Serotonin Research and Sudden Infant Death Syndrome (SIDS):
A Selected Annotated Bibliography

This bibliography provides information about serotonin and sudden infant death. Animal studies are excluded.

These articles have been selected by Resource Center staff from PubMed, a service of the National Library of Medicine that includes over 19 million citations from MEDLINE and other life science journals for biomedical articles back to 1948. PubMed includes links to full text articles and other related resources.

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Duncan JR, Paterson DS, Hoffman JM, Mokler DJ, Borenstein NS, Belliveau RA, Krous HF, Haas EA, Stanley C, Nattie EE, Trachtenberg FL, Kinney HC.
Brainstem serotonergic deficiency in sudden infant death syndrome.
JAMA. 2010 Feb 3;303(5):430-7.

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-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. MAIN OUTCOME MEASURES: 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). CONCLUSION: Compared with controls, SIDS was associated with lower 5-HT and TPH2 levels, consistent with a disorder of medullary 5-HT deficiency.

 

Casale V, Oneda R, Lavezzi AM, Matturri L.
Optimisation of postmortem tissue preservation and alternative protocol for serotonin transporter gene polymorphisms amplification in SIDS and SIUD cases.
Exp Mol Pathol. 2010 Feb;88(1):202-5. Epub 2009 Oct 23.

The major obstacle to genetic research in SIUD (sudden intrauterine unexplained death) and SIDS (sudden infant death syndrome) cases is the complex characteristics of the human anatomic samples available. In fact, in Italy autopsies are performed at least 24 h post-mortem and tissues can be left in formalin for long fixation times (>4/5 days), thus compromising nucleic acids integrity. In this study we compared the quality of DNA and RNA extracted from tissues differently preserved. As expected, the DNA and RNA from formalin-fixed and paraffin-embedded tissues, formalin-acetic acid-alcohol tissues and ethanol tissues were of poor quality and not adequate for subsequent molecular analysis. The best results were obtained with RNAlater preserved tissues: this buffer was equivalent, if not superior, to freezing method for preservation of postmortem DNA and RNA. In addition, we introduce a new protocol for the amplification of the serotonin transporter gene promoter region (5-HTT) ideal to obtain the increase of specific product, avoiding artifacts formation. Copyright 2009 Elsevier Inc. All rights reserved.

 

Broadbelt KG, Barger MA, Paterson DS, Holm IA, Haas EA, Krous HF, Kinney HC, Markianos K, Beggs AH.
Serotonin-related FEV gene variant in the sudden infant death syndrome is a common polymorphism in the African-American population.
Pediatr Res. 2009 Dec;66(6):631-5.

An important subset of the sudden infant death syndrome (SIDS) is associated with multiple serotonergic (5-HT) abnormalities in regions of the medulla oblongata. The mouse ortholog of the fifth Ewing variant gene (FEV) is critical for 5-HT neuronal development. A putatively rare intronic variant [IVS2-191_190insA, here referred to as c.128-(191_192)dupA] has been reported as a SIDS-associated mutation in an African-American population. We tested this association in an independent dataset: 137 autopsied cases (78 SIDS, 59 controls) and an additional 296 control DNA samples from Coriell Cell Repositories. In addition to the c.128-(191_192)dupA variant, we observed an associated single-base deletion [c.128-(301-306)delG] in a subset of the samples. Neither of the two FEV variants showed significant association with SIDS in either the African-American subgroup or the overall cohort. Although we found a significant association of c.128-(191_192)dupA with SIDS when San Diego Hispanic SIDS cases were compared with San Diego Hispanic controls plus Mexican controls (p = 0.04), this became nonsignificant after multiple testing correction. Among Coriell controls, 33 of 99 (33%) African-American and 0 of 197 (0%) of the remaining controls carry the polymorphism (c.128-(191_192)dupA). The polymorphism seems to be a common, likely nonpathogenic, variant in the African-American population.

 

Paterson DS, Hilaire G, Weese-Mayer DE.
Medullary serotonin defects and respiratory dysfunction in sudden infant death syndrome.
Respir Physiol Neurobiol. 2009 Aug 31;168(1-2):133-43. Epub 2009 May 27.

Sudden infant death syndrome (SIDS) is defined as the sudden and unexpected death of an infant less than 12 months of age that occurs during sleep and remains unexplained after a complete autopsy, death scene investigation, and review of the clinical history. It is the leading cause of postneonatal mortality in the developed world. The cause of SIDS is unknown, but is postulated to involve impairment of brainstem-mediated homeostatic control. Extensive evidence from animal studies indicates that serotonin (5-HT) neurons in the medulla oblongata play a role in the regulation of multiple aspects of respiratory and autonomic function. A subset of SIDS infants have several abnormalities in medullary markers of 5-HT function and genetic polymorphisms impacting the 5-HT system, informing the hypothesis that SIDS results from a defect in 5-HT brainstem-mediated control of respiratory (and autonomic) regulation. Here we review the evidence from postmortem human studies and animal studies to support this hypothesis and discuss how the pathogenesis of SIDS is likely to originate in utero during fetal development.

 

Kinney HC, Richerson GB, Dymecki SM, Darnall RA, Nattie EE.
The brainstem and serotonin in the sudden infant death syndrome.
Annu Rev Pathol. 2009;4:517-50.

The sudden infant death syndrome (SIDS) is the sudden death of an infant under one year of age that is typically associated with sleep and that remains unexplained after a complete autopsy and death scene investigation. A leading hypothesis about its pathogenesis is that many cases result from defects in brainstem-mediated protective responses to homeostatic stressors occurring during sleep in a critical developmental period. Here we review the evidence for the brainstem hypothesis in SIDS with a focus upon abnormalities related to the neurotransmitter serotonin in the medulla oblongata, as these are the most robust pathologic findings to date. In this context, we synthesize the human autopsy data with genetic, whole-animal, and cellular data concerning the function and development of the medullary serotonergic system. These emerging data suggest an important underlying mechanism in SIDS that may help lead to identification of infants at risk and specific interventions to prevent death.

 

Rognum IJ, Haynes RL, Vege A, Yang M, Rognum TO, Kinney HC.
Interleukin-6 and the serotonergic system of the medulla oblongata in the sudden infant death syndrome.
Acta Neuropathol. 2009 Oct;118(4):519-30. Epub 2009 Apr 26.

Mild infection may trigger sudden death in the vulnerable infant by cytokine interactions with a compromised medullary serotonergic (5-HT) system, leading to disrupted cardiorespiratory regulation and sleep-related sudden death. The cytokine interleukin (IL)-6 is elevated in the cerebrospinal fluid in SIDS. We tested the hypothesis that the expression of IL-6 receptors (IL-6R) and/or gp130 (involved in IL-6R signaling) is altered in the medullary 5-HT system in SIDS. Immunohistochemistry of IL-6R and gp130 was performed on medullae from 25 SIDS infants, 20 infectious deaths, and 14 controls using a semi-quantitative grading system. In the SIDS cases, mean IL-6R intensity grade in the arcuate nucleus (major component of medullary 5-HT system) was significantly higher than in the control group (2.00 +/- 0.07 vs. 1.77 +/- 0.08, P = 0.04), with no other differences in IL-6R or gp130 expression at any other site. Arcuate 5-HT neurons expressed IL-6R, indicating a site of IL-6/5-HT interaction. In SIDS, IL-6R expression is abnormal in the arcuate nucleus, the putative human homolog of rodent ventral medullary chemosensitivity sites involving 5-HT. Aberrant interactions between IL-6 and the arcuate nucleus may contribute to impaired responses to hypercapnia generated by infection (hyper-metabolism) combined with rebreathing.

 

Lavezzi AM, Casale V, Oneda R, Weese-Mayer DE, Matturri L.
Sudden infant death syndrome and sudden intrauterine unexplained death: correlation between hypoplasia of raphé nuclei and serotonin transporter gene promoter polymorphism.
Pediatr Res. 2009 Jul;66(1):22-7.

This study, besides to delineate the cytoarchitecture and the localization in the brainstem of the human raphé nuclei, aims to evaluate the correlation between neuropathological raphé defects and serotonin transporter gene (5-HTT) promoter region polymorphisms in a cohort of 28 SIDS victims, 12 sudden intrauterine unexplained deaths (SIUD), and 17 controls. Hypoplasia of one or more nuclei of both the rostral and caudal raphé groups was found in 57% of SIDS, in 67% of SIUD, and only in 12% of controls. Furthermore, a significant correlation among 5-HTT Long (L) allele, hypoplasia of the raphé nuclei, and maternal smoking in pregnancy was observed in sudden fetal and infant deaths. The presence of the L allele represents a predisposing factor for sudden fetal and infant death in association with morphologic developmental defects of the raphé nuclei and prenatal smoke exposure. A further consideration of the authors is that SIUD should not be regarded as a separate entity from SIDS, given the potentially shared neuropathological and genetic bases.

 

Haas C, Braun J, Bär W, Bartsch C.
No association of serotonin transporter gene variation with sudden infant death syndrome (SIDS) in Caucasians.
Leg Med (Tokyo). 2009 Apr;11 Suppl 1:S210-2. Epub 2009 Mar 3.

Genetic studies on SIDS have been motivated by clinical, epidemiological, and/or neuropathological observations made of SIDS victims. One of the candidate genes is the serotonin transporter (5-HTT) gene, based on decreased serotonergic receptor binding observed in the brain-stems of SIDS victims. Two polymorphisms in the regulatory region of the 5-HTT gene differentially modulate gene expression (promoter, intron 2). The promoter allelic variants long (L) and extra long (XL) and the intron 2 12-repeat allele seem to be associated with SIDS; however, the 5-HTT promoter allele distribution varies widely by ethnicity. We investigated the DNA of 145 Caucasian SIDS cases and 58 controls and could find no significant association between our Caucasian SIDS cases and controls either for the promoter L allele and the intron 2 12-repeat allele, or for the combined L-12 haplotype as well as the L- or 12-containing genotypes.

 

Dergacheva O, Kamendi H, Wang X, Pinol RM, Frank J, Jameson H, Gorini C, Mendelowitz D.
The role of 5-HT3 and other excitatory receptors in central cardiorespiratory responses to hypoxia: implications for sudden infant death syndrome.
Pediatr Res. 2009 Jun;65(6):625-30.

Although brainstem serotonergic (5-HT) systems are involved in the protective responses to hypoxia, abnormalities of 5-HT function are strongly implicated in SIDS, and the neurochemical mechanisms by which 5-HT receptors influence brainstem cardiorespiratory responses to hypoxia remains unclear. This study focuses on the role of excitatory neurotransmission, including 5-HT3 signaling, to cardiac vagal neurons (CVNs) that dominate the control of heart rate. Excitatory synaptic inputs to CVNs, located in the nucleus ambiguus (NA), were recorded simultaneously with respiratory activity in in vitro brainstem slices. During control conditions excitatory inputs to CVNs were blocked by application of NMDA and AMPA/kainate glutamatergic receptor antagonists, whereas the 5-HT3 and purinergic receptor antagonists ondansetron and pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), respectively, had no effect. However, during hypoxia ondansetron inhibited excitatory neurotransmission to CVNs. In recovery from hypoxia, spontaneous and respiratory-related excitatory events were blocked by glutamatergic and purinergic receptor blockers, respectively, whereas ondancetron had no effect. These results demonstrate that hypoxia recruits a 5-HT pathway to CVNs that activates 5-HT3 receptors on CVNs to maintain parasympathetic cardiac activity during hypoxia. Exaggeration of this 5-HT neurotransmission could increase the incidence of bradycardia and risk of sudden infant death during hypoxia.

 

Kinney HC.
Brainstem mechanisms underlying the sudden infant death syndrome: evidence from human pathologic studies.
Dev Psychobiol. 2009 Apr;51(3):223-33.
Comment in: Dev Psychobiol. 2009 Apr;51(3):213-4.

The brainstem hypothesis is one of the leading hypotheses concerning the sudden infant death syndrome (SIDS). It states that SIDS, or an important subset of SIDS, is due to abnormal brainstem mechanisms in the control of respiration, chemosensitivity, autonomic regulation, and/or arousal which impairs the infant's response to life-threatening, but often occurring, stressors during sleep (e.g., hypoxia, hypercarbia, asphyxia, hyperthermia) and leads to sudden death in a vulnerable developmental period. In this review, we summarize neuropathologic evidence from SIDS cases that support this hypothesis, beginning with the seminal report of subtle brainstem gliosis three decades ago. We focus upon recent neurochemical studies in our laboratory concerning the neurotransmitter serotonin (5-HT) and its key role in mediating protective responses to homeostatic stressors via medullary circuits. The possible fetal origin of brainstem defects in SIDS is reviewed, including evidence for adverse effects of prenatal exposure to maternal cigarette smoking and alcohol upon the postnatal development of human brainstem 5-HT pathways. (c) 2009 Wiley Periodicals, Inc.

 

Machaalani R, Say M, Waters KA.
Serotoninergic receptor 1A in the sudden infant death syndrome brainstem medulla and associations with clinical risk factors.
Acta Neuropathol. 2009 Mar;117(3):257-65. Epub 2008 Dec 4.
Comment in: Acta Neuropathol. 2009 Mar;117(3):247-55.

The immunoreactivity of the serotoninergic receptor subtype 1A (5HT(1A)R) was quantitatively analyzed in the human infant brainstem medulla (caudal and rostral levels). We hypothesized that immunoreactivity of 5HT(1A)R would be reduced in infants diagnosed with sudden infant death syndrome (SIDS). In particular that those infants with known clinical risk factors (including cigarette smoke exposure, bed sharing and sleep position) would have greater changes than those without clinical risks. Comparing SIDS (n = 67) to infants who died suddenly with another diagnosis (non-SIDS, n = 25), we found decreased 5HT(1A)R immunoreactivity in the majority of the nuclei studied at the rostral medulla level including dorsal motor nucleus of the vagus (DMNV), nucleus of the solitary tract, vestibular, and inferior olivary nucleus (ION). There was a significant relationship with all risk factors for 5HT(1A)R, especially for DMNV, suggesting that 5HT(1A)Rs are highly vulnerable to various insults within the SIDS DMNV. This study not only provides further evidence of abnormalities within the brainstem serotoninergic system of SIDS infants, but also shows that these changes may be associated with exposure to clinical risk factors.

 

Duncan JR, Paterson DS, Kinney HC.
The development of nicotinic receptors in the human medulla oblongata: inter-relationship with the serotonergic system.
Auton Neurosci. 2008 Dec 15;144(1-2):61-75. Epub 2008 Nov 5.
Erratum in: Auton Neurosci. 2009 Jan 28;145(1-2):108.

Maternal cigarette smoking during pregnancy adversely affects fetal development and increases the risk for the sudden infant death syndrome (SIDS). In SIDS we have reported abnormalities in the medullary serotonergic (5-HT) system, which is vital for homeostatic control. In this study we analyzed the inter-relationship between nicotinic receptors (nAChRs), to which nicotine in cigarette smoke bind, and the medullary 5-HT system in the human fetus and infant as a step towards determining the mechanisms whereby smoking increases SIDS risk in infants with 5-HT defects. Immunohistochemistry for the alpha4 nAChR subunit and 5-HT neurons was applied in fetal and infant medullae (15-92 postconceptional weeks, n=9). The distribution of different nAChRs was determined from 39-82 postconceptional weeks (n=5) using tissue autoradiography for 3H-nicotine, 3H-epibatidine, 3H-cytisine, and 125I-bungarotoxin; the findings were compared to laboratory 5-HT1A and 5-HT transporter binding data, and 5-HT neuronal density. Alpha4 immunoreactivity was ubiquitously expressed in medullary nuclei related to homeostatic functions from 15 weeks on, including rhombic lip germinal cells. At all ages, alpha4 co-localized with 5-HT neurons, indicating a potential site of interaction whereby exogenous nicotine may adversely affect 5-HT neuronal development and function. Binding for heteromeric nAChRs was highest in the inferior olive, and for homomeric nAChRs, in the vagal complex. In the paragigantocellularis lateralis, 5-HT1A receptor binding simultaneously increased as alpha7 binding decreased across infancy. This study indicates parallel dynamic and complex changes in the medullary nicotinic and 5-HT systems throughout early life, i.e., the period of risk for SIDS.

 

Filonzi L, Magnani C, Lavezzi AM, Rindi G, Parmigiani S, Bevilacqua G, Matturri L, Marzano FN.
Association of dopamine transporter and monoamine oxidase molecular polymorphisms with sudden infant death syndrome and stillbirth: new insights into the serotonin hypothesis.
Neurogenetics. 2009 Feb;10(1):65-72. Epub 2008 Sep 23.

Recent findings demonstrated the role of neurotransmitters in the aetiopathogenesis of sudden unexpected deaths in infancy. Although genes involved in serotonin metabolism have been proposed as risk factors for sudden infant death syndrome (SIDS), the contribution of additional neurotransmitters and genes different from the serotonin transporter (SLC6A4, 5-HTT) has not been investigated. Considering the common metabolic pathway and synergism between dopamine and serotonin, the role of dopamine transporter (SLC6A3, DAT) and monoamine oxidase A (MAOA) genes in SIDS and stillbirth (sudden intrauterine unexplained death, SIUD) was investigated. Genotypes and allelic frequencies of DAT and MAOA were determined in 20 SIDS and five stillbirth cases and compared with 150 controls. No association was found between DAT polymorphisms and SIDS either at genotype (P = 0.64) or allelic (P = 0.86) level; however, a highly significant association was found between MAOA genotypes (P = 0.047) and alleles (P = 0.002) regulating different expression patterns (3R/3R vs 3.5R/3.5R + 4R/4R) in SIDS + SIUD and controls. Analysis of combined 5-HTTLPR (serotonin transporter linked polymorphic region)/MAOA genotypes revealed that frequency of L/L-4R/4R genotype combination was eightfold higher in SIDS + SIUD than in controls (P < 0.001). Findings are discussed considering the metabolic association among DAT, 5-HTT and MAOA with special emphasis on the linked action of 5-HTT/MAOA in regulating serotonin metabolism of SIDS and SIUD infants.

 

Rand CM, Berry-Kravis EM, Fan W, Weese-Mayer DE.
HTR2A variation and sudden infant death syndrome: a case-control analysis.
Acta Paediatr. 2009 Jan;98(1):58-61. Epub 2008 Sep 2.

AIM: The serotonergic (5-HT) system functions in central autonomic regulation with homeostatic roles in cardiorespiratory control, thermoregulation, arousal and sleep-wake cycling. Altered function and development of this system in cases of sudden infant death syndrome (SIDS) have been established, but the aetiology of these disturbances remains unclear. The serotonin receptor, HTR2A, functions within this system with roles in the homeostatic response to hypoxia including excitatory effects on respiration, gasping and rhythm generation, all functions potentially compromised in SIDS. The objective of this study was to examine the relationship between SIDS risk and HTR2A variation. METHODS: All coding regions, intron-exon boundaries and the promoter region of HTR2A were PCR amplified and analysed by standard sequencing in 96 SIDS cases and 96 matched controls. RESULTS: Twenty-one HTR2A variations were identified in this case-control cohort, including four novel variations (c.C-1185A, c.T-923C, c.T-17C and c.C50T). None of the variations identified showed a significant association with SIDS. CONCLUSION: This report provides evidence that despite known alterations of the 5-HT system in SIDS, and the logical role for the HTR2A receptor, genetic variation of HTR2A as studied in our cohort is not responsible for these alterations. These results represent a further step in the investigation of the aetiology of the altered serotonin system in SIDS cases.

 

Doi A, Ramirez JM.
Neuromodulation and the orchestration of the respiratory rhythm.
Respir Physiol Neurobiol. 2008 Dec 10;164(1-2):96-104.

The respiratory system is continuously modulated by numerous aminergic and peptidergic substances that act at all levels of integration: from the sensory level to the level of central networks and motor nuclei. The same neuronal networks receive inputs from multiple modulators released locally as well as from distal nuclei. All parameters of respiratory control are controlled by multiple neuromodulators. By partly converging onto similar G-proteins and second messenger systems, acetylcholine, norepinephrine, histamine, serotonin (5-HT), dopamine, ATP, substance P, cholecystokinin (CCK) can increase frequency, regularity and amplitude of respiratory activity. Yet, the same modulator can also exert differential effects on respiratory activity by acting on different receptors partly in the same neurons. In the pre-Bötzinger complex (pre-BötC) modulators can differentially modulate frequency and amplitude in different types of pacemaker neurons. Similarly motoneurons located in different motor nuclei receive differential amplitude modulation from different modulators. Thus, modulators are capable of orchestrating and modulating different parameters of respiratory activity by differentially targeting different cellular targets. A disturbance in modulatory control may lead to Sudden Infant Death Syndrome (SIDS) and erratic breathing.

 

Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Rand CM.
Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS): kindred disorders of autonomic regulation.
Respir Physiol Neurobiol. 2008 Dec 10;164(1-2):38-48.

Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS) were long considered rare disorders of respiratory control and more recently have been highlighted as part of a growing spectrum of disorders within the rubric of autonomic nervous system (ANS) dysregulation (ANSD). CCHS typically presents in the newborn period with a phenotype including alveolar hypoventilation, symptoms of ANSD and, in a subset of cases, Hirschsprung disease and later tumors of neural crest origin. Study of genes related to autonomic dysregulation and the embryologic origin of the neural crest led to the discovery of PHOX2B as the disease-defining gene for CCHS. Like CCHS, SIDS is thought to result from central deficits in control of breathing and ANSD, although SIDS risk is most likely defined by complex multifactorial genetic and environmental interactions. Some early genetic and neuropathological evidence is emerging to implicate serotonin systems in SIDS risk. The purpose of this article is to review the current understanding of the genetic basis for CCHS and SIDS, and discuss the impact of this information on clinical practice and future research directions.

 

Opdal SH, Vege A, Rognum TO.
Serotonin transporter gene variation in sudden infant death syndrome.
Acta Paediatr. 2008 Jul;97(7):861-5. Epub 2008 May 12.
Comment in: Acta Paediatr. 2008 Jul;97(7):846-7

AIM: To investigate polymorphisms in the serotonin transporter (5-HTT) gene in cases of sudden infant death syndrome (SIDS) and controls, and further to elucidate a possible relationship between 5-HTT genotypes and external risk factors for SIDS. METHOD: The subjects investigated consist of 163 SIDS cases and 243 controls. Polymorphisms in both the promoter and intron 2 of the 5-HTT gene were investigated, and the genotypes were determined using polymerase chain reaction (PCR) and gel electrophoresis. RESULTS: In the promoter, there was a tendency for the L allele and L/L genotype to be found more often in the SIDS cases than in the controls (p=0.05 and p=0.07, respectively). Regarding the intron 2 polymorphism, there were no differences between the groups, and the SIDS cases were not found to have a higher frequency of either the L/L-12/12 genotype or the L-12 haplotype than the controls. When investigating possible correlations between genotype and risk factors for SIDS, there was a tendency towards different distribution of the promoter genotypes in cases found dead prone compared to cases found dead in other sleeping positions (p=0.06). CONCLUSION: Polymorphisms in the promoter of the 5-HTT gene may be of importance with regard to SIDS.

 

Nonnis Marzano F, Maldini M, Filonzi L, Lavezzi AM, Parmigiani S, Magnani C, Bevilacqua G, Matturri L.
Genes regulating the serotonin metabolic pathway in the brain stem and their role in the etiopathogenesis of the sudden infant death syndrome.
Genomics. 2008 Jun;91(6):485-91. Epub 2008 Apr 2.

Genotypes and allelic frequencies of TPH2, 5-HTTLPR, the 5-HTT (SLC6A4) intron 2 variable-number tandem repeat (VNTR) region, and the MAOA VNTR region were determined in brain-stem samples of 20 "genuine" SIDS cases and compared with results obtained from 150 healthy controls. The SNP G1463A responsible for 80% functionality loss of TPH2 (tryptophan hydroxylase 2) was not detected, neither in SIDS infants nor in the controls. In contrast, a strict relation was found between the 5-HTTLPR genotype and its allelic frequencies with SIDS cases. The L/L genotype and the long allele (L) of the promoter region of the serotonin transporter were significantly associated (likelihood ratio (LR) test, p<0.001) with the syndrome (L/L, 60% SIDS vs 14% controls; L, 80% SIDS vs 42.6% controls). Polymorphisms of the intron 2 VNTR of the same gene showed a trend for significant differences between genotypes 10/10 and 12/12 (LR test, p=0.068), with the L-12 haplotype being almost twofold in SIDS (44.5%) with respect to controls (23.4%). Differences were even higher considering the genotype combination L/L-12/12 (20% SIDS vs 2.6%), and variations among categories were statistically highly significant (p<0.001). Although additional differences were observed in the frequency of the MAOA (monoamine oxidase A) VNTR genotype 3R/3R between SIDS and controls (respectively 15% vs 26%), the results were not supported by statistical significance. Molecular polymorphisms are discussed considering their functional role in regulating serotonin synthesis (TPH2), neuronal reuptake (5-HTTLPR and 5-HTT intron 2), and catabolism (MAOA) in the nervous system of Italian SIDS infants. Comparisons are made with previous data obtained in different ethnic groups.

 

Moon RY, Horne RS, Hauck FR.
Sudden infant death syndrome.
Lancet. 2007 Nov 3;370(9598):1578-87.

Despite declines in prevalence during the past two decades, sudden infant death syndrome (SIDS) continues to be the leading cause of death for infants aged between 1 month and 1 year in developed countries. Behavioural risk factors identified in epidemiological studies include prone and side positions for infant sleep, smoke exposure, soft bedding and sleep surfaces, and overheating. Evidence also suggests that pacifier use at sleep time and room sharing without bed sharing are associated with decreased risk of SIDS. Although the cause of SIDS is unknown, immature cardiorespiratory autonomic control and failure of arousal responsiveness from sleep are important factors. Gene polymorphisms relating to serotonin transport and autonomic nervous system development might make affected infants more vulnerable to SIDS. Campaigns for risk reduction have helped to reduce SIDS incidence by 50-90%. However, to reduce the incidence even further, greater strides must be made in reducing prenatal smoke exposure and implementing other recommended infant care practices. Continued research is needed to identify the pathophysiological basis of SIDS.

 

Pearson KH, Nonacs RM, Viguera AC, Heller VL, Petrillo LF, Brandes M, Hennen J, Cohen LS.
Birth outcomes following prenatal exposure to antidepressants.
J Clin Psychiatry. 2007 Aug;68(8):1284-9.
Comment in: J Clin Psychiatry. 2007 Aug;68(8):1277-8.

BACKGROUND: Antidepressant use during pregnancy and the peripartum period is common despite the absence of clear evidence-based guidelines to direct clinical use of these compounds. METHOD: We compared obstetrical and neonatal outcomes as recorded in medical records among 84 pregnant women with major depressive or anxiety disorders (DSM-IV criteria) who took antidepressants during pregnancy (cases) versus a 2:1 age- and parity-matched control group of 168 unexposed women. Women in the case group had sought psychiatric consultation regarding the use of medication from the Perinatal and Reproductive Psychiatry Program at the Massachusetts General Hospital between 1996 and 2000. RESULTS: There were no significant differences among cases versus controls and their offspring, with respect to various neonatal and obstetrical outcomes, including gestational age and weight, although 1-minute Apgar scores were slightly lower in exposed infants. Admissions to the special care nursery were more frequent, but briefer and based on relatively minor indications, among case newborns. There were no significant differences in neonatal outcomes between exposures to serotonin reuptake inhibitor (SRI) and tricyclic (TCA) antidepressants. CONCLUSION: This retrospective cohort study found no evidence of major increases in risk of adverse obstetrical or neonatal outcomes following prenatal exposure to antidepressants, nor between SRIs and TCAs. Larger, prospective studies with specific neurobehavioral measures are required to resolve current uncertainties about safe and effective use of antidepressants by pregnant women.

 

Rand CM, Berry-Kravis EM, Zhou L, Fan W, Weese-Mayer DE.
Sudden infant death syndrome: rare mutation in the serotonin system FEV gene.
Pediatr Res. 2007 Aug;62(2):180-2.

Recent studies have identified abnormalities in the development and function of medullary serotonin (5-HT) pathways in postmortem brain from sudden infant death syndrome (SIDS) cases, suggesting 5-HT-mediated dysregulation of the autonomic nervous system (ANS) in SIDS. The human fifth Ewing variant (FEV) gene is specifically expressed in central 5-HT neurons in the brain, with a predicted role in specification and maintenance of serotonergic neuronal phenotype. We hypothesized that variations of FEV may underlie abnormalities of the 5-HT system in SIDS cases and thus may be associated with SIDS risk. To elucidate the relationship between variation in FEV and SIDS, DNA was prepared from 96 African American and Caucasian SIDS cases and 96 gender- and ethnicity-matched controls. Standard sequencing and analysis of FEV revealed a heterozygous insertion mutation (IVS-191_190insA) upstream of the 5' exon 3 splice site occurring more frequently in SIDS cases (6/96) compared with controls (0/96; p = 0.01) and in the overall African American group (6/98) compared with the Caucasian group (0/94; p = 0.03). Identification of a variation in a gene responsible for 5-HT neuronal development, exclusively in a subset of African American SIDS cases in this cohort, may help explain both the observed abnormalities of this system in some SIDS cases and the ethnic disparity observed in SIDS.

 

Rand CM, Berry-Kravis EM, Zhou L, Fan W, Weese-Mayer DE.
Sudden infant death syndrome: Rare mutation in the serotonin system FEV gene.
Pediatr. Res. 2007 Jun 25; [Epub ahead of print].

Recent studies have identified abnormalities in the development and function of medullary serotonin (5-HT) pathways in postmortem brain from sudden infant death syndrome (SIDS) cases, suggesting 5-HT-mediated dysregulation of the autonomic nervous system (ANS) in SIDS. The human fifth Ewing variant gene FEV is specifically expressed in central 5-HT neurons in the brain, with a predicted role in specification and maintenance of serotonergic neuronal phenotype. We hypothesized that variations of FEV may underlie abnormalities of the 5-HT system in SIDS cases and thus may be associated with SIDS risk. To elucidate the relationship between variation in FEV and SIDS, DNA was prepared from 96 African American and white SIDS cases and 96 gender- and ethnicity-matched controls. Standard sequencing and analysis of FEV revealed a heterozygous insertion mutation (IVS-191_190insA) upstream of the 5' exon 3 splice site occurring more frequently in SIDS cases (6/96) compared with controls (0/96; p = 0.01) and in the overall African American group (6/98) compared with the white group (0/94; p = 0.03). Identification of a variation in a gene responsible for 5-HT neuronal development, exclusively in a subset of African American SIDS cases in this cohort, may help explain both the observed abnormalities of this system in some SIDS cases and the ethnic disparity observed in SIDS.

 

Paterson DS, Trachtenberg FL, Thompson EG, Belliveau RA, Beggs AH, Darnall R, Chadwick AE, Krous HF, Kinney HC.
Multiple serotonergic brainstem abnormalities in sudden infant death syndrome.
JAMA. 2006 Nov 1; 296(17):2124-32.

Context: The serotonergic (5-hydroxytryptamine [5-HT]) neurons in the medulla oblongata project extensively to autonomic and respiratory nuclei in the brainstem and spinal cord and help regulate homeostatic function. Previously, abnormalities in 5-HT receptor binding in the medullae of infants dying from sudden infant death syndrome (SIDS) were identified, suggesting that medullary 5-HT dysfunction may be responsible for a subset of SIDS cases. Objective: To investigate cellular defects associated with altered 5-HT receptor binding in the 5-HT pathways of the medulla in SIDS cases. Design, Setting, and Participants: Frozen medullae from infants dying from SIDS (cases) or from causes other than SIDS (controls) were obtained from the San Diego Medical Examiner's office between 1997 and 2005. Markers of 5-HT function were compared between SIDS cases and controls, adjusted for postconceptional age and postmortem interval. The number of samples available for each analysis ranged from 16 to 31 for SIDS cases and 6 to 10 for controls. An exploratory analysis of the correlation between markers and 6 recognized risk factors for SIDS was performed. Main Outcome Measures: 5-HT neuron count and density, 5-HT(1A) receptor binding density, and 5-HT transporter (5-HTT) binding density in the medullary 5-HT system; correlation between these markers and 6 recognized risk factors for SIDS. Results: Compared with controls, SIDS cases had a significantly higher 5-HT neuron count (mean [SD], 148.04 [51.96] vs 72.56 [52.36] cells, respectively; P<.001) and 5-HT neuron density (P<.001), as well as a significantly lower density of 5-HT(1A) receptor binding sites (P<or=.01 for all 9 nuclei) in regions of the medulla involved in homeostatic function. The ratio of 5-HTT binding density to 5-HT neuron count in the medulla was significantly lower in SIDS cases compared with controls (mean [SD], 0.70 [0.33] vs 1.93 [1.25] fmol/mg, respectively; P = .001). Male SIDS cases had significantly lower 5-HT(1A) binding density in the raphe obscurus compared with female cases (mean [SD], 16.2 [2.0] vs 29.6 [16.5] fmol/mg, respectively; P = .04) or with male and female controls combined (mean [SD], 53.9 [19.8] fmol/mg; P = .005). No association was found between 5-HT neuron count or density, 5-HT(1A) receptor binding density, or 5-HTT receptor binding density and other risk factors. Conclusions: Medullary 5-HT pathology in SIDS is more extensive than previously delineated, potentially including abnormal 5-HT neuron firing, synthesis, release, and clearance. This study also provides preliminary neurochemical evidence that may help explain the increased vulnerability of boys to SIDS.

 

Kinney HC.
Abnormalities of the brainstem serotonergic system in the sudden infant death syndrome: A review.
Pediatr Dev Pathol. 2005 Sep-Oct; 8(5):507-24. E-pub 2005 Oct 12.

This report presents a review of findings related to brainstem serotonergic (5-HT) abnormalities in a subset of SIDS cases. From 1990 to 2003, author and her colleagues published a series of reports concerning 6 neurotransmitter systems in step tissue sections of the same SIDS and control brainstems [5:10-15]. Our overall conclusion was that the 5-HT system in the medulla oblongata, i.e., the so-called medullary 5-HT system, is abnormal in at least 50% of SIDS cases [16]. We focused on brainstem systems involved in the control of respiration, autonomic function, sleep, and arousal because of an increasing body of prospective studies involving infants who subsequently died of SIDS that indicate subtle abnormalities in respiratory and/or autonomic control during sleep and arousal patterns before death [17-19]. Moreover, studies in normal preterm and term infants have indicated that the period of SIDS risk is associated with diminished arousal and altered respiratory and autonomic functions in the prone position or face-covered, supine position that potentially increase vulnerability to SIDS [20-25]. They used the technique of tissue receptor autoradiography in these studies because it allowed us to make precise neurochemical measurements in selected nuclei involved in respiratory and autonomic control, arousal, and sleep (Fig. 1). In addition, it allowed them to compare these measurements with those in nuclei not involved in cardiorespiratory control and arousal as an index of specificity to the postulated preferential involvement of homeostatic-related nuclei. We selected the analysis of receptor binding as a marker of neurotransmitter-related dysfunction as a "first pass" in determining possible brainstem regions and neurotransmitter systems involved in SIDS. This technique essentially allowed a survey of all brainstem regions neurochemically. Thus, it is a ideal method to target potential neurotransmitter abnormalities in SIDS, particularly because the cardiorespiratory- and arousal-related regions of interest were unremarkable with conventional histology, except for subtle gliosis in some sites.

 

Kinney HC, Myers MM, Belliveau RA, Randall LL, Trachtenberg FL, Fingers ST, Youngman M, Habbe D, Fifer WP.
Subtle autonomic and respiratory dysfunction in sudden infant death syndrome associated with serotonergic brainstem abnormalities: A case report.
J Neuropathol Exp Neurol. 2005 Aug; 64(8):689-94.

Sudden infant death syndrome (SIDS) is characterized by a sleep-related death in a seemingly healthy infant. Previously, we reported abnormalities in the serotonergic (5-HT) system of the medulla in SIDS cases in 2 independent datasets, including in the Northern Plains American Indians. The medullary 5-HT system is composed of 5-HT neurons in the raphe, extra-raphe, and arcuate nucleus at the ventral surface. This system is thought to modulate respiratory and autonomic function, and thus abnormalities within it could potentially lead to imbalances in sympathetic and parasympathetic tone. We report the case of a full-term American Indian boy who died of SIDS at 2 postnatal weeks, and who had subtle respiratory and autonomic dysfunction measured prospectively on the second postnatal day. Cardiorespiratory assessment of heart rate variability suggested that the ratio of parasympathetic to sympathetic tone was higher than normal in active sleep and lower than normal in quiet sleep in this case. At autopsy, arcuate nucleus hypoplasia and 5-HT receptor-binding abnormalities in the arcuate nucleus and other components of the medullary 5-HT system were found. This case suggests that medullary 5-HT system abnormalities may be able to be identified by such physiological tests before death. Replication of these findings in a large population may lead to the development of predictive cardiorespiratory assessment tools for future screening to identify infants with medullary 5-HT abnormalities and SIDS risk.

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Updated: March 2010

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