CLINICAL AND GENETIC-ASPECTS OF THE LONG QT SYNDROME

The idiopathic long QT syndrome (LQTS) is a congenital disorder charac terized by a prolongation of the QT interval and by the occurrence of stress-induced syncope or cardiac arrest due to ventricular tachyarrhy thmias. Such lethal events may be prevented by quite effective pharmac ological or surgical antiadrenergic therapies. Two pathophysiological hypotheses have been considered: 1. a ''sympathetic imbalance'' caused by a lower than normal right sympathetic activity and 2. a cardiac ce llular dysfunction, possibly an altered potassium channel. Although on e may find clinical features of LQTS compatible with both hypotheses, there is no proof for either of them. Since a locus has been mapped fo r the long QT syndrome on the short arm of chromosome 11 in several fa milies, tightly linked to the Harvey-ras-1 (H-ras-1) gene, this gene b ecame a candidate gene for LQTS. It is an attractive hypothesis that a n alteration in the H-ras-1 gene may cause LQTS by modulation of acety lcholin-activated potassium channels through guanine-nucleotide-bindin g RAS proteins. No mutation in the H-ras-1 gene has been found until n ow, so that other genes located in this region close to H-ras-1 have t o be considered to cause LQTS. Moreover, the variability of the clinic al picture in patients with LQTS and the absence of linkage to the H-r as-1 locus in other families make genetic heterogeneity likely. Advanc es in recombinant DNA technology raise the possibility to identify the abnormal gene(s). This could be the basis to understand the pathogene tic of LQTS leading to a more accurate diagnosis and possibly new ther apeutic concepts.