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Objective <p><i>CACNA1A</i> 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 <i>CACNA1A</i> c.5610del, detail electroclinical features, assess sex-stratified penetrance, and discuss individualised therapy.</p> Methods <p>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.</p> Results <p>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 <i>CACNA1A</i> c.5610del (p.His1871IlefsTer30) variant, absent from population databases and classified as pathogenic (PVS1 + PM2 + PP3). Segregation analysis revealed epilepsy or vestibular symptoms among female carriers, whereas male carriers were asymptomatic at last follow-up, suggesting possible sex-biased penetrance within the pedigree.</p> Conclusions <p>This pedigree supports Cav2.1 loss-of-function presenting with epilepsy, EA2, and FHM features plus BPPV. Within this family, clinical expression to date appears female-skewed while male carriers remained asymptomatic at last follow-up; this observation is hypothesis-generating. Mechanism-aware ASM selection and structured family counselling may aid management; larger cohorts and functional studies are needed.</p>

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CACNA1A c.5610del in a three-generation family: epilepsy with ataxia/migraine

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月1日

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  • Zhongyuan Long,
  • Shuxian Gong,
  • Dongyan Ji,
  • Xuan Guo,
  • Lisen Sui,
  • Xiaofeng Yang,
  • Jiabin Yu

摘要

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 epilepsy or vestibular symptoms among female carriers, whereas male carriers were asymptomatic at last follow-up, suggesting possible sex-biased penetrance within the pedigree.

Conclusions

This pedigree supports Cav2.1 loss-of-function presenting with epilepsy, EA2, and FHM features plus BPPV. Within this family, clinical expression to date appears female-skewed while male carriers remained asymptomatic at last follow-up; this observation is hypothesis-generating. Mechanism-aware ASM selection and structured family counselling may aid management; larger cohorts and functional studies are needed.