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Serotonin Abnormalities Confirmed in Sudden Infant Death

ARTICLE IN BRIEF

Investigators compared tissue of babies who died of known cases and from sudden infant syndrome (SIDS), finding that the SIDS babies on average had 26 percent lower serotonin levels than the controls in specific brainstem sites.

Babies who die suddenly and for no apparent reason may have depletions in serotonin and its metabolites in brainstem regions that regulate basic physiological processes necessary to sustain life, according to a Feb. 3 report in the Journal of the American Medical Association.

The study was a collaborative multicenter effort, led by Harvard Medical School's Hannah C. Kinney, MD, and David S. Paterson, PhD. They compared the brain tissue from 35 babies whose deaths were ruled to be the result of sudden infant death syndrome (SIDS) to five infants who died of known reasons and five other babies hospitalized with chronic hypoxia-ischemia.

Dr. Kinney said that they knew there were abnormalities in the serotonin system but did not know if the levels were too high or too low. They worked with the medical examiners office in San Diego to procure tissue within hours (not more than 30) of death and measured serotonin levels in brain circuits that (in the healthy subject) control breathing, heart rate, temperature, and blood pressure during sleep.

They measured serotonin and its metabolites, tryptophan hydroxlase and serotonin receptor binding and identified three abnormalities: decreases in serotonin levels, tryptophan hydroxylase and 5-HT receptors.

The SIDS babies on average had 26 percent lower serotonin (5-HT) levels than the controls in specific brainstem sites. They also had on average 22 percent lower levels of tryptophan hydroxlase, the key biosynthetic enzyme for 5-HT. The 5-HT receptor binding was even more reduced — over 50 percent lower than the non-SIDS brainstems — in regions of the medulla oblongata that are involved with the control of autonomic function and breathing.

The investigators also looked at the case records to assess environmental risk factors, including sleep position, bed sharing, or a minor illness prior to death. They found that 95 percent of the SIDS babies had one risk factor, either extrinsic factors like prone or side sleeping position or intrinsic factors such as prematurity and being male; and 88 percent had two or more in this study population.

The scientists suspect that multiple events culminate in a SIDS death: The age of a child (under 1 year old) and the continued development of the infant brain, an external stressor and perhaps, as this and other studies are suggesting, a serotonin deficiency.

Dr. Kinney, a neuropathologist, and her colleagues have spent almost two decades looking at brain tissue from independent cohorts of babies who have died of SIDS in an attempt to understand why some babies are vulnerable to sudden death in the critical developmental period of the first year of life. They focused on the brainstem because this region is involved in the control of breathing, blood pressure, heart rate, wakefulness, and sleep, the vital functions that are thought to be abnormal in SIDS infants.

Years of research led them to their focus upon the serotonergic system. The investigative team has published serotonin-related defects now in four independent studies using different groups of SIDS babies and controls — two in the Journal of Neuropathology and Experimental Neurology (in 2000 and 2003); and two in JAMA (in 2006 and in February).

INDEPENDENT COMMENTARY

“This study is very much in keeping with prior studies from the Kinney laboratory,” said Debra E. Weese-Mayer, MD, professor of pediatrics at Northwestern University Feinberg School of Medicine and director of the Center for Autonomic Medicine in Pediatrics at Children's Memorial Hospital in Chicago. “Despite its small sample size, few controls and almost no African-Americans, it is fairly thorough and carefully written. It adds one more piece to the complex puzzle of SIDS.”

Other SIDS researchers, including Dr. Weese-Mayer, have looked for differences in various genes that regulate serotonin. While this current JAMA study did not offer any genetic information on the infants, Dr. Weese-Mayer said that her group and others have identified several genetic variants that are more likely among SIDS victims: the long allele in the promoter region of the serotonin transporter gene (5-HTT) and the 12 variable number tandem repeat (VNTR) in intron 2, also of the 5-HTT gene. These alleles are more efficient 5-HT transporters so synaptic 5-HT levels would be lower in infants with these alleles, Dr. Weese-Mayer explained. Others are just beginning to replicate these studies.

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DR. DEBRA E. WEESE-MAYER: “As proposed previously, and confirmed in this new manuscript, there is likely a spectrum of serotonin deficiency such that some babies will need to be exposed to modifiable risk factors to succumb to SIDS but others will die regardless of risk factor exposure. It was this logic that originally led us to consider a genetic basis for SIDS at the beginning of this millennium.”

“The hypothesis that there is an abnormality of serotonin (5-HT) in the brains of SIDS victims is not new,” added Dr. Weese-Mayer. “Through the work of the Kinney laboratory and other academic laboratories we know that there is something intrinsically deficient in the 5-HT system of babies who succumb to SIDS. As proposed previously, and confirmed in this new manuscript, there is likely a spectrum of serotonin deficiency such that some babies will need to be exposed to modifiable risk factors to succumb to SIDS but others will die regardless of risk factor exposure. It was this logic that originally led us to consider a genetic basis for SIDS at the beginning of this millennium.”

Many parents were “doing everything right” in terms of modifiable risk factors for SIDS — yet their babies were still dying, Dr. Weese-Mayer continued.

Indeed, in the last 10 years scientists have identified specific treatable genetic causes for SIDS. Writing in a 2007 paper in the American Journal of Medical Genetics, Dr. Weese-Mayer and Michael Ackerman, MD, and his colleagues at the Mayo Clinic said that the candidate genes linked to SIDS spanned five different types: genes for ion channel proteins; for serotonin receptors; for early embryology of the autonomic nervous system; nicotine metabolizing enzymes; and those that regulate inflammation, energy production hypoglycemia, and thermal regulation. These findings are leading the way to not only identify markers for at-risk infants but also to provide intervention strategies, Dr. Weese-Mayer said.

Dr. Weese-Mayer noted that the Kinney study did not look at genetics and the role of genes in abnormal serotonin levels.

EXTRINSIC RISK FACTORS

Experts continue to push for reducing the known extrinsic risk factors like sleep position and smoke exposure. “These new results should impress upon parents, caregivers, and medical personnel the critical need to comply with all known modifiable risk factors for SIDS,” Dr. Weese-Mayer added. Parents and caregivers should always place the baby to sleep on his or her back. They should protect the baby from any smoke exposure during the pregnancy or after the birth. They should avoid overheating the baby and should create a safe sleep environment for the baby that includes no soft bedding material, no soft sleep surfaces, and ideally no co-sleeping in an adult bed.

Dr. Weese-Mayer posed additional questions: “If a subset of babies with intermediate levels of 5-HT will die only if exposed to environmental risk factors, what becomes of these babies who never meet with those risk factors and survive? What kinds of symptoms will they have in childhood or adulthood? How will they be identified? Could they be at risk for sudden death in childhood? Or will they manifest symptoms of autonomic dysregulation?”

Dr. Kinney said their next step is to figure out how genetics and environment interact to reduce serotonin levels and understand how the circuit controls the behavior of a developing infant's homeostatic function.

This molecular abnormality in a specific brain region is a neurochemical one that requires special techniques for detection at autopsy. This serotonin-rich circuit apparently works like an alarm to warn people to increase their breathing to rid themselves of excess carbon dioxide.

Here's how a so-called triple risk model (age, environmental factors like soft bedding, smoking and prone positioning during sleep, and a serotonin deficiency) might work, Dr. Kinney explained. Babies, particularly those sleeping on their stomachs, may breathe in higher levels of carbon dioxide in stale air trapped under their blankets. While a healthy baby might wake up to cough or clear the airway, these babies may not respond in the same way, the researchers said.

“These receptors must function properly for babies to survive,” said Dr. Kinney.

References

Duncan JR, Paterson DS, Kinney HC, et al. Brainstem serotonergic deficiency in sudden infant death syndrome. JAMA 2010; 303(5):430–437.
Weese-Mayer DE, Berry-Kravis EM, Marazita ML, et al. Sudden infant death syndrome: Association with a promoter polymorphism of the serotonin transporter gene. Am J Med Genet 2003; E-pub 2003 Jan. 16.
    Weese-Mayer DE, Berry-Kravis EM, Rand CM, et al. Congenital central hypoventilation syndrome and sudden infant death syndrome: Kindred disorders of autonomic regulation. Respir Physiol Neurobiol 2008;164:38–48.