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LONG Q-T SYNDROME (LQTS) A prolonged QTc interval on the EKG may be a marker for diffuse abnormalities of ventricular depolarization, which in turn may predispose to ventricular tachycardia of the torsade de pointes variety. A long Q-T may be seen as a congenital disorder, or it may be acquired from exposure to certain drugs, toxins or electrolyte disturbances. Although many cases are sporadic, there is a clear genetic pattern in the Romano-Ward (autosomal dominant) and Jervell-Lange-Nielsen (autosomal recessive) syndromes. The dominant disorder has no clinical marker aside from the arrhythmia, whereas the recessive syndrome is associated with hereditary nerve deafness. Unfortunately, the Romano-Ward syndrome is often identified in a family only after a serious event happens to one member of the family. The current understanding of the pathogenetic mechanism of the LQTS involves the sympathetic nervous system either as the primary defect (sympathetic imbalance hypothesis) or an intracardiac abnormality probably related to the control of potassium currents. Another hypothesis, involving inadequate Q-T interval shortening during heart rate increases, has been more recently proposed. The typical clinical presentation of LQTS is the occurrence of syncope or cardiac arrest, precipitated by emotional or physical stress, in a young individual with a prolonged Q-T interval on the EKG. If these patients remain untreated, the syncopal episodes recur and eventually prove to be fatal in most cases. When family screening is performed, a prolongation of the Q-T interval can often be detected, and a history of spells or sudden, unexpected deaths in early age is sometimes recorded. The syncopal episodes are due to torsade de pointes, often degenerating into ventricular fibrillation. These episodes are characteristically associated with sudden increases in sympathetic activity, such as during violent emotions (particularly fright, but also anger) or physical activity (notably swimming). Sudden awakening (alarm clock, telephone ring and thunder) seem almost specific trigger for some patients. A higher incidence of correspondence with menses has also been noted. A few families have been reported in which cardiac arrest almost exclusively occurred at rest or during sleep. The condition may sometimes be confused with a neurologic disorder, for this reason an EKG should be obtained as a routine part of the work-up for any patient with unexplained syncope or first seizure. The Q-T syndrome may also be involved in some cases of sudden infant death syndrome. In the LQTS, the extent of Q-T interval prolongation is variable and is not strictly correlated with the likelihood of syncopal episodes. The EKG is not always diagnostic since the Q-T interval can be prolonged for other reasons (including pre-excitation syndrome, CNS insult, some antiarrhythmic agents, and tricyclic antidepressants). Alternation of T wave, in polarity or amplitude, may be present at rest for brief moments but most commonly during emotional or physical stresses and may precede torsade de pointes. In addition, T wave morphology may be altered, it may be biphasic, bifid or have notches. Recently, a large, prospective, long term follow-up study of patients with LQTS indicated that this disorder is largely familial (85%). In addition, 3 factors were noted to have significant independent contributions to the risk of subsequent syncope or probable LQTS-related deaths. These factors were longer Q-T, faster heart rate and history of cardiac event. The study also showed an increased risk of experiencing cardiac event in females relative to males. Since the electrocardiographic Q-T intervals vary in a given individual from day to day, and since Q-T prolongation in affected individuals may be mild, the diagnosis may be missed even if an EKG is performed. Therefore, this becomes a matter of considerable importance since effective treatment exists, but the patients may not get them in time because the condition which can kill quickly is sometimes very hard to diagnose. This dilemma has led to the discovery of a mutation at a single genetic locus on the short arm of chromosome 11 that predisposes individuals to ventricular arrhythmia and sudden death. This tight linkage of LQTS to the DNA marker at the Harvey-ras-1 locus has been reported so far in 7 unrelated families. Therefore, analysis using tightly linked DNA markers is available for clinical diagnosis in some families with the long Q-T gene. Families with LQTS and Jervell-lange-Nielsen syndrome need to be tested for this marker. It is possible, however, that families will be identified whose mutation is not linked to chromosome 11, in that event, these markers would not be useful. In those families with the mutation linked to chromosome 11, the analysis could help to avoid the misclassification of the carriers that could happen when you make the diagnosis based on QTc interval since there is substantial overlap in the distribution of QTc for carriers and non-carriers. False classification of a gene as normal is a serious problem because such a person is at risk for sudden death. Dr. Rene R. Roth, M.Sc., Ph.D.