Long QT syndrome type 3

The long QT syndrome (LQTS) is a heart disease in which there is an abnormally long delay between the electrical excitation (or depolarization) and relaxation (repolarization) of the ventricles of the heart. It is associated with syncope (loss of consciousness) and with sudden death due to ventricular arrhythmias. Arrhythmias in individuals with LQTS are often associated with exercise or excitement. The cause of sudden cardiac death in individuals with LQTS is ventricular fibrillation. more...

Individuals with LQTS have a prolongation of the QT interval on the ECG. The Q point on the ECG corresponds to the beginning of ventricular depolarization while the T point corresponds to the beginning of ventricular repolarization. The QT interval is measured from the Q point to the end of the T wave. While many individuals with LQTS have persistent prolongation of the QT interval, some individuals do not always show the QT prolongation; in these individuals, the QT interval may prolong with the administration of certain medications.

Genetics

The two most common types of LQTS are genetic and drug-induced. Genetic LQTS can arise from mutation to one of several genes. These mutations tend to prolong the duration of the ventricular action potential (APD), thus lengthening the QT interval. LQTS can be inherited in an autosomal dominant or an autosomal recessive fashion. The autosomal recessive forms of LQTS tend to have a more severe phenotype, with some variants having associated syndactyly or congenital neural deafness. A number of specific genes loci have been identified that are associated with LQTS. Following is a list of the most common mutations:

• LQT1 - mutations to the alpha subunit of the slow delayed rectifier potassium channel (KvLQT1 or KCNQ1). The current through the heteromeric channel (KvLQT1+minK) is known as I_Ks. This mutation is thought to cause LQT by reducing the amount of repolarizing action potential current that prolongs action potential duration (APD). These mutations tend to be the most common yet least severe.
• LQT2 - mutations to the alpha subunit of the fast delayed rectifier potassium channel (HERG + miRP). Current through this channel is known as I_Kr. This phenotype is also probably caused by a reduction in repolarizing current.
• LQT3 - mutations to the alpha subunit of the sodium channel (SCN5A). Current through is channel is commonly referred to as I_Na. Depolarizing current through the channel late in the action potential is thought to prolong APD. The late current is due to failure of the channel to remain inactivated and hence enter a bursting mode in which significant current can enter when it should not. These mutations are more lethal but less common.
• LQT4 - mutations in an anchor protein Ankyrin B which anchors the ion channels in the cell. Very rare.
• LQT5 - mutations in the beta subunit MinK which coassembles with KvLQT1.
• LQT6 - mutations in the beta subunit MiRP1 which coassembles with HERG.
• LQT7 - mutations in the potassium channel KCNJ2 which leads to Andersen-Tawil syndrome.
• LQT8 - mutations in the calcium channel Cav1.2 encoded by the gene CACNA1c leading to Timothy's syndrome

Other mutations affect the beta subunits ion channels. For example LQT6 affects minK (aka KCNE1) which is the beta subunit that coassembles with KCNQ1 to form I_Ks channels.

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