Calmodulinopathies: throwing back the veil on the newest life-threatening genetic arrhythmia syndrome.

Abstract

This review provides a basic understanding of the calmodulin gene and its role in calcium homeostasis. We outline the functional effects and clinical expression of CALM mutations and review disease expression and management. Calmodulinopathies are rare life-threatening arrhythmia syndromes affecting young individuals. They are caused by mutations in any of the three genes (CALM 1-3) that encode calmodulin (CaM), a ubiquitously expressed Ca signaling protein with multiple targets that in the heart, modulates several ion channels. Patients express varied phenotypes: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, sudden death, idiopathic ventricular fibrillation, hypertrophic cardiomyopathy, or mixed disease. This is severe disease. Over half of 2019 International Calmodulin Registry patients experienced recurrent cardiac events despite management strategies that included: monotherapy and combination therapy with beta blockers, sodium channel blockers, other antiarrhythmics, sympathetic denervation, and pacing. Induced pluripotent stem cell-derived cardiomyocytes from patients harboring CALM mutations have provided a platform for better understanding pathogenic mechanisms and avenues for therapy. Calmodulinopathies are among the more novel inherited arrhythmia syndromes. These are rare but highly lethal diseases with diverse clinical expressions. The practicing electrophysiologist should be aware these conditions, how to recognize them clinically, and understand the challenges in management.