Long QT syndromes

Long QT syndromes

Long QT syndromes (LQTS) are a group of inherited arrhythmogenic disorders characterised by prolonged QT interval and life threatening ventricular arrhythmias. The prevalence of long QT syndrome varies from one in five thousand to one in ten thousand in various regions. The initially described syndromes were an autosomal dominant Romano Ward syndrome and the autosomal recessive Jervell and Lange-Nielsen (JLN) syndrome. Now it is known that both are two ends of a spectrum with homozygous individuals having deafness due to defective endolymph secretion in the middle ear which is mediated by potassium channels.

Most common varieties of LQTS are LQT1, LQT2 and LQT3. LQTI contributes about 50%, LQT2 about 35-40% and LQT3 about 10-15%. The other varieties are quite rare, with only few families being described.

LQT1 is due to defect in the gene encoding for the alpha subunit of the potassium channel (KvLQT1) conducting the slow component (IKs) of the delayed rectifier current. Delayed rectifier current (IK) is the major repolarizing current during phase 3 of the cardiac action potential. Defect in the beta subunit (MinK) leads to LQT5. A functional channel will be constituted by a tetramer of KvLQT1 and a MinK. The gene for LQT1 is KCNQ1 and in those who are homozygous for it, JLN1 is manifested. The gene for LQT5 is KCNE1 and JLN2 manifests when it is homozygous.
Just as LQT1 and LQT5 are related to the same channel, LQT2 and LQT6 are related to the rapid component (IKr) of the delayed rectifier current. KCNH2 (LQT2) encodes for the alpha subunit (HERG) and KCNE2 (LQT6) encodes for the beta subunit (MiRP). LQT2 is more severe and has a higher penetrance than LQT1 and females are more affected than males, while it is the other way round in LQT1. While LQT2 events are precipitated by sudden arousal, LQT1 events are related to exercise.

LQT3 is different from the other varieties as it is mediated by the sodium channel (SCN5A). The channel protein is called Nav 1.5. While the previously discussed varieties are due to loss of function of the channel, LQT3 is due to gain of function of the sodium channel. The allelic disorder in which there is a loss of function of sodium channels is the Brugada syndrome, another important arrhythmogenic disorder prone for life threatening ventricular arrhythmias. While LQT1 and LQT2 are related to sympathetic states, the arrhythmias in LQT3 occur during rest or sleep and hence the role of beta blockers, the sheet anchor of therapy in other varieties, is less effective.

LQT4 is unique in that it is not due to a defect in a cardiac ion channel, but due a defect in the anchoring proteins which anchor the ion channels to the plasma membrane or the sarcoplasmic reticulum. It is due to mutation in ankyrin-B gene ANK2 [1] and LQT4 is characterised by severe sinus bradycardia and paroxysmal atrial fibrillation, in addition to a long QT interval.

LQT7 (Andersen syndrome) is also due to a defect in the potassium channel, but has additional features of hypokalemic periodic paralysis and dysmorphic features. KCNJ2 encoding for the inwardly rectifier potassium channel Kir2.1, the ion channel conducting IK1 current is the culprit in Andersen syndrome.

LQT8 is also called Timothy syndrome and is due to a defect in the calcium channel CACNA1c. Timothy syndrome is also associated with other features like congenital heart disease (patent ductus arteriosus, ventricular septal defect, tetralogy of Fallot) and dysmorphic facial features like flat nasal bridge, low set ears and deformed teeth.

LQT9 is due to a defect in CAV3 (Caveolin 3) and has been associated with sudden infant death syndrome (SIDS).

LQT10 is another disorder of sodium channel SCNB4 with the gene located on chromosome 11q23. It is also associated with familial atrial fibrillation-17 (ATFB17) [2].

LQT11 is caused by heterozygous mutation in the gene encoding A-kinase anchor protein-9 (AKAP9) on chromosome 7q21 [3]. LQT12 is described on another page. LQT13 is detailed in another article here.

LQT14 is caused by heterozygous mutation in the CALM1 gene on chromosome 14q32 [4]. LQT15 is caused by heterozygous mutation in the CALM2 gene on chromosome 2p21 [4]. LQT16 and catecholaminergic polymorphic ventricular tachycardia-6 (CPVT6) are caused by heterozygous mutation in the CALM3 gene on chromosome 19q13 [4].

Implantable defibrillators are often needed in LQTS symptomatic on maximally tolerated doses of beta blockers for prevention of sudden cardiac death.

References

1. Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, Song LS, Haurogné K, Kyndt F, Ali ME, Rogers TB, Lederer WJ, Escande D, Le Marec H, Bennett V. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003 Feb 6;421(6923):634-9.
2. Li RG, Wang Q, Xu YJ, Zhang M, Qu XK, Liu X, Fang WY, Yang YQ. Mutations of the SCN4B-encoded sodium channel β4 subunit in familial atrial fibrillation. Int J Mol Med. 2013 Jul;32(1):144-50.
3. Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS. Mutation of an A-kinase-anchoring protein causes long-QT syndrome. Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20990-5.
4. Boczek NJ, Gomez-Hurtado N, Ye D, Calvert ML, Tester DJ, Kryshtal D, Hwang HS, Johnson CN, Chazin WJ, Loporcaro CG, Shah M, Papez AL, Lau YR, Kanter R, Knollmann BC, Ackerman MJ. Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G. Circ Cardiovasc Genet. 2016 Apr;9(2):136-146.