ATP1A3 ‐Encoded Sodium‐Potassium ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Bradycardia

Background Pathogenic variation in the ATP1A3 ‐encoded sodium‐potassium ATPase, ATP1A3, is responsible for alternating hemiplegia of childhood (AHC). Although these patients experience a high rate of sudden unexpected death in epilepsy, the pathophysiologic basis for this risk remains unknown. The objective was to determine the role of ATP1A3 genetic variants on cardiac outcomes as determined by QT and corrected QT (QTc) measurements. Methods and Results We analyzed 12‐lead ECG recordings from 62 patients (male subjects=31, female subjects=31) referred for AHC evaluation. Patients were grouped according to AHC presentation (typical versus atypical), ATP1A3 variant status (positive versus negative), and ATP1A3 variant (D801N versus other variants). Manual remeasurements of QT intervals and QTc calculations were performed by 2 pediatric electrophysiologists. QTc measurements were significantly shorter in patients with positive ATP1A3 variant status ( P <0.001) than in patients with genotype‐negative status, and significantly shorter in patients with the ATP1A3‐D801N variant than patients with other variants ( P <0.001). The mean QTc for ATP1A3‐D801N was 344.9 milliseconds, which varied little with age, and remained <370 milliseconds throughout adulthood. ATP1A3 genotype status was significantly associated with shortened QTc by multivariant regression analysis. Two patients with the ATP1A3‐D801N variant experienced ventricular fibrillation, resulting in death in 1 patient. Rare variants in ATP1A3 were identified in a large cohort of genotype‐negative patients referred for arrhythmia and sudden unexplained death. Conclusions Patients with AHC who carry the ATP1A3‐D801N variant have significantly shorter QTc intervals and an increased likelihood of experiencing bradycardia associated with life‐threatening arrhythmias. ATP1A3 variants may represent an independent cause of sudden unexplained death. Patients with AHC should be evaluated to identify risk of sudden death.

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Differential Methylation in the GSTT1 Regulatory Region in Sudden Unexplained Death and Sudden Unexpected Death in Epilepsy

International Journal of Molecular Sciences ◽

10.3390/ijms22062790 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2790

Author(s):

Steffan Noe Christiansen ◽

Stine Bøttcher Jacobsen ◽

Jeppe Dyrberg Andersen ◽

Marie-Louise Kampmann ◽

Linea Christine Trudsø ◽

...

Keyword(s):

Dna Methylation ◽

Cardiac Tissue ◽

Heart Diseases ◽

Regulatory Region ◽

Differential Methylation ◽

Sudden Unexpected Death ◽

Diagnostic Challenge ◽

Unexpected Death ◽

Sudden Unexplained Death ◽

Unexplained Death

Sudden cardiac death (SCD) is a diagnostic challenge in forensic medicine. In a relatively large proportion of the SCDs, the deaths remain unexplained after autopsy. This challenge is likely caused by unknown disease mechanisms. Changes in DNA methylation have been associated with several heart diseases, but the role of DNA methylation in SCD is unknown. In this study, we investigated DNA methylation in two SCD subtypes, sudden unexplained death (SUD) and sudden unexpected death in epilepsy (SUDEP). We assessed DNA methylation of more than 850,000 positions in cardiac tissue from nine SUD and 14 SUDEP cases using the Illumina Infinium MethylationEPIC BeadChip. In total, six differently methylated regions (DMRs) between the SUD and SUDEP cases were identified. The DMRs were located in proximity to or overlapping genes encoding proteins that are a part of the glutathione S-transferase (GST) superfamily. Whole genome sequencing (WGS) showed that the DNA methylation alterations were not caused by genetic changes, while whole transcriptome sequencing (WTS) showed that DNA methylation was associated with expression levels of the GSTT1 gene. In conclusion, our results indicate that cardiac DNA methylation is similar in SUD and SUDEP, but with regional differential methylation in proximity to GST genes.

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1. Sudden Unexplained Death in a Psychiatric Patient – A Case Report: The Role of Phenothiazines and Physical Restraint

Medicine Science and the Law ◽

10.1177/002580249703700214 ◽

1997 ◽

Vol 37 (2) ◽

pp. 170-175 ◽

Cited By ~ 23

Author(s):

Anil Kumar

Keyword(s):

Case Report ◽

Sudden Cardiac Death ◽

Cardiac Death ◽

Psychiatric Patients ◽

Physical Restraint ◽

Unexpected Death ◽

Sudden Unexplained Death ◽

Unexplained Death ◽

The Subject

Psychotropic drug use has long been associated with sudden unexplained and unexpected death in psychiatric patients despite controversies surrounding the issue. Physical restraint following violent episodes in psychiatric in-patients is also associated with neurally mediated sudden cardiac death. A case where these two mechanisms have jointly resulted in sudden death is reported. The literature on the subject is reviewed and the measures which may be useful in reducing the incidence of such deaths are discussed. The need for accurate and detailed reporting of such cases is emphasized.

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Sudden Infant Death Syndrome (SIDS), Sudden Unexpected Death in Infancy (SUDI), and Sudden Unexplained Death in Childhood (SUDC)

Forensic Pathology of Infancy and Childhood ◽

10.1007/978-1-61779-403-2_32 ◽

2014 ◽

pp. 193-206 ◽

Cited By ~ 1

Author(s):

Henry Krous

Keyword(s):

Sudden Infant Death Syndrome ◽

Infant Death ◽

Sudden Infant Death ◽

Sudden Unexpected Death ◽

Sudden Infant ◽

Unexpected Death ◽

Sudden Unexplained Death ◽

Unexplained Death

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Broad-based molecular autopsy: a potential tool to investigate the involvement of subtle cardiac conditions in sudden unexpected death in infancy and early childhood

Archives of Disease in Childhood ◽

10.1136/archdischild-2015-308200 ◽

2015 ◽

Vol 100 (10) ◽

pp. 952-956 ◽

Cited By ~ 16

Author(s):

Montserrat Santori ◽

Alejandro Blanco-Verea ◽

Rocio Gil ◽

Judith Cortis ◽

Katrin Becker ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Genetic Variants ◽

Early Onset ◽

Cardiac Death ◽

Sudden Unexpected Death ◽

Unexpected Death ◽

Molecular Autopsy ◽

Sudden Unexplained Death ◽

Unexplained Death ◽

In Infants And Children

ObjectivesSudden unexplained death in children is a tragic and traumatic event, often worsened when the cause of death cannot be determined. This work aimed to investigate the presence of putative pathogenic genetic variants in a broad spectrum of cardiomyopathy, channelopathy and aortic disease associated genes that may have increased these children's vulnerability to sudden cardiac death.DesignWe performed molecular autopsy of 41 cases of sudden unexplained death in infants and children through massive parallel sequencing of up to 86 sudden cardiac death-related genes. Multiple in silico analyses were conducted together with a thorough review of the literature in order to prioritise the putative pathogenic variants.ResultsA total of 63 variants in 35 cases were validated. The largest proportion of these variants is located within cardiomyopathy genes although this would have been more expected of channelopathy gene variants. Subtle microscopic features of heart tissue may indicate the presence of an early onset cardiomyopathy as a predisposing condition to sudden unexpected death in some individuals.ConclusionsNext-generation sequencing technologies reveal the existence of a wide spectrum of rare and novel genetic variants in sarcomere genes, compared with that of cardiac ion channels, in sudden unexplained death in infants and children. Our findings encourage further investigation of the role of early onset inherited cardiomyopathies and other diseases involving myocardial dysfunction in these deaths. Early detection of variants in these individuals could help to unmask subtle forms of disease within their relatives, who would eventually benefit from better counselling about their genetic history.

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The role of sodium channels in sudden unexpected death in pediatrics

10.1101/383562 ◽

2018 ◽

Author(s):

Anne M. Rochtus ◽

Richard D. Goldstein ◽

Ingrid A. Holm ◽

Catherine A. Brownstein ◽

Eduardo Pérez-Palma ◽

...

Keyword(s):

Amino Acid ◽

Sodium Channel ◽

Cardiac Arrhythmia ◽

Sodium Channels ◽

Acid Sites ◽

Unexpected Death ◽

Channel Gene ◽

Sudden Unexplained Death ◽

Unexplained Death ◽

Protein Model

AbstractSudden Unexpected Death in Pediatrics (SUDP) is a tragic condition with hypothesized multifactorial etiology. While there is recent evidence implicating genes related to cardiac arrhythmia and epilepsy as genetic risk factors contributing to some cases of SUDP, the underlying mechanisms of SUDP remain under active investigation. SUDP encompasses Sudden Infant Death Syndrome (SIDS) and Sudden Unexplained Death in Childhood (SUDC), affecting children under and over 1 year of age, respectively. The presence of developmental hippocampal malformations in many children with SIDS and SUDC suggests that a subset of patients may share epilepsy-related mechanisms with Sudden Unexplained Death in Epilepsy Patients (SUDEP). Pathogenic variants in both epilepsy- and arrhythmia-related sodium channel genes have recently been identified in patients with SIDS, SUDC, and SUDEP.We performed a candidate gene analysis for genes encoding sodium channel subunits in whole exome sequencing (WES) data from 73 SUDP patients. After a thorough literature review, we mapped all reported SUDP-associated sodium channel variants alongside variants from the population on a structural protein model to evaluate whether patient variants clustered in important protein domains compared to controls.In our cohort, 13 variants met criteria for pathogenicity or potential pathogenicity. While SCN1A, SCN1B, and SCN5A have established disease associations, we also considered variants in the paralogs SCN3A, SCN4A and SCN9A. Overall, the patient-associated variants clustered at conserved amino acid sites across the sodium channel gene family that do not tolerate variation in these genes.This study provides a molecular overview of sodium channel variants present in cases with SUDP and reveals key amino acid sites that do not tolerate variation across the SCN paralog family. Further research will lead to an improved understanding of the contribution of sodium channels to SUDP, with a goal of one day implementing prevention strategies to avoid untimely deaths in at-risk children.Author SummaryThe sudden unexplained death of an infant or a child is a tragic event, which is likely caused by the complex interaction of multiple factors. Besides environmental factors, genes related to epilepsy and cardiac arrhythmia have been identified as risk factors. The sodium channel family encompasses genes, related to both cardiac arrhythmia as well as epilepsy, whose proteins share structural homology. We evaluated sodium channel gene variants in our cohort, examined all known variants in sodium genes in SUDP patients from the literature, and mapped patient variants alongside variants from the population on a 3D protein model. The patient variants clustered at conserved amino acid sites with low rates of variation in the general population, not only in the particular gene involved but also in the gene family. This study illustrates that sodium channel variants contribute to the complex phenotype of sudden death in pediatrics, suggesting complex mechanisms of neurologic and/or cardiac dysfunction contributing to death.

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Developmental Changes in Erythrocyte Sodium-Potassium-ATPase (Na,K-ATPase) Subunit Isoform Abundance, ATPase Activity, and Cation-Pump Function in Neonates

Pediatric Research ◽

10.1203/00006450-199904020-00380 ◽

1999 ◽

Vol 45 (4, Part 2 of 2) ◽

pp. 63A-63A

Author(s):

Barna Vasarhelyi ◽

Tivadar Tulassay ◽

Agota Ver ◽

Mariann Dobos ◽

Istvan Seri

Keyword(s):

Atpase Activity ◽

Developmental Changes ◽

Sodium Potassium ◽

Atpase Subunit ◽

Pump Function ◽

Cation Pump ◽

Erythrocyte Sodium ◽

Potassium Atpase

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Bangungot Among Filipino Men: Folk Explanatory Models of Sudden Unexplained Death Syndrome (SUDS)

PsycEXTRA Dataset ◽

10.1037/e635792011-001 ◽

2010 ◽

Author(s):

Satish Kedia ◽

Florencia Palis ◽

Bjarke Oxlund

Keyword(s):

Explanatory Models ◽

Sudden Unexplained Death ◽

Unexplained Death

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Adenosine Receptor Modulation of Hypoxic-ischemic Injury in Striatum of Newborn Piglets

Current Neurovascular Research ◽

10.2174/1567202617999200831152233 ◽

2020 ◽

Vol 17 (4) ◽

pp. 510-517

Author(s):

Santiago Ortega-Gutierrez ◽

Brandy Jones ◽

Alan Mendez-Ruiz ◽

Pankhil Shah ◽

Michel T. Torbey

Keyword(s):

Oxidative Stress ◽

Atpase Activity ◽

Neuronal Injury ◽

Receptor Activation ◽

Adult Mortality ◽

Vehicle Group ◽

Sodium Potassium ◽

Receptor Modulation ◽

A2a Receptor ◽

Potassium Atpase

Background: Hypoxic-ischemic encephalopathy (HIE) is a major cause of pediatric and adult mortality and morbidity. Unfortunately, to date, no effective treatment has been identified. In the striatum, neuronal injury is analogous to the cellular mechanism of necrosis observed during NMethyl- D-Aspartate (NMDA) excitotoxicity. Adenosine acts as a neuromodulator in the central nervous system, the role of which relies mostly on controlling excitatory glutamatergic synapses. Objective: To examine the effect of pretreatment of SCH58261, an adenosine 2A (A2A) receptor antagonist and modulator of NMDA receptor function, following hypoxic-ischemia (HI) on sodium- potassium ATPase (Na+, K+-ATPase) activity and oxidative stress. Methods: Piglets (4-7 days old) were subjected to 30 min hypoxia and 7 min of airway occlusion producing asphyxic cardiac arrest. Groups were divided into four categories: HI samples were divided into HI-vehicle group (n = 5) and HI-A2A group (n = 5). Sham controls were divided into Sham vehicle (n = 5) and Sham A2A (n = 5) groups. Vehicle groups were pretreated with 0.9% saline, whereas A2A animals were pretreated with SCH58261 10 min prior to intervention. Striatum samples were collected 3 h post-arrest. Sodium-potassium ATPase (Na+, K+-ATPase) activity, malondialdehyde (MDA) + 4-hydroxyalkenals (4-HDA) and glutathione (GSH) levels were compared. Results: Pretreatment with SCH58261 significantly attenuated the decrease in Na+, K+-ATPase, decreased MDA+4-HDA levels and increased GSH in the HI-A2A group when compared to HIvehicle. Conclusion: A2A receptor activation may contribute to neuronal injury in newborn striatum after HI in association with decreased Na+, K+-ATPase activity and increased oxidative stress.

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