Chapter 203

## Abstract

1. Long QT syndrome is characterized clinically by (a) recurrent syncope; (b) sudden death and aborted sudden death; (c) episodic ventricular tachyarrhythmias such as torsade de pointes and ventricular fibrillation; and (d) prolongation of the QT interval on surface electrocardiogram. In some cases, long QT syndrome is associated with simple syndactyly. This disorder is inherited as an autosomal dominant trait (Romano-Ward syndrome; MIM 192500, 152427, 600163, 600919, 601005, and 176261). Long QT syndrome can be associated with congenital deafness in the Jervell and Lange-Nielsen syndrome (MIM 220400). In this disorder, congenital deafness is inherited as an autosomal recessive trait. Prolongation of the QT interval and arrhythmia susceptibility is inherited as an autosomal semidominant trait—that is, homozygotes are more severely affected than heterozygotes.

2. The frequency of heterozygotes for all dominant long QT syndromes is estimated to be 1 in 10,000 persons. Risk of sudden death in heterozygotes is approximately 0.5 percent per year.

3. Homozygotes are rare. They have profound prolongation of the QT interval and risk of arrhythmia. Untreated, most homozygotes die in childhood.

4. Idiopathic ventricular fibrillation (MIM 600163) is characterized clinically by (a) sudden death and aborted sudden death; (b) episodic ventricular fibrillation; and (c) variable electrocardiographic findings including prolongation of the QRS complex with a right bundle branch block pattern (Brugada syndrome). This disorder is inherited as an autosomal dominant trait. Prevalence is not known.

5. The primary defect in long QT syndrome and idiopathic ventricular fibrillation is a mutation in a gene encoding a cardiac myocyte ion channel. Genes identified to date include KVLQT1 (GenBank U89364), KCNE1 or minK (GenBank L33815), and HERG (GenBank U04270), which encode potassium channel subunits, and SCN5A (GenBank M77235), which encodes the cardiac sodium channel. These proteins are located on the surface of cardiac myocytes and regulate configuration of the cardiac action potential.

6. KVLQT1, gene symbol for potassium voltage-gated channel KQT-like subfamily -member 1- is located on the short arm of chromosomal 11. It comprises 16 exons that span 400 kb. The gene encodes a protein of 676 amino acids. More than 78 different mutant alleles have been identified, which represents 45 percent of the arrhythmia-associated mutations discovered.

7. HERG is located on the long arm of chromosome 7. It comprises 16 exons that span 55 kb. The gene encodes a protein of 1159 amino acids. More than 81 mutations of HERG have been identified thus far. This represents 45 percent of the long QT-associated mutations.

8. SCN5A, gene symbol for sodium channel voltage-gated -type V-α-protein , is located on the short arm of chromosome 3. It comprises 28 exons that span 80 kb. The gene encodes a single protein that contains 2016 amino acids. Thirteen distinct SCN5A mutations have been associated with long QT syndrome. Several SCN5A mutations have been associated with idiopathic ventricular fibrillation.

9. KCNE1 encoding minK is located on the short arm of chromosome 21. It comprises 3 exons that span 4 kb. The gene encodes a protein that contains 129 amino acids. Three missense mutations of minK have been associated with long QT syndrome.

10. A fifth long QT syndrome locus (LQT4) has been localized to chromosome 4. The gene for this form of long QT syndrome has not been identified.

11. Additional locus heterogeneity for long QT syndrome has been defined.

12. SCN5A encodes the cardiac sodium channel. This gene is expressed in cardiac myocytes and initiates the action potential. KVLQT1 encodes a voltage-gated potassium channel α subunit. This gene is expressed in cardiac myocytes. KvLQT1 α subunits coassemble with minK β subunits to form cardiac slow activating delayed rectifier potassium current (IKs) potassium channels. HERG is expressed in cardiac myocytes and encodes α subunits that form cardiac IKr potassium channels. IKr and IKs potassium channels terminate the cardiac action potential.

13. Long QT syndrome-associated mutations of KVLQT1 , KCNE1, and HERG result in loss of channel function. In most cases, these are missense mutations that result in dominant-negative suppression of channel function. The extent of this dominant-negative effect is variable. As a result, channel function (IKr or IKs) is reduced by 50 to 90 percent. This results in prolongation of action potential duration in individual cardiac myocytes, abnormal inhomogeneity of repolarization in the myocardium, and a substrate for arrhythmia.

14. Long QT syndrome-associated mutations of SCN5A result in a gain-of-channel function. Normally, individual sodium channels open to initiate the action potential, close, and remain closed for the remainder of the action potential. Long QT syndrome-associated mutations of the cardiac sodium channel destabilize the inactivation gate, resulting in repetitive reopening of a few sodium channels during the plateau phase of the action potential. This prolongs action potential duration in individual cardiac myocytes, resulting in an abnormal inhomogeneity of repolarization and a substrate for arrhythmia.

15. SCN5A mutations associated with idiopathic ventricular fibrillation result in a loss-of-channel function. This results in an abnormal inhomogeneity of cardiac conduction and a substrate for ventricular fibrillation.

16. KVLQT1 and minK are also expressed in the inner ear. Here the channel functions to conduct potassium ions into the inner ear, creating the potassium-rich fluid endolymph. Individuals harboring two loss-of-function mutations of KvLQT1 or minK have inadequate endolymph production, resulting in degeneration of the organ of Corti and congenital neural deafness.

17. Treatment for long QT syndrome includes: (a) β adrenergic blockers that appear to reduce the incidence of arrhythmia in susceptible individuals, but do not eliminate the substrate for arrhythmia; (b) potassium therapy to maintain a high normal serum potassium concentration; (c) placement of an automatic internal defibrillator; and (d) avoidance of drugs that induce long QT syndrome, such as erythromycin, terfenadine, and class III antiarrhythmic agents.

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