LONG QT SYNDROME
Section snippets
MOLECULAR GENETICS OF LQTS
Inherited LQTS is an autosomal dominant genetic disorder caused by mutations of genes that encode for cardiac ion channels. Five genes have been discovered as of this time. Four encode for potassium ion channels and one for the cardiac sodium channel. An additional locus has been discovered on chromosome 4, but the gene has not yet been identified. The currently known genes are listed in Table 3.
Over 180 different mutations of the five known genes have been described. LQTS, therefore, shows a
RELATIVE FREQUENCY OF THE LQTS GENOTYPES
In genotyped patients, the KvLQT1 gene is the most common, being found in about 50% of patients. HERG accounts for about 45% of cases. Thus, mutations of the potassium genes KvLQT1 and HERG together cause about 95% of cases. The SCN5A gene accounts for about 3% to 5% of the cases. The MinK and MiRP1 genes each account for 1% or less. The LQT4 genotype is very rare. As noted previously, approximately 50% of families who appear to have LQTS by clinical criteria cannot be genotyped to one of these
CLINICAL GENETICS
Historically, two forms of LQTS have been recognized. Jervell and Lange–Nielsen syndrome is characterized by severe LQTS with a high incidence of sudden death, severe congenital deafness, and autosomal recessive inheritance.26, 27 Romano–Ward syndrome shows autosomal dominant inheritance and normal hearing. The molecular findings have clarified the genetics of Jervell and Lange–Nielsen syndrome and have demonstrated all LQTS to be autosomal dominant, but with reduced penetrance and variable
CLINICAL MANIFESTATIONS
LQTS occurs in all races and ethnic groups, although the relative frequency in each group is as yet unknown, because no systematic screening of different groups has been attempted. The principal symptoms are syncope and sudden death, from TDP (Fig. 1). Most often, TDP is self-terminating and causes a syncopal episode from which the patient quickly recovers. Cardiac arrest occurs if the TDP is more persistent, and sudden death results if the rhythm does not return to normal spontaneously and the
ECG MANIFESTATIONS
The predominant feature is, of course, QT prolongation. The QTc averages 0.49 seconds82, 83, 98 in both LQT1 and LQT2 genotypes. In the modest number of LQT3 patients available for study, the values appear to be somewhat longer, with a mean value around 0.51 seconds.98 The range of QTc intervals extends from about 0.41 seconds to more than 0.60 seconds. Although QT-interval prolongation is the characteristic feature of LQTS, it is not always present. We first demonstrated this finding in 1992
PATHOPHYSIOLOGY
Although the physiologic defects in the different LQTS genotypes are diverse, all cause prolongation of the APD. The APD prolongation renders the myocytes vulnerable to early afterdepolarizations (EADs), which are the initiating mechanism for the TDP arrhythmia. APD prolongation produces a baseline propensity to EADs by activation of L-type Ca++ channels,25 providing the inward depolarizing current necessary for generating the EAD. It would appear, though, that additional physiologic
MANAGEMENT OF LQTS
The gold-standard therapy for LQTS remains β-blocker administration, which is effective in the large majority of patients. Like virtually all treatments, there are treatment failures and partial responders, but it is estimated that β-blocker treatment is effective in 80% to 90% of patients with a significant reduction in rate of sudden death.10, 19, 33, 52, 74, 80, 97 Our long-term follow-up of a number of LQT1 patients suggest that β-blockers are particularly effective in this genotype.77, 79
SUMMARY
In conclusion, much has been learned in the past several years regarding the molecular biology of LQTS, and this information has been directly applicable to the clinical care of patients with this syndrome. The knowledge also has been of considerable importance for understanding the molecular basis of arrhythmias in general and is providing insights into potential molecular-based therapies for arrhythmias.
ACKNOWLEDGMENTS
Sincere appreciation is expressed to Don Atkinson in Dr Mark Keating's laboratory at the University of Utah, who kindly provided the graphic representations of the LQTS gene morphologies, Figs. 3 through 6. Also, great appreciation to Raymond Woosley, MD, PhD, of Georgetown University, who compiled the list of drugs to avoid, shown in Table 1, for the sudden arrhythmia death syndromes (SADS Foundation, Salt Lake City, UT), and to the SADS Foundation for permission to reproduce the list for this
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