Sudden cardiac death among workers: a systematic review and meta-analysis.

OBJECTIVE: Sudden cardiac death (SCD) is a rare and yet unexplained condition. The most frequent cause is myocardial infarction, while a small proportion is due to arrhythmogenic syndromes (e.g., channelopathies). This systematic review and meta-analysis aimed to provide a comprehensive overview of the prevalence and risk factors associated with SCD in workers. MATERIAL AND METHODS: A search for eligible studies was performed utilizing three databases (PubMed, ISI Web of Knowledge, and Scopus). The inclusion criteria were fulfilled if sudden cardiac death due to channelopathy in workers was mentioned. RESULTS: Out of the 1408 articles found across three databases, 6 articles were included in the systematic review but the meta-analysis was conducted on 3 studies The total sample included was 23,450 participants. The pooled prevalence of channelopathies in employees was 0.3% (95% CI 0.07-0.43%), of sudden cardiac death in employees was 2.8% (95% CI 0.37-5.20%), and of sudden cardiac death in employees with a diagnosis of cardiac channelopathies was 0.2% (95% CI 0.02- 0.30%). CONCLUSIONS: SCD is a serious and potentially preventable condition that can occur among workers. By identifying and addressing work-related risk factors, providing appropriate screening and interventions, and promoting healthy lifestyle behaviors, we can work to reduce the incidence of SCD and improve the cardiovascular health and well-being of workers.

Primary Electrical Heart Disease-Principles of Pathophysiology and Genetics.

Primary electrical heart diseases, often considered channelopathies, are inherited genetic abnormalities of cardiomyocyte electrical behavior carrying the risk of malignant arrhythmias leading to sudden cardiac death (SCD). Approximately 54% of sudden, unexpected deaths in individuals under the age of 35 do not exhibit signs of structural heart disease during autopsy, suggesting the potential significance of channelopathies in this group of age. Channelopathies constitute a highly heterogenous group comprising various diseases such as long QT syndrome (LQTS), short QT syndrome (SQTS), idiopathic ventricular fibrillation (IVF), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and early repolarization syndromes (ERS). Although new advances in the diagnostic process of channelopathies have been made, the link between a disease and sudden cardiac death remains not fully explained. Evolving data in electrophysiology and genetic testing suggest previously described diseases as complex with multiple underlying genes and a high variety of factors associated with SCD in channelopathies. This review summarizes available, well-established information about channelopathy pathogenesis, genetic basics, and molecular aspects relative to principles of the pathophysiology of arrhythmia. In addition, general information about diagnostic approaches and management is presented. Analyzing principles of channelopathies and their underlying causes improves the understanding of genetic and molecular basics that may assist general research and improve SCD prevention.

Disrupted Neural Regeneration in Dry Eye Secondary to Ankylosing Spondylitis-With a Theoretical Link between Piezo2 Channelopathy and Gateway Reflex, WDR Neurons, and Flare-Ups.

This study aimed at analyzing the corneal neural regeneration in ankylosing spondylitis patients using in vivo corneal confocal microscopy in correlation with Langerhans cell density, morphology, and dry eye parameters. Approximately 24 ankylosing spondylitis subjects and 35 age- and gender-matched control subjects were enrolled. Data analysis showed that all corneal nerve-fiber descriptives were lower in the ankylosing spondylitis group, implicating disrupted neural regeneration. Peripheral Langerhans cell density showed a negative correlation with nerve fiber descriptions. A negative correlation between tear film break-up time and corneal nerve fiber total branch density was detected. The potential role of somatosensory terminal Piezo2 channelopathy in the pathogenesis of dry eye disease and ankylosing spondylitis is highlighted in our study, exposing the neuroimmunological link between these diseases. We hypothesized earlier that spinal neuroimmune-induced sensitization due to this somatosensory terminal primary damage could lead to Langerhans cell activation in the cornea, in association with downregulated Piezo1 channels on these cells. This activation could lead to a Th17/Treg imbalance in dry eye secondary to ankylosing spondylitis. Hence, the corneal Piezo2 channelopathy-induced impaired Piezo2-Piezo1 crosstalk could explain the disrupted neural regeneration. Moreover, the translation of our findings highlights the link between Piezo2 channelopathy-induced gateway to pathophysiology and the gateway reflex, not to mention the potential role of spinal wide dynamic range neurons in the evolution of neuropathic pain and the flare-ups in ankylosing spondylitis and dry eye disease.

From Death to Life/Back to the Future: Detailed Premorbid Clinical and Family History Can Save Lives and Address the Final Diagnosis in Sudden Unexplained Deaths With Negative Autopsy.

Sudden cardiac death is a sudden, unexpected death developed by one of the many different causes of cardiac arrest that occur within 1 hour of the onset of new symptoms. Sudden unexplained death (SUD) comprises a normal heart at postmortem examination and negative toxicological analysis. SUD often arises from cardiac genetic disease, particularly channelopathies. Channelopathies, or inherited arrhythmia syndromes, are a group of disorders characterized by an increased risk of sudden cardiac death, abnormal cardiac electrical function, and, typically, a structurally normal heart. They share an underlying genetic etiology where disease-causing genetic variants may lead to the absence or dysfunction of proteins involved in the generation and propagation of the cardiac action potential. Our study aimed to evaluate the importance of next-generation sequencing in the postmortem investigations of SUD cases. In this study, 5 forensic SUD cases were investigated for inherited cardiac disorders. We screened a total of 68 cardiac genes for the sibling of case 1, as well as case 2, and 51 genes for cases 3, 4, and 5. Of the 12 variants identified, 2 likely pathogenic variants (16.7%) were the TMEM43 _ c.1000+2T>C splice site mutation and the SCN5A _ p.W703X nonsense mutation. The remaining 10 variants of uncertain significance were detected in the TRPM4 , RANGRF , A KAP9 , KCND3 , KCNE1 , DSG2 , CASQ1 , and SNTA1 genes. Irrespective of genetic testing, all SUD families require detailed clinical testing to identify relatives who may be at risk. Molecular autopsy and detailed premorbid clinical and family histories can survive family members of SUD cases.

Modern subcutaneous implantable defibrillator therapy in patients with cardiomyopathies and channelopathies: data from a large multicentre registry.

AIMS: Patients with cardiomyopathies and channelopathies are usually younger and have a predominantly arrhythmia-related prognosis; they have nearly normal life expectancy thanks to the protection against sudden cardiac death provided by the implantable cardioverter defibrillator (ICD). The subcutaneous ICD (S-ICD) is an effective alternative to the transvenous ICD and has evolved over the years. This study aimed to evaluate the rate of inappropriate shocks (IS), appropriate therapies, and device-related complications in patients with cardiomyopathies and channelopathies who underwent modern S-ICD implantation. METHODS AND RESULTS: We enrolled consecutive patients with cardiomyopathies and channelopathies who had undergone implantation of a modern S-ICD from January 2016 to December 2020 and who were followed up until December 2022. A total of 1338 S-ICD implantations were performed within the observation period. Of these patients, 628 had cardiomyopathies or channelopathies. The rate of IS at 12 months was 4.6% [95% confidence interval (CI): 2.8-6.9] in patients with cardiomyopathies and 1.1% (95% CI: 0.1-3.8) in patients with channelopathies (P = 0.032). No significant differences were noted over a median follow-up of 43 months [hazard ratio (HR): 0.76; 95% CI: 0.45-1.31; P = 0.351]. The rate of appropriate shocks at 12 months was 2.3% (95% CI: 1.1-4.1) in patients with cardiomyopathies and 2.1% (95% CI: 0.6-5.3) in patients with channelopathies (P = 1.0). The rate of device-related complications was 0.9% (95% CI: 0.3-2.3) and 3.2% (95% CI: 1.2-6.8), respectively (P = 0.074). No significant differences were noted over the entire follow-up. The need for pacing was low, occurring in 0.8% of patients. CONCLUSION: Modern S-ICDs may be a valuable alternative to transvenous ICDs in patients with cardiomyopathies and channelopathies. Our findings suggest that modern S-ICD therapy carries a low rate of IS. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/Identifier: NCT02275637.

Precision Medicine and Cardiac Channelopathies: Human iPSCs Take the Lead.

Sudden cardiac death (SCD) is one of the leading causes of death worldwide, usually involving young people. SCD remains a critical public health problem accounting for 185,000-450,000 deaths annually, representing around 7%-18% of all deaths globally. As per evidence, ∼2%-54% of sudden unexpected deaths in people under the age of 35 years fail to show evidence of structural cardiac abnormalities at autopsy, making ion channelopathies the probable causes in such cases. The most generally recognized cardiac ion channelopathies with genetic testing are long QT syndrome (LQTS), Brugada syndrome (BrS), short QT syndrome (SQTS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). The substantial progress in understanding the genetics of ion channelopathies in the last 2 decades has obliged the early diagnosis and prevention of SCD to a certain extent. In this review, we analyze the critical challenges and recent advancements in the identification, risk stratification, and clinical management of potentially fatal cardiac ion channel disorders. We also emphasize the application of precision medicine (PM) and artificial intelligence (AI) for comprehending the underlying genetic mechanisms, especially the role of human induced pluripotent stem cell (iPSC) based platforms to unravel the primary refractory clinical problems associated with channelopathies.

Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy.

The KCNA1 gene encodes Kv1.1 voltage-gated potassium channel α subunits, which are crucial for maintaining healthy neuronal firing and preventing hyperexcitability. Mutations in the KCNA1 gene can cause several neurological diseases and symptoms, such as episodic ataxia type 1 (EA1) and epilepsy, which may occur alone or in combination, making it challenging to establish simple genotype-phenotype correlations. Previous analyses of human KCNA1 variants have shown that epilepsy-linked mutations tend to cluster in regions critical for the channel's pore, whereas EA1-associated mutations are evenly distributed across the length of the protein. In this review, we examine 17 recently discovered pathogenic or likely pathogenic KCNA1 variants to gain new insights into the molecular genetic basis of KCNA1 channelopathy. We provide the first systematic breakdown of disease rates for KCNA1 variants in different protein domains, uncovering potential location biases that influence genotype-phenotype correlations. Our examination of the new mutations strengthens the proposed link between the pore region and epilepsy and reveals new connections between epilepsy-related variants, genetic modifiers, and respiratory dysfunction. Additionally, the new variants include the first two gain-of-function mutations ever discovered for KCNA1, the first frameshift mutation, and the first mutations located in the cytoplasmic N-terminal domain, broadening the functional and molecular scope of KCNA1 channelopathy. Moreover, the recently identified variants highlight emerging links between KCNA1 and musculoskeletal abnormalities and nystagmus, conditions not typically associated with KCNA1. These findings improve our understanding of KCNA1 channelopathy and promise to enhance personalized diagnosis and treatment for individuals with KCNA1-linked disorders.

Evidence of Disruption in Neural Regeneration in Dry Eye Secondary to Rheumatoid Arthritis.

The purpose of our study was to analyze abnormal neural regeneration activity in the cornea through means of confocal microscopy in rheumatoid arthritis patients with concomitant dry eye disease. We examined 40 rheumatoid arthritis patients with variable severity and 44 volunteer age- and gender-matched healthy control subjects. We found that all examined parameters were significantly lower (p < 0.05) in rheumatoid arthritis patients as opposed to the control samples: namely, the number of fibers, the total length of the nerves, the number of branch points on the main fibers and the total nerve-fiber area. We examined further variables, such as age, sex and the duration of rheumatoid arthritis. Interestingly, we could not find a correlation between the above variables and abnormal neural structural changes in the cornea. We interpreted these findings via implementing our hypotheses. Correspondingly, one neuroimmunological link between dry eye and rheumatoid arthritis could be through the chronic Piezo2 channelopathy-induced K2P-TASK1 signaling axis. This could accelerate neuroimmune-induced sensitization on the spinal level in this autoimmune disease, with Langerhans-cell activation in the cornea and theorized downregulated Piezo1 channels in these cells. Even more importantly, suggested principal primary-damage-associated corneal keratocyte activation could be accompanied by upregulation of Piezo1. Both activation processes on the periphery would skew the plasticity of the Th17/Treg ratio, resulting in Th17/Treg imbalance in dry eye, secondary to rheumatoid arthritis. Hence, chronic somatosensory-terminal Piezo2 channelopathy-induced impaired Piezo2-Piezo1 crosstalk could result in a mixed picture of disrupted functional regeneration but upregulated morphological regeneration activity of these somatosensory axons in the cornea, providing the demonstrated abnormal neural corneal morphology.

KCNH2 variants in a family with epilepsy and long QT syndrome: A case report and literature review.

OBJECTIVE: Genes associated with Long QT syndromes (LQTS), such as KCNQ1, KCNH2, and SCN5A, are common causes of epilepsy. The Arg 744* variant of KCNH2 has been previously reported in people with epilepsy or LQTS, but none of these patients were reported to simultaneously suffer from epilepsy and LQTS. Herein, we report the case of a family with epilepsy and cardiac disorders. METHOD: The proband, a 25-year-old woman, with a family history of epilepsy and LQTS was followed at West China Hospital. The proband experienced her first seizure at the age of seven. Video electroencephalograms (vEEGs) showed epileptic discharges. Her 24-h dynamic electrocardiograms 2 (ECGs) showed QTc prolongation. The proband's mother, who is 50 years old, had her first generalized tonic-clonic seizure (GTCS) at the age of 18 years old. After she gave birth at the age of 25, the frequency of seizures increased, so antiepileptic therapy was initiated. When she was 28 years old, she complained of palpitations and syncope for the first time, and QTc prolongation was detected on her 24-h dynamic ECGs. The proband's grandmother also had complaints of palpitations and syncope at the age of 73. Her 24-h dynamic ECGs indicated supraventricular arrhythmia, with the lowest heart rate being 41 bpm, so she agreed to a pacemaker. Considering the young patient's family history, blood samples of the patient and her parents were collected for genetic analysis. RESULTS: A heterozygous variant of KCNH2 [c.2230 (exon9) C>T, p. Arg744Ter, 416, NM_000238, rs189014161] was found in the proband and her mother. According to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, we classified the KCNH2 variant as pathogenic. SIGNIFICANCE: This study expands the clinical phenotype of the Arg 744* KCNH2 pathogenic variant. In the context of channelopathies, because of the genetic susceptibility of the brain and the heart, the risk of comorbidity should be considered. This also indicates the importance of precise antiepileptic drug (AED) management and regular ECG monitoring for patients with channelopathies.

Sudden arrhythmic death and cardiomyopathy are important causes of sudden cardiac death in the UK: results from a national coronial autopsy database.

AIMS: Sudden cardiac death (SCD) is defined as natural unexpected death in witnessed cases occurring < 1 h and in unwitnessed cases as last seen alive < 24 h. SCD due to ischaemic heart disease (IHD) is frequent in older age groups; in younger people genetic cardiac causes, including channelopathies and cardiomyopathies, are more frequent. This study aimed to present the causes of SCD from a large specialist pathology registry. METHODS AND RESULTS: Cases were examined macroscopically and microscopically by two expert cardiac pathologists. The hearts from 7214 SCD cases were examined between 1994 and 2021. Sudden arrhythmic death syndrome (SADS), a morphologically normal heart, which can be underlaid by cardiac channelopathies, is most common (3821, 53%) followed by the cardiomyopathies (1558, 22%), then IHD (670, 9%), valve disease (225, 3%), congenital heart disease (213, 3%) and myocarditis/sarcoidosis (206, 3%). Hypertensive heart disease (185, 3%), aortic disease (129, 2%), vascular disease (97, 1%) and conduction disease (40, 1%) occur in smaller proportions. DISCUSSION: To our knowledge, this is the largest SCD cohort with autopsy findings ever reported from one country. SADS and cardiomyopathies predominate. This study highlights the importance of the autopsy in SCD, which is a significant public health concern in all age groups. Knowing the true incidence in our population will improve risk stratification and develop preventative strategies for family members. There is now a national pilot study integrating molecular autopsy and family screening into the assessment of SCD victims.

Gene mutations in comorbidity of epilepsy and arrhythmia.

Epilepsy is one of the most common neurological disorders, and sudden unexpected death in epilepsy (SUDEP) is the most severe outcome of refractory epilepsy. Arrhythmia is one of the heterogeneous factors in the pathophysiological mechanism of SUDEP with a high incidence in patients with refractory epilepsy, increasing the risk of premature death. The gene co-expressed in the brain and heart is supposed to be the genetic basis between epilepsy and arrhythmia, among which the gene encoding ion channel contributes to the prevalence of "cardiocerebral channelopathy" theory. Nevertheless, this theory could only explain the molecular mechanism of comorbid arrhythmia in part of patients with epilepsy (PWE). Therefore, we summarized the mutant genes that can induce comorbidity of epilepsy and arrhythmia and the possible corresponding treatments. These variants involved the genes encoding sodium, potassium, calcium and HCN channels, as well as some non-ion channel coding genes such as CHD4, PKP2, FHF1, GNB5, and mitochondrial genes. The relationship between genotype and clinical phenotype was not simple linear. Indeed, genes co-expressed in the brain and heart could independently induce epilepsy and/or arrhythmia. Mutant genes in brain could affect cardiac rhythm through central or peripheral regulation, while in the heart it could also affect cerebral electrical activity by changing the hemodynamics or internal environment. Analysis of mutations in comorbidity of epilepsy and arrhythmia could refine and expand the theory of "cardiocerebral channelopathy" and provide new insights for risk stratification of premature death and corresponding precision therapy in PWE.

AKAP9-Related Channelopathy: Novel Pathogenic Variant and Review of the Literature.

Disease-associated pathogenic variants in the A-Kinase Anchor Protein 9 (AKAP9) (MIM *604001) have been recently identified in patients with autosomal dominant long QT syndrome 11 (MIM #611820), lethal arrhythmia (ventricular fibrillation, polymorphic ventricular tachycardia), Brugada syndrome, and sudden unexpected death. However, AKAP9 sequence variations were rarely reported and AKAP9 was classified as a "disputed evidence" gene to support disease causation due to the insufficient genetic evidence and a limited number of reported AKAP9-mutated patients. Here, we describe a 47-year-old male carrying a novel frameshift AKAP9 pathogenic variant who presented recurrent syncopal attacks and sudden cardiac arrest that required a semi-automatic external defibrillator implant and an electric shock treatment of ventricular arrhythmia. This study provides insight into the mechanism underlying cardiac arrest and confirms that AKAP9 loss-of-function variants predispose to serious, life-threatening ventricular arrhythmias.

Research Progress and Forensic Application of Postmortem Genetic Testing in Hereditary Cardiac Diseases.

Hereditary cardiac disease accounts for a large proportion of sudden cardiac death (SCD) in young adults. Hereditary cardiac disease can be divided into hereditary structural heart disease and channelopathies. Hereditary structural heart disease mainly includes hereditary cardiomyopathy, which results in arhythmia, heart failure and SCD. The autopsy and histopathological examinations of SCD caused by channelopathies lack characteristic morphological manifestations. Therefore, how to determine the cause of death in the process of examination has become one of the urgent problems to be solved in forensic identification. Based on the review of recent domestic and foreign research results on channelopathies and hereditary cardiomyopathy, this paper systematically reviews the pathogenesis and molecular genetics of channelopathies and hereditary cardiomyopathy, and discusses the application of postmortem genetic testing in forensic identification, to provide reference for forensic pathology research and identification of SCD.

From diagnostic testing to precision medicine: the evolving role of genomics in cardiac channelopathies and cardiomyopathies in children.

Pediatric sudden cardiac death (SCD) is the sudden unexpected death of a child or adolescent due to a presumed cardiac etiology. Heritable causes of pediatric SCD are predominantly cardiomyopathies and cardiac ion channelopathies. This review illustrates recent advances in determining the genetic cause of established and emerging channelopathies and cardiomyopathies, and how broader genomic sequencing is uncovering complex interactions between genetic architecture and disease manifestation. We discuss innovative models and experimental platforms for resolving the variant of uncertain significance as both the variants and genes associated with disease continue to evolve. Finally, we highlight the growing problem of incidentally identified variants in cardiovascular disease-causing genes and review innovative methods to determining whether these variants may ultimately result in penetrant disease. Overall, we seek to illustrate both the promise and inherent challenges in bridging the traditional role for genetics in diagnosing cardiomyopathies and channelopathies to one of true risk-predictive precision medicine.

COVID-19 infection and vaccination in patients with skeletal muscle channelopathies.

INTRODUCTION/AIMS: Although we have gained insight into coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 since the beginning of the pandemic, our understanding of the consequences for patients with neuromuscular disorders is evolving. In this study we aimed to study the impact of COVID-19 and COVID-19 vaccination on skeletal muscle channelopathies. METHODS: We conducted a survey of patients with genetically confirmed skeletal muscle channelopathies seen at the UK Nationally Commissioned Channelopathy Service. RESULTS: Thirty-eight patient responses were received. Six patients had COVID-19 infection leading to exacerbation of their underlying muscle channelopathy. No major complications were reported. Thirty-six patients had received one or two COVID-19 vaccinations and the majority (68%) had no worsening of their underlying channelopathy. Thirty-two percent reported worsening of their usual symptoms of their muscle channelopathy, but all reported recovery to baseline levels. No serious adverse events were reported. DISCUSSION: The overall rates of COVID-19 infection were low in our study and COVID-19 vaccine uptake rates were high. Our results have been useful to inform patients that a subset of patients have reversible worsening of their channelopathy post-COVID-19 vaccination. Our study provides information for giving advice to patients with skeletal muscle channelopathies regarding COVID-19 infection and vaccination.

A Gardos channelopathy associated with nonimmune hydrops and fetal loss.

Dehydrated hereditary stomatocytosis (DHS) (MIM#194380) is a rare autosomal dominant disorder of red blood cell permeability, characterized by a partially or fully compensated nonimmune hemolytic anemia. PIEZO1 is the major gene involved with hundreds of families described, some of which present transient perinatal edema of varying severity. A smaller subset of individuals harbors pathogenic variants in KCNN4, sometimes referred as "Gardos channelopathy." Up to now, only six pathogenic variants in KCNN4 have been reported in 13 unrelated families. Unlike PIEZO1-DHS, neither perinatal edema nor fetal loss has ever been observed linked to KCNN4-DHS. We report the first fetal loss due to non-immune hydrops fetalis related to a pathogenic 28 bp deletion (NM_002250.2: c.1109_1119+17del) in KCNN4. This observation underlies the need for very close monitoring of pregnancies when one parent is affected by DHS regardless of genotype (PIEZO1 or KCNN4).

Cardiac Causes of Sudden Unexpected Infant Death and the Role of the Primary Pediatrician.

Sudden death of an infant can be from numerous causes. The leading cardiac causes include major congenital heart disease, myocarditis, cardiomyopathies, and channelopathies. There are new approaches to evaluating these patients and surviving family members. Pediatricians are a key component in support of the family, investigation of other at-risk family members, and coordination of subspecialty consultation. [Ped Ann. 2022;51(6):e228-e233.].

Cardiac ion channels associated with unexplained stillbirth - an immunohistochemical study.

OBJECTIVES: Despite the use of post-mortem investigations, approximately 20% of stillbirths remain unexplained. Cardiac ion channelopathies have been identified as a cause of death in Sudden Infant Death Syndrome (SIDS) and could be associated with unexplained stillbirths. This study aimed to understand if the expression or localisation of cardiac ion channels associated with channelopathies were altered in cases of unexplained stillbirths. METHODS: A case control study was conducted using formalin-fixed cardiac tissue from 20 cases of unexplained stillbirth and a control group of 20 cases of stillbirths from intrapartum hypoxia. 4 µm tissue sections were stained using haematoxylin and eosin, Masson's trichrome (MT) and Elastic van Gieson (EVG). Immunohistochemistry (IHC) was performed using antibodies against CACNA1G, KCNJ2, KCNQ1, KCNH2 and KCNE1. The cardiac conduction system in samples stained with MT and EVG could not be identified. Therefore, the levels of immunoperoxidase staining were quantified using QuPath software. RESULTS: The nuclear-cytoplasmic ratio of sections stained with haematoxylin and eosin was higher for the hypoxia group (hypoxia median 0.13 vs. 0.04 unexplained, p < 0.001). CACNA1G (unexplained median 0.26 vs. hypoxia 0.30, p=0.009) and KCNJ2 (unexplained median 0.35 vs. hypoxia 0.41, p=0.001) had lower staining intensity in the unexplained stillbirth group. There were no statistically significant differences in the staining intensity of KCNQ1, KCNH2 and KCNE1. CONCLUSIONS: Two ion channels associated with channelopathies demonstrated lower levels of expression in cases of unexplained stillbirth. Further genetic studies using human tissue should be performed to understand the association between channelopathies and otherwise unexplained stillbirths.

Causes of sudden cardiac death in young athletes and non-athletes: systematic review and meta-analysis: Sudden cardiac death in the young.

INTRODUCTION: The etiology of sudden cardiac death (SCD) in young people continues to attract much attention. This meta-analysis aimed to identify the most frequent causes of SCD in individuals aged ≤35 years, the differences between athletes and non-athletes and geographic areas. METHODS: Studies published between 01/01/1990 and 01/31/2020 and evaluating post-mortem the aetiology of SCD in young individuals (≤35 years) were included. Individuals were divided into athletes and non-athletes. Studies that did not report separate data between athletes and non-athletes were excluded. RESULTS: Thirty-four studies met the inclusion criteria, and a total population of 5,060 victims of SCD were analyzed (2,890 athletes, 2,170 non-athletes). Comparing the causes of SCD between athletes and non-athletes, non-ischemic left ventricular scar (NILVS) (5.1% vs. 1.1%, p=0.01) was more frequent in the former, while coronary artery disease (CAD) (19.6% vs. 9.1%, p=0.009), arrhythmogenic cardiomyopathy (ACM) (11.5% vs. 4.7%, p=0.03) and channelopathies (8.4% vs. 1.9%, p=0.02) were more frequent in the latter. In studies published in the last decade, hypertrophic cardiomyopathy (HCM) (p=0.002), dilated cardiomyopathy (p=0.047), and anomalous origin of coronary arteries (AOCA) (p=0.009) were more frequently the causes of SCD in athletes while aortic dissection (0.022) was the cause in non-athletes. HCM (p=0.01) and AOCA (p=0.004) were more frequently the causes of SCD in the US while ACM (p=0.001), structurally normal heart (p=0.02), and channelopathies (p=0.02) were more frequent in Europe. CONCLUSIONS: Among the causes of SCD, NILVS was the more frequent cause in athletes, while CAD, ACM and channelopathies were more frequent causes in non-athletes. The causes of SCD differ between the US and Europe.

Polymicrogyria in a child with KCNMA1-related channelopathy.

BACK GROUND: Polymicrogyria is a malformation of cortical development with overfolding of the cerebral cortex and abnormal cortical layering. Polymicrogyria constitutes a heterogenous collection of neuroimaging features, neuropathological findings, and clinical associations, and is due to multiple underlying etiologies. In the last few years, some glutamate and sodium channelopathies have been associated with cortical brain malformations such as polymicrogyria. The potassium calcium-activated channel subfamily M alpha 1 (KCNMA1) gene encodes each of the four alpha-subunits that make up the large conductance calcium and voltage-activated potassium channel "Big K+". KCNMA1-related channelopathies are associated with various neurological abnormalities, including epilepsy, ataxia, paroxysmal dyskinesias, developmental delay and cognitive disorders. CASE REPORT: We report the observation of a patient who presented since the age of two months with drug-resistant epilepsy with severe developmental delay initially related to bilateral asymmetric frontal polymicrogyria. Later, exome sequencing revealed a de novo heterozygous variation in the KCNMA1 gene (c.112delG) considered pathogenic. CONCLUSION: This first case of polymicrogyria associated with KCNMA1-related channelopathy may expand the phenotypic spectrum of KCNMA1-related channelopathies and enrich the recently identified group of developmental channelopathies with polymicrogyria.