Brainstem Serotonergic Deficiency in Sudden Infant Death Syndrome | Pediatrics | JAMA | JAMA Network
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Preliminary Communication
February 3, 2010

Brainstem Serotonergic Deficiency in Sudden Infant Death Syndrome

Author Affiliations

Author Affiliations: Department of Pathology, Children's Hospital Boston, and Harvard Medical School, Boston, Massachusetts (Drs Duncan, Paterson, and Kinney, Mss Hoffman and Borenstein, and Mr Belliveau); Department of Biochemical Sciences, University of New England College of Osteopathic Medicine, Biddeford, Maine (Dr Mokler); Rady Children's Hospital San Diego and University of California, San Diego, School of Medicine, La Jolla (Dr Krous and Ms Haas); San Diego County Medical Examiner's Office, San Diego, California (Dr Stanley); Department of Physiology, Dartmouth School of Medicine, Lebanon, New Hampshire (Dr Nattie); and New England Research Institutes, Watertown, Massachusetts (Dr Trachtenberg). Dr Duncan is currently affiliated with the Howard Florey Institute, University of Melbourne, Parkville, Victoria, Australia.

JAMA. 2010;303(5):430-437. doi:10.1001/jama.2010.45
Abstract

Context Sudden infant death syndrome (SIDS) is postulated to result from abnormalities in brainstem control of autonomic function and breathing during a critical developmental period. Abnormalities of serotonin (5-hydroxytryptamine [5-HT]) receptor binding in regions of the medulla oblongata involved in this control have been reported in infants dying from SIDS.

Objective To test the hypothesis that 5-HT receptor abnormalities in infants dying from SIDS are associated with decreased tissue levels of 5-HT, its key biosynthetic enzyme (tryptophan hydroxylase [TPH2]), or both.

Design, Setting, and Participants Autopsy study conducted to analyze levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA); levels of TPH2; and 5-HT1A receptor binding. The data set was accrued between 2004 and 2008 and consisted of 41 infants dying from SIDS (cases), 7 infants with acute death from known causes (controls), and 5 hospitalized infants with chronic hypoxia-ischemia.

Main Outcome Measures Serotonin and metabolite tissue levels in the raphé obscurus and paragigantocellularis lateralis (PGCL); TPH2 levels in the raphé obscurus; and 5-HT1A binding density in 5 medullary nuclei that contain 5-HT neurons and 5 medullary nuclei that receive 5-HT projections.

Results Serotonin levels were 26% lower in SIDS cases (n = 35) compared with age-adjusted controls (n = 5) in the raphé obscurus (55.4 [95% confidence interval {CI}, 47.2-63.6] vs 75.5 [95% CI, 54.2-96.8] pmol/mg protein, P = .05) and the PGCL (31.4 [95% CI, 23.7-39.0] vs 40.0 [95% CI, 20.1-60.0] pmol/mg protein, P = .04). There was no evidence of excessive 5-HT degradation assessed by 5-HIAA levels, 5-HIAA:5-HT ratio, or both. In the raphé obscurus, TPH2 levels were 22% lower in the SIDS cases (n = 34) compared with controls (n = 5) (151.2% of standard [95% CI, 137.5%-165.0%] vs 193.9% [95% CI, 158.6%-229.2%], P = .03). 5-HT1A receptor binding was 29% to 55% lower in 3 medullary nuclei that receive 5-HT projections. In 4 nuclei, 3 of which contain 5-HT neurons, there was a decrease with age in 5-HT1A receptor binding in the SIDS cases but no change in the controls (age × diagnosis interaction). The profile of 5-HT and TPH2 abnormalities differed significantly between the SIDS and hospitalized groups (5-HT in the raphé obscurus: 55.4 [95% CI, 47.2-63.6] vs 85.6 [95% CI, 61.8-109.4] pmol/mg protein, P = .02; 5-HT in the PGCL: 31.4 [95% CI, 23.7-39.0] vs 71.1 [95% CI, 49.0-93.2] pmol/mg protein, P = .002; TPH2 in the raphé obscurus: 151.2% [95% CI, 137.5%-165.0%] vs 102.6% [95% CI, 58.7%-146.4%], P = .04).

Conclusion Compared with controls, SIDS was associated with lower 5-HT and TPH2 levels, consistent with a disorder of medullary 5-HT deficiency.

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