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.