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.

Cardiac Genetic Investigation of Sudden Infant and Early Childhood Death: A Study From Victims to Families

“… 53 In the study that focused also on a 1‐ to 5‐year‐old SUDC subgroup, 11 in the few cases that the CALM genes were screened, no clinically relevant variants were identified either. 11 , 55 This could be partly explained by the lack of significant numbers in SUDC cohorts, impeding the possibility of identifying such a rare disease as calmodulinopathy, 56 and the fact that infants with calmodulinopathy manifest with extreme phenotypes that, in many cases, are likely to come to medical attention before a sentinel event occurs. Another possible explanation could be related to the differential expression of the CALM genes between fetal, infant, and adult stages of development.…”

“…Another possible explanation could be related to the differential expression of the CALM genes between fetal, infant, and adult stages of development. 57 However, in the International Calmodulinopathy Registry, 56 SUDC represents a small subgroup (9/140) of an already rare clinical entity, and among these 9 cases, all CALM genes are represented.…”

Unraveling Complexities in Genetically Elusive Long QT Syndrome

“…Notably, patients with pathogenic variants in CALM1-3 genes show either LQTS or catecholaminergic polymorphic ventricular tachycardia phenotypes, but certain patients may have coexistence of both LQTS and catecholaminergic polymorphic ventricular tachycardia. 3,[45][46][47] In addition, pleiotropy in presentations, ranging from channelopathy to syndromic forms that may include cardiomyopathy, congenital heart disease, and primary neurological manifestations have been described. As medical knowledge and genetic testing technologies advance, many forms of currently considered elusive or unidentified genetic variants may become detectable in the future.…”

Calmodulin variants in schizophrenia patients display gain-of-function or loss-of-function effects

“…This link has since been confirmed in several other studies and explained molecularly (1, 5). Today, patients with disease-causing calmodulin variants are described in the International Calmodulinopathy Registry (ICalmR) (6,7). In 2023, the ICalmR covered 140 patients worldwide, thus demonstrating that calmodulin variants are ultra-rare.…”

“…Moreover, calmodulin variants in LQTS patients affect calmodulin's ability to regulate the voltage-gated calcium channel 1.2 (CaV1.2) (9)(10)(11)(12). Recently, the phenotypic spectrum of calmodulinopathies has expanded to include structural heart disease as well as developmental delay, but systematic studies on the effect of these variants on Ca 2+ sensing and CaV1.2 function are lacking (7).…”