Skip to main content

Conference Program

Subpage Hero

Loading

Novel Genetic Mutation in CACNA1B Linked to Pediatric Focal Epilepsy 

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
Voltage-gated calcium channels (VGCCs) control the release of presynaptic transmitters in dendrites, which is vital for maintaining neuronal excitability and preventing seizure activity. The association between VGCCs and epilepsy is significant, highlighting the critical role of calcium channels in the pathophysiology of epileptic disorders. CACNA1B gene is of particular interest for its potential involvement in epilepsy.



CACNA1B encodes the alpha-1B subunit of the high-voltage activated N-type calcium channel Cav2.2. Cav2.2 is localized in the presynaptic region and regulates neurotransmitter release. Although Cav2.2 is known to play a key role in pain pathways, a few reports have linked mutations in CACNA1B and dysfunction of Cav2.2 to epilepsy. This report presents a pediatric case involving a girl with a nonsense mutation in CACNA1B, diagnosed with non-lesional focal epilepsy.



Case Presentation
A 4-year-old girl with a previously unremarkable birth and early developmental history presented with poor language development from the age of 3 years. She experienced her first generalized tonic seizure shortly thereafter. After the initial seizure, standard neurological evaluations, including brain magnetic resonance imaging (MRI) and electroencephalography (EEG), demonstrated no abnormalities.

 

Following a second seizure several weeks later, treatment was initiated with oxcarbazepine (OXC), yet only partial seizure control was achieved. Valproic acid (VPA) was subsequently added, resulting in seizure stability for a few months. However, breakthrough seizures recurred, and repeat EEG studies revealed persistent focal epileptiform discharges. Multiple additional anti-seizure medications (ASMs), including ethosuximide, zonisamide, and levetiracetam (LEV), were attempted but discontinued due to side effects.

Diagnostic Workup
At the age of seven, the patient was referred for specialized genetic evaluation due to persistent epilepsy and developmental concerns. Targeted gene panel analysis identified a heterozygous pathogenic nonsense mutation, c.5968C>T, p.Gln1990*, in the CACNA1B gene. This mutation resides in the cytoplasmic region adjacent to the sixth transmembrane segment (S6) of the fourth homologous domain in the Cav2.2 channel structure.

Treatment and Management
The patient’s seizure management included combination therapy with OXC and VPA, which ultimately achieved reasonable seizure control after multiple treatment adjustments. However, prior attempts with alternative ASMs were limited due to intolerable side effects. The OXC/VPA regimen has successfully maintained seizure freedom since her referral to our clinic.

Outcome and Follow-Up
Since the referral, the patient has been seizure-free on OXC/VPA for nearly 2 years. However, she continues to exhibit moderate-to-severe developmental delays in all aspects of neurocognitive function and requires ongoing treatment.

Discussion
Although there is extensive literature on CACNA1A and CACNA1E mutations associated with epilepsy, studies on epilepsy linked to CACNA1B mutations remain rare. ClinVar has 75 reported pathogenic variants for CACNA1B. Groen et al. reported a patient with an inherited missense mutation that was associated with myoclonus-dystonia syndrome. Bayanova et al. described a case of a CACNA1B missense mutation presenting with generalized tonic seizures and psychomotor and speech delays. Gorman et al. detailed six pathogenic variants with biallelic mutations, leading to phenotypes of epileptic encephalopathy, neurodevelopmental delay, hyperkinetic movement disorder, postnatal microcephaly, and childhood death.





Our case report highlights a unique nonsense mutation in CACNA1B, associated with generalized tonic seizures and developmental delays, without movement disorders such as myoclonic dystonia. Unlike most cases described by Gorman et al., our patient, now 9 years old, remains alive and seizure-free on a regimen of only two ASMs (OXC and VPA). The patient’s clinical stability and long-term survival highlight variability in phenotypic expression and treatment response among individuals with CACNA1B mutations.

Conclusion
Our case adds to the limited body of literature on CACNA1B-associated epilepsy, highlighting the need for heightened clinical awareness and genetic testing in pediatric epilepsy patients with atypical presentations. The identification of specific mutations and their phenotypic correlations will aid in prognostication and the development of personalized treatment plans.

Agenda

Sponsors