Brainstem serotonergic deficiency in sudden infant death syndrome.
BACKGROUND
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.


METHODS
Autopsy study conducted to analyze levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA); levels of TPH2; and 5-HT(1A) 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.


METHODS
Serotonin and metabolite tissue levels in the raphé obscurus and paragigantocellularis lateralis (PGCL); TPH2 levels in the raphé obscurus; and 5-HT(1A) 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-HT(1A) 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-HT(1A) receptor binding in the SIDS cases but no change in the controls (age x 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).


CONCLUSIONS
Compared with controls, SIDS was associated with lower 5-HT and TPH2 levels, consistent with a disorder of medullary 5-HT deficiency.
Duncan
Jhodie R
JR
Department of Pathology, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA.
Paterson
David S
DS
Hoffman
Jill M
JM
Mokler
David J
DJ
Borenstein
Natalia S
NS
Belliveau
Richard A
RA
Krous
Henry F
HF
Haas
Elisabeth A
EA
Stanley
Christina
C
Nattie
Eugene E
EE
Trachtenberg
Felicia L
FL
Kinney
Hannah C
HC
D001344:Autopsy; D001933:Brain Stem / Q000737:chemistry*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D000860:Hypoxia; D007223:Infant; D007231:Infant, Newborn; D007511:Ischemia; D008297:Male; D044282:Receptor, Serotonin, 5-HT1A / Q000032:analysis*; D012307:Risk Factors; D012701:Serotonin / Q000032:analysis / Q000172:deficiency*; D013398:Sudden Infant Death; D014365:Tryptophan Hydroxylase / Q000032:analysis*
D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase