Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry-Reference-Cited by-同舟云学术

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry

Published:2023-08-02 Issue:35 Volume:44 Page:3357-3370
ISSN:0195-668X
Container-title:European Heart Journal
language:en
Short-container-title:

Author:

Crotti Lia¹²^ORCID,Spazzolini Carla¹^ORCID,Nyegaard Mette³^ORCID,Overgaard Michael T⁴^ORCID,Kotta Maria-Christina¹^ORCID,Dagradi Federica¹^ORCID,Sala Luca¹⁵^ORCID,Aiba Takeshi⁶^ORCID,Ayers Mark D⁷^ORCID,Baban Anwar⁸⁹^ORCID,Barc Julien¹⁰^ORCID,Beach Cheyenne M¹¹^ORCID,Behr Elijah R¹²^ORCID,Bos J Martijn¹³^ORCID,Cerrone Marina¹⁴^ORCID,Covi Peter¹⁵,Cuneo Bettina¹⁶^ORCID,Denjoy Isabelle¹⁷^ORCID,Donner Birgit¹⁸^ORCID,Elbert Adrienne¹⁹^ORCID,Eliasson Håkan²⁰²¹^ORCID,Etheridge Susan P²²^ORCID,Fukuyama Megumi²³^ORCID,Girolami Francesca²⁴^ORCID,Hamilton Robert²⁵^ORCID,Horie Minoru²³^ORCID,Iascone Maria²⁶^ORCID,Jaimez Juan Jiménez²⁷^ORCID,Jensen Henrik Kjærulf²⁸^ORCID,Kannankeril Prince J²⁹^ORCID,Kaski Juan P³⁰³¹^ORCID,Makita Naomasa³²³³^ORCID,Muñoz-Esparza Carmen⁸³⁴^ORCID,Odland Hans H³⁵^ORCID,Ohno Seiko³⁶^ORCID,Papagiannis John³⁷^ORCID,Porretta Alessandra Pia³⁸^ORCID,Prandstetter Christopher³⁹⁴⁰^ORCID,Probst Vincent⁴¹^ORCID,Robyns Tomas⁸⁴²^ORCID,Rosenthal Eric⁴³^ORCID,Rosés-Noguer Ferran⁸⁴⁴⁴⁵^ORCID,Sekarski Nicole⁴⁶^ORCID,Singh Anoop⁴⁷^ORCID,Spentzou Georgia⁴⁸^ORCID,Stute Fridrike⁴⁹^ORCID,Tfelt-Hansen Jacob⁸⁵⁰⁵¹^ORCID,Till Jan⁴⁵^ORCID,Tobert Kathryn E¹³,Vinocur Jeffrey M¹¹^ORCID,Webster Gregory⁵²^ORCID,Wilde Arthur A M⁸⁵³⁵⁴^ORCID,Wolf Cordula M⁵⁵^ORCID,Ackerman Michael J¹³^ORCID,Schwartz Peter J¹^ORCID

Affiliation:

1. Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics , Via Pier Lombardo 22, 20135 Milan , Italy

2. Department of Medicine and Surgery, University of Milano-Bicocca , Piazza dell'Ateneo Nuovo, 1, 20126 Milan , Italy

3. Department of Health Science and Technology, Aalborg University , Aalborg , Denmark

4. Department of Chemistry and Bioscience, Aalborg University , Aalborg , Denmark

5. Department of Biotechnology and Biosciences, University of Milano-Bicocca , Milan , Italy

6. Division of Arrhythmia, National Cerebral and Cardiovascular Center , Suita , Japan

7. Department of Pediatrics, Division of Pediatric Cardiology, Indiana University School of Medicine , Indianapolis, IN , USA

8. Member of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart

9. Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children’s Hospital, IRCCS , Rome , Italy

10. Université de Nantes, CHU Nantes, CNRS, INSERM, L’institut du Thorax , Nantes , France

11. Pediatric Cardiology, Yale School of Medicine , New Haven, CT , USA

12. Cardiology Section, Institute of Molecular and Clinical Sciences, St George’s University of London and Cardiovascular Clinical Academic Group, St George’s University Hospitals NHS Foundation Trust , UK

13. Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Division of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic , 200 First Street SW, Rochester, MN 55905 , USA

14. Inherited Arrhythmias Clinic, Leon H. Charney Division of Cardiology, NYU Grossmann School of Medicine , New York, NY , USA

15. Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University , Salzburg , Austria

16. Department of Pediatrics, Section of Cardiology, University of Denver School of Medicine , Aurora, CO , USA

17. Centre de Référence Maladies Cardiaques Héréditaires Filière Cardiogen, Département de Rythmologie, Groupe Hospitalier Bichat-Claude Bernard , Paris , France

18. Kardiologie, Universitäts-Kinderspital beider Basel (UKBB) , Basel , Switzerland

19. Department of Medical Genetics, University of British Columbia , Vancouver, BC , Canada

20. Department of Women’s and Children’s Health, Karolinska Institutet , Stockholm , Sweden

21. Pediatric Cardiology C8:34, Karolinska University Hospital , Stockholm , Sweden

22. Department of Pediatrics, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital , Salt Lake City, UT , USA

23. Department of Cardiovascular Medicine, Shiga University of Medical Science , Shiga , Japan

24. Cardiology Unit, Meyer Children’s Hospital , Florence , Italy

25. Division of Cardiology, The Hospital for Sick Children (SickKids) , Toronto, ON , Canada

26. Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII , Bergamo , Italy

27. Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitario IBS Granada , Spain

28. Department of Cardiology, Department of Clinical Medicine, Aarhus University Hospital, Aarhus University , K-8200 Aarhus N , Denmark

29. Department of Pediatrics, Vanderbilt University Medical Center , Nashville, TN , USA

30. Centre for Paediatric Inherited and Rare Cardiovascular Disease, Institute of Cardiovascular Science, University College London, Zayed Centre for Research into Rare Disease in Childhood , London , UK

31. Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital , London , UK

32. National Cerebral and Cardiovascular Center , Suita , Japan

33. Sapporo Teishinkai Hospital , Sapporo , Japan

34. Inherited Cardiac Disease Unit, Hospital Universitario Virgen Arrixaca , Murcia , Spain

35. Department of Cardiology and Pediatric Cardiology, Section for Arrhythmias, Oslo University Hospital, Oslo, Norway

36. Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center , Osaka , Japan

37. Pediatric and Adult Congenital Heart Disease, Onassis Cardiac Surgery Center , Athens , Greece

38. Unité des Troubles du Rythme, Service de Cardiologie, Centre Hospitalier Universitaire Vaudois , Lausanne , Switzerland

39. Medical Faculty, Johannes Kepler University Linz , Linz , Austria

40. Department of Pediatric Cardiology, Kepler University Hospital , Linz , Austria

41. Service de Cardiologie, L’institut du Thorax, CHU Nantes , Nantes , France

42. Department of Cardiovascular Diseases, University Hospitals Leuven , Leuven , Belgium

43. Evelina London Children’s Hospital, St Thomas’ Hospital , London , UK

44. Lead Paediatric Cardiology Department, Vall d’Hebron University Hospital , Barcelona , Spain

45. Royal Brompton Hospital NHS Guy’s and St Thomas Foundation Trust , London , UK

46. Unité de Cardiologie Pédiatrique, Département Médico-Chirurgical de Pédiatrie, CHUV | Centre Hospitalier Universitaire Vaudois , Lausanne , Switzerland

47. Department of Pediatrics, Medical College of Wisconsin , Wauwatosa, WI , USA

48. Bristol Royal Hospital for Children , Bristol , UK

49. Department of Pediatric Cardiology, University Heart & Vascular Center Hamburg , Hamburg , Germany

50. Section of Genetics, Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen , Denmark

51. Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet , Copenhagen , Denmark

52. Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine , Chicago, IL , USA

53. Department of Cardiology, Amsterdam UMC Location University of Amsterdam , Amsterdam , The Netherlands

54. Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias , Amsterdam , The Netherlands

55. Center for Rare Congenital Heart Diseases, Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, Technical University Munich, School of Medicine & Health , Munich , Germany

Abstract

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.

Funder

ERN GUARD-Heart

Italian Ministry of Health Ricerca Corrente

Registro internazionale delle calmodulinopatie

Fondation Leducq

Canadian Institutes of Health Research

Heart and Stroke Foundation of Canada

The Labatt Family Heart Centre

Cartwright Family Fellowship

Carter Heart Arrhythmia Trainee Fund and the Caitlin Elizabeth Morris fund

Medical Research Council

Clinical Academic Research Partnership