calmodulinopathies

Calmodulinopathies are genetic disorders caused by mutations in CALM1, CALM2, or CALM3, which encode calmodulin, a ubiquitous calcium-binding messenger protein essential for numerous cellular signaling pathways. Calmodulin acts as a key intracellular calcium sensor that regulates processes such as cardiac excitation–contraction coupling and neurotransmission.

Most pathogenic CALM variants are de novo, heterozygous missense mutations that cluster in the EF-hand calcium-binding domains of calmodulin. Because CALM1, CALM2, and CALM3 produce the same protein, mutations in any gene can disrupt calcium signaling in multiple tissues, with pronounced effects on the heart.

Clinically, calmodulinopathies predominantly present with severe, early-onset arrhythmias. The core cardiac phenotypes include long QT syndrome types 14, 15, and 16 (LQTS14–16), often manifesting in infancy or early childhood, and catecholaminergic polymorphic ventricular tachycardia (CPVT)-like presentations or mixed phenotypes. These conditions carry a high risk of sudden cardiac death, particularly if not recognized and treated promptly.

Pathophysiology involves disrupted calmodulin regulation of calcium channels and calcium release channels. Calmodulin normally modulates L-type calcium channel inactivation and stabilizes ryanodine receptor–mediated calcium release. Pathogenic CALM variants can impair calcium binding or target interactions, leading to prolonged ventricular repolarization, abnormal repolarization waves, and increased susceptibility to arrhythmias under stress.

Diagnosis relies on clinical assessment supported by genetic testing confirming CALM1–3 mutations. Electrocardiography often shows markedly prolonged QT intervals, and exercise or catecholamine challenges may provoke arrhythmias. Management emphasizes aggressive beta-blockade, avoidance of triggers, and consideration of additional therapies such as antiarrhythmic drugs or device therapy (implantable cardioverter-defibrillator) in high-risk individuals. Family screening and genetic counseling are advised.

Prognosis varies but is generally guarded due to the potential for early, life-threatening events. Ongoing research seeks to clarify genotype–phenotype correlations and develop targeted treatments that address the underlying calcium-signaling defects.