A Molecular Link between the Sudden Infant Death Syndrome and the Long-QT Syndrome

Abstract

THE sudden infant death syndrome (SIDS) remains the leading cause of death in the first year of life and has a devastating impact on the affected families. 1-4 Despite the fact that there have been many hypotheses, 3,4 the cause or causes of SIDS are still uncertain; as a consequence, the only preventive measure recommended is to avoid having infants sleep in a prone position. 5 In 1998, we reported the results of a 19-year prospective study of more than 34,000 infants who underwent electrocardiography on the third or fourth day of life. 6 We tested the hypothesis 7,8 that the congenital long-QT syndrome accounts for a portion of the cases of SIDS. 9,10 We found that 50 percent of the infants who died of SIDS had a prolonged QT interval corrected for heart rate (QTc) and that the presence of a prolonged QTc (>440 msec) in the first week of life increased the risk of SIDS by a factor of 41. 6 This finding had implications with respect to the potential value of neonatal electrocardiograph-ic screening. Among the hypotheses that we had advanced to explain the origin of a prolonged QT interval in in-T fants, its relation to the increased risk of sudden death, and the fact that the parents of these infants had apparently normal electrocardiograms, two were testable. The first was that a spontaneous mutation occurs in one of the genes responsible for the long-QT syndrome, 11 and the second was that these infants are affected by a long-QT syndrome with a low penetrance. 12 In this report we describe an infant who nearly died of SIDS, whose parents had normal QT intervals , and in whom the long-QT syndrome was diagnosed and a spontaneous mutation on the cardiac sodium-channel gene (SCN5A) was identified. Neo-natal electrocardiographic screening would have made possible early identification of the prolonged long-QT interval and preventive treatment of this infant. Our findings in this single case report prove the validity of our first hypothesis and provide evidence of a link between the long-QT syndrome and SIDS. Our findings also demonstrate that spontaneous mutations in long-QT syndrome genes may manifest as and be indistinguishable from classic cases of near-SIDS or of SIDS itself. CASE REPORT On October 19, 1995, the parents of a 44-day-old infant who had a completely normal clinical history found him cyanotic, ap-neic, and pulseless. They rushed him to the emergency room of the local hospital, where an electrocardiogram showed ventricular fibrillation (Fig. 1A). Multiple DC shocks and mechanical ventilation were needed to restore sinus rhythm, and a marked prolon-gation of the QT interval was documented (QTc, 648 msec) (Fig. 1B). The plasma electrolyte levels were normal. Torsade de pointes recurred several times, often degenerating into ventricular fibril-lation. The long-QT syndrome was diagnosed, treatment with propranolol (4 mg per kilogram of body weight) and mexiletine (10 mg per kilogram) was begun, and there were no recurrences of arrhythmias. At nearly five years of age, the child remains free of symptoms, and there have been no neurologic sequelae. At the time of the last follow-up examination at our institution, when he was three years old, the QT interval was still prolonged, but less severely so (QTc, 510 msec) (Fig. 1C). The child had no family history of the long-QT syndrome or SIDS, and the QT intervals of both his parents were within normal limits: his mother's QTc was 380 msec, and his father's QTc was 425 msec.