Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.

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.

• Authors: Lia Crotti, Carla Spazzolini, David J Tester, Alice Ghidoni, Alban-Elouen Baruteau, Britt-Maria Beckmann, Elijah R Behr, Jeffrey S Bennett, Connie R Bezzina, Zahurul A Bhuiyan, Alpay Celiker, Marina Cerrone, Federica Dagradi, Gaetano M De Ferrari, Susan P Etheridge, Meena Fatah, Pablo Garcia-Pavia, Saleh Al-Ghamdi, Robert M Hamilton, Zuhair N Al-Hassnan, Minoru Horie, Juan Jimenez-Jaimez, Ronald J Kanter, Juan P Kaski, Maria-Christina Kotta, Najim Lahrouchi, Naomasa Makita, Gabrielle Norrish, Hans H Odland, Seiko Ohno, John Papagiannis, Gianfranco Parati, Nicole Sekarski, Kristian Tveten, Matteo Vatta, Gregory Webster, Arthur A M Wilde, Julianne Wojciak, Alfred L George, Michael J Ackerman, Peter J Schwartz
• Journal: European heart journal (Eur Heart J) Vol. 40 Issue 35 Pg. 2964-2975 (09 14 2019) ISSN: 1522-9645 [Electronic] England
• PMID: 31170290 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected].

Chemical References

• CALM1 protein, human
• CALM2 protein, human
• CALM3 protein, human
• Calmodulin

Topics

• Age of Onset
• Arrhythmias, Cardiac (genetics, mortality)
• Calmodulin (genetics)
• Child
• Child, Preschool
• DNA Mutational Analysis
• Death, Sudden, Cardiac (etiology)
• Female
• Genetic Variation (genetics)
• Humans
• Long QT Syndrome (genetics)
• Phenotype
• Registries
• Survival Rate
• Tachycardia, Ventricular (genetics)