Clinical and molecular spectrum of P/Q type calcium channel Cav2.1 in epileptic patients

Background: Epilepsy is a neurological disorder characterized by the potential to induce seizure and accompanied by cognitive, psychological, and social consequences. CACNA1A gene is a voltage-gated P/Q-type Cav2.1 channel that is broadly expressed in the central nervous system, and the pathogenic variants within this gene may be associated with the epileptic phenotype. In the present study, we collected clinical and molecular data related to epileptic patients with CACNA1A pathogenic variants and investigated possible meaningful relationship between age at onset, neurodevelopmental disorders, type of seizures, brain imaging abnormalities, genotype, and protein domains. Results: In our retrospective literature studies, from among 890 articles reviewed, a total of 90 individuals were related to epilepsy phenotype. Our findings showed that about 90 percent of patients have shown the first symptoms in childhood and teenage years and different types of neurodevelopmental disorders, such as intellectual disability, developmental arrest, and behavioral disorders, have been common findings for these patients. Further, a wide range of abnormalities have been observed in their brain imaging, and generalized seizures have been the most type of seizures in these patients. However, our data showed no specific genotype�phenotype correlation in epileptic patients with CACNA1A pathogenic alterations. Conclusions: Our study focused on epileptic phenotype in patients with CACNA1A pathogenic variants and showed a wide range of clinical and molecular heterogeneity with no specific genotype�phenotype correlation. It seems that incomplete penetrance, de-novo variants, and modifier genes are obstacles in predicting the clinical outcome. © 2021, The Author(s)

Leu226Trp CACNA1A variant associated with juvenile myoclonic epilepsy with and without intellectual disability

Objective: Epilepsy is a disease of Central Nervous System (CNS) characterized by abnormal brain activity and recurrent seizures and is considered a clinically and genetically heterogeneous disease. Here, we investigated pathogenic genetic alteration and described the clinical characteristics of three Iranian family members affected by Idiopathic Generalized Epilepsy (IGE) with and without intellectual disability. Methods: A non-consanguineous Iranian family with juvenile myoclonic epilepsy was enrolled in the study. The comprehensive neurological evaluation included motor and sensory skills, vision, hearing, speech, coordination, and mood. Whole-exome Sequencing (WES) was performed on the proband to detect probable pathogenic variant, and after the filtering process, probable variants were evaluated with familial segregation analysis using Sanger sequencing. Results: Using WES, we identified a heterozygous missense substitution (NM023035.3:c.T677G:p.Leu226Trp) in CACNA1A gene in the studied family with juvenile myoclonic epilepsy with and without intellectual disability and psychiatric phenotype. Considering the patients� clinical synopsis, familial segregation analysis, and literature review, we postulated this variant to be causative of the disease. Indeed, the resulting missense mutation of Leu226Trp affects a highly conserved residue supporting our hypothesis that this mutation is potentially pathogenic. Conclusion: To the best of our knowledge, this is the first report of juvenile myoclonic epilepsy related to CACNA1A gene. Our results provide evidence for expanding the clinical and molecular findings related to the CACNA1A gene. © 2022 Elsevier B.V