Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry
Lia Crotti, Carla Spazzolini, Mette Nyegaard, Michael T Overgaard, Maria-Christina Kotta, Federica Dagradi, Luca Sala, Takeshi Aiba, Mark D Ayers, Anwar Baban, Julien Barc, Cheyenne M Beach, Elijah R Behr, J Martijn Bos, Marina Cerrone, Peter Covi, Bettina Cuneo, Isabelle Denjoy, Birgit Donner, Adrienne Elbert, Håkan Eliasson, Susan P Etheridge, Megumi Fukuyama, Francesca Girolami, Robert Hamilton, Minoru Horie, Maria Iascone, Juan Jiménez Jaimez, Henrik Kjærulf Jensen, Prince J Kannankeril, Juan P Kaski, Naomasa Makita, Carmen Muñoz-Esparza, Hans H Odland, Seiko Ohno, John Papagiannis, Alessandra Pia Porretta, Christopher Prandstetter, Vincent Probst, Tomas Robyns, Eric Rosenthal, Ferran Rosés-Noguer, Nicole Sekarski, Anoop Singh, Georgia Spentzou, Fridrike Stute, Jacob Tfelt-Hansen, Jan Till, Kathryn E Tobert, Jeffrey M Vinocur, Gregory Webster, Arthur A M Wilde, Cordula M Wolf, Michael J Ackerman, Peter J Schwartz- Cardiology and Cardiovascular Medicine
Abstract
Aims
Calmodulinopathy due to mutations in any of the three CALM genes (CALM1–3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms.
Methods and results
The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5–19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing.
Conclusion
Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter–defibrillator.