ARTICLE IN BRIEF
A team of Italian investigator suggest that an animal model for sudden infant death syndrome (SIDS) indicates that disrupted serotonin regulation may cause SIDS in humans, and could form the foundation for a diagnostic test for SIDS risk.
Researchers studying serotonin signaling in mice may have created the first animal model of sudden infant death syndrome (SIDS), according to a report in the July 4 Science. They suggest that the model indicates that disrupted serotonin regulation may cause SIDS in humans, as well, and could form the foundation for a diagnostic test for SIDS risk.
SIDS kills approximately 2,700 seemingly healthy infants each year in the US, most between the ages of one month and six months.
Cornelius Gross, PhD, and colleagues at the European Molecular Biology Laboratory in Monterotondo, Italy, had genetically engineered the mice with an excessive number of serotonin 1A receptors, as part of a study on the role of serotonin in aggression and anxiety. But in an unanticipated finding, the mice began dying at an early age after developing symptoms that the authors likened to SIDS, including declining heart rate and body temperature. The modified mice showed a 20 percent drop in serotonin levels and serotonin neuron firing compared to normal mice.
At first, the modified mice appeared normal. “But then they showed sporadic and unpredictable drops in heart rate and body temperature. More than half of the mice eventually died of these crises during a restricted period of early life. It was at that point that we thought it might have something to do with SIDS,” Dr. Gross told Reuters.
These findings jibe with research reported in 2006 by Hannah Kinney, MD, and colleagues at Boston Children's Hospital, in which autopsy results for infants who had died of SIDS revealed abnormal serotonin-producing cells in their brain stems. [For more on the study, see Neurology Today's Dec. 5, 2006 article, “Study Finds Neurological Component to SIDS,” on www.neurotodayonline.com.]
IS THE DATA CLINICALLY RELEVANT?
Steven Rothman, MD, director of the division of pediatric clinical neuroscience at the University of Missouri Medical School, called the finding that manipulation of serotonin receptors could influence autonomic stability in animals “…interesting, but not totally shocking.”
“A body of literature already exists, showing some abnormalities in serotonergic neurons in the brain stem that sometimes seem to correlate with respiratory and cardiac responses that might lead to instability and ultimately to death. All this seems to hang together with this paper in a sensible way,” said Dr. Rothman.
But he's skeptical of its clinical relevance in the near term. “The paper indicates that in order to detect these functional changes in animals, you actually have to monitor them for an awfully long period of time — four days before they at least saw the temperature changes, which is a long time in the life cycle of a mouse,” he said. “So, the hypothesis that some people have had, that infants at risk for SIDS would show some instability over shorter periods of time that would allow you to predict it, seems inconsistent. If this really is analogous to the problem in humans, it'd be over a longer time than you'd ever want to monitor.”
Dr. Rothman also noted that the temperature changes described in the genetically engineered mice were fairly extreme. “One of the animals that survived dropped from 36 or 37 to 32 degrees, and then bounced back up to baseline,” he said. “That's a big temperature change. I think it would be unprecedented to see an analogous temperature change in humans.”
Those temperature drops are just part of the reason that Warren Guntheroth, MD, professor of pediatrics (cardiology) at the University of Washington, whose research helped spur the “Back to Sleep” movement that cut SIDS deaths by 40 percent, is skeptical of the study's findings.
“This experiment suggests that the serotonin modification produced hypo thermia — and our findings and the literature all agree that SIDS in humans is connected with hyper thermia,” he said. “This isn't consistent with SIDS at all.”
In a review published in Pediatrics in 2001, Dr. Guntheroth and colleagues concluded that “thermal stress” from overwrapping (especially around the head) and excessive room temperatures plays a key role in SIDS.
QUESTIONS ABOUT THE SIDS MODEL
That doesn't necessarily end the discussion, said Debra Weese-Mayer, MD, professor of pediatrics at Northwestern University's Feinberg School of Medicine and director of the Center for Autonomic Medicine in Pediatrics (CAMP) at Children's Memorial Hospital. “Enough has been described on autonomic dysregulation when it comes to temperature to think about what's going on in SIDS. More broadly, maybe these babies don't have the flexibility that a normal baby has when exposed to a ‘stressful’ situation, be it overheating, smoke, or any bad environmental thing that could happen.”
Dr. Weese-Mayer praised the study, calling it a very elegant design. Still, she suggested that all the talk of the SIDS connection may be premature. “Is it a leap to make the connection to SIDS? I can understand why they'd be tempted,” she said. “SIDS is sitting out there as a plum that no one has deciphered yet, despite all our efforts. Do I think it's a model for SIDS? No. But it's a beautiful model for serotonin, and teaches us more about serotonin as a master regulator of the autonomic nervous system.
“I like this paper more because it puts a chink into the master puzzle of autonomic regulation. The fact that the animals got bradycardic before they got cold is fascinating to me, especially since we tend to assume that physiologically, you get cold and then your heart rate drops. It behooves us to think in a more focused fashion about SIDS, because enough has been described on autonomic dysregulation when it comes to temperature to think about what's going on here,” she said.
Dr. Guntheroth suggested that there is a more fundamental concern with the study: “This is a created, genetic defect in the mice. SIDS is not a genetic disorder and not inheritable, as multiple studies show, and it isn't even congenital.”
He points to the fact that deaths from congenital defects peak in the first month after birth, while SIDS deaths peak later, between two and three months, according to a 2002 report in Pediatrics.
But that's not the whole story, said Dr. Weese-Mayer. Several genes have already been identified as related to SIDS, as she described in a review published in the American Journal of Medical Genetics in 2007. These include cardiac channelopathy and metabolic genes as well as genes in the serotonergic system, such as the fifth Ewing variant (FEV) gene. Some of the mutations implicated in SIDS deaths have been de novo, germline mutations, she explained.
“I think there has to be a genetic basis for SIDS. It's easy to say that there's no answer, but we just haven't had the right tools or the right information to put it together yet,” she said. “Wouldn't it be wonderful if it were as simple as ‘this is the pathway, this is the gene?’ It's not — but there is a growing body of literature implicating genetic factors as everybody's hunting at other things. And this is such a regulatory pathway that you have to investigate further.”
“The authors don't suggest that this could be the sole explanation for SIDS,” noted Missouri's Dr. Rothman. “They argue that neurobiological alterations, when combined with something in addition, could predispose susceptible infants to autonomic instability and ultimately death. That's plausible; whether this changes anyone's thinking about the problem is not going to be so clear.”
Dr. Weese-Mayer agreed. “They're honest in not saying that this is end-all and be-all on SIDS, but if it gives us insight, that's great. It encourages investigators to have their wits about them. Sometimes you're not looking for what you're going to find, and it's kind of exciting when that happens.”