Expanding the Phenotype of CALM1-Associated LQT14: First Report of Focal Epilepsy
Abstract number :
3.019
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2025
Submission ID :
958
Source :
www.aesnet.org
Presentation date :
12/8/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Amanda Brand, BS – Institute of Neurology and Neurosurgery at Cooperman Barnabas
Aliza Alter, MD – Institute of Neurology and Neurosurgery at Cooperman Barnabas
Rationale: Calmodulin, encoded by CALM1, CALM2, and CALM3, is a calcium-binding protein essential for regulation of ion channels in excitable tissues. Pathogenic variants in these genes are linked to severe arrhythmogenic syndromes, including Long QT Syndrome type 14 (LQT14) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Although calmodulin is also known to be highly expressed in the brain and modulate voltage-gated calcium and potassium channels, there is limited existing literature that describes the role of pathogenic calmodulin expression on the central nervous system.
Methods: We describe a pediatric patient with a pathogenic CALM1 variant and a clinical diagnosis of LQT14 who developed focal epilepsy. We describe clinical course, electroencephalography (EEG) findings, magnetic resonance imaging (MRI) findings, and cardiology evaluations, including effects of anti-seizure medication trials on the corrected QT interval (QTc).
Results: A six-year-old girl with LQT14 due to a de novo pathogenic CALM1 mutation (c.389A >G) presented with new-onset focal seizures. EEG demonstrated frequent right occipital spikes, and brain MRI was unremarkable. An implantable loop recorder showed no arrhythmias at the times of her seizures. Levetiracetam significantly worsened QTc. Oxcarbazepine had no effect on QTc but was stopped due to rash. Lacosamide was initiated at 3 mg/kg/day with seizure control for over 20 months. Dose was increased when seizures recurred to about 6 mg/kg/day. Serial ECGs showed only minimal increase in QTc with lacosamide.
Conclusions: This case demonstrates a possible association between CALM1-gene function and central nervous system regulation. Calmodulin dysregulation may contribute to epileptogenesis by disrupting calcium signaling and altering the function of voltage-gated ion channels. To our knowledge, this represents the first reported case of focal epilepsy in a patient with CALM1-associated long QT syndrome type 14 (LQT14), thereby expanding the phenotypic spectrum of CALM1-related disorders to include focal epilepsy. An implanted loop recorder was helpful in differentiating epileptic seizures from symptoms produced by cardiac arrhythmias; without continuous cardiac monitoring, epileptic seizures in patients with long QT syndrome could be falsely attributed to cardiac arrhythmias and vice versa. Recognition of the association of epilepsy with CALM1 gene mutations is significant for guiding diagnostic workup and optimizing anti-seizure medication selection for affected individuals.
Funding: None.
Basic Mechanisms