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 IKs potassium channel; LQT2, or HERG,
encodes the IKr potassium channel; and LQT5, or KCNE1, encodes the (beta)
subunit of the IKs 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 IKs (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