ABSTRACT: AIMS:Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. METHODS AND RESULTS:A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n?=?36), CALM2 (n?=?23), or CALM3 (n?=?15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n?=?36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n?=?21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594?±?73?ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5?years [interquartile range (IQR) 0.1-5.5?years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0?years (IQR 3.0-8.5?years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n?=?7), sudden unexplained death (SUD, n?=?4), overlapping features of CPVT/LQTS (n?=?3), and predominant neurological phenotype (n?=?1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. CONCLUSION:Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.
