. Valproate reduced but did not abolish seizures; after oxcarbazepine, EA2-like paroxysmal symptoms emerged and responded to acetazolamide. Since 2023, she has experienced episodic diplopia, vertigo, bilateral tinnitus, and pulsatile temporal headaches consistent with FHM-like features, typically independent of epileptic seizures. Video-EEG monitoring demonstrated generalised, bilaterally synchronous spike-and-slow-wave discharges with frontal predominance, with a reduction in interictal epileptiform burden observed after treatment optimisation. Genetic analysis identified a heterozygous CACNA1A c.5610del (p.His1871IlefsTer30) variant, absent from population databases and classified as pathogenic (PVS1 + PM2 + PP3). Segregation analysis revealed…
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Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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