Dataset Information

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.

SUBMITTER: Crotti L

PROVIDER: S-EPMC10499544 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.

Crotti Lia L Spazzolini Carla C Nyegaard Mette M Overgaard Michael T MT Kotta Maria-Christina MC Dagradi Federica F Sala Luca L Aiba Takeshi T Ayers Mark D MD Baban Anwar A Barc Julien J Beach Cheyenne M CM Behr Elijah R ER Bos J Martijn JM Cerrone Marina M Covi Peter P Cuneo Bettina B Denjoy Isabelle I Donner Birgit B Elbert Adrienne A Eliasson Håkan H Etheridge Susan P SP Fukuyama Megumi M Girolami Francesca F Hamilton Robert R Horie Minoru M Iascone Maria M Jiménez-Jaimez Juan J Jensen Henrik Kjærulf HK Kannankeril Prince J PJ Kaski Juan P JP Makita Naomasa N Muñoz-Esparza Carmen C Odland Hans H HH Ohno Seiko S Papagiannis John J Porretta Alessandra Pia AP Prandstetter Christopher C Probst Vincent V Robyns Tomas T Rosenthal Eric E Rosés-Noguer Ferran F Sekarski Nicole N Singh Anoop A Spentzou Georgia G Stute Fridrike F Tfelt-Hansen Jacob J Till Jan J Tobert Kathryn E KE Vinocur Jeffrey M JM Webster Gregory G Wilde Arthur A M AAM Wolf Cordula M CM Ackerman Michael J MJ Schwartz Peter J PJ

European heart journal 20230901 35

<h4>Aims</h4>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.<h4>Methods and results</h4>The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positiv ...[more]

PMID: 37528649

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Project description:AimsCalmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome.Methods and resultsA dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1-5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0-8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively.ConclusionCalmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.

Project description:BackgroundCaM (calmodulin) mutations are associated with congenital arrhythmia susceptibility (calmodulinopathy) and are most often de novo. In this report, we sought to broaden the genotype-phenotype spectrum of calmodulinopathies with 2 novel calmodulin mutations and to investigate mosaicism in 2 affected families.MethodsCaM mutations were identified in 4 independent cases by DNA sequencing. Biochemical and electrophysiological studies were performed to determine functional consequences of each mutation.ResultsGenetic studies identified 2 novel CaM variants (CALM3-E141K in 2 cases; CALM1-E141V) and one previously reported CaM pathogenic variant (CALM3-D130G) among 4 probands with shared clinical features of prolonged QTc interval (range 505-725 ms) and documented ventricular arrhythmia. A fatal outcome occurred for 2 of the cases. The parents of all probands were asymptomatic with normal QTc duration. However, 2 of the families had multiple affected offspring or multiple occurrences of intrauterine fetal demise. The mother from the family with recurrent intrauterine fetal demise exhibited the CALM3-E141K mutant allele in 25% of next-generation sequencing reads indicating somatic mosaicism, whereas CALM3-D130G was present in 6% of captured molecules of the paternal DNA sample, also indicating mosaicism. Two novel mutations (E141K and E141V) impaired Ca2+ binding affinity to the C-domain of CaM. Human-induced pluripotent stem cell-derived cardiomyocytes overexpressing mutant or wild-type CaM showed that both mutants impaired Ca2+-dependent inactivation of L-type Ca2+ channels and prolonged action potential duration.ConclusionsWe report 2 families with somatic mosaicism associated with arrhythmogenic calmodulinopathy, and demonstrate dysregulation of L-type Ca2+ channels by 2 novel CaM mutations affecting the same residue. Parental mosaicism should be suspected in families with unexplained fetal arrhythmia or fetal demise combined with a documented CaM mutation.

Dataset Information

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.

Aims

Methods and results

Conclusion

Publications

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.

Similar Datasets

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