Calmodulinopathy in the updated registry was associated with a reduced frequency of all cardiac events compared with the original 2019 cohort (61% vs. 85%; P=0.001).
Observational (n=140)
Yes
The International Calmodulinopathy Registry reveals a broadening phenotypic spectrum of CALM mutations, with an increasing proportion of milder and familial forms, though the risk of life-threatening arrhythmias remains high.
Absolute Event Rate: 61% vs 85%
p-value: p=.001
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.
“Calmodulinopathies are very rare genetic disorders associated with a high risk for sudden cardiac death. Disease-causing variants in 1 of the 3 identical CALM genes cause severe forms of long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, or idiopathic ventricular fibrillation, and there are many unanswered questions concerning management and underlying mechanisms. What is currently known depends largely on the initial publications from the ICamR (International Calmodulinopathy Registry). However, progress is delayed because the accrual of patients in ICamR is slow.”
Crotti et al. (Wed,) conducted a observational in Calmodulinopathy (n=140). Calmodulinopathy in the updated registry was associated with a reduced frequency of all cardiac events compared with the original 2019 cohort (61% vs. 85%; P=0.001).
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: