Sudden Infant Death Syndrome Patients Research Articles

X-linked serotonin 2C receptor is associated with a non-canonical pathway for sudden unexpected death in epilepsy.

Sudden Unexpected Death in Epilepsy is a leading cause of epilepsy-related mortality, and the analysis of mouse Sudden Unexpected Death in Epilepsy models is steadily revealing a spectrum of inherited risk phenotypes based on distinct genetic mechanisms. Serotonin (5-HT) signalling enhances post-ictal cardiorespiratory drive and, when elevated in the brain, reduces death following evoked audiogenic brainstem seizures in inbred mouse models. However, no gene in this pathway has yet been linked to a spontaneous epilepsy phenotype, the defining criterion of Sudden Unexpected Death in Epilepsy. Most monogenic models of Sudden Unexpected Death in Epilepsy invoke a failure of inhibitory synaptic drive as a critical pathogenic step. Accordingly, the G protein-coupled, membrane serotonin receptor 5-HT2C inhibits forebrain and brainstem networks by exciting GABAergic interneurons, and deletion of this gene lowers the threshold for lethal evoked audiogenic seizures. Here, we characterize epileptogenesis throughout the lifespan of mice lacking X-linked, 5-HT2C receptors (loxTB Htr2c). We find that loss of Htr2c generates a complex, adult-onset spontaneous epileptic phenotype with a novel progressive hyperexcitability pattern of absences, non-convulsive, and convulsive behavioural seizures culminating in late onset sudden mortality predominantly in male mice. RNAscope localized Htr2c mRNA in subsets of Gad2+ GABAergic neurons in forebrain and brainstem regions. To evaluate the contribution of 5-HT2C receptor-mediated inhibitory drive, we selectively spared their deletion in GAD2+ GABAergic neurons of pan-deleted loxTB Htr2c mice, yet unexpectedly found no amelioration of survival or epileptic phenotype, indicating that expression of 5-HT2C receptors in GAD2+ inhibitory neurons was not sufficient to prevent hyperexcitability and lethal seizures. Analysis of human Sudden Unexpected Death in Epilepsy and epilepsy genetic databases identified an enrichment of HTR2C non-synonymous variants in Sudden Unexpected Death in Epilepsy cases. Interestingly, while early lethality is not reflected in the mouse model, we also identified variants mainly among male Sudden Infant Death Syndrome patients. Our findings validate HTR2C as a novel, sex-linked candidate gene modifying Sudden Unexpected Death in Epilepsy risk, and demonstrate that the complex epilepsy phenotype does not arise solely from 5-HT2C-mediated synaptic disinhibition. These results strengthen the evidence for the serotonin hypothesis of Sudden Unexpected Death in Epilepsy risk in humans, and advance current efforts to develop gene-guided interventions to mitigate premature mortality in epilepsy.

Intact Numbers of Cerebellar Purkinje and Granule Cells in Sudden Infant Death Syndrome

Despite much research during recent decades, the etiology and pathogenesis of sudden infant death syndrome (SIDS) remain unknown. Because of the role of the cerebellum in respiratory and cardiovascular control, it has been proposed that it plays an important role in the pathogenesis of SIDS. To date, 5 postmortem studies on the cerebellum of SIDS cases have yielded conflicting results. Using a rigorous design-based stereologic approach, we investigated postmortem cerebella from 9 SIDS patients who died between 2 and 10 months of age and from 9 age- and sex-matched control children. Neither the volumes of the cerebellar external granule cell layer, molecular layer, internal granule cell layer (including the Purkinje cell layer), and white matter nor the total numbers of Purkinje cells, granule cells in the internal granule cell layer, and the number of granule cells per Purkinje cell showed statistically significant differences between the SIDS cases and the controls. Based on these observations, we conclude that structural alterations in cerebellar development are not involved in the etiology and pathogenesis of SIDS.

Panhypopituitarism, a Cause of Early Sudden Infant Death Syndrome?

Panhypopituitarism can manifest itself with variable signs and symptoms, and in some cases it may be responsible for serious events such as cardio-respiratory insufficiency and hypoglycemia which can be fatal. It can be assumed that a condition of panhypopituitarism can cause early sudden death that occurs in the first hours of life. For this reason it is important that the post mortem examination in SIDS (Sudden Infant Death Syndrome) patients includes the study of the pituitary gland. We present a newborn with panhypopituitarism, in which the onset was dramatic, with severe cardio-respiratory insufficiency and severe hypoglycemia and only the accidentally detection by midwives was life saving. Array CGH analysis showed a microdeletion of chromosome 5q34, including part of the intronic region of the gene ODZ2 inherited from the mother, not related to the patient’s symptoms so far.

Significant Association of TH01 Allele 9.3 and SIDS

Sudden infant death syndrome (SIDS) constitutes a considerable percentage of infant death of unknown etiology. Individual catecholamine response variation is suspected to play a role in SIDS. TH01 is a tetrameric short tandem repeat marker in the tyrosine hydroxylase gene, which regulates gene expression and catecholamine production with allele 9.3 exerting a particularly strong effect on noradrenaline production. We investigated in an age-controlled study the TH01 allele frequencies in 127 cases of SIDS and 406 control cases to assess whether in SIDS cases a distinct TH01 allele distribution could be determined as has been reported by a previous study. We found that genotypes containing one or two 9.3 alleles were significantly more frequent in SIDS patients (58.2%) than in control subjects (48.4%, p=0.038), whereas all other alleles were more frequent in the control subjects. Our findings support the notion that there exists a significant association between TH01 gene configuration and SIDS.

Airway dimensions in bronchopulmonary dysplasia: Implications for airflow obstruction

The cause of lung function abnormalities in bronchopulmonary dysplasia (BPD) is incompletely understood, even in the "new era" of this disease. Altered airway wall dimensions are important in the pathogenesis of airflow obstruction in diseases such as asthma and chronic obstructive pulmonary disease. Whether airway wall dimensions contribute to lung function abnormalities in BPD is unknown. The purpose of this study was to investigate airway wall dimensions in relation to airway size in BPD. Lung tissue of patients with BPD was obtained at autopsy, and lung tissue from children who died from sudden infant death syndrome (SIDS) served as control. Airway wall dimensions and epithelial loss were measured in 75 airways from 5 BPD patients and 176 airways from 11 SIDS patients. Repeated measures analysis of variance was used to assess the relationships between airway wall dimensions and airway size for BPD and SIDS patients. Little epithelial loss was present in the BPD patients while extensive loss was observed in some of the SIDS patients. The inner wall area, outer wall area, epithelium area and smooth muscle area were all substantially larger (all P < 0.001) in BPD than in SIDS patients. It is likely that the increased thickness of the airway wall components contributes to airflow obstruction in BPD patients.

Presentation andSurvival of Prehospital Apparent Sudden Infant Death Syndrome

Background. Prehospital providers are often involved in the resuscitation of apparent sudden infant death syndrome (SIDS) victims; however, data are few on the presentation andoutcome of these patients.Objectives. To describe the presentation anddetermine the survival rate of infants who have an unwitnessed, prehospital arrest consistent with SIDS (apparent SIDS), andto compare the presentation of infants with a final diagnosis of SIDS with those who presented as apparent SIDS but had a different final diagnosis.Methods. This was a secondary analysis of data from a controlled trial whose methodology has been previously described. The setting was two large, urban emergency medical services (EMS) systems of Los Angeles andOrange Counties, California. The population included 113 apparent SIDS victims from the original interventional study who had a prehospital, unwitnessed arrest consistent with SIDS, defined by the scenario of an infant aged ≤12 months being placed to sleep andlater found in full arrest (pulseless andapneic). Data collected included ethnicity, gender, arrest etiology, signs of death (lividity, rigor mortis), prehospital interventions, return of spontaneous circulation (ROSC), arrest rhythm, code 3 transport (lights andsirens), andsurvival to hospital discharge.Results. One hundred ten of 113 apparent SIDS patients had survival data; 0 of 110 (95% CI 0% to 3.3%) survived, although ROSC was achieved in 5%; for three patients data on survival were missing. Arrest rhythms were determined in 94% of the subjects: asystole 87%, pulseless electrical activity (PEA) 8%, andventricular fibrillation 4%. Only 50 of 113 (44%) of the EMS records documented code 3 transport; the remainder of the records were ambiguous. SIDS was the final coroner's diagnosis for 79 of 113 (70%) of the cases. Other causes of death in these apparent SIDS victims included respiratory causes (12%), asphyxiation (3%), abuse (2%), congenital heart disease (2%), sepsis (2%), other (4%), andunknown (5%). Apparent SIDS victims with a final diagnosis of SIDS were more likely to show signs of death (27/79, 34% vs. 5/34, 15%, p = 0.035) andwere less likely to have a rhythm of PEA (4/77, 5% vs. 5/31, 16%, p = 0.08), although the latter result was not statistically significant.Conclusions. Apparent SIDS victims have a dismal prognosis; all infants presenting with apparent SIDS died, even the 30% whose final diagnosis was not SIDS. Given that there were no survivors, new prehospital policies are needed governing the use of lights andsirens, resuscitation decisions including termination of resuscitation, provision of grief support to families, andincident stress debriefing for prehospital personnel.

Il-10 gene polymorphisms are associated with infectious cause of sudden infant death

Cytokines are involved in regulating the intensity and duration of the immune response, and cytokine production is carefully regulated. With regard to sudden infant death, interleukin-10 (IL-10) is of special interest. This is an immunregulatory cytokine that plays an important role in the development of infectious disease. The purpose of this study was to elucidate the relationship between polymorphisms in the promoter region of the IL-10 gene and sudden infant death due to either sudden infant death syndrome (SIDS) or infection. The polymorphisms investigated include the SNPs in base pairs (bp) -1082, -819, -592, and the two microsatellites IL-10G and IL-10R. The main finding is an association between the ATA haplotype and the ATA/ATA genotype and infectious death. The group of infectious deaths also had a higher percentage of the genotypes G21/G22 and G21/G23, compared with the SIDS patients. In addition, G21/G22 was found in a higher percentage of the SIDS patients than in the controls. These findings lead us to speculate that, in some situations, an infant with an unfavorable IL-10 genotype may exhibit aberrant IL-10 production, which in turn leads to an imbalance in the immune response and renders the infant unable to cope with the infection.

Possible role of mtDNA mutations in sudden infant death

Variation in hypervariable region I (HVR-I) and mutations in coding areas of mtDNA were studied in 257 patients of sudden infant death caused by infections, sudden infant death syndrome (SIDS), and borderline SIDS and in a control group of 102 living infants. Nine different point mutations were detected in the coding areas investigated: T3290C, T3308C, T3308G (three patients), A9299G (two patients), G9300A (two patients), T10034C (nine patients), A10042T, C10043T, and A10044G. An association was found between a high number of HVR-I substitutions and potentially pathogenic mtDNA point mutations in coding areas ( P = 0.024, odds ratio = 1.3). The mean number of substitutions in HVR-I was 3.28 in the infectious death group, 2.63 in the borderline SIDS group, 2.58 in the SIDS group, and 2.02 in the control group ( P = 0.005). In coding areas, 11.1% of the infectious death patients had a mutation, and the same was true for 9.8% of the borderline SIDS patients, 5.6% of the SIDS patients, and 2.9% of the control subjects ( P = 0.21). The results indicate that increased levels of HVR-I substitutions may be an indicator of mtDNA instability. Furthermore, mtDNA mutations may play a role in some patients with sudden unexpected infant death that was unexplained or thought to be caused by infection.

Adventitial changes in pulmonary vasculature in congenital diaphragmatic hernia complicated by pulmonary hypertension

Purpose: The purpose of this study was to characterize structural changes in the pulmonary vasculature in congenital diaphragmatic hernia (CDH) complicated by persistent pulmonary hypertension (PPH) with particular emphasis on adventitial thickness. Methods: Victorian blue Van Gieson (VVG) staining and immunostaining with antialpha smooth muscle actin (ASMA) were performed on lung tissues obtained at autopsy from 23 patients with CDH complicated by PPH and 11 age-matched control tissues of sudden infant death syndrome patients (SIDS). The degree of medial and adventitial thickening was measured in pulmonary arteries with an external diameter (ED) of less than 75 μm, 75 to 100 μm, 100 to 150 μm, 150 to 250 μm, 250 to 500 μm, and greater than 500 μm by IPS-4.01 image analyzer and compared statistically. The degree of medial thickening and adventitial thickening was also measured in pulmonary veins with an ED of less than 100 μm, 100 to 200 μm, and greater than 200 μm. To determine whether the characteristic structural changes were size related, each was related to ED. The area of adventitia and media of the pulmonary arteries and veins was measured using image analyzer. Results: There was a significant increase in medial and adventitial thickness in arteries of all sizes in CDH patients compared with controls ( P < .01). The degree of adventitial area was significantly increased for arteries of all sizes ( P < .01) and the degree of medial area was significantly increased only for arteries less than 100 μm size ( P < .05) in CDH patients compared with controls. Calculation of the areas of the various components in the wall of each artery showed that for small arteries (<100 μm ED), the area of the lumen was smaller, and the areas of the media and adventitia were larger in CDH patients compared with controls ( P < .01). There was a significant increase in adventitial thickness and area in veins of all sizes in CDH patients compared with controls ( P < .01). The adventitial thickness of pulmonary veins were ED of less than 100 μm: CDH, 13.5 μm ± 3.5; control, 9.21 μm ± 2.0; ED 100 to 200 μm: CDH, 21.3 μm ± 7.5; control, 13.0 μm ± 4.8; ED greater than 200 μm: CDH, 34.4 μm ± 12.5; control, 22.3 μm ± 4.2. Conclusions: The present study provides the first quantitative demonstration of structural alterations in pulmonary veins in addition to pulmonary arteries in CDH complicated by PPH. The structural remodeling of the pulmonary vein is perhaps as a result of an increase in transvascular pressure in PPH.

Active collagen synthesis by pulmonary arteries in pulmonary hypertension complicated by congenital diaphragmatic hernia

The high mortality rate for patients with congenital diaphragmatic hernia (CDH) has been attributed to pulmonary hypoplasia and persistent pulmonary hypertension (PPH). The factors that cause vasoconstriction and vascular remodeling in PPH are not fully understood. Immunohistochemistry was performed on lung tissue obtained from postmortem CDH patients with pulmonary hypoplasia and PPH (n = 21) using the following antibodies: alpha smooth muscle-actin (ASMA), transforming growth factor-beta (TGF-β), isoform specific (TGF-β 1, -β 2, -β 3), and M-57. Normal lung tissues from age-matched sudden infant death syndrome patients (SIDS, n = 8) were obtained as controls. TGF-β 3 immunoreactivity was observed in the adventitia but not in the media of pulmonary muscular arteries in patients with CDH. TGF-β 1, -β 2 immunoreactivity was either absent or faintly expressed in pulmonary arteries in CDH patients. No TGF-β staining was observed in the pulmonary vasculature of SIDS patients. Newly synthesized procollagen (M-57) was easily detected in the media and adventitia in a large number of pulmonary arteries in all patients with CDH and in the neointima in two patients with long standing PPH. No M-57 staining was seen in the media of pulmonary arteries of the lungs of SIDS patients. These observations suggest a potential role of TGF-β 3 but not TGF-β 1 or TGF-β 2 in pulmonary vascular remodeling and that smooth muscle cells in muscular pulmonary arteries are actively synthesizing collagen in patients with CDH complicated by PPH.

Vagal nerve complex in normal development and sudden infant death syndrome.

Although the pathogenesis of sudden infant death syndrome (SIDS) is not understood, one of the major hypotheses is that a subtle defect in respiratory circuitry is an important underlying factor. The vagus nerve is a critical component of respiratory control, but its neuroanatomic complexity has limited its investigation in human disease. Correlating developmental studies on different parts of the vagus nerve allows a more comprehensive assessment of its maturation process. Comparison of the normal developing vagus nerve with nerves examined in SIDS patients suggests alterations in the nucleus tractus solitarius and dorsal vagal nucleus as well as in the peripheral vagus nerve. The persistence of dendritic spines and lack of appropriate axonal growth implies delays in vagal maturation. Since nodose ganglia can be examined in vitro from autopsy material, perturbation to this system can be explored to evaluate further the mechanism involved in terminal vagal maturation. Although the reason for the delayed vagal maturation in SIDS is not apparent, the presence of astrogliosis in the region of the vagal nuclei is consistent with an exposure to hypoxic-ischemic events some time before death.

Scottish frequency of the common G985 mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene and the role of MCAD deficiency in sudden infant death syndrome (SIDS).

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, is an autosomal recessive inborn error of metabolism associated with various clinical presentations, including sudden unexplained death in young children. We have determined the Scottish frequency of the common G985 mutation found in Caucasians and in samples from Scottish patients with sudden infant death syndrome (SIDS). The heterozygote frequency of the mutation was found to be 1 in 276 (95% confidence interval: 1/76-1/2279) in 552 healthy controls and 1 in 74 (95% confidence interval: 1/27-1/377) in 233 SIDS patients: a difference that was not statistically significant (Fisher's exact test; two-sided; p = 0.316). None of the SIDS samples was found to be homozygous for the G985 mutation.

Neurological maladaptation in the neonate

The development of neuronal dentrites dramatically changes in the medullary respiratory centers from prenatal to postnatal periods. The number of spines increases with gestation and decreases rapidly afterbirth in controls, but persist in sudden infant death syndrome patients. These abnormalities including neurotransmitters may cause a maladaptation in the development of cardiorespiratory control.

Ultrastructural Abnormalities of the Carotid Body in Sudden Infant Death Syndrome

The carotid bodies of four infants who died of sudden infant death syndrome (SIDS) were compared, using electron microscopic techniques, with the carotid bodies of various control subjects. In the SIDS patients, there was a marked reduction or absence of the dense cytoplasmic granules of the carotid chemorecptor cells, as well as a reduction in cell number and size. These ultrastructural abnormalities may be pathophysiologically related to SIDS. A defect in this respiratory control organ could block normal stimulation of respiration during the periods of hypoxia that occur during episodes of sleep apnea in infancy. Further studies by electron microscopy are required to confirm degranulation of the carotid body as a pathognomonic sign of SIDS. Screening of high-risk infants should be directed at studying the carotid body and its mediated responses to hypoxia.

Studies of the Sudden Infant Death Syndrome in King County, Washington

Since January 1965, a study of the sudden infant death syndrome (SIDS) in King County, Washington, has been conducted. Between August 1966 and June 1968, major changes in the protocol included the study of SIDS patients and controls as soon as possible after death, with extensive respiratory sampling, and strict avoidance of freezing of specimens before inoculation into tissue cultures. With use of this protocol, "significant" (nonpoliovirus) isolates were found in 37.5% of SIDS cases and in only 16.2% of controls. A diversity of serotypes was found. Viruses may have a significant role in the pathogenesis of SIDS, and some serotypes may have relatively greater importance than others. However, until the pathogenesis of this syndrome is more clearly defined, the relative significance of any single factor must remain speculative.