Dallas, TX Researchers in Italy have identified mutations believed to cause a potentially fatal childhood arrhythmia: catecholaminergic polymorphic ventricular tachycardia (VT). The finding could help in recognizing children at risk, and allow early preventative measures to be taken. The report is a 'breakthrough,' according to the editor of Circulation, who released it early in the "Rapid Track" section of the journal website.1 The culprit mutations were located in the gene of a cardiomyocyte calcium channel known as the ryanodine receptor (RyR-2). It is the second time this year that the RyR-2 has been identified in heart disease. In the previous case, RyR-2 dysfunction was linked to heart failure. (See related links)

Catecholaminergic polymorphic VT is an inherited disorder that often strikes in childhood or adolescence. It is characterized by stress-induced bi-directional VT, in the absence of structural heart abnormalities or prolonged QT. Patients experience recurrent syncope in stressful situations, and are at risk of cardiac arrest and sudden death.

Dr Silvia Priori (IRCCS Fondazione Salvatore Maugeri, Pavia, Italy) and colleagues suspected a link between RyR-2 and catecholaminergic polymorphic VT for two reasons. First, RyR-2 dysfunction can result in calcium overload, an effect suggested by the disorder's bi-directional VT. Second, the RyR-2 gene is located on the long arm of chromosome 1, on the same stretch of DNA recently linked to catecholaminergic polymorphic VT.

The authors looked for mutations in the human RyR-2 gene in 12 unrelated individuals presenting with catecholaminergic polymorphic VT. The researchers looked along most of the length of the gene (90 of 103 exons), ultimately finding mutations in four of the 12 patients. The mutations segregated with stress-induced arrhythmia in the patient families, and were absent from a control population of healthy subjects. The four mutations were missense mutations, and occurred in highly conserved regions of the RyR-2 gene, suggesting they were likely to disrupt the function of the resulting calcium channel.

Priori concluded, "In agreement with our hypothesis, hRyR-2 is a gene responsible for catecholaminergic polymorphic ventricular tachycardia." Priori was careful not to say "the gene responsible," as she believes mutations in other genes than RyR-2 may also cause the disorder possibly the case in eight of her study subjects.