Research Progress and Forensic Application of Postmortem Genetic Testing in Hereditary Cardiac Diseases / 法医学杂志

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.

Novel compound heterozygous SCN9A variations causing congenital insensitivity to pain in a patient / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child featuring congenital insensitivity to pain (CIP).@*METHODS@#Targeted capture and next generation sequencing (NGS) was carried out for the proband. Suspected pathogenic variants were confirmed by Sanger sequencing of the proband and his parents.@*RESULTS@#The proband was found to harbor compound heterozygous variants of SCN9A gene, namely c.1598delA (p.N533Ifs*31) and c.295_296delCGinsAT (p.R99I), which were respectively inherited from his father and mother. Both variants were predicted to be pathogenic, and neither was reported previously.@*CONCLUSION@#The compound heterozygous variants of the SCN9A gene probably underlay the CIP in this child. Above finding has enabled genetic counseling for this family.

Malformaciones cardíacas causantes de muerte súbita en adulto / Cardiac malformations causing sudden death in adults

Resumen La muerte súbita cardiaca se define como la muerte que ocurre dentro de una hora después de inicio de síntomas en los casos presenciados y en los no presenciados dentro de las últimas 24 horas de haberse visto con vida. Su incidencia anual en el mundo ronda entre 4-5 millones de casos. Aproximadamente un 90-95% de las víctimas de muerte súbita cardíaca sufren una cardiopatía estructural. Siendo la cardiopatía isquémica la causa principal en mayores de 35 años y las afectaciones congénitas y hereditarias en adultos jóvenes entre 18-35 años. La etiología de la muerte súbita cardíaca se puede clasificar en coronariopatías, miocardiopatías, cardiopatías congénitas, enfermedades eléctricas hereditarias y cardiopatías adquiridas. Siendo la aterosclerosis y la miocardiopatía dilatada las más prevalentes y de las cardiopatías congénitas la que tiene mayor mortalidad por muerte súbita cardíaca es la coartación de aorta. Múltiples mecanismos pueden derivar en muerte súbita cardíaca como fibrilación ventricular, taquicardia ventricular polimorfa y actividad eléctrica sin pulso. Sin embargo, en la actualidad la muerte súbita cardíaca continúa siendo un reto en la salud pública, tanto el diagnóstico como el tratamiento oportuno. Mediante la prevención de factores de riesgo modificables y con el control adecuado de los no modificables, así como la optimización de la terapéutica, se podrá reducir la incidencia de muerte súbita cardíaca.

Abstract Sudden cardiac death is defined as death that occurs within one hour after the onset of symptoms in the presence and not witnessed cases within the last 24 hours of having seen life. Its annual incidence in the world is between 4-5 million cases. Approximately 90-95% of victims of sudden cardiac death suffered from structural heart disease. Ischemic heart disease is the main cause in people older than 35 years and the congenital and hereditary affectations in young adults between 18-35 years. The etiology of sudden cardiac death can be classified as coronary artery disease, cardiomyopathy, congenital heart disease, hereditary diseases and acquired heart disease. Being atherosclerosis and dilated cardiomyopathy the most frequent and congenital cardiopathies, the one with the highest mortality due to sudden cardiac death is the coarctation of the aorta. Multiple mechanisms can lead to sudden cardiac death such as ventricular fibrillation, polymorphic ventricular tachycardia and pulseless electrical activity. However, at the right time. Through the prevention of modifiable risk factors and with the adequate control of the non-modifiable ones, as well as the optimization of therapeutics, the incidence of sudden cardiac death can be reduced.

Analysis of SCN4A gene variation in a Chinese pedigree affected with skeletal muscle sodium channelopathies / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical features of a Chinese pedigree affected with skeletal muscle sodium channelopathies due to variation of SCN4A gene.@*METHODS@#Potential variation of the 24 exons of the SCN4A gene was screened using PCR and Sanger sequencing.@*RESULTS@#Four family members were affected with the disease in an autosomal dominant inheritance pattern. Three patients had normekalemic periodic paralysis, while 1 showed paramyotonia congenita. Genetic analysis detected a missense variation c.2078T>C (p.Ile693Thr) in exon 13 of the SCN4A gene in the proband and other 3 affected relatives.@*CONCLUSION@#Normokalemic periodic paralysis and paramyotonia congenita can occur in different family members with skeletal muscle sodium channelopathies due to c.2078T>C(p.Ile693Thr) variation of SCN4A gene.

Congenital insensitivity to pain with anhidrosis: A case report and literature review / 中南大学学报(医学版)

To analyze the clinical manifestations and gene mutations in children with congenital insensitivity to pain with anhidrosis (CIPA), and review related literature. An infant diagnosed with congenital insensitivity to pain with anhidrosis was reported. The main clinical manifestations of the infant were painless, no sweat, and repeated fever. Peripheral blood of the infant and his parents was collected, and candidate variants were confirmed by Sanger sequencing. The results of molecular genetic analysis showed that there were compound heterozygous mutations (c.36G>A, c.851-33T>A) of neurotrophic tyrosine kinase receptor type 1 (NTRK1) in the infant. c.36G>A and c.851-33T>A were inherited from his father and mother, respectively. c.851-33T>A is a previously reported mutation, c.36G>A is an unreported mutation, which can lead to the tryptophan changing into a stop codon. According to the American College of Medical Genetics and Genomics (ACMG) variant interpretation guidelines, the mutation is interpreted as pathogenic, and the biological hazard is potentially harmful. Congenital insensitivity to pain with anhidrosis is a rare inherited disorder. Genetic molecular genetic analysis is helpful to diagnose and discover new gene mutations.

2018 KHRS Guidelines for Catheter Ablation of Ventricular Arrhythmias: Part 2

The recommendations outlined constitute the first clinical practice guidelines of the Korean Heart Rhythm Society regarding catheter ablation of ventricular arrhythmias (VA). This is a guideline PART 2, which includes VA in the structurally normal heart, inherited primary arrhythmia syndromes, VA related to congenital heart disease, as well as VA and sudden cardiac death observed in specific populations. In the structurally normal heart, treatment is guided by the occurrence of symptoms or the frequency of arrhythmias that cause ventricular dysfunction over time. Catheter ablation can be recommended in patients in whom anti-arrhythmic medications are ineffective. The sites of origin of arrhythmic activity are known to be the outflow tract, fascicles, papillary muscle, or the annulus. Specific cardiac channelopathies include congenital long QT and Brugada syndrome. This guideline discusses the diagnostic criteria, risk stratification, and treatment of these syndromes. We have included recommendations for adult congenital heart disease. Moreover, we have discussed the management of VA occurring in specific populations such as in patients with psychiatric and neurological disorders, pregnant patients, those with obstructive sleep apnea or drug-related pro-arrhythmias, athletes, and elderly patients.

Síndrome de Brugada como causa de muerte súbita de origen cardíaco / Brugada syndrome as a cause of sudden cardiac death

ResumenMuerte súbita se define como un evento fatal e inesperado que ocurre en un individuo aparentemente sano. Una de las principales causas son las de origen cardiovascular, entre las cuales se encuentran las anormalidades electrofisiológicas primarias como lo es el síndrome de Brugada. Este se define como una canalopatía que afecta canales de sodio, producto de una variante genética, principalmente de herencia autosómica dominante.Se ha determinado que la mutación del gen SCN5A es la más asociada con el síndrome. El diagnóstico se realiza mediante historia clínica y patrones electrocardiográficos específicos y generalmente se presenta como síncope o como muerte súbita resucitada debida a taquicardia ventricular polimórfica o fibrilación ventricular. El desfibrilador automático implantable es la principal herramienta para la prevención de muerte súbita, sin embargo, previo a su uso debe hacerse una adecuada estratificación de los pacientes, tanto para prevenir muerte súbita, como para evitar el uso innecesario del dispositivo.

AbstractSudden death is defined as an unexpected fatal event occurring in an apparently healthy subject. Sudden cardiac death is a leading cause, among which are primary electrical abnormalities such as Brugada Syndrome. Brugada Syndrome is an autosomal dominant channelopathy affecting the sodium channel. SCN5A has emerged as the most common gene associated with Brugada syndrome. The diagnosis is suggested by the clinical history in a patient with specific electrocardiographic pattern. The most typical presentation is syncope or resuscitated sudden death due to polymorphic ventricular tachycardia or ventricular fibrillation. An implantable cardioverter defibrillator is the main tool for preventing sudden death, and correct risk stratification in these patients is important both to prevent sudden death and to avoid unnecessary implantable cardioverter defibrillator use.

Canalopatías en muerte súbita: Relevancia clínica de autopsia molecular / Channelopathies in sudden death: Clinical relevance of molecular autopsy

ResumenLas canalopatías abarcan una serie síndromes arrítmicos caracterizados por una presentación inicial de muerte súbita o síncope, en personas en su mayoría jóvenes y conocidas sanas, que poseen una autopsia normal. Éstas se deben a mutaciones en los genes que codifican para canales iónicos de los miocitos cardíacos, así como las proteínas asociadas a si funcionamiento o traducción. Dada su asociación hereditaria, los familiares podrían tener un riesgo aumentado de presentar el trastorno pese a estar asintomáticas. Allí radica la importancia del mapeo genético en aquellas autopsias en las que no se ha identificado la causa de muerte. La autopsia molecular permite buscar e identificar estas mutaciones y correlacionar la muerte súbita con una canalopatía. Lo cual resulta esencial para la evaluación del riesgo y la prevención de otro episodio de muerte súbita cardíaca en familiares portadores.En este artículo se exponen las canalopatías más importantes asociadas a muerte súbita, y el impacto del mapeo genético en la prevención y manejo en familiares portadores.

AbstractChannelopathies include a series of syndromes characteristic of an initial presentation of sudden death or syncope, in persons mostly young and known healthy, who have a normal autopsy. These are due to mutations in the genes encoding ionic channels of cardiac myocytes, as well as the proteins associated with whether functioning or translation. Because of their hereditary association, relatives may be at increased risk of developing the disorder despite being asymptomatic. There lies the importance of genetic mapping in those autopsies in which the cause of death has not been identified. Molecular autopsy allows searching and identifying these mutations and correlating sudden death with a channelopathy. This is essential for the evaluation of risk and prevention of another episode of sudden cardiac death in family members. This article discusses the most important channelopathies associated with sudden death, and the impact of genetic mapping on prevention and management in family members.

Ménière's Disease and Electrophysiology / 대한평형의학회지

Inner ear is composed of cochlea, vestibule, and endolymphatic sac which are enclosed by thin layer of epithelial cells. The enclosed space is filled with fluid named as endolymph where the [K⁺] is high and [Na⁺] is low. This unique ion composition is very important in maintaining normal hearing and balance function by providing K⁺ ions into sensory hair cells, which finally depolarize hair cells to facilitate the transport of sound and acceleration stimulation to central nervous system. The ion composition of inner ear is maintained by various ion transport through ion channels, transporters, and exchangers in the inner ear sensory and extra-sensory epithelium. The disruption of normal endolymphatic ion composition by the deterioration of the function of those ion channels can cause dysfunction of sensory epithelium, which consequently results in hearing and balance disorders. One of the possible pathology from the disruption of inner ear ion homeostasis is endolymphatic hydrops which is a phenomenon of excessive fluid accumulation of inner ear. The dysfunction of ion channels in inner ear epithelium can be an etiology of Ménière's disease since endolymphatic hydrops is a main pathological finding of the disease. In this review, we discussed about the possible pathological mechanism of Ménière's disease as a perspective of channelopathy as well as the role of various ion channels in the regulation of inner ear fluid volume based on the findings revealed by electrophysiological studies.

Structure-based assessment of disease-related mutations in human voltage-gated sodium channels

Voltage-gated sodium (Na) channels are essential for the rapid upstroke of action potentials and the propagation of electrical signals in nerves and muscles. Defects of Na channels are associated with a variety of channelopathies. More than 1000 disease-related mutations have been identified in Na channels, with Na1.1 and Na1.5 each harboring more than 400 mutations. Na channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Na channels are required to understand their function and disease mechanisms. The recently determined atomic structure of the rabbit voltage-gated calcium (Ca) channel Ca1.1 provides a template for homology-based structural modeling of the evolutionarily related Na channels. In this Resource article, we summarized all the reported disease-related mutations in human Na channels, generated a homologous model of human Na1.7, and structurally mapped disease-associated mutations. Before the determination of structures of human Na channels, the analysis presented here serves as the base framework for mechanistic investigation of Na channelopathies and for potential structure-based drug discovery.

Parálisis periódica hipocalémica: reporte de caso y revisión del tema / Hypokalemic periodic paralysis: A case report and a topic review

Las parálisis periódicas primarias son canalopatías poco frecuentes, de las cuales hacen parte: la parálisis periódica hipocalémica, la parálisis periódica hipercalémica y el síndrome Andersen-Tawil; son caracterizadas por ataques de debilidad muscular generalizada, con recuperación de la fuerza entre los ataques. Presentamos el caso de una mujer de 21 años con el segundo episodio de parálisis y documentación de hipocalemia, sin antecedentes de importancia, sin factores clínicos o paraclínicos que expliquen el trastorno electrolítico, con recuperación posterior de la fuerza al realizar tratamiento de la hipocalemia. Posteriormente se lleva a cabo una revisión del tema.

Primary periodic paralyses are rare channelopathies which include: hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and Andersen-Tawil Syndrome. These entities are characterized by attacks of generalized muscle weakness and recovery of muscle strength between attacks. A case is presented of a 21-year-old woman who presented a second episode of paralysis and documented hypokalemia, with no important antecedents, with no clinical or diagnostic test factors which explain her electrolyte disorder, with recovery of muscle strength after receiving treatment for hypokalemia. A review of the topic was conducted.

Research Progress of the Correlation between Caveolin and Unexpected Sudden Cardiac Death / 法医学杂志

Due to the negative autopsy and without cardiac structural abnormalities, unexpected sudden cardiac death （USCD） is always a tough issue for forensic pathological expertise. USCD may be associated with parts of fatal arrhythmic diseases. These arrhythmic diseases may be caused by disorders of cardiac ion channels or channel-related proteins. Caveolin can combine with multiple myocardial ion channel proteins through its scaffolding regions and plays an important role in maintaining the depolarization and repolarization of cardiac action potential. When the structure and function of caveolin are affected by gene mutations or abnormal protein expression, the functions of the regulated ion channels are correspondingly impaired, which leads to the occurrence of multiple channelopathies, arrhythmia or even sudden cardiac death. It is important to study the effects of caveolin on the functions of ion channels for exploring the mechanisms of malignant arrhythmia and sudden cardiac death.

Potassium Channelopathies and Gastrointestinal Ulceration

Potassium channels and transporters maintain potassium homeostasis and play significant roles in several different biological actions via potassium ion regulation. In previous decades, the key revelations that potassium channels and transporters are involved in the production of gastric acid and the regulation of secretion in the stomach have been recognized. Drugs used to treat peptic ulceration are often potassium transporter inhibitors. It has also been reported that potassium channels are involved in ulcerative colitis. Direct toxicity to the intestines from nonsteroidal anti-inflammatory drugs has been associated with altered potassium channel activities. Several reports have indicated that the long-term use of the antianginal drug Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, increases the chances of ulceration and perforation from the oral to anal regions throughout the gastrointestinal (GI) tract. Several of these drug features provide further insights into the role of potassium channels in the occurrence of ulceration in the GI tract. The purpose of this review is to investigate whether potassium channelopathies are involved in the mechanisms responsible for ulceration that occurs throughout the GI tract.

Potassium Channelopathies and Gastrointestinal Ulceration

Potassium channels and transporters maintain potassium homeostasis and play significant roles in several different biological actions via potassium ion regulation. In previous decades, the key revelations that potassium channels and transporters are involved in the production of gastric acid and the regulation of secretion in the stomach have been recognized. Drugs used to treat peptic ulceration are often potassium transporter inhibitors. It has also been reported that potassium channels are involved in ulcerative colitis. Direct toxicity to the intestines from nonsteroidal anti-inflammatory drugs has been associated with altered potassium channel activities. Several reports have indicated that the long-term use of the antianginal drug Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, increases the chances of ulceration and perforation from the oral to anal regions throughout the gastrointestinal (GI) tract. Several of these drug features provide further insights into the role of potassium channels in the occurrence of ulceration in the GI tract. The purpose of this review is to investigate whether potassium channelopathies are involved in the mechanisms responsible for ulceration that occurs throughout the GI tract.

Management of Patients with Long QT Syndrome

Long QT syndrome (LQTS) is a rare cardiac channelopathy associated with syncope and sudden death due to torsades de pointes and ventricular fibrillation. Syncope and sudden death are frequently associated with physical and emotional stress. Management of patients with LQTS consists of life-style modification, β-blockers, left cardiac sympathetic denervation (LCSD), and implantable cardioverter-defibrillator (ICD) implantation. Prohibition of competitive exercise and avoidance of QT-prolonging drugs are important issues in life-style modification. Although β-blockers are the primary treatment modality for patients with LQTS, these drugs are not completely effective in some patients. Lifelong ICD implantation in young and active patients is associated with significant complications. LCSD is a relatively simple and highly effective surgical procedure. However, LCSD is rarely used.

Intractable hyperkalemia due to nicorandil induced potassium channel syndrome.

Nicorandil is a commonly used antianginal agent, which has both nitrate‑like and ATP‑sensitive potassium (KATP) channel activator properties. Activation of potassium channels by nicorandil causes expulsion of potassium ions into the extracellular space leading to membrane hyperpolarization, closure of voltage‑gated calcium channels and finally vasodilatation. However, on the other hand, being an activator of KATP channel, it can expel K+ ions out of the cells and can cause hyperkalemia. Here, we report a case of nicorandil induced hyperkalemia unresponsive to medical treatment in a patient with diabetic nephropathy.

Whole-Body Muscle MRI in Patients with Hyperkalemic Periodic Paralysis Carrying the SCN4A Mutation T704M: Evidence for Chronic Progressive Myopathy with Selective Muscle Involvement

BACKGROUND AND PURPOSE: Hyperkalemic periodic paralysis (hyperKPP) is a muscle sodium-ion channelopathy characterized by recurrent paralytic attacks. A proportion of affected individuals develop fixed or chronic progressive weakness that results in significant disability. However, little is known about the pathology of hyperKPP-induced fixed weakness, including the pattern of muscle involvement. The aim of this study was to characterize the patterns of muscle involvement in hyperKPP by whole-body magnetic resonance imaging (MRI). METHODS: We performed whole-body muscle MRI in seven hyperKPP patients carrying the T704M mutation in the SCN4A skeletal sodium-channel gene. Muscle fat infiltration, suggestive of chronic progressive myopathy, was analyzed qualitatively using a grading system and was quantified by the two-point Dixon technique. RESULTS: Whole-body muscle MRI analysis revealed muscle atrophy and fatty infiltration in hyperKPP patients, especially in older individuals. Muscle involvement followed a selective pattern, primarily affecting the posterior compartment of the lower leg and anterior thigh muscles. The muscle fat fraction increased with patient age in the anterior thigh (r=0.669, p=0.009), in the deep posterior compartment of the lower leg (r=0.617, p=0.019), and in the superficial posterior compartment of the lower leg (r=0.777, p=0.001). CONCLUSIONS: Our whole-body muscle MRI findings provide evidence for chronic progressive myopathy in hyperKPP patients. The reported data suggest that a selective pattern of muscle involvement-affecting the posterior compartment of the lower leg and the anterior thigh-is characteristic of chronic progressive myopathy in hyperKPP.