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 it regulates neurotransmitter release. It is widely expressed throughout the central nervous system, particularly in the cerebral white matter, cortex, hippocampus, basal ganglia, and cerebellum [3]. Cav2.2 is involved in immature neuron migration, synaptic plasticity, synaptogenesis, gene transcription, and neuronal survival [4]. Although Cav2.2 plays a key role in pain pathways, a few reports have linked mutations in CACNA1B and Cav2.2 dysfunction to epilepsy. This report presents a pediatric case involving a girl with a nonsense mutation in CACNA1B who was diagnosed with non-lesional focal epilepsy.

A 4-year-old girl with an unremarkable birth history but poor language development since the age of 3 years experienced her first generalized tonic seizure. The patient had a history of multiple febrile seizures; however, these events were not clinically associated with her condition at the time of presentation. The initial evaluations, including brain magnetic resonance imaging and electroencephalography (EEG), revealed no significant findings. After a second seizure several weeks later, oxcarbazepine (OXC) was administered, which had limited effect. Therefore, valproic acid (VPA) was added. The OXC/VPA combination was effective for several months; however, breakthrough seizures occurred, and subsequent EEG revealed persistent focal epileptiform discharges (Fig. 1). Additional anti-seizure medications (ASMs), including ethosuximide, zonisamide, and levetiracetam (LEV), were administered but were discontinued shortly thereafter because of their side effects, including increased irritability.

The patient was referred to our clinic at the age of 7 for further evaluation. Targeted gene panel analysis revealed a heterozygous pathogenic nonsense variant, c.5968C>T, p.Gln1990*, in CACNA1B, located in the cytoplasmic region after S6 of repeat IV. The three-dimensional structure of Cav2.2, encoded by the CACNA1B gene, consists of four homologous domains (I-IV), each comprising six transmembrane helices (S1-S6). The mutation identified in our patient is situated within the terminal region of the fourth domain, at the distal end of this repeat. 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.

Mutations in VGCC subunit genes are implicated in a wide range of neurological and cardiovascular disorders. Dysregulation of the alpha-1 subunit is particularly associated with conditions such as ataxia, migraine, neurodevelopmental disorders, and myoclonic dystonia. Although there is extensive literature dealing with the associations of CACNA1A and CACNA1E mutations with epilepsy, studies on epilepsy linked to CACNA1B mutations remain rare. ClinVar has 75 reported pathogenic variants for CACNA1B, most of which are copy number variants, including deletions and duplications [5]. Groen et al. [6] reported a patient with an inherited gain-of-function missense mutation that was associated with myoclonus dystonia syndrome. Bayanova et al. [7] described a case of a CACNA1B missense mutation in a patient who presented with generalized tonic seizures and psychomotor and speech delays. Gorman et al. [8] detailed six pathogenic variants with biallelic loss-of-function mutations, leading to phenotypes of epileptic encephalopathy, neurodevelopmental delay, hyperkinetic movement disorder, postnatal microcephaly, and childhood death (Table 1).

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. [8], 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. Although a trio analysis could have provided further insights into the identified heterozygous mutation, the decision was made not to conduct a trio analysis given the patient's seizure resolution and favorable diagnostic outcomes. It remains unclear whether the clinical course of epilepsy differs between CACNA1B gain-of-function and loss-of-function mutations, as this distinction has not been sufficiently investigated.

The management of epilepsy in patients with CACNA1B mutations can be challenging due to the variable response to different ASMs. Certain drugs, such as lamotrigine, carbamazepine, gabapentin, lacosamide, and levetiracetam, are known to inhibit N-type VGCCs [5]. However, Gorman et al. [8] showed that GABAergic ASMs (clobazam, vigabatrin, phenobarbital), along with broader ASMs such as levetiracetam, VPA, and sodium channel blockers like rufinamide, are more effective for treating patients with CACNA1B variants. This efficacy is likely due to the inhibitory effect of GABA on calcium channels, which reduces calcium levels and stabilizes membrane potential. Our patient also exhibited seizure reduction and improved EEG findings in response to the combined use of OXC and VPA, supporting the use of these agents in managing CACNA1B-related epilepsy.

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. Identifying specific mutations and understanding their phenotypic correlations are crucial for accurate prognostication and the creation of personalized treatment plans.

This study was approved by the Institutional Review Board of Severance Hospital, Yonsei University College of Medicine (4-2004-0661). The board waived the requirement for informed consent.