Congenital short QT syndrome

Johnson Francis — Mon, 26 Jan 2009 16:25:10 +0000

Congenital short QT syndrome is new inherited clinical syndrome which was described by Gussak et al in 2000. (Cardiology. 2000;94:99-102). A gene mutation causing short QT syndrome was first demonstrated by Brugada et al in January 2004. This mutation in HERG (KCNH2) gene was later called as SQT1 and was due to gain in function of Iks, the slow component of the delayed rectifier potassium current. Later on in the same year, SQT2 was described by Bellocq et al as a mutation in KCNQ1 (KvLQT1) which caused a gain in function of Ikr, the rapid component of delayed rectifier potassium current. SQT3 was identified by Priori et al as a mutation in KCNJ2 gene which causes a gain in function of Ik1 potassium current.

Short QT syndrome is characterized by consistently short QT intervals, usually below 300 msec, which does not lengthen with bradycardia. There is a propensity for sudden cardiac death and atrial fibrillation. Family history of sudden death may be forthcoming. Electrophysiologically short QT syndrome is characterized by short refractory periods and inducible VF (ventricular fibrillation) at EP (electrophysiological) study.

Shortening of QT interval can occur in tachycardia, hyperthermia and hypercalcemia. Digoxin can also shorten the QT interval. These should be excluded before considering a diagnosis of short QT syndrome.

Treatment options for short QT syndrome are limited. Some have reported lengthening of QT interval with quinidine. Most patients with short QT syndrome and a risk of sudden cardiac death get an ICD (implantable cardioverter defibrillator) implanted.

Long QT syndrome (LQTS) genes

Johnson Francis — Sat, 06 Dec 2008 14:51:50 +0000

10 LQTS genes have been described from 1991 to 2007. LQT1 gene is KCNQ1 and it encodes for alpha (KvLQT1) subunit of the potassium channel conducting the IKs current. IKs is the slow component of the delayed rectifier current, which in turn is the major repolarizing current during phase 3 of the cardiac action potential. LQT1 accounts for 50% of the genotyped cases and is the commonest variety of LQTS. Individuals homozygous for LQT1 mutation will have Jervell and Lange-Nielsen (JLN) syndrome with long QT interval and congenital deafness. This is because at least one functioning gene is required for synthesis of potassium rich endolymph in the cochlea. Jervell and Lange-Nielsen syndrome due to KCNQ1 mutation is called JLN1. Heterozygous individuals will have some potassium channels active enough to produce endolymph so that they will not have deafness, but only long QT interval, presenting the phenotype of Romano Ward syndrome. LQT1 has lower penetrance and a more benign prognosis compared with LQT2 and LQT3.

LQT2 is KCNH2 and it encodes for alpha (HERG: human Ether-a-go-go Related Gene) subunit of the potassium channel conducting IKr current the rapid component of the delayed rectifier current. HERG forms homotetramers in the plasmalemma to make up functional potassium channels. LQT2 is the second most common LQTS mutation, contributing about 35%-40% of mutations. LQT2 has a higher penetrance than LQT1 and it is more severe, especially in females.

SCN5A is the LQT3 gene and it encodes for cardiac sodium channel conducting the sodium inward current (INa). LQT3 mutation results in gain of function of the channel and hence is the allele of Brugada syndrome in which there is loss of function of the same channel. The prevalence of LQT3 is about 10-15% of LQTS. It is a more malignant form of LQTS and has poor response to beta-blockers.

The LQT4 gene ANK2 encodes for an intracellular protein (Ankyrin B) that regulates the proper intracellular localization of plasmalemmal ion channels like calcium channel, sodium channel, sodium/calcium exchanger and sarcoplasmic reticulum channels. Just as Brugada syndrome mutation is the allele of LQT3, LQT4 is mutation is the allele of catecholaminergic polymorphic ventricular tachycardia (CPVT).

KCNE1 is the LQT5 gene which encodes for beta (MinK) subunit of potassium channel conducting IKs. KvLQT1 (LQT1 gene) proteins form homotetramers and co-assemble with minK (KQT5 gene) subunits to form a functional potassium channel. Jervell and Lange-Nielsen syndrome due to homozygous KCNE1 mutation is called JLN2.

KCNE2 the LQT6 gene encodes the beta (MiRP) subunit of the potassium channel conducting the IKr current the rapid component of the delayed rectifier current. This variant is quite rate (less than 1%), has incomplete penetrance and very mild manifestations.

KCNJ2, the LQT7 gene mutation causes Andersen syndrome, characterised by long QT interval and dysmorphic facial appearance. KCNJ2 encodes Kir2.1, an inwardly rectifier potassium channel, which conducts the IK1 current. Due to the facial dsymorphism seen in Andersen syndrome, Kir2.1 is thought to play a major role in developmental signaling.

CACNA1c, the LQT8 gene mutation causes Timothy syndrome. The mutation causes nearly complete loss of voltage-dependent inactivation of calcium channels. The resultant prolonged calcium current delays repolarization and increases the risk of arrhythmia.

CAV3, the LQT9 gene mutation causes a rare form of LQTS. CAV3 encodes for caveolin 3 and has been linked with sudden infant death syndrome (SIDS).

Sodium channel B4 subunit (SCNB4) mutation has been linked with LQT10, a rare form of long QT syndrome in 2007.

Cardiophile MD Archive » KvLQT1

Congenital short QT syndrome

Long QT syndrome (LQTS) genes