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Correlation with Other Diseases
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1. Known Correlations

There are at least two disorders that are correlating with long-QT syndrome.

Andersen-Tawil syndrome (ATS) is characterised by episodic paralysis, ventricular arrhythmias and like long-QT syndrome, prolonged QT-interval. It recently has been established that ATS is caused by mutations in the gene KCNJ2. Because these  findings support the notion that ATS is a disorder of myocellular repolarization, it has been classified as LQT7.

Similar to the other forms of inherited long-QT syndrome, the primary cardiac manifestation of AS was a prolonged QT-interval, identified in 71% of all gene carriers. The mean corrected QT-interval (QTc) of male and female probands with ATS was 479 and 493 ms, respectively, compared with 497 and 510 ms for males and females with other forms of LQTS.

While a prolonged QT-interval was present in most KCNJ2 mutation carriers, the ventricular arrhythmias manifested by these individuals were clearly distinct from the other forms of inherited long-QT syndrome.

Therefore, ATS is considered a subtype of long-QT syndrome. However, this proposal is controversial at present.

Timothy syndrome (TS) is a rare childhood disorder showing features of long-QT syndrome. Timothy syndrome, named after researcher Katherine W. Timothy of the University of Utah, is characterized by severe cardiac arrhythmia, webbing of the fingers and toes, congenital heart disease, low blood sugar, cognitive abnormalities and autism.

The research shows that children who have Timothy syndrome develop spontaneous genetic mutations that interfere with the Cav1.2 calcium channels that regulate the excitation and contraction of the heart. In defining the precise nature of the molecular abnormality, however, the researchers have also identified a class of drugs that they hope will alleviate the arrhythmia.

2. Suspected Correlations

Further correlations are suspected with the following disorders:

Sudden Infant Death Syndrome (SIDS) is the leading cause of death among infants between 1 month and 1 year of age and strikes one or two of every 1000 babies.

Researchers have advanced a number of theories on the causes of SIDS. None have been proved. Some researchers believe that SIDS may be related to breathing problems, especially long, breathing pauses called apnea.

A prolonged QT interval may be an important cause for SIDS. A study published in the June 11, 1998, issue of the New England Journal of Medicine supports this suspicion formulated by Prof. Dr. Peter J. Schwartz and his team in Italy.

The Multicenter Italian Study of Neonatal Electrocardiography and SIDS, coordinated by Prof. Peter J. Schwartz of the University of Milan, Italy, recorded the electrocardiograms (ECGs) of 34,442 newborns. In Italy, seven out of 10,000 newborns die of SIDS. Half of these victims were suffering from a prolonged QT interval, as the study showed.

Specifically, Schwartz and his colleagues studied the QT interval of the infants' heartbeats on ECGs, then followed the newborns to learn whether those babies who subsequently died of SIDS had QT intervals that were different from other babies.

"Our finding of a strong association between SIDS and prolongation of the QT intervals suggests that some infants may have an increased susceptibility to life-threatening arrhythmias (abnormal heart rhythms)," Schwartz and his colleagues wrote.

The study's findings support a hypothesis first proposed by Schwartz in 1976 that abnormal development of the nerves controlling the heart's rhythm may predispose some infants to potentially lethal, abnormal heart rhythms during the first year of life.

The authors found "that prolongation of the QT interval on the electrocardiogram is an important risk factor, and . . . may be useful in the early identification of infants at risk for SIDS." The authors also said that traditional SIDS risk factors such as maternal smoking, bed sharing and sleeping on the abdomen, had markedly lower predictive value than prolonged QT intervals among the infants studied.

Given their findings, Schwartz and his colleagues suspect that the risk of SIDS may be decreased by finding prolonged QT intervals on ECGs and using medicines like beta blockers to reduce the likelihood of abnormal heart rhythms. But they caution, "our study contains no data to justify new therapeutic recommendations."

"Even if our hypothesis were proved correct, however, such identification and treatment would not be a simple task," the authors of the study conclude.

A genetic abnormality may be involved in some cases of SIDS. The parents of the victims all had a normal QT interval, thus ruling out a traditional long QT syndrome (LQTS) family history. However, some infant may have a de novo (new) mutation in a LQTS gene. If they die of ventricular fibrillation during the first few months of life without an ECG they would be labeled as SIDS victims; if they develop syncope later on in life they would be diagnosed as "sporadic" cases of LQTS.

Another intriguing possibility, which Schwartz is currently testing, is that some of these cases may be due to LQTS with a very low penetrance so that, despite a normal QT and some symptoms, one of the parents may actually be a "silent" gene carrier. Without molecular disgnosis in the family, these deaths would be ascribed to SIDS.

In 2002, more recent research by Dr. Michael J. Ackermann of the Mayo Clinic in Rochester (Minnesota) suggests that approximately 5% of SIDS cases are the result of long QT syndrome.

Brugada syndrome is a genetic disease that is manifested by abnormal electrocardiogram findings and an increased risk of sudden cardiac death. It is also known as Sudden Unexpected Death Syndrome (SUDS). First described in 1992, the Brugada syndrome causes sudden death by causing ventricular fibrillation (a lethal arrhythmia) in the heart.

Brugada syndrome is due to a mutation in the gene that encodes for the sodium ion channel in the cell membranes of the muscle cells of the heart. The gene, named SCN5A, is located on the short arm of the third chromosome (3p21). It is the same gene that, if defect in a different way, causes the LQT3 type of long-QT syndrome.

Last update: January 2007

Sources: Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen Syndrome): J. Clin. Invest. 110:381-388 (2002).

Long QT syndrome: from channels to cardiac arrhythmias: Arthur J Moss and Robert S. Kass; The Journal of Clinical Investigation; Volume 115, Number 8, August 2005

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