Medullary Serotonergic Binding Deficits and Hippocampal Abnormalities in Sudden Infant Death Syndrome: One or Two Entities?

Sudden infant death syndrome (SIDS) is understood as a syndrome that presents with the common phenotype of sudden death but involves heterogenous biological causes. Many pathological findings have been consistently reported in SIDS, notably in areas of the brain known to play a role in autonomic control and arousal. Our laboratory has reported abnormalities in SIDS cases in medullary serotonin (5-HT) receptor 1A and within the dentate gyrus of the hippocampus. Unknown, however, is whether the medullary and hippocampal abnormalities coexist in the same SIDS cases, supporting a biological relationship of one abnormality with the other. In this study, we begin with an analysis of medullary 5-HT1A binding, as determined by receptor ligand autoradiography, in a combined cohort of published and unpublished SIDS (n = 86) and control (n = 22) cases. We report 5-HT1A binding abnormalities consistent with previously reported data, including lower age-adjusted mean binding in SIDS and age vs. diagnosis interactions. Utilizing this combined cohort of cases, we identified 41 SIDS cases with overlapping medullary 5-HT1A binding data and hippocampal assessment and statistically addressed the relationship between abnormalities at each site. Within this SIDS analytic cohort, we defined abnormal (low) medullary 5-HT1A binding as within the lowest quartile of binding adjusted for age and we examined three specific hippocampal findings previously identified as significantly more prevalent in SIDS compared to controls (granular cell bilamination, clusters of immature cells in the subgranular layer, and single ectopic cells in the molecular layer of the dentate gyrus). Our data did not find a strong statistical relationship between low medullary 5-HT1A binding and the presence of any of the hippocampal abnormalities examined. It did, however, identify a subset of SIDS (~25%) with both low medullary 5-HT1A binding and hippocampal abnormalities. The subset of SIDS cases with both low medullary 5-HT1A binding and single ectopic cells in the molecular layer was associated with prenatal smoking (p = 0.02), suggesting a role for the exposure in development of the two abnormalities. Overall, our data present novel information on the relationship between neuropathogical abnormalities in SIDS and support the heterogenous nature and overall complexity of SIDS pathogenesis.

Association between auditory system pathology and sudden infant death syndrome (SIDS): a systematic review

ObjectiveA theory has emerged, suggesting that abnormalities in the auditory system may be associated with sudden infant death syndrome (SIDS). However, current clinical evidence has never been systematically reviewed.DesignA systematic review was conducted according to the guideline of Preferred Reporting Items for Systematic Reviews and Meta-Analyses.Data sourcesPubMed, Embase and Web of Science were systematically searched through 7 September 2020.Eligibility criteria for selecting studiesOnly human studies with a reference group were included. Studies were eligible for inclusion if they examined infants exposed to otoacoustic emissions (OAEs), auditory brainstem response (ABR) or had autopsies with brainstem histology of the auditory system. SIDS was the primary outcome, while the secondary outcome was near-miss sudden infant death syndrome episodes.Data extraction and synthesisTwo independent reviewers extracted data and assessed risk of bias, and the quality of evidence. Due to high heterogeneity, a narrative synthesis was conducted. Risk of bias and quality of evidence was assessed using the Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development and Evaluation.ResultsTwelve case–control studies were included. Seven studies on OAEs or ABR had a high degree of inconsistency. Contrarily, four out of five studies reporting on brainstem histology found that auditory brainstem abnormalities were more prevalent in SIDS cases than in controls. However, the quality of evidence across all studies was very low.ConclusionThis systematic review found no clear association between auditory system pathology and SIDS. The higher prevalence of histological abnormalities in the auditory system of SIDS may indicate an association. However, further studies of higher quality and larger study populations are needed to determine whether these findings are valid.PROSPERO registration numberCRD42020208045.

Comprehensive Analysis of Genes Associated With Sudden Infant Death Syndrome

Background: Sudden infant death syndrome (SIDS) is a tragic incident which remains a mystery even after post-mortem investigation and thorough researches.Methods: This comprehensive review is based on the genes reported in the molecular autopsy studies conducted on SIDS so far. A total of 20 original studies and 7 case reports were identified and included in this analysis. The genes identified in children or adults were not included. Most of the genes reported in these studies belonged to cardiac channel and cardiomyopathy. Cardiac channel genes in SIDS were scrutinized for further analysis.Results: After screening and removing the duplicates, 42 unique genes were extracted. When the location of these genes was assessed, it was observed that most of these belonged to Chromosomes 11, 1 and 3 in sequential manner. The pathway analysis shows that these genes are involved in the regulation of heart rate, action potential, cardiac muscle cell contraction and heart contraction. The protein-protein interaction network was also very big and highly interactive. SCN5A, CAV3, ALG10B, AKAP9 and many more were mainly found in these cases and were regulated by many transcription factors such as MYOG C2C1 and CBX3 HCT11. Micro RNA, “hsa-miR-133a-3p” was found to be prevalent in the targeted genes.Conclusions: Molecular and computational approaches are a step forward toward exploration of these sad demises. It is so far a new arena but seems promising to dig out the genetic cause of SIDS in the years to come.