2. Academic Validation
  3. Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry

  • Eur Heart J. 2023 Sep 14;44(35):3357-3370. doi: 10.1093/eurheartj/ehad418.
Lia Crotti 1 2,  Carla Spazzolini 1,  Mette Nyegaard 3,  Michael T Overgaard 4,  Maria-Christina Kotta 1,  Federica Dagradi 1,  Luca Sala 1 5,  Takeshi Aiba 6,  Mark D Ayers 7,  Anwar Baban 8 9,  Julien Barc 10,  Cheyenne M Beach 11,  Elijah R Behr 12,  J Martijn Bos 13,  Marina Cerrone 14,  Peter Covi 15,  Bettina Cuneo 16,  Isabelle Denjoy 17,  Birgit Donner 18,  Adrienne Elbert 19,  Håkan Eliasson 20 21,  Susan P Etheridge 22,  Megumi Fukuyama 23,  Francesca Girolami 24,  Robert Hamilton 25,  Minoru Horie 23,  Maria Iascone 26,  Juan Jiménez-Jaimez 27,  Henrik Kjærulf Jensen 28,  Prince J Kannankeril 29,  Juan P Kaski 30 31,  Naomasa Makita 32 33,  Carmen Muñoz-Esparza 8 34,  Hans H Odland 35,  Seiko Ohno 36,  John Papagiannis 37,  Alessandra Pia Porretta 38,  Christopher Prandstetter 39 40,  Vincent Probst 41,  Tomas Robyns 8 42,  Eric Rosenthal 43,  Ferran Rosés-Noguer 8 44 45,  Nicole Sekarski 46,  Anoop Singh 47,  Georgia Spentzou 48,  Fridrike Stute 49,  Jacob Tfelt-Hansen 8 50 51,  Jan Till 45,  Kathryn E Tobert 13,  Jeffrey M Vinocur 11,  Gregory Webster 52,  Arthur A M Wilde 8 53 54,  Cordula M Wolf 55,  Michael J Ackerman 13,  Peter J Schwartz 1
Affiliations

Affiliations

  • 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
  • 47
  • 48 Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, WI, USA.
  • 49 Bristol Royal Hospital for Children, Bristol, UK.
  • 50 Department of Pediatric Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany.
  • 51 Section of Genetics, Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Denmark.
  • 52 Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
  • 53 Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 54 Department of Cardiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.
  • 55 Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, The Netherlands.
  • 56 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.
PMID: 37528649 DOI: 10.1093/eurheartj/ehad418
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; Cardiomyopathies; Catecholaminergic polymorphic ventricular tachycardia; Idiopathic ventricular fibrillation; Long QT syndrome; Neurological disorders; Sudden death.

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