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

doi:10.1093/eurheartj/ehad418

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 ElbertHåkan 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^*

^*Kontaktforfatter

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

10 Citationer (Scopus)

35 Downloads (Pure)

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.

Originalsprog	Engelsk
Tidsskrift	European Heart Journal
Vol/bind	44
Udgave nummer	35
Sider (fra-til)	3357-3370
Antal sider	14
ISSN	0195-668X
DOI	https://doi.org/10.1093/eurheartj/ehad418
Status	Udgivet - 14 sep. 2023

Bibliografisk note

Adgang til dokumentet

10.1093/eurheartj/ehad418Licens: CC BY-NC 4.0

Open Access articleForlagets udgivne version, 2,07 MBLicens: CC BY-NC 4.0

AUB Link

Søg efter materialet i Aalborg Universitetsbiblioteks søgemaskine

Andre filer og links

Link to publication in Scopus

Forskning i genfejl kan benåde australsk kvinde
Helene Halkjær Jensen (Deltager), Malene Bredal Brohus (Deltager), Michael Toft Overgaard (Deltager) & Mette Nyegaard (Deltager)
Impact: Social impact

Citationsformater

Crotti, L., Spazzolini, C., Nyegaard, M., Overgaard, M. T., Kotta, M-C., Dagradi, F., Sala, L., Aiba, T., Ayers, M. D., Baban, A., Barc, J., Beach, C. M., Behr, E. R., Bos, J. M., Cerrone, M., Covi, P., Cuneo, B., Denjoy, I., Donner, B., ... Schwartz, P. J. (2023). Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry. European Heart Journal, 44(35), 3357-3370. Advance online publication. https://doi.org/10.1093/eurheartj/ehad418

@article{0d6c12c0aa8248359b5788fd0a315b3e,

title = "Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry",

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.",

keywords = "Calmodulin/genetics, Child, Death, Sudden, Cardiac/etiology, Humans, Long QT Syndrome/diagnosis, Mutation/genetics, Registries, Tachycardia, Ventricular/diagnosis, Sudden death, Idiopathic ventricular fibrillation, Long QT syndrome, Cardiomyopathies, Catecholaminergic polymorphic ventricular tachycardia, Calmodulin, Neurological disorders",

author = "Lia Crotti and Carla Spazzolini and Mette Nyegaard and Overgaard, {Michael T} and Maria-Christina Kotta and Federica Dagradi and Luca Sala and Takeshi Aiba and Ayers, {Mark D} and Anwar Baban and Julien Barc and Beach, {Cheyenne M} and Behr, {Elijah R} and Bos, {J Martijn} and Marina Cerrone and Peter Covi and Bettina Cuneo and Isabelle Denjoy and Birgit Donner and Adrienne Elbert and H{\aa}kan Eliasson and Etheridge, {Susan P} and Megumi Fukuyama and Francesca Girolami and Robert Hamilton and Minoru Horie and Maria Iascone and Jaimez, {Juan Jim{\'e}nez} and Jensen, {Henrik Kj{\ae}rulf} and Kannankeril, {Prince J} and Kaski, {Juan P} and Naomasa Makita and Carmen Mu{\~n}oz-Esparza and Odland, {Hans H} and Seiko Ohno and John Papagiannis and Porretta, {Alessandra Pia} and Christopher Prandstetter and Vincent Probst and Tomas Robyns and Eric Rosenthal and Ferran Ros{\'e}s-Noguer and Nicole Sekarski and Anoop Singh and Georgia Spentzou and Fridrike Stute and Jacob Tfelt-Hansen and Jan Till and Tobert, {Kathryn E} and Vinocur, {Jeffrey M} and Gregory Webster and Wilde, {Arthur A M} and Wolf, {Cordula M} and Ackerman, {Michael J} and Schwartz, {Peter J}",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.",

year = "2023",

month = sep,

day = "14",

doi = "10.1093/eurheartj/ehad418",

language = "English",

volume = "44",

pages = "3357--3370",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "35",

}

Crotti, L, Spazzolini, C, Nyegaard, M , Overgaard, MT, Kotta, M-C, Dagradi, F, Sala, L, Aiba, T, Ayers, MD, Baban, A, Barc, J, Beach, CM, Behr, ER, Bos, JM, Cerrone, M, Covi, P, Cuneo, B, Denjoy, I, Donner, B, Elbert, A, Eliasson, H, Etheridge, SP, Fukuyama, M, Girolami, F, Hamilton, R, Horie, M, Iascone, M, Jaimez, JJ, Jensen, HK, Kannankeril, PJ, Kaski, JP, Makita, N, Muñoz-Esparza, C, Odland, HH, Ohno, S, Papagiannis, J, Porretta, AP, Prandstetter, C, Probst, V, Robyns, T, Rosenthal, E, Rosés-Noguer, F, Sekarski, N, Singh, A, Spentzou, G, Stute, F, Tfelt-Hansen, J, Till, J, Tobert, KE, Vinocur, JM, Webster, G, Wilde, AAM, Wolf, CM, Ackerman, MJ & Schwartz, PJ 2023, 'Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry', European Heart Journal, bind 44, nr. 35, s. 3357-3370. https://doi.org/10.1093/eurheartj/ehad418

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

PY - 2023/9/14

Y1 - 2023/9/14

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/genetics

KW - Child

KW - Death, Sudden, Cardiac/etiology

KW - Humans

KW - Long QT Syndrome/diagnosis

KW - Mutation/genetics

KW - Registries

KW - Tachycardia, Ventricular/diagnosis

KW - Sudden death

KW - Idiopathic ventricular fibrillation

KW - Long QT syndrome

KW - Cardiomyopathies

KW - Catecholaminergic polymorphic ventricular tachycardia

KW - Calmodulin

KW - Neurological disorders

UR - http://www.scopus.com/inward/record.url?scp=85170699059&partnerID=8YFLogxK

U2 - 10.1093/eurheartj/ehad418

DO - 10.1093/eurheartj/ehad418

M3 - Journal article

C2 - 37528649

SN - 0195-668X

VL - 44

SP - 3357

EP - 3370

JO - European Heart Journal

JF - European Heart Journal

IS - 35

ER -

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry

Abstract

Bibliografisk note

Adgang til dokumentet

AUB Link

Andre filer og links

Fingeraftryk

Impacts

Forskning i genfejl kan benåde australsk kvinde

Citationsformater