LQT8

LQT8 is a rare form of congenital long QT syndrome caused by mutations in the calmodulin genes CALM1, CALM2, and CALM3. Calmodulin plays a key role in calcium signaling in heart muscle, and mutations can disrupt the normal process of cardiac repolarization, leading to a prolonged QT interval on the electrocardiogram. Inheritance is typically autosomal dominant, with high penetrance in many families.

Clinically, LQT8 often presents in infancy or early childhood. Affected individuals may experience syncope, seizures mistaken for epilepsy, or, less commonly, sudden cardiac death due to torsades de pointes. The QT interval tends to be markedly prolonged, and arrhythmias can be triggered by stress, illness, or activity.

Diagnosis relies on a combination of clinical history, family history, and genetic testing. An electrocardiogram shows a prolonged QT interval, and sequencing of CALM1, CALM2, and CALM3 can identify pathogenic variants. Calmodulinopathy-related LQTS may coexist with other phenotypes such as catecholaminergic polymorphic ventricular tachycardia in some cases.

Management follows general long QT syndrome principles. Treatment typically includes beta-blocker therapy and avoidance of drugs that prolong the QT interval, along with careful electrolyte management. In high-risk individuals or those with prior cardiac arrest, options may include left cardiac sympathetic denervation or implantable cardioverter-defibrillator implantation. Acute torsades de pointes is treated with magnesium and supportive measures; pacing may be considered in certain situations.

Prognosis varies, but LQT8 is associated with a substantial risk of life-threatening events in early life. Ongoing research into calmodulinopathies aims to improve understanding and develop targeted therapies.