Mutacja CACNA1A c.5610del w rodzinie trzech pokoleń: epilepsja z zaburzeniami równowagi i migreną

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.