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Leu226trp Cacna1a Variant Associated With Juvenile Myoclonic Epilepsy With and Without Intellectual Disability Publisher Pubmed



Alehabib E1, 2 ; Kokotovic T2, 3, 4 ; Ranjiburachaloo S5 ; Tafakhori A5 ; Ramshe SM6 ; Esmaeilizadeh Z6 ; Darvish H7 ; Movafagh A6 ; Nagy V2, 3, 4
Authors
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Authors Affiliations
  1. 1. Student Research Committee, Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  2. 2. Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, 1090, Austria
  3. 3. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, 1090, Austria
  4. 4. Department of Neurology, Medical University of Vienna, Vienna, 1090, Austria
  5. 5. Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
  6. 6. Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  7. 7. Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran

Source: Clinical Neurology and Neurosurgery Published:2022


Abstract

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 (NM_023035.3: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.
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