TY - JOUR

T1 - Clinical presentation of calmodulin mutations

T2 - the International Calmodulinopathy Registry

AU - Crotti, Lia

AU - Spazzolini, Carla

AU - Nyegaard, Mette

AU - Overgaard, Michael T.

AU - Kotta, Maria Christina

AU - Dagradi, Federica

AU - Sala, Luca

AU - Aiba, Takeshi

AU - Ayers, Mark D.

AU - Baban, Anwar

AU - Barc, Julien

AU - Beach, Cheyenne M.

AU - Behr, Elijah R.

AU - Bos, J. Martijn

AU - Cerrone, Marina

AU - Covi, Peter

AU - Cuneo, Bettina

AU - Denjoy, Isabelle

AU - Donner, Birgit

AU - Elbert, Adrienne

AU - Eliasson, Håkan

AU - Etheridge, Susan P.

AU - Fukuyama, Megumi

AU - Girolami, Francesca

AU - Hamilton, Robert

AU - Horie, Minoru

AU - Iascone, Maria

AU - Jaimez, Juan Jiménez

AU - Jensen, Henrik Kjærulf

AU - Kannankeril, Prince J.

AU - Kaski, Juan P.

AU - Makita, Naomasa

AU - Muñoz-Esparza, Carmen

AU - Odland, Hans H.

AU - Ohno, Seiko

AU - Papagiannis, John

AU - Porretta, Alessandra Pia

AU - Prandstetter, Christopher

AU - Probst, Vincent

AU - Robyns, Tomas

AU - Rosenthal, Eric

AU - Rosés-Noguer, Ferran

AU - Sekarski, Nicole

AU - Singh, Anoop

AU - Spentzou, Georgia

AU - Stute, Fridrike

AU - Tfelt-Hansen, Jacob

AU - Till, Jan

AU - Tobert, Kathryn E.

AU - Vinocur, Jeffrey M.

AU - Webster, Gregory

AU - Wilde, Arthur A.M.

AU - Wolf, Cordula M.

AU - Ackerman, Michael J.

AU - Schwartz, Peter J.

N1 - Publisher Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - Calmodulin

KW - Cardiomyopathies

KW - Catecholaminergic polymorphic ventricular tachycardia

KW - Idiopathic ventricular fibrillation

KW - Long QT syndrome

KW - Neurological disorders

KW - Sudden death

U2 - 10.1093/eurheartj/ehad418

DO - 10.1093/eurheartj/ehad418

M3 - Journal article

C2 - 37528649

AN - SCOPUS:85170699059

VL - 44

SP - 3357

EP - 3370

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

IS - 35

ER -