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Research Article

High serum serotonin in sudden infant death syndrome

View ORCID ProfileRobin L. Haynes, Andrew L. Frelinger III, Emma K. Giles, Richard D. Goldstein, Hoa Tran, Harry P. Kozakewich, Elisabeth A. Haas, Anja J. Gerrits, Othon J. Mena, Felicia L. Trachtenberg, David S. Paterson, Gerard T. Berry, Khosrow Adeli, Hannah C. Kinney, and Alan D. Michelson
PNAS July 18, 2017 114 (29) 7695-7700; first published July 3, 2017; https://doi.org/10.1073/pnas.1617374114
Robin L. Haynes
aDepartment of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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  • ORCID record for Robin L. Haynes
  • For correspondence: robin.haynes@childrens.harvard.edu
Andrew L. Frelinger III
bCenter for Platelet Research Studies, Division of Hematology/Oncology, Boston Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
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Emma K. Giles
aDepartment of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Richard D. Goldstein
cDivision of General Pediatrics, Department of Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Hoa Tran
aDepartment of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Harry P. Kozakewich
aDepartment of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Elisabeth A. Haas
dDepartment of Pathology, Rady Children’s Hospital, San Diego, CA 92123;
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Anja J. Gerrits
bCenter for Platelet Research Studies, Division of Hematology/Oncology, Boston Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
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Othon J. Mena
eOffice of the Medical Examiner, County of San Diego, San Diego, CA 92123;
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Felicia L. Trachtenberg
fNew England Research Institutes, Watertown, MA 02472;
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David S. Paterson
aDepartment of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Gerard T. Berry
gManton Center for Orphan Disease Research, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Khosrow Adeli
hThe Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1X8, Canada
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Hannah C. Kinney
aDepartment of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Alan D. Michelson
bCenter for Platelet Research Studies, Division of Hematology/Oncology, Boston Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;
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  1. Edited by Barry S. Coller, The Rockefeller University, New York, NY, and approved June 8, 2017 (received for review October 21, 2016)

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Significance

Sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality, is defined as the sudden death of an infant less than 1 y of age that remains unexplained after a complete autopsy and death scene investigation. Although SIDS has been associated with deficiencies in central (brainstem) serotonin (5-hydroxytryptamine, 5-HT), there are no known peripheral biomarkers for SIDS. Here we demonstrate increased serum serotonin levels in a subset (31%) of SIDS infants compared with control infants. These findings suggest the potential of a high serum serotonin level as a forensic biomarker at autopsy to differentiate SIDS deaths with serotonergic defects from other causes of sudden death and, importantly, as evidence of a peripheral 5-HT abnormality in SIDS.

Abstract

Sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality, likely comprises heterogeneous disorders with the common phenotype of sudden death without explanation upon postmortem investigation. Previously, we reported that ∼40% of SIDS deaths are associated with abnormalities in serotonin (5-hydroxytryptamine, 5-HT) in regions of the brainstem critical in homeostatic regulation. Here we tested the hypothesis that SIDS is associated with an alteration in serum 5-HT levels. Serum 5-HT, adjusted for postconceptional age, was significantly elevated (95%) in SIDS infants (n = 61) compared with autopsied controls (n = 15) [SIDS, 177.2 ± 15.1 (mean ± SE) ng/mL versus controls, 91.1 ± 30.6 ng/mL] (P = 0.014), as determined by ELISA. This increase was validated using high-performance liquid chromatography. Thirty-one percent (19/61) of SIDS cases had 5-HT levels greater than 2 SDs above the mean of the controls, thus defining a subset of SIDS cases with elevated 5-HT. There was no association between genotypes of the serotonin transporter promoter region polymorphism and serum 5-HT level. This study demonstrates that SIDS is associated with peripheral abnormalities in the 5-HT pathway. High serum 5-HT may serve as a potential forensic biomarker in autopsied infants with SIDS with serotonergic defects.

  • asphyxia
  • brainstem
  • pulmonary neuroepithelial bodies
  • platelets
  • high-performance liquid chromatography

Footnotes

  • ↵1To whom correspondence should be addressed. Email: robin.haynes{at}childrens.harvard.edu.
  • Author contributions: R.L.H., A.L.F., R.D.G., H.C.K., and A.D.M. designed research; R.L.H., E.K.G., H.T., A.J.G., and D.S.P. performed research; R.L.H., A.L.F., E.K.G., and F.L.T. analyzed data; R.L.H., A.L.F., R.D.G., H.P.K., E.A.H., O.J.M., F.L.T., G.T.B., H.C.K., and A.D.M. wrote the paper; E.A.H. collected autopsy SIDS and control samples; O.J.M. collected SIDS and control autopsy samples; and K.A. provided healthy subject samples.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1617374114/-/DCSupplemental.

Freely available online through the PNAS open access option.

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High serum serotonin in SIDS
Robin L. Haynes, Andrew L. Frelinger, Emma K. Giles, Richard D. Goldstein, Hoa Tran, Harry P. Kozakewich, Elisabeth A. Haas, Anja J. Gerrits, Othon J. Mena, Felicia L. Trachtenberg, David S. Paterson, Gerard T. Berry, Khosrow Adeli, Hannah C. Kinney, Alan D. Michelson
Proceedings of the National Academy of Sciences Jul 2017, 114 (29) 7695-7700; DOI: 10.1073/pnas.1617374114

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High serum serotonin in SIDS
Robin L. Haynes, Andrew L. Frelinger, Emma K. Giles, Richard D. Goldstein, Hoa Tran, Harry P. Kozakewich, Elisabeth A. Haas, Anja J. Gerrits, Othon J. Mena, Felicia L. Trachtenberg, David S. Paterson, Gerard T. Berry, Khosrow Adeli, Hannah C. Kinney, Alan D. Michelson
Proceedings of the National Academy of Sciences Jul 2017, 114 (29) 7695-7700; DOI: 10.1073/pnas.1617374114
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