The unexpected and unexplained death of an infant is a tragic occurrence. When the infant is less than one year of age and the cause remains unknown despite a thorough investigation including a complete autopsy, examination of the death scene, and review of the clinical and family history, the term "sudden infant death syndrome" (SIDS) is applied. (1,2) This disorder has an incidence of 1.6 per 1000 live births in the United States, 0.7 per 1000 live births in Italy, and 2.5 per 1000 live births in the United Kingdom, making it the most common cause of death among children from one month to six months of age. (3,4) In most instances, these children die in their sleep.

The potential causes of sudden death in infants are many, including cardiac disorders, respiratory abnormalities, gastrointestinal diseases, metabolic disorders, injury, and child abuse. (5) In this issue of the Journal, Schwartz and colleagues (4) present compelling evidence that the long-QT syndrome should be considered an important factor in the pathogenesis of SIDS. Schwartz and other investigators have suggested this association since the 1970s, (5,6,7,8,9) but until now, definitive data were lacking.

The long-QT syndrome is a cardiac disorder characterized by a prolonged QT interval on the electrocardiogram, syncope, seizures, and sudden death from ventricular arrhythmias, specifically torsade de pointes. (10,11) Both autosomal dominant forms of the long-QT syndrome (Romano-Ward syndrome), (12,13) and autosomal recessive forms (Jervell and Lange-Nielsen syndrome) (14) have been described, with the Jervell and Lange-Nielsen syndrome associated with sensorineural deafness, longer QT intervals, and a worse prognosis. (10,14)

To date, five genes involved in the pathogenesis of the Romano-Ward syndrome have been mapped to chromosome 11p15.5 (LQT1), chromosome 7q35-36 (LQT2), chromosome 3p21-24 (LQT3), chromosome 4q25-27 (LQT4), and chromosome 21 (LQT5) (10,11); four of these genes have been identified as encoding ion-channel proteins (LQT1, LQT2, LQT3, and LQT5). Three of them (LQT1, LQT2, and LQT5) encode potassium channels (LQT1, also referred to as KVLQT1, encodes the (alpha) subunit of the I_Ks potassium channel; LQT2, or HERG, encodes the I_Kr potassium channel; and LQT5, or KCNE1, encodes the (beta) subunit of the I_Ks potassium channel). The fourth, LQT3 or SCN5A, encodes the cardiac sodium channel. The protein encoded by LQT4 remains unknown.

Heterozygous mutations in these genes result in the Romano-Ward syndrome, whereas homozygous mutations in a gene encoding I_Ks (either KVLQT1 or KCNE1) have been shown to cause the Jervell and Lange-Nielsen syndrome. (10) The severity of the clinical findings and outcome vary widely even within families, and it has been speculated that modifier genes could be responsible for this clinical heterogeneity; the sympathetic nervous system is most commonly considered to be involved. Although syncope and sudden death are classically associated with physical or emotional stress, some patients reportedly die in their sleep.

Although Schwartz et al. (4) performed no molecular genetic studies, they present strong clinical evidence of an association between SIDS and the long-QT syndrome. Between 1976 and 1994, the authors, remarkably, were able to record electrocardiograms on the third or fourth day of life in 34,442 Italian newborns; they then followed these babies prospectively for one year. During this period, 34 of the children died, 24 of them from SIDS. The victims of SIDS were found to have longer QT intervals, corrected for heart rate (the so-called QTc, which is calculated with use of Bazett's formula: QTc=QT /(square root)RR), (15) than the infants who were alive at one year (435±45 vs. 400±20 msec, P<0.01) or the infants who died from causes other than SIDS (393±24 msec, P<0.05). In addition, half the infants who died of SIDS (12 of 24) and none of the survivors or the infants who died of other causes had a prolonged QTc. It is plausible that the prolonged QTc intervals in the victims of SIDS were caused by mutations in genes encoding ion channels.

Despite the sudden deaths of 12 infants whose QTc was greater than 440 msec (the definition of a prolonged QTc), the clinical implications of this study with respect to screening are still to be determined. It would be premature to recommend that all newborns have a routine electrocardiogram for measurement of the QTc. Considerable resources would be needed, including reliable electrocardiographic laboratories skilled at performing these tests on newborns and pediatric cardiologists to read the electrocardiograms and the Holter-monitor tracings that would be likely to follow, prescribe and monitor the effects of medications such as beta-blockers, and treat potential toxic side effects of the drugs. In addition, the emotional cost to a family with a newborn in whom a potentially lethal problem is diagnosed is difficult to quantify. However, the screening of high-risk infants (those with a family history of SIDS or the long-QT syndrome, or those who have had an acute life-threatening event) is appropriate and justified.

An important question is what the physician should do in the case of an infant who has undergone electrocardiography and whose QTc is greater than 440 msec. Genetic testing is still a research tool and not clinically helpful in most cases. Measurements of the QTc may vary among different observers, depending on whether U waves are included in the measurement, the magnitude of sinus arrhythmia, and the choice of which cycle to use for the measurement. Consequently, it is uncertain whether all such patients should receive beta-blocker therapy, the treatment of choice for the long-QT syndrome. If there are other findings on the electrocardiogram, such as T-wave alternans or ventricular arrhythmia, it seems prudent to consider this option seriously. Certainly when the QTc approaches 470 to 500 msec, as was the case in 3 of the 12 infants who died suddenly in the study by Schwartz et al., (4) many physicians would initiate therapy. It has been our experience, however, that there are many infants whose QTc measures in the range of 450 to 460 msec. Rather than begin therapy in such cases, we repeat the electrocardiography at two to three weeks of age and, if the results are normal, again at two to three months of age. Since most cases of SIDS occur after this time, this approach seems reasonable.

In terms of screening infants in the future, the development of a more useful tool that can be used in the physician's office and can measure the QTc, rather than a full electrocardiogram, would be welcome. Abnormalities of the QT interval identified in this way could then be evaluated more formally by a pediatric cardiologist, thus optimizing the use of resources.

Schwartz and colleagues are to be commended for conducting this forward-thinking, long-term prospective study (involving nearly 20 years of data) of a tragic disorder. Over time, their work will almost certainly help to improve the outcome of infants at risk.

Jeffrey A. Towbin, M.D.
Richard A. Friedman, M.D.
Baylor College of Medicine
Houston, TX 77030