Knowledge on rare diseases and orphan drugs

The most prevalent form, Romano-Ward syndrome (RWS), has a prevalence close to 1/2,500 live births. The other forms of familial LQTS are extremely rare.

The two cardinal manifestations of LQTS are syncopal episodes, which may lead to cardiac arrest and sudden cardiac death, and electrocardiographic abnormalities: prolongation of the QT interval and T wave abnormalities. Where there are no extracardiac features, the disease is referred to as RWS. RWS related to SCN5A is sometimes associated with 2:1 atrioventricular block and very early occurrence of cardiac arrhythmias, especially in de novo cases. The Jervell and Lange-Nielsen syndrome also has congenital deafness. Timothy syndrome can be associated with syndactyly, facial dysmorphism and neurodevelopmental features. The Andersen-Tawil syndrome is no longer considered part of LQTS.

All the LQTS genes identified so far encode cardiac ion channel subunits or proteins involved in modulating ionic currents. Mutations in the genes that encode the cardiac potassium and sodium channels (KCNQ1, 11p15.5-p15.4 ; KCNH2, 7q36.1 ; SCN5A, 3p22.2) mainly cause the disease by prolonging the duration of repolarization and, thus, of the action potential. KCNQ1 is the most common LQTS variant.

Given the characteristic features of LQTS, the typical cases present no diagnostic difficulties for physicians aware of the disease. However, borderline cases are more complex and require the evaluation of various electrocardiographic, clinical, and familial findings, as proposed in the specific diagnostic criteria (the Schwartz score). The molecular screening is now part of the diagnostic process.

Differential diagnosis must be made with epilepsy, catecholaminergic polymorphic ventricular tachycardia (CPVT), and drug-induced LQTS.

Prenatal diagnosis should be considered when one of the parents has LQTS.

Inheritance may be autosomal dominant or autosomal recessive and depends on the genes involved and the form of familial LQTS. Genetic counseling should be offered to affected families.

Treatment should always begin with beta-blockers, unless there are valid contraindications. If the patient has a further syncopal episode despite a full dose beta-blockade, left cardiac sympathetic denervation (LCSD) should be performed without hesitation. Implantable cardioverter-defibrillator (ICD) therapy should be considered when the degree of protection afforded by beta-blockers and LCSD does not appear sufficient, with the final decision being based on individual patient characteristics (age, sex, clinical history, genetic subgroup including mutation-specific features in some cases, and the presence of ECG signs from 24-hour Holter recordings, indicating high electrical instability).

The prognosis is usually good in patients that are correctly diagnosed and treated. The exceptions are patients with Timothy syndrome, Jervell and Lange-Nielsen syndrome patients carrying KCNQ1 mutations and patients with LQTS related to either Calmodulin, TRDN or SCN5A variants.

Last update: April 2021 - Expert reviewer(s): Pr Peter SCHWARTZ