Sudden Unexplained Nocturnal Death Syndrome: The Hundred Years' Enigma.
Ontology highlight
ABSTRACT:
SUBMITTER: Zheng J
PROVIDER: S-EPMC5866328 | biostudies-literature | 2018 Mar
REPOSITORIES: biostudies-literature
Publications
Sudden Unexplained Nocturnal Death Syndrome: The Hundred Years' Enigma.
Zheng Jingjing J Zheng Da D Su Terry T Cheng Jianding J
Journal of the American Heart Association 20180303 5
Similar Datasets
Project description:AimSudden unexplained nocturnal death syndrome (SUNDS) has been linked to the Brugada syndrome. In some places, acute haemorrhagic pancreatitis is widely held to cause it. We conducted a systematic, controlled autopsy study on Filipino SUNDS victims to rule out structural heart findings as well as acute haemorrhagic pancreatitis as causes.Methods and resultsA case control autopsy study was conducted comparing SUNDS victims between 18 and 50 years of age who died within 1 h of symptom onset with age- and gender-matched controls. There were 24 SUNDS (mean age 34.5 years) and 24 controls (mean 32.7 years). The autopsy incidence of structural heart disease was 8.3% (95% CI (1% to 27%)) and focal pancreatic haemorrhage was 4.17% (95% CI (0.1% to 20%)) but zero for true acute haemorrhagic pancreatitis among SUNDS victims. Autopsy findings in SUNDS versus controls were not significantly different from each other, showing no diagnostic abnormality in any of the organs. There was no significant difference in the incidence of acute haemorrhagic pancreatitis in both the SUNDS and control groups. We did not find fetal dispersion of the atrioventricular (AV) node, sclerosis or fibrosis of the AV conduction system, in a substudy of SUNDS cases.ConclusionsWe have shown that there is no significant difference in the overall autopsy findings between SUNDS and controls. Autopsy findings were normal in 70% of SUNDS; no cardiac structural pathology was found in 87% of cases. Haemorrhagic pancreatitis is the cause of death in a minority of SUNDS. The cardiac conduction system is normal in a subgroup of SUNDS studied.
| S-EPMC4832694 | biostudies-literature
Project description:Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative disorder with unclear etiology. Vinculin (VCL) was linked to sudden arrhythmia death in VCL knockout mice prior to the appearance of cardiomyopathy. We hypothesized VCL mutations underlie risk for SUNDS. A rare heterozygous variant VCL-M94I was found in a SUNDS victim who suffered sudden nocturnal tachypnea and lacked pathogenic variants in known arrhythmia-causing genes. VCL was identified to interact with SCN5A in vitro/vivo. The VCL-M94I was co-expressed with the cardiac sodium channel in HEK293 cells and also overexpressed in induced pluripotent stem cells derived cardiomyocytes (iPSCs-CM). In HEK293 cells with pH 7.4, VCL-M94I caused ~30% decrease in peak sodium current (INa) amplitude compared to WT; under acidotic conditions (pH 7.0) typically found with hypoxia during sleep apnea, M94I resulted in 37% reduction in peak INa compared to WT and the combination of VCL-M94I and pH 7.0 decreased peak INa by ~56% compared to WT at pH 7.4. In iPSCs-CM, similar effects of M94I on reduction of peak INa were observed. This study initially shows both physical and functional interaction between VCL and cardiac sodium channel, and suggests an important role for respiratory acidosis in triggering the fatal arrhythmia underlying SUNDS.
| S-EPMC5317164 | biostudies-literature
Project description:Sudden unexplained nocturnal death syndrome (SUNDS) is a perplexing disorder to both forensic pathologists and clinic physicians. Clinical features of SUNDS survivors suggested that SUNDS is similar to Brugada syndrome (BrS). Leucine-rich repeat containing 10 (LRRC10) gene was a newly identified gene linked to dilated cardiomyopathy, a disease associated with sudden cardiac death. To investigate the prevalence and spectrum of genetic variants of LRRC10 gene in SUNDS and BrS, the coding regions of LRRC10 were genetically screened in 113 sporadic SUNDS victims (from January 2005 to December 2015, 30.7 ± 7.5 years) and ten BrS patients (during January 2010 to December 2014, 38.7 ± 10.3 years) using direct Sanger sequencing. Afterwards, LRRC10 missense variant carriers were screened for a panel of 80 genes known to be associated with inherited cardiac arrhythmia/cardiomyopathy using target-captured next-generation sequencing. In this study, an in silico-predicted malignant LRRC10 mutation p.E129K was detected in one SUNDS victim without pathogenic rare variant in a panel of 80 arrhythmia/cardiomyopathy-related genes. We also provided evidence to show that rare variant p.P69L might contribute to the genetic cause for one SUNDS victim and two BrS family members. This is the first report of genetic screening of LRRC10 in Chinese SUNDS victims and BrS patients. LRRC10 may be a new susceptible gene for SUNDS, and LRRC10 variant was initially and genetically linked to BrS-associated arrhythmia.
| S-EPMC5603906 | biostudies-literature
Project description:Increasing evidence observed in clinical phenotypes show that abrupt breathing disorders during sleep may play an important role in the pathogenesis of sudden unexplained nocturnal death syndrome (SUNDS). The reported Brugada syndrome causing mutation R1512W in cardiac sodium channel α subunit encoded gene SCN5A, without obvious loss of function of cardiac sodium channel in previous in vitro study, was identified as the first genetic cause of Chinese SUNDS by us. The R1512W carrier was a 38-year-old male SUNDS victim who died suddenly after tachypnea in nocturnal sleep without any structural heart disease. To test our hypothesis that slight acidosis conditions may contribute to the significant loss of function of mutant cardiac sodium channels underlying SUNDS, the biophysical characterization of SCN5A mutation R1512W was performed under both extracellular and intracellular slight acidosis at pH 7.0. The cDNA of R1512W was created using site-directed mutagenesis methods in the pcDNA3 plasmid vector. The wild type (WT) or mutant cardiac sodium channel R1512W was transiently transfected into HEK293 cells. Macroscopic voltage-gated sodium current (INa) was measured 24 hours after transfection with the whole-cell patch clamp method at room temperature in the HEK293 cells. Under the baseline conditions at pH 7.4, R1512W (-175 ± 15 pA/pF) showed about 30% of reduction in peak INa compared to WT (-254 ± 23 pA/pF, P < 0.05). Under the acidosis condition at pH 7.0, R1512W (-130 ± 17 pA/pF) significantly decreased the peak INa by nearly 50% compared to WT (-243 ± 23 pA/pF, P < 0.005). Compared to baseline condition at pH 7.4, the acidosis at pH 7.0 did not affect the peak INa in WT (P > 0.05) but decreased peak INa in R1512W (P < 0.05). This initial functional study for SCN5A mutation in the Chinese SUNDS victim revealed that the acidosis aggravated the loss of function of mutant channel R1512W and suggested that nocturnal sleep disorders-associated slight acidosis may trigger the lethal arrhythmia underlying the sudden death of SUNDS cases in the setting of genetic defect.
| S-EPMC4907667 | biostudies-literature
Project description:Sudden unexplained nocturnal death syndrome (SUNDS) is a perplexing disorder to both forensic pathologists and clinic physicians. Desmoplakin (DSP) gene was the first desmosomal gene linked to arrhythmogenic right ventricular cardiomyopathy (ARVC) which was associated with sudden death. To identify the genetic variants of the DSP gene in SUNDS in the southern Chinese Han population, we genetically screened the DSP gene in 40 sporadic SUNDS victims, 16 Brugada syndrome (BrS) patients, and 2 early repolarization syndrome (ERS) patients using next generation sequencing (NSG) and direct Sanger sequencing. A total of 10 genetic variants of the DSP gene were detected in 11 cases, comprised of two novel missense mutations (p.I125F and p.D521A) and eight previously reported rare variants. Of eight reported variants, two were previously considered pathogenic (p.Q90R and p.R2639Q), three were predicted in silico to be pathogenic (p.R315C, p.E1357D and p.D2579H), and the rest three were predicted to be benign (p.N1234S, p.R1308Q, and p.T2267S). This is the first report of DSP genetic screening in Chinese SUNDS and Brugada syndrome. Our results imply that DSP mutations contribute to the genetic cause of some SUNDS victims and maybe a new susceptible gene for Brugada syndrome.
| S-EPMC4951159 | biostudies-literature
Project description:We have identified the cardiomyopathy-susceptibility gene vinculin (VCL) mutation M94I may account for a sudden unexplained nocturnal death syndrome (SUNDS) case. We addressed whether VCL common variant D841H is associated with SUNDS. In 8 of 120 SUNDS cases, we detected an East Asian common VCL variant p.Asp841His (D841H). Comparing the H841 allele frequency of the general population in the local database (15 of 1818) with SUNDS victims (10 of 240) gives an odds ratio for SUNDS of 5.226 (95% CI, 2.321, 11.769). The VCL-D841H variant was engineered and either coexpressed with cardiac sodium channel (SCN5A) in HEK293 cells or overexpressed in human induced pluripotent stem-cell-derived cardiomyocytes to examine its effects on sodium channel function using the whole-cell patch-clamp method. In HEK293 cells, under physiological pH conditions (pH 7.4), D841H caused a 29% decrease in peak INa amplitude compared to wild type (WT), whereas under acidotic conditions (pH 7.0), D841H decreased further to 43% along with significant negative shift in inactivation compared to WT at pH 7.4. In induced pluripotent stem-cell-derived cardiomyocytes, similar effects of D841H on INa were observed. VCL colocalized with SCN5A at the intercalated disk in human cardiomyocytes. VCL was also confirmed to directly interact with SCN5A, and VCL-D841H did not disrupt the association of VCL and SCN5A. A VCL common variant was genetically and biophysically associated with Chinese SUNDS. The aggravation of loss of function of SCN5A caused by VCL-D841H under acidosis supports that nocturnal sleep respiratory disorders with acidosis may play a key role in the pathogenesis of SUNDS.
| S-EPMC5533021 | biostudies-literature
Project description:ObjectiveTo look for previously unrecognized cardiac structural abnormalities and address the genetic cause for sudden unexplained nocturnal death syndrome (SUNDS).MethodsData for 148 SUNDS victims and 444 controls (matched 1:3 on sex, race, and age of death within 1 year) were collected from Sun Yat-sen University from January 1, 1998, to December 31, 2014, to search morphological changes. An additional 17 patients with Brugada syndrome (BrS) collected from January 1, 2006, to December 31, 2014, served as a comparative disease cohort. Target-captured next-generation sequencing for 80 genes associated with arrhythmia/cardiomyopathy was performed in 44 SUNDS victims and 17 patients with BrS to characterize the molecular spectrum.ResultsThe SUNDS victims had slight but statistically significant increased heart weight and valve circumference compared with controls. Twelve of 44 SUNDS victims (SCN5A, SCN1B, CACNB2, CACNA1C, AKAP9, KCNQ1, KCNH2, KCNJ5, GATA4, NUP155, ABCC9) and 6 of 17 patients with BrS (SCN5A, CACNA1C; P>.05) carried rare variants in primary arrhythmia-susceptibility genes. Only 2 of 44 SUNDS cases compared with 5 of 17 patients with BrS hosted a rare variant in the most common BrS-causing gene, SCN5A (P=.01). Using the strict American College of Medical Genetics guideline-based definition, it was found that only 2 of 44 (KCNQ1) SUNDS and 3 of 17 (SCN5A) patients with BrS hosted a "(likely) pathogenic" variant. Fourteen of 44 SUNDS cases with cardiomyopathy-related variants had a subtle but significantly decreased circumference of cardiac valves, and tended to die on average 5 to 6 years younger compared with the remaining 30 cases (P=.02).ConclusionWe present the first comprehensive autopsy evidence that SUNDS victims may have concealed cardiac morphological changes. SUNDS and BrS may result from different molecular pathological underpinnings. The distinct association between cardiomyopathy-related rare variants and SUNDS warrants further investigation.
| S-EPMC5097692 | biostudies-literature
Project description:BackgroundSudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative entity with unclear etiology. Arrhythmia has been implicated in SUNDS. Mutations/deficiencies in intercalated disc components have been shown to cause arrhythmias. Human cardiomyopathy-associated 1 (XIRP1) and 3 (XIRP2) are intercalated disc-associated, Xin repeats-containing proteins. Mouse Xirp1 is necessary for the integrity of intercalated disc and for the surface expression of transient outward and delayed rectifier K+ channels, whereas mouse Xirp2 is required for Xirp1 intercalated disc localization. Thus, XIRP1 and XIRP2 may be potentially causal genes for SUNDS.Methods and resultsWe genetically screened XIRP genes in 134 sporadic SUNDS victims and 22 Brugada syndrome (BrS) cases in a Chinese Han population. We identified 16 rare variants (6 were in silico predicted as deleterious) in SUNDS victims, including a novel variant, XIRP2-E215K. There were also four rare variants (2 were in silico predicted as deleterious) detected in BrS cases, including a novel variant, XIRP2-L2718P. Interestingly, among these 20 variants, we detected 2 likely pathogenic variants: a nonsense variant (XIRP2-Q2875*) and a frameshift variant (XIRP2-T2238QfsX7). Analyzing available Xirp2 knockout mice, we further found that mouse hearts without Xirp2 exhibited prolonged PR and QT intervals, slow conduction velocity, atrioventricular conduction block, and an abnormal infranodal ventricular conduction system. Whole-cell patch-clamp detected altered ionic currents in Xirp2-/- cardiomyocytes, consistent with the observed association between Xirp2 and Nav1.5/Kv1.5 in co-immunoprecipitation.ConclusionsThis is the first report identifying likely pathogenic XIRP rare variants in arrhythmogenic disorders such as SUNDS and Brugada syndrome, and showing critical roles of Xirp2 in cardiac conduction.
| S-EPMC5778954 | biostudies-literature
Project description:There is growing awareness of sudden unexplained death in alcohol misuse (SUDAM) in which there is no obvious cause of death, no evidence of acute alcohol toxicity or alcoholic ketoacidosis, and the heart is morphologically normal. This study describes the characteristics of a cohort with SUDAM from a tertiary cardiovascular referral center and compares the findings with those of individuals who died from sudden arrhythmic death syndrome (SADS). Cases in this retrospective cross-sectional study were identified from a database of referrals to our center spanning approximately 40 years. Cases with recorded heavy use of alcohol and non-alcohol users were selected, then limited to those with SUDAM or SADS aged 16 to 64 years. 62 cases of SUDAM and 41 cases of SADS were identified. The SUDAM group were older than the SADS group; mean age 35.8 years and 27.7 years respectively (P=0.0002). There was also a higher incidence of significant psychiatric illness in SUDAM (19.7%) than SADS (2.4%) cases. Post mortem liver examination was more likely to reveal heavy livers in SUDAM than SADS (2196.1g and 1572.4g respectively; P=0.0033) and more fatty liver change (24.2% and 2.4%). SUDAM tends to occur in individuals who are older and have heavier livers than those with SADS. Psychiatric illness is also more common. SADS, unlike SUDAM, is often associated with heritable channelopathies that may affect surviving family members. Therefore, differentiating between SUDAM and SADS identifies families likely to benefit from screening for these mutations, thus preventing further sudden arrhythmic deaths.
| S-EPMC5554285 | biostudies-other
Project description:Rates of Sudden Unexplained Infant Death (SUID), bronchiolitis, and central apnea increase in winter in temperate climates. Though associations between these three conditions are suggested, more work is required to establish if there is a causal pathway linking bronchiolitis to SUID through inducing central apnea. Utilizing a large population-based cohort of infants studied over a 20-year period (n = 834,595, from birth years 1989-2009)), we analyzed ecological associations between timing of SUID cases, bronchiolitis, and apnea healthcare visits. Data were analyzed between 2013 and 2015. We used a Cox Proportional Hazards model to analyze possible interactions between maternal smoking and maternal asthma with infant bronchiolitis on time to SUID. SUID and bronchiolitis both occurred more frequently in winter. An increase in bronchiolitis clinical visits occurred within a few days prior to apnea visits. We found a temporal relationship between infant bronchiolitis and apnea. In contrast, no peak in SUID cases was seen during peaks of bronchiolitis. Among those without any bronchiolitis visits, maternal smoking was associated with an increased risk of SUID: Hazard Ratio (HR) of 2.38 (95% CI: 2.11, 2.67, p-value <0.001). Maternal asthma was associated with an increased risk of SUID among infants with at least one bronchiolitis visit: HR of 2.40 (95% CI: 1.04, 5.54, p-value = 0.04). Consistent trends between bronchiolitis, apnea, and SUID were not established due to small numbers of SUID cases. However, interaction analysis revealed potential differential associations of bronchiolitis and SUID by maternal smoking, maternal asthma status.
| S-EPMC4942135 | biostudies-literature