Molecular Link between Sudden Infant Death Syndrome and Long-QT Syndrome Is “Proof of Concept”
When the parents of a 1-month-old infant found him blue and lifeless on an October day in 1995, they rushed him to the nearest hospital emergency room. Physicians there discovered the infant in ventricular fibrillation and, by countershock, were able to revive him. After doing so, they documented a marked prolongation of the QT interval.
That success and the parents’ quick thinking saved the child’s life and also provided Peter J. Schwartz, MD, with the perfect case in which to look for the molecular clue that he hoped would link long-QT syndrome with Sudden Infant Death Syndrome (SIDS) (N Engl J Med. 2000;343:262–267). Dr Schwartz, chairman of the Department of Cardiology at the University of Pavia and Policlinico San Matteo in Pavia, Italy, had already established a strong association between the 2 syndromes in a large prospective study of 34 442 newborns for whom he and his colleagues had recorded ECGs on the third or fourth day of life between 1976 and 1994 (N Engl J Med. 1998;338:1709–1714.).
In an analysis of 1-year follow-up data on 33 034 infants, the researchers discovered 34 deaths, of which 24 were attributed to SIDS. The infants who died of SIDS had longer corrected QT intervals than did the survivors and the 10 babies who died of other causes. The researchers found that 12 of the 24 babies who died of SIDS had prolonged QT intervals corrected for a heart rate >440 ms. Statistical analysis proved a strong association between the 2 conditions. In these cases of SIDS, the parents were apparently unaffected by long-QT syndrome.
In the 1998 article, Dr Schwartz pointed out that newborn ECG screening might permit the early identification of many infants at risk for SIDS and thus allow the use of drugs to prevent that sad occurrence. In his current article in the New England Journal of Medicine, he strengthens that recommendation. In response to those who may complain that the cost-benefit ratio is not in favor of screening, he said, “What is the value of saving a young life?” In countries such as Italy, the cost of screening is fairly low (≈$15 to $20), and he would opt for the procedure for the safety of infants. However, ECGs for infants in the United States are apt to cost more. Nonetheless, he expects that most parents would be willing to pay a small amount for peace of mind.
In the 1998 article, Dr Schwartz and his colleagues had postulated that the association between the 2 syndromes was either caused by a spontaneous mutation in one of the genes responsible for long-QT syndrome or that the infants were affected by a long-QT syndrome with low penetrance.
Analysis of the DNA of the infant who nearly died on October 19, 1995, was performed by Dr Schwartz’s associates, Drs Priori and Napolitano, and it showed a mutation (S941N) on the cardiac sodium-channel gene (SCN5A); this gene is associated with long-QT syndrome. Co-authors Drs Antzelevitch and Dumaine demonstrated that the S941N mutation increases the amplitude of the late sodium channel, which explains the prolongation of the QT interval observed in this infant. Analysis of the parents’ DNA (which also confirmed paternity) showed no similar mutation, thus proving that the infant had a “spontaneous” mutation.
Dr Schwartz called the finding a “proof of concept” and the culmination of work that started almost 25 years ago. He knows that long-QT syndrome is only one of many diseases that have been lumped under the heading of SIDS; however, this distinction is important and could save lives in the future. This finding would not have been possible without molecular screening.
This finding also provided the key to understanding how infants whose parents do not have long-QT syndrome can suddenly die of the problem. It is particularly important because screening can identify those infants most at risk, and they can be given β-blockers to reduce the threat. The practical importance of this concept lies in the fact that most deaths due to long-QT syndrome can be prevented. “This implies that if the infants at risk were identified early, on the basis of a consistently prolonged QT interval, preventive therapy could be instituted, at least for a few months,” Dr Schwartz said in his article.
Therapy could be discontinued in those children who are “false positives” for the syndrome. That number would be unavoidably large. In fact, the researchers estimated that as many as 100 babies would have to be treated to save 2 lives.
“This case raises disquieting issues,” Dr Schwartz said. “Much of the current controversy surrounding neonatal ECG screening concerns the high number of false positives. This number could be decreased by postponing the screening until the second or third week of life. What has not been considered is the emotional impact and the medicolegal consequences of cases such as the present one, in which diagnosis would be easy and treatment lifesaving. How would the parents of a SIDS victim react to the demonstration, by a post mortem molecular screening, of a genetic mutation causing long-QT syndrome? This would imply that an ECG would have unmasked the life-threatening disease and allowed therapy. Who would they blame?”
Although Dr Schwartz agrees that the decision about how many, when, and whom to screen will have to be determined by society, he is adamantly in favor of the testing. Young lives are worth the cost.
Grade the Health of Your County
Want to know how many teen mothers there are in your county or the top 5 causes of death? The US Department of Health and Human Services is making this information easily available on the Web at www.communityhealth.hrsa.gov
The data are found in the Community Health Status Indicators Reports (CHSI), which are funded by the department’s Health Resources and Services Administration (HRSA) and produced in collaboration with the National Association of County and City Health Officials (NACCHO), the National Association of State and Territorial Health Officials (ASTHO), and the Public Health Foundation (PHF). The data cover the period from 1988 to 1998.
“We encourage counties to compare their health status with the nation and ‘peer counties’ with similar characteristics and challenges, identify strengths and areas needing improvement, and share solutions for improving public health,” said HRSA Administrator Claude Earl Fox, MD, MPH, in a released statement. “In responding to requests from local and state public health leaders for more data, we wanted the project to be a bottom-up effort, with city, county, state, and public health representatives involved in producing the reports and helping to guide the process. Community planning efforts have historically been hindered by the lack of comprehensive data at the local level. The CHSI reports help to fill this gap, but they do not serve as a substitute for rigorous community needs assessment.”
The reports not only contain data on causes of death, infant mortality, and the incidence and prevalence of disease, but they also allow comparison with similar counties across the nation.
Birth outcomes, including low birth weight babies, unmarried mothers, and prenatal care, as well as death data, including breast cancer, homicide, and heart disease can be compared with peer counties. It is also possible to compare the information for a specific county with similar data for the nation as a whole and with the targets set by the federal Healthy People 2010 initiative.
Influenza Vaccine Shortages Threaten Those With Chronic Diseases
Production of the influenza vaccine for winter 2000 is lagging, according to a report in the August 14, 2000 issue of American Medical News. In response, officials from the federal Centers for Disease Control and Prevention (CDC) are warning public health authorities at the city and state level to postpone flu vaccination campaigns, which are already in the planning stages.
Ordinarily, public health officials begin alerting people to the need to receive a flu vaccine in late September or early October. Now, they are postponing those plans until they determine how much vaccine they will receive.
The slowdown in producing the vaccine occurred because manufacturers had trouble growing one new component of the vaccine, the A/Panama strain. The influenza vaccine for winter 2000 contains inactivated strains of A/Panama, A/New Caledonia, and B/Yamanashi, the forms of the influenza virus considered most likely to strike this winter. It can take 6 to 8 months to make a flu vaccine, and public health officials said they do not know the full impact of the problem yet. The vaccine will probably be available later than it usually is, but there are also worries that there may be less of it available, according to American Medical News.
In the July 14 edition of the Morbidity and Mortality Weekly Report published by the CDC, experts recommend that vaccination campaigns be delayed until November. The CDC and the US Food and Drug Administration are telling doctors that there will be enough vaccine to protect those at highest risk, such as the elderly and those whose immune systems have been suppressed by drugs or disease. “We want to alert [doctors] to focus on high risk,” said Tim Uyeki, MD, MPH, an epidemiologist in the CDC’s influenza branch. “There’s no change in how one goes about vaccinating these people. It should be routine.”
Health officials had considered recommending the immunization of all people between the ages of 50 and 64 years, rather than focusing only on those 65 and older. However, with a potential shortage in the offing, they are asking doctors to focus on those aged 50 to 64 years who have risk factors that make getting the flu particularly dangerous.
Although no agency is recommending against flu vaccines for the well, the CDC and Food and Drug Administration are most concerned that those at risk of serious complications or even death from the influenza virus receive the vaccine. Each year in the United States, the deaths attributed to the flu and its complications total between 20 000 and 40 000. More than 90% of these deaths occur in people over the age of 65 years.
- Copyright © 2000 by American Heart Association