SYNOPSIS

The first report of the so-called "short QT syndrome" (SQTS) was provided by Gussak et al. who described a familial distribution of a persistently short QT interval associated paroxysmal atrial fibrillation in one patient. They also reported similar ECG changes in an unrelated case associated with sudden cardiac death. More recently, these observation have been refined by Gaita et al. who described two families with severe history of sudden cardiac death, QTc interval constantly below 290ms, ventricular premature beats and documented ventricular fibrillation.

SQTS is also characterized by the absence of structural heart disease, a remarkable familial history of sudden cardiac death and a typical, hyperkalemic-like T wave pattern (tall and peak T wave) on the resting ECG. ICD implantation is currently the treatment of choice for symptomatic patients with short QT syndrome and a family history of sudden cardiac death (Schimpf et al.). Quindine has been shown to normalized ventricular repolarization (at variance with other antiarrhythmic drugs including sotalol and amiodarone) in some patients but at present its role in preventing recurrences of cardiac events is not known. Therefore, at present this approach may not be considered an alternative to ICD.

The prevalence of the SQTS is currently unknown and less than 50 families have been reported worldwide.
In the two families reported by Gaita et al., genetic investigation led to the identification of a coding defect in the KCNH2 gene (ref): N588K in the S5-P loop region. In vitro functional characterization demonstrated a remarkable increase of IKr current, and reduced the affinity of the channels to IKr blockers. Thus, it is suggested that, at variance with the LQT2 variant of Long QT Syndrome associated with loss of function KCNH2 mutation, the SQTS phenotype is caused by gain of function mutations.

More recently, Bellocq et al. reported another sporadic case of SQTS with a missense mutation of the KCNQ1 gene. In vitro expression demonstrated a gain of function with an increase of the IKs current.

Thus, SQTS is a genetically heterogeneous disease. Genotype-phenotype correlation and clinical data on natural history, risk stratification and optimal therapeutic management are still lacking.

In March 2005 Priori et al. identified a novel SQTS locus (SQTS3) by reporting a gain of function mutation in the KCNJ2 gene, encoding the Inward rectifier potassium channel. This is a voltage-gated channel responsible for the IK1 current. Interestingly loss of function mutations in the KCNJ2 gene have been identified in patients affected by Andersen Syndrome, which is also referred to as the type seven form of the Long QT Syndrome (LQT7) and is characterized by prolonged repolarization and by periodic hypokalemic paralysis. In the Andersen syndrome, reduction of IK1 leads to prolongation of the QT interval and predisposes to cardiac arrhythmias. Therefore, SQTS3 is allelic to LQT7.

Besides an abnormally short QT interval, the T wave was noticeably narrow and peaked with a very fast terminal phase of repolarization.