Sudden Infant Death Syndrome Victims Research Articles

Exome analysis focusing on epilepsy-related genes in children and adults with sudden unexplained death

PurposeGenetic studies in sudden infant death syndrome (SIDS) and sudden unexplained death (SUD) cohorts have indicated that cardiovascular diseases might have contributed to sudden unexpected death in 20–35 % of autopsy-negative cases. Sudden unexpected death can also occur in people with epilepsy, termed as sudden unexpected death in epilepsy (SUDEP). The pathophysiological mechanisms of SUDEP are not well understood, but are likely multifactorial, including seizure-induced hypoventilation and arrhythmias as well as genetic risk factors. The sudden death of some of the SIDS/SUD victims might also be explained by genetic epilepsy, therefore this study aimed to expand the post-mortem genetic analysis of SIDS/SUD cases to epilepsy-related genes. MethodsExisting whole-exome sequencing data from our 155 SIDS and 45 SUD cases were analyzed, with a focus on 365 epilepsy-related genes. Nine of the SUD victims had a known medical history of epilepsy, seizures or other underlying neurological conditions and were therefore classified as SUDEP cases. ResultsIn our SIDS and SUD cohorts, we found epilepsy-related pathogenic/likely pathogenic variants in the genes OPA1, RAI1, SCN3A, SCN5A and TSC2. ConclusionPost-mortem analysis of epilepsy-related genes identified potentially disease-causing variants that might have contributed to the sudden death events in our SIDS/SUD cases. However, the interpretation of identified variants remains challenging and often changes over time as more data is gathered. Overall, this study contributes insight in potentially pathophysiological epilepsy-related mechanisms in SIDS, SUD and SUDEP victims and underlines the importance of sensible counselling on the risk and preventive measures in genetic epilepsy.

Cell death in the lateral geniculate nucleus, and its possible relationship with nicotinic receptors and sudden infant death syndrome (SIDS)

The role of the lateral geniculate nucleus (LGN) in vision has been extensively studied, yet its extraretinal capacities are still being investigated, including its role in arousal from sleep. The β2 nicotinic acetylcholine receptor (nAChR) subunit is involved in the laminal organisation of the LGN with magnocellular (MC) and parvocellular (PC) neurons. Sudden infant death syndrome (SIDS) occurs during a sleep period and, neuropathologically, is associated with increased neuronal cell death and altered nAChRs. A recent qualitative pilot study from our group implicates the possibility of increased neuronal death/apoptosis in the SIDS LGN. The present study used quantitative analysis to report the baseline expression of apoptotic and nAChR subunits α7 and β2 in the PC and MC layers of the LGN, to determine correlations amongst these markers within layers and across layers, and to evaluate changes in the expression of these markers in the LGN of SIDS infants, along with associations with SIDS risk factors, such as age, sex, cigarette smoke exposure, bed-sharing, and presence of an upper respiratory tract infection (URTI). Tissue was immunohistochemically stained for cell death markers of active caspase-3 (Casp-3) and TUNEL, and for the α7 and β2 nAChR subunits. Amongst 43 cases of sudden and unexpected deaths in infancy (SUDI), classifications included explained deaths (eSUDI, n = 9), SIDS I (n = 5) and SIDS II (n = 29). Results indicated a strong correlation of the apoptotic markers and β2 nAChR subunit between the LGN layers, but not across the markers within the layers. Amongst the diagnostic groups, compared to eSUDI, the SIDS II cases had decreased Casp-3 expression while β2 nAChR expression was increased in both PC and MC layers. Amongst the SIDS risk factors, URTI and bed-sharing were associated with changes in neuronal death but not in the α7 and β2 markers. In conclusion, our findings do not support a role for the α7 and β2 nAChRs in apoptotic regulation of the LGN layers during infancy. However, for SIDS victims, an inverse correlation between the changes for markers of apoptosis and the β2 nAChR subunit expression suggests altered LGN function.

Hyperthermia and Heat Stress as Risk Factors for Sudden Infant Death Syndrome: A Narrative Review.

Background and ObjectivesHeat stress and hyperthermia are common findings in sudden infant death syndrome (SIDS) victims. It has been suggested that thermal stress can increase the risk of SIDS directly via lethal hyperthermia or indirectly by altering autonomic functions. Major changes in sleep, thermoregulation, cardiovascular function, and the emergence of circadian functions occur at the age at which the risk of SIDS peaks—explaining the greater vulnerability at this stage of development. Here, we review the literature data on (i) heat stress and hyperthermia as direct risk factors for SIDS, and (ii) the indirect effects of thermal loads on vital physiological functions.ResultsVarious situations leading to thermal stress (i.e., outdoors temperatures, thermal insulation from clothing and bedding, the prone position, bed-sharing, and head covering) have been analyzed. Hyperthermia mainly results from excessive clothing and bedding insulation with regard to the ambient thermal conditions. The appropriate amount of clothing and bedding thermal insulation for homeothermia requires further research. The prone position and bed-sharing do not have major thermal impacts; the elevated risk of SIDS in these situations cannot be explained solely by thermal factors. Special attention should be given to brain overheating because of the head's major role in body heat losses, heat production, and autonomic functions. Thermal stress can alter cardiovascular and respiratory functions, which in turn can lead to life-threatening events (e.g., bradycardia, apnea with blood desaturation, and glottal closure). Unfortunately, thermal load impairs the responses to these challenges by reducing chemosensitivity, arousability, and autoresuscitation. As a result, thermal load (even when not lethal directly) can interact detrimentally with vital physiological functions.ConclusionsWith the exception of excessive thermal insulation (which can lead to lethal hyperthermia), the major risk factors for SIDS appears to be associated with impairments of vital physiological functions when the infant is exposed to thermal stress.

Mitochondrial DNA content: a new potential biomarker for Sudden Infant Death Syndrome.

Sudden Infant Death Syndrome (SIDS) occurs in apparently healthy infants and is unpredictable and unexplained despite thorough investigations and enormous research efforts. The hypothesis tested in this case-control study concerns mitochondrial involvement in SIDS occurrence. Mitochondrial DNA content (MtDNAcn) was measured in 24 SIDS cerebral cortex samples and 18 controls using real-time PCR. The median (interquartile range) mtDNAcn in SIDS and controls was 2578 (2224-3838) and 1452 (724-2517) copies per nuclear DNA, respectively (P = 0.0001). MtDNAcn values were higher in SIDS victims born to non-smoking parents (n = 7) 4984 (2832-6908) compared to the controls (n = 5) 2020 (478-2386) (P = 0.006). Increased levels of mtDNAcn have been observed in the SIDS cases with mild defects in nuclei not essential for life compared to those found in SIDS cases with severe alterations of respiratory function (P = 0.034) 3571 (2568-5053) (n = 14) 2356 (1909-3132) (n = 8), respectively. Our study revealed for the first time higher mtDNAcn in the cerebral cortex of the SIDS cases than the controls, indicating metabolic alterations. MtDNAcn plays an important role in compensatory mechanisms against environmental factors affecting human health. Despite the small sample size, mtDNA may prove to be a potential forensic biomarker for autopsied SIDS victims for gaining new insights into the etiology of SIDS. Mitochondrial DNA content evaluated in cerebral cortex samples is higher in SIDS victims than controls. These results represent a novel line of investigation for the etiology of SIDS and could have a significant role in the compensatory mechanism due to environmental factors affecting human health. These findings suggest that the mitochondria are involved in SIDS: mtDNA content may represent a biomarker of this syndrome.

SIDS associated RYR2 p.Arg2267His variant may lack pathogenicity

Sudden infant death syndrome (SIDS) is the sudden death of an infant under 1 year of age that remains unexplained after death scene and medicolegal investigation, including a complete autopsy and clinical history review. The fatal event typically occurs during sleep and heart rhythm during the event is rarely documented. Large series which have utilized molecular autopsy show that long QT syndrome (LQTS) associated cardiac channel mutations contribute to between 5 and 10% of SIDS deaths. In addition, rare novel RYR2 variants have been identified in SIDS victims. Given the lack of a phenotype, the pathogenicity of these variants is inferred from in vitro studies. We report a family with 5 members (mother and 4 children) who are carriers of a rare RYR2 variant (c.6800G > A, p.Arg2267His [Exon: 45], heterozygous) which has previously been identified in a SIDS victim and shown to confer a gain-of-function CPVT phenotype in vitro. All of these 5 family members including the mother (age range 7 to 41 years) have had negative exercise stress tests, echocardiograms and Holter monitors. These findings suggest that caution should be exercised in inferring pathogenicity of rare RYR2 variants based on in vitro functional data which does not always translate to human phenotype.

Central and peripheral chemoreceptors in sudden infant death syndrome.

The pathogenesis of sudden infant death syndrome (SIDS) has been ascribed to an underlying biological vulnerability to stressors during a critical period of development. This paper reviews the main data in the literature supporting the role of central (e.g. retrotrapezoid nucleus, serotoninergic raphe nuclei, locus coeruleus, orexinergic neurons, ventral medullary surface, solitary tract nucleus) and peripheral (e.g. carotid body) chemoreceptors in the pathogenesis of SIDS. Clinical and experimental studies indicate that central and peripheral chemoreceptors undergo critical development during the initial postnatal period, consistent with the age range of SIDS (<1year). Most of the risk factors for SIDS (gender, genetic factors, prematurity, hypoxic/hyperoxic stimuli, inflammation, perinatal exposure to cigarette smoke and/or substance abuse) may structurally and functionally affect the developmental plasticity of central and peripheral chemoreceptors, strongly suggesting the involvement of these structures in the pathogenesis of SIDS. Morphometric and neurochemical changes have been found in the carotid body and brainstem respiratory chemoreceptors of SIDS victims, together with functional signs of chemoreception impairment in some clinical studies. However, the methodological problems of SIDS research will have to be addressed in the future, requiring large and highly standardized case series. Up-to-date autopsy protocols should be produced, involving substantial, and exhaustive sampling of all potentially involved structures (including peripheral arterial chemoreceptors). Morphometric approaches should include unbiased stereological methods with three-dimensional probes. Prospective clinical studies addressing functional tests and risk factors (including genetic traits) would probably be the gold standard, allowing markers of intrinsic or acquired vulnerability to be properly identified.

518Risk of sudden infant death syndrome (SIDS) among siblings of SIDS victims: a Danish nationwide cohort study

518Risk of sudden infant death syndrome (SIDS) among siblings of SIDS victims: a Danish nationwide cohort study

Functional characterization of a novel hERG variant in a family with recurrent sudden infant death syndrome: Retracting a genetic diagnosis

Long QT syndrome (LQTS) is the most common cardiac ion channelopathy and has been found to be responsible for approximately 10% of sudden infant death syndrome (SIDS) cases. Despite increasing use of broad panels and now whole exome sequencing (WES) in the investigation of SIDS, the probability of identifying a pathogenic mutation in a SIDS victim is low. We report a family-based study who are afflicted by recurrent SIDS in which several members harbor a variant, p.Pro963Thr, in the C-terminal region of the human-ether-a-go-go (hERG) gene, published to be responsible for cases of LQTS type 2. Functional characterization was undertaken due to the variable phenotype in carriers, the discrepancy with published cases, and the importance of identifying a cause for recurrent deaths in a single family. Studies of the mutated ion channel in in vitro heterologous expression systems revealed that the mutation has no detectable impact on membrane surface expression, biophysical gating properties such as activation, deactivation and inactivation, or the amplitude of the protective current conducted by hERG channels during early repolarization. These observations suggest that the p.Pro963Thr mutation is not a monogenic disease-causing LQTS mutation despite evidence of co-segregation in two siblings affected by SIDS. Our findings demonstrate some of the potential pitfalls in post-mortem molecular testing and the importance of functional testing of gene variants in determining disease-causation, especially where the impacts of cascade screening can affect multiple generations.

Pathobiological expression of the brain-derived neurotrophic factor (BDNF) in cerebellar cortex of sudden fetal and infant death victims

Brain-derived neurotrophic factor (BDNF), a neurotrophin of the central nervous system, is able to regulate neuronal differentiation and modulate synaptic plasticity, being particularly involved in the development of the cerebellar cortical structure. The main aim of this study was to delineate, by immunohistochemistry, the BDNF expression in human cerebellar cortex of victims of fetal and infant death. The study was performed on a total of 45 cases, aged between 25 gestational weeks and 6 postnatal months, including 29 victims of sudden fetal and infant death and 16 age-matched subjects who died of known causes (Controls). We observed, in sudden death groups compared with Controls, a significantly higher incidence of defective BDNF expression in granule layers of the cerebellar cortex, which was particularly evident in the posterior lobule, a region that participates in respiratory control. These results were related to maternal smoking, allowing to speculate that nicotine, in addition to the well-known damages, can exert adverse effects during cerebellar cortex development, in particular in hindering the BDNF expression in the posterior lobule. This implies modifications of synaptic transmission in the respiratory circuits, with obvious deleterious consequences on survival.

Medullary Serotonin Neuron Abnormalities in an Australian Cohort of Sudden Infant Death Syndrome.

Serotonin (5-hydroxytryptamine [5-HT]) neurons in the medulla oblongata project extensively to key autonomic and respiratory nuclei in the brainstem and spinal cord regulating critical homeostatic functions. Multiple abnormalities in markers of 5-HT function in the medulla in sudden infant death syndrome (SIDS) have been reported, informing the hypothesis that at least a subset of SIDS cases is caused by deficits in 5-HT function resulting in impaired homeostatic responses to potentially life-threatening events during sleep. To investigate medullary 5-HT defects in SIDS further, we undertook qualitative analysis immunohistochemical assessment of 5-HT neuron expression within the medulla of SIDS infants (n41) and nonSIDS controls (n = 28) in an independent cohort from Forensic Science South Australia. Compared with controls SIDS cases had significantly higher 5-HT neuron numbers and density in addition to significantly altered 5-HT neuron morphology. Thus, for the first time, we replicated and corroborated previous observations of a significant abnormality in medullary 5-HT neuron expression in SIDS in a separate independent SIDS cohort. This study further supports the hypothesis that medullary 5-HT defects contribute to the pathogenesis of a subset of SIDS victims and provides additional evidence of a more complex abnormality in 5-HT neuron dysfunction specifically within the different caudal and rostral medullary 5-HT domains.

Nicotinic Receptor Abnormalities in the Cerebellar Cortex of Sudden Unexplained Fetal and Infant Death Victims—Possible Correlation With Maternal Smoking

Nicotinic acetylcholine receptors (nAChRs) are cationic channels of the neuronal cell membrane, differentially expressed in the central nervous system which, when activated by endogenous acetylcholine or exogenous nicotine, are able to enhance cholinergic transmission. The aim of this study was to investigate in human perinatal age the immunohistochemical expression of the α7-nAChR subtype, given its involvement in neuronal differentiation and its significant vulnerability to the toxic effects of nicotine. Thirty fetuses (with a gestational age between 25 and 40 weeks) and 35 infants (1–6 months old), suddenly died of known (controls) and unknown causes (unexplained deaths), with smoking and nonsmoking mothers, were included in this study. A negative or low immunoexpression of α7-nAChRs, indicative of their inactivation, was observed in the granular layers of the cerebellar cortex in 66% of the sudden unexplained perinatal deaths and 11% of the controls. A high correlation was also observed between these findings and maternal smoking. Apart from the well-known adverse effects of nicotine exposure during pregnancy, it may also cause significant alterations in cerebellar cholinergic transmission in areas of the brain involved in vital functions. These events may give us insights into the pathogenetic mechanisms leading to sudden unexplained fetal and infant death.

Infant sudden death: Mutations responsible for impaired Nav1.5 channel trafficking and function.

Two genetic variants in SCN5A, encoding the Nav1.5 Na+ channel α-subunit, were found in a 5-month-old girl who died suddenly in her sleep. The first variant is a missense mutation, resulting in an amino acid change (Q1832E), which has been described (but not characterized) in a patient with Brugada syndrome. The second is a nonsense mutation that produces a premature stop codon and a C-terminal truncation (R1944Δ). To investigate their functional relevance with patch clamp experiments in transfected HEK-293 cells. The Q1832E mutation drastically reduced Nav1.5 current density. The R1944Δ C-terminal truncation had negligible effects on Nav1.5 current density. Neither of the mutations affected the voltage dependence of steady activation and inactivation or influenced the late Na+ current or the recovery from inactivation. Biochemical and immunofluorescent approaches demonstrated that the Q1832E mutation caused severe trafficking defects. Polymerase chain reaction cloning and sequencing the victim's genomic DNA allowed us to determine that the two variants were in trans. We investigated the functional consequences by coexpressing Nav1.5(Q1832E) and Nav1.5(R1944Δ), which led to a significantly reduced current amplitude relative to wild-type. These sudden infant death syndrome (SIDS)-related variants caused a severely dysfunctional Nav1.5 channel, which was mainly due to trafficking defects caused by the Q1832E mutation. The decreased current density is likely to be a major contributing factor to arrhythmogenesis in Brugada syndrome and the sudden death of this SIDS victim.

Low cerebrospinal fluid hypocretin levels during sudden infant death syndrome (SIDS) risk period

ObjectivesThe temporal association between sudden infant death syndrome (SIDS) and sleep suggests that the arousability from sleep provides a protective mechanism for survival. Recently, the hypocretin system, which promotes wakefulness, has been implicated in SIDS, since it has been reported that SIDS victims have fewer hypocretin neurons than infants who have died from other causes. To understand the role of hypocretin in SIDS, it is essential to better understand how this system matures. The present study compared cerebrospinal fluid (CSF) hypocretin in children aged 2–6 months, which is the age of peak incidence for SIDS, to both younger and older children. MethodHypocretin levels were measured in CSF samples from 101 children who underwent a clinically relevant lumbar puncture. Children were separated into five age groups: 0–2 months, 2–6 months, 1–5 years, 5–10 years, and 10–18 years. ResultsHypocretin levels were not significantly different between 1–5 years, 5–10 years, and 10–18 years. Therefore, these three groups were pooled into a single one (1–18 years) for further analysis. Between the 0–2 month, 2–6 month, and 1–18 year groups, a significant difference in CSF hypocretin levels existed (p = 0.001). Simple comparisons showed that CSF hypocretin levels in the 2–6 month age group were significantly lower than hypocretin levels in both the 0–2 month and 1–18 year group (p < 0.001 and p = 0.008, respectively), but not significantly between 0–2 month and 1–18 year children. ConclusionsThe CSF hypocretin levels were lower at the age of peak incidence for SIDS. This could underlie an increased vulnerability to SIDS at this specific age.

SIDS-CDF Hypothesis Revisited: Cause vs. Contributing Factors.

The sudden infant death syndrome (SIDS)–critical diaphragm failure (CDF) hypothesis was first published by Siren and Siren in 2011 (1). Since its publication, the hypothesis has continued to generate interest and several colleagues have contributed perspectives and insights to it (2–5). The basic premise of the hypothesis is that the diaphragm is a vital organ that must continuously generate adequate force to maintain ventilation, and that CDF is a terminal event and the cause of death in SIDS. I have argued in two follow-up articles that all SIDS factors either increase the workload of the respiratory muscles, the diaphragm being the primary muscle affected, or reduce its force generating capacity (6, 7). The SIDS–CDF hypothesis posits that SIDS has many contributing factors but only one cause, namely, the failure of the vital respiratory pump. There are several known SIDS factors, such as the prone sleeping position, non-lethal infections, deep sleep, gestational prematurity, low birth weight, cigarette smoke, male gender, and altitude, but of these, some such as the prone sleeping position more significantly both impact diaphragm function and correlate with SIDS. However, SIDS cases are multifactorial and as such can be caused by different combinations of factors. An infection combined with a prone sleeping position and elevated room temperature could lead to SIDS, whereas in other circumstances, low birth weight, cigarette smoke, prone sleeping position, and altitude could result in CDF and SIDS. The SIDS–CDF hypothesis also posits that SIDS does not have a congenital or genetic origin, and that efforts to identify significant genetic anomalies in SIDS victims are unlikely to be successful (8–11).

Metabolomic profiling of brain from infants who died from Sudden Infant Death Syndrome reveals novel predictive biomarkers.

Sudden Infant Death Syndrome (SIDS) is defined as the sudden death of an infant <1 year of age that cannot be explained following a thorough investigation. Currently, no reliable clinical biomarkers are available for the prediction of infants who will die of SIDS. This study aimed to profile the medulla oblongata from postmortem human brain from SIDS victims (n=16) and compare their profiles with that of age-matched controls (n=7). Using LC-Orbitrap-MS, we detected 12 710 features in electrospray ionization positive (ESI+) mode and 8243 in ESI- mode from polar extracts of brain. Five features acquired in ESI+ mode produced a predictive model for SIDS with an area under the receiver operating characteristic curve (AUC) of 1 (confidence interval (CI): 0.995-1) and a predictive power of 97.4%. Three biomarkers acquired in ESI- mode produced a predictive model with an AUC of 0.866 (CI: 0.767-0.942) and a predictive power of 77.6%. We confidently identified 5 of these features (l-(+)-ergothioneine, nicotinic acid, succinic acid, adenosine monophosphate and azelaic acid) and putatively identify another 4 out of the 15 in total. This study underscores the potential value of metabolomics for studying SIDS. Further characterization of the metabolome of postmortem SIDS brains could lead to the identification of potential antemortem biomarkers for novel prevention strategies for SIDS.

Negative Role of the Environmental Endocrine Disruptors in the Human Neurodevelopment.

The endocrine disruptors (EDs) are able to influence the endocrine system, mimicking or antagonizing hormonal molecules. They are bio-persistent for their degradation resistance in the environment. Our research group has investigated by gas chromatography–mass spectrometry (GC–MS) the EDs presence in 35 brain samples, coming from 27 cases of sudden intrauterine unexplained death syndrome (SIUDS) and 8 cases of sudden infant death syndrome (SIDS), collected by centralization in the last year (2015). More in detail, a mixture of 25 EDs has been subjected to analytical procedure, following standard protocols. Among the target analytes, some organochlorine pesticides, that is α-chlordane, γ-chlordane, heptachlor, p,p-DDE, p,p-DDT, and the two most commonly used organophosphorus pesticides (OPPs), chlorpyrifos and chlorfenvinfos, have been found in seven and three samples, respectively. The analytical procedure used to detect the presence of environmental EDs in cortex samples has been successfully implemented on SIUDS and SIDS victims. The environmental EDs have been found to be able to overcome the placental barrier, reaching also the basal ganglia assigned to the control of the vital functions. This finding, related to the OPPs bio-persistence, implies a conceptual redefinition of the fetal–placental and fetal blood–brain barriers: not real safety barriers but simply time-deferral mechanisms of absorption.

Anatomopathological changes of the cardiac conduction system in sudden cardiac death, particularly in infants: advances over the last 25 years.

Sudden cardiac death (SCD) is defined as the unexpected death without an obvious noncardiac cause that occurs within 1 h of witnessed symptom onset (established SCD) or within 24 h of unwitnessed symptom onset (probable SCD). In the United States, its incidence is 69/100,000 per year. Dysfunctions of the cardiac conduction and autonomic nervous systems are known to contribute to SCD pathogenesis, even if most clinicians and cardiovascular pathologists lack experience with detailed examination of the cardiac conduction system and fail to recognize lesions that are crucial to explain the SCD itself. In this review, we sought to describe the advances over the last 25 years in the study of the anatomopathological changes of the conducting tissue, in SCD, in mature hearts and particularly in sudden infant death syndrome (SIDS) and sudden intrauterine unexpected death syndrome (SIUDS), through the articles published in our journal Cardiovascular Pathology (CVP). We carried out an extensive Medline search to retrieve and review all articles published in CVP in which the sudden unexpected death of one or more subjects believed healthy was reported, especially if associated with lesions of the conducting tissue in settings that revealed no other explained causes of death, particularly in infants and fetuses. The cardiac conduction findings of resorptive degeneration, His bundle dispersion, Mahaim fibers, cartilaginous meta-hyperplasia, persistent fetal dispersion, left-sided His bundle, septation of the bifurcation, atrioventricular node dispersion, sinus node hypoplasia, Zahn node, His bundle hypoplasia, atrioventricular node, and His bundle dualism were similarly detected in SIDS and SIUDS victims.

Sudden Infant Death

The association between Long QT syndrome (LQTS) and sudden infant death syndrome (SIDS) remains highly topical and even polarizing.1 Because the landmark Italian study of the QT interval and SIDS2 triggered extensive controversy,3,4 there has been a substantial and commendable effort to establish LQTS as one of the true causes of SIDS.5 The motivation underlying this effort is based on the fact that true LQTS is a potentially preventable cause of sudden death. Many questions, however, remain.6 Where and how does LQTS fit into the spectrum of SIDS? Have we reached the stage where we can describe a typical phenotype for SIDS because of LQTS? Is it conceivable that some SIDS victims die with contribution from a channelopathy genetic variant, rather than because of it in isolation? After SIDS, can we identify those cases that are more likely to have been LQTS and, therefore, warrant genetic testing? When should family clinical screening be undertaken?7 To facilitate clarity of academic discussion, research and clinical care, we suggest a paradigm shift in how to analytically view the LQTS–SIDS association. Over the years there have been multiple working definitions of SIDS including many contradictions.8–10 The definition includes the sudden unexpected death of an infant <1 year of age, with onset of the fatal episode apparently occurring during sleep, that remains unexplained after a thorough investigation, including performance of a complete autopsy and review of the circumstances of death and the clinical history. In the most widely accepted definition, there is a graded classification based predominantly on the thoroughness of the autopsy investigation in excluding potential causes, and the possibility of positional asphyxia.10,11 Type 1 occurs between the ages of 21 days and 9 months in otherwise healthy, normal infants, …

Impact Assessment of Endocrine Disruptors on Sudden Intrauterine and Infant Death Syndromes

Background and Objectives: The endocrine disruptors (EDs) are able to interfere with the endocrine system, mimicking or antagonizing the hormonal activity. They can persist in the environment, due to their degradation resistance. The aim of our research has been to analyze the possible link between unexplained intrauterine and infant mortality and chronic exposure to EDs. Materials and Methods: We have investigated 16 cases of sudden intrauterine unexplained death syndrome (SIUDS) and 8 cases of sudden infant death syndrome (SIDS), collected over a 3-year period (2012-2014). Brain samples were submitted to chemical analysis of 25 EDs, consisting in a liquid-solid extraction procedure, followed by a purification step and by a gas chromatography-mass spectrometry analysis. Results: The analytical method to detect the presence of EDs in brain samples has been successfully applied to SIUDS and SIDS victims. At the level of the brainstem, the frequent association between the hypoplasia of the facial/parafacial complex and the hypoplasia of the raphe system has been ascertained. In particular, the hypodevelopment of the parafacial nucleus, consisting of ‘pre-inspiratory’ neurons with the main function of hierarchical modulation of breathing circuitry, appears an exclusive finding of unexplained stillbirths. Conclusions: The environmental EDs have been found able to cross the placental barrier, reaching also the brain nuclei assigned to the control of vital functions. This is consistent with literature data that report the presence of these selected pollutants in other human tissue. For this reason, environmental EDs should be searched during autopsy in order to establish a possible correlation with unexplained intrauterine and infant deaths.

Developmental alterations of the auditory brainstem centers — Pathogenetic implications in Sudden Infant Death Syndrome

Sudden Infant Death Syndrome (SIDS), despite the success of campaigns to reduce its risks, is the leading cause of infant death in the Western world. Even though the pathogenesis remains unexplained, brainstem abnormalities of the neuronal network that mediates breathing and protective responses to asphyxia, particularly in the arousal phase from sleep, are believed to play a fundamental role. This is the first study to identify, in SIDS, developmental defects of specific brainstem centers involved in hearing pathways, particularly in the cochlear and vestibular nuclei, in the superior olivary complex and in the inferior colliculus, suggesting a possible influence of the acoustic system on respiratory activity. In 49 SIDS cases and 20 controls an in-depth anatomopathological examination of the autonomic nervous system was performed, with the main aim of detecting developmental alterations of brainstem structures controlling both the respiratory and auditory activities. Overall, a significantly higher incidence of cytoarchitectural alterations of both the auditory and respiratory network components were observed in SIDS victims compared with matched controls. Even if there is not sufficient evidence to presume that developmental defects of brainstem auditory structures can affect breathing, our findings, showing that developmental deficit in the control respiratory areas are frequently accompanied by alterations of auditory structures, highlight an additional important element for the understanding the pathogenetic mechanism of SIDS.