The Search for the Explanation behind Sudden Unexplained Death

During an uneventful afternoon on March 19, 2012, Guy and Lena Wolfe laid their daughter, three-month old Mia Roance Wolfe, down for a nap. Within twenty minutes, she was dead. Mia had been a perfectly healthy baby, having just completed her routine checkup without any problems. However, the same absence of problems resulted in the belated diagnosis of any parent’s worst nightmare—Sudden Infant Death Syndrome. “You cannot put into words what losing a child feels like,” her heartbroken father said, especially when “the only symptom is death.”1

Sudden Infant Death Syndrome (SIDS) is sufficiently described by its name: postmortem studies of the victims return negative autopsy, toxicology, histology, and death scene investigation results2. In 2008, there were a total of 2,353 SIDS deaths in the United States, which made the syndrome the leading cause of death for infants between 1 and 12 months old3. The syndrome is thought to be multifactorial, and the varied hypotheses that have attempted to explain the causes of SIDS have pointed at sleeping behavior, neurological cytokines, and cardiac ion channel mutations4,5,6. Molecular biological research into the causes of SIDS has highlighted the prevalence and potential importance of cardiac malfunction, but results are still inconclusive. On the other hand, behavioral correlations to SIDS have found statistical and scientific support and have resulted in successful new policies.

Courtesy of Wikimedia Commons

In the search for biological explanations for SIDS, researchers have often begun with the fact that SIDS victims often suffer from mild infections or inflammatory conditions directly preceding their deaths. Both infections and inflammatory conditions cause the body to increase levels of immune-inflammatory cytokines4. One such cytokine is interleukin-2 (IL-2), a neuroregulatory cytokine with many known roles. For instance, IL-2 controls the chemical and neurotransmitter levels in tissue, influences neuronal firing activity, and regulates and hormone release. These functions make IL-2 crucial in maintaining homeostasis, and IL-2 imbalance would cause potentially lethal cardiorespiratory instability. Additionally, IL-2 seems to exert some control over sleep pathophysiology, since the injection of IL-2 into laboratory animal brain stems induced soporific effects.

The role of IL-2 in regulating cardiorespiratory activity seems particularly relevant to SIDS, since most SIDS victims experience prior inflammatory conditions that could result in IL-2 imbalance. Additionally, cytokine responses to IL-2 imbalance reach a peak at 1-2 hours after induction, which correlates to the fact that SIDS victims die suddenly. Thus, cytokine over-expression, particularly that of IL-2, could have strong ties to SIDS4.

Another potential biological cause of SIDS is a gene controlling specific cardiac ion channels; in the past, SCN1B, SCN3B, MOG1, and KCND3 have all been suggested7. These genes have been studied in connection with Brugada syndrome (BrS), a condition characterized by asymptomatic ventricular arrhythmias that could directly precede SIDS8. For instance, it has been shown experimentally that the potassium channel coded by KCND3 controls the transient outward current (Ito) and that mutations in the gene disrupt the current by “significantly” increasing Ito current density, total charge, and peak current density. While studies have not shown a conclusive correlation between specific KCND3 mutations and SIDS, the dramatic effects of these mutations on cardiac currents cannot be understated6.

A similar gene, SCN5A, has also been studied due to its connection to cardiac currents. Scientists identified and analyzed 140 definite SIDS cases collected from 1988 to 2004 in Norway, and SCN5A mutations were found to be a leading genetic variant. SCN5A mutations are also known to cause arrhythmias during sleep9. In an independent study, it was found that SCN5A mutations resulted in a 300% increase in sodium current. The impact that SCN5A gene mutations have on cardiac currents, as well as the clear implications of other cardiac genes and the IL-2 cytokine, leads to a promising subject of study in the quest to understand SIDS10.

Overall, studies into potential biological factors behind SIDS have yet to yield definitive measures. Cytokines and cardiac ion channel proteins that could induce sudden death are still being specified and researched. Meanwhile, the degree to which sleep-related risk factors connect to SIDS has been highly researched and publicized; additionally, the research has led to new policies. The prone sleeping position was most strongly connected to SIDS, which ultimately led to the institution of the Back to Sleep campaign in the United States in 1994. This public education program detailed the risks of having infants sleep in a prone position and instead recommended the supine or lateral sleeping position 11. To measure the impact of the campaign, scientists conducted a study on 1000 different infants in 48 states and found that the percentage of infants placed in a supine position increased from 17% to 35% by 1995, while the percentage of prone infants decreased from 70% in 1992 to 24% three years after that6. At the same time, the number of SIDS cases in the United States declined by 38%11.

Besides the prone sleeping position, bed-sharing is also an important factor that is possibly connected to SIDS. A study conducted in New York City showed that 66% of the sleep-related SIDS cases studied were due to bed-sharing. Due to the prevalence of bed-sharing in sleep-related deaths, NYC started the Cribs for Kids program in 2007 and has since distributed more than 3100 cribs5.

Great strides have been taken to identify the multifarious causes of SIDS, which remains largely unexplained. At the molecular level, SIDS cases have been analyzed for microscopic malfunctions that could have magnified effects. For now, though, Guy Wolfe is looking at the bigger picture as he mows lawns, sells cupcakes, and holds fundraisers in order to raise money for the new Baby Butterfly Foundation, a newly established SIDS research charity named after Mia—his own baby butterfly who flew away too soon.



  1. Family Starts Charity to Support Victims of SIDS,” 17 June 2012
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  3. Statistics. National SUID / SIDS Resource Center. Retrieved May 18, 2012.
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  5. Senter Lindsay, Sackoff Judith, Landi Kristen, Boyd Lorraine. Studying sudden and unexpected infant deaths in a time of changing death certification and investigation practices: evaluating sleep-related risk factors for infant death in New York City. Matern Child Health J 2011; 15: 242-248.
  6. Giudicessi John, Ye Dan, Kritzberger    Chad, Nesterenko Vladislav, Tester David, Antzelevitch Charles, Ackerman Michael. Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death. Human Mutation 2012; 33: 989-997.
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  8. Holst Anders, Saber Siamak, et al. Sodium current and potassium transient outward current genes in Brugada syndrome: screening and bioinformatics. Canadian Journal of Cardiology 2012; 28: 196-200.
  9. Arnestad Marianne, Crotti Lia, Rognum Torleiv, Insolia Roberto, Pedrazzini Matteo, Ferrandi Chiara, Vege Ashild, Wang Dao, Rhodes Troy, George Alfred, Schwartz Peter. Prevalence of Long-QT Syndrome Gene Variants in Sudden Infant Death Syndrome. Circulation 2006; 115: 361-367.
  10. Ackerman MH, Siu BL, Sturner WQ, Tester DJ, Makielski JC, Towbin JA. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.  Jama-Journal of the American Medical Association 2001; 296: 2264-2269.
  11. Willinger, M., et al. Factors associated with the transition to nonprone sleep positions of infants in the United States: The National Infant Sleep Position Study. The Journal of the American Medical Association 1998; 280: 329-335

Cecilia Jiang is a second-year student at the University of Chicago majoring in Biology and Chemistry and minoring in History and the Philosophy of Science.  Follow The Triple Helix Online on Twitter and join us on Facebook.

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