离子通道病所致的心源性猝死与死后基因检测技术

心脏疾病引起的猝死占人类各类疾病所致猝死的首位.多数心源性猝死案例通过尸体解剖、病理组织学检验可以明确死因为心源性疾病,但尚有少数案例虽经过详细检验并高度怀疑为心源性猝死,但仍不能明确检测到可说明死因的心脏疾病.随着现代分子生物学技术的进步,发现此类猝死者中相当一部分属于先天性心肌细胞离子通道疾病所致,主要包括Brugada综合征、长QT综合征、儿茶酚胺敏感性多形性室性心动过速、短QT综合征等.本文对此类疾病的分子遗传学、心电图所见、临床表现和猝死机制以及死后基因检测技术在死因鉴定中的作用进行了详细的阐述,以期为法医学实践中先天性心肌细胞离子通道疾病所致猝死原因的鉴定提供指导.     

夜间不明原因猝死综合征和阻塞性睡眠呼吸暂停低通气综合征关系的研究进展

夜间不明原因猝死综合征一直是法医学研究的难点,近年来分子遗传学的发展促进了其病因学研究,但仍有大部分案例病因不明。睡眠呼吸暂停综合征是一种常见的睡眠障碍性疾病,其中以阻塞性睡眠呼吸暂停低通气综合征最为常见。近年来,国内外研究表明阻塞性睡眠呼吸暂停低通气综合征与心血管疾病的发生密切相关,可以导致心律失常甚至引起猝死。本文主要综述了夜间不明原因猝死综合征与阻塞性睡眠呼吸暂停低通气综合征之间的关系,从而为不明原因猝死的发病机制提供新的思路。     

KCNE、KCNQ1与心性猝死的相关性研究进展

部分心性猝死由于缺乏明确的病理学改变,其鉴定工作一直是法医工作者的一大难题。近年来,与长QT综合征、心房颤动等致死性心律失常疾病相关基因（KCNE基因家族与KCNQl）等研究逐渐增多。国内外研究发现KCNE和KCNQ1基因编码心肌钾离子通道,其基因异常可引起严重的心律失常,甚至导致心性猝死。因此,死后KCNE和KCNQl的基因检测对于心性猝死鉴定具有重要意义。本文对KCNE、KCNQl与心性猝死的相关性研究进展进行综述,希望能为法医学研究和实践提供参考。     

心脏钠通道SCN5A基因突变与致心律失常性疾病

致心律失常性疾病患者死后尸检时心脏没有发现病理学异常的证据,过去都将其归为原因不明的猝死,近年研究显示,很多致心律失常性疾病与心脏钠通道基因(SCN5A)突变相关。本文对钠通道SCN5A基因的基本结构、SCN5A基因突变与几种相关的致心律失常性疾病的相关性等进行了综述,旨在为原因不明猝死的研究提供新思路。     

青壮年猝死综合征与SCN5A基因突变的相关性

近几年来,国内外青壮年不明原因猝死的报道逐年增多,对其死因的界定是法医工作者深感棘手的问题。随着病因学向分子水平的深入,心脏病研究已用分子遗传学技术证实了一类“原发性心电紊乱”导致的心律失常与SCN5A突变引发的钠通道疾病有关,本文回顾了法医学中青壮年猝死综合征(SMDS)的特征及临床医学中几种疾病的基因型和表型,分析其相关性,期望为进一步研究获得一些启示。     

KCNE、KCNQ1与心性猝死的相关性研究进展

部分心性猝死由于缺乏明确的病理学改变,其鉴定工作一直是法医工作者的一大难题。近年来,与长QT综合征、心房颤动等致死性心律失常疾病相关基因(KCNE基因家族与KCNQ1)等研究逐渐增多。国内外研究发现KCNE和KCNQ1基因编码心肌钾离子通道,其基因异常可引起严重的心律失常,甚至导致心性猝死。因此,死后KCNE和KCNQ1的基因检测对于心性猝死鉴定具有重要意义。本文对KCNE、KCNQ1与心性猝死的相关性研究进展进行综述,希望能为法医学研究和实践提供参考。     

全外显子组测序对肥厚型心肌病猝死者的基因分析

目的在全外显子组水平分析1例肥厚型心肌病(hypertrophic cardiomyopathy,HCM)猝死病例的相关致病性基因突变。方法对1例具有HCM病理学特征的猝死病例样本,利用Illumina~Hi Seq 2500平台进行全外显子组测序(whole exome sequencing,WES)。测序数据分析以hg19为参照序列,筛选可疑的单核苷酸变异位点,通过PhyloP、PolyPhen-2、SIFT等软件进行突变的保守性和功能分析。结果经过筛选,发现该病例的MYBPC3基因发生C719R杂合突变。结论利用二代测序技术进行全外显子组水平的分子解剖(基因突变检测和分析),有助于明确HCM的分子机制,并为死因分析提供新的方法和思路。     

分子印迹技术及其在司法鉴定领域的应用

分子印迹技术（MIT）是制备对特定目标分子具有分子识别功能聚合物（MIPs）的一门技术,由于MIPs具有的选择性,被广泛应用于各领域。对MIT和MIPs进行了介绍,并对其在司法鉴定领域的应用进行了综述。     

致死性心律失常的法医学研究进展

据文献报道,有很多心源性猝死是由于致死性心律失常所致。在法医学鉴定工作中,心律失常所引起的猝死往往很突然,尸检及镜下病理学检查又缺乏特征性的改变,使得鉴定其死亡机制成为一大难点。因此,寻找一种客观、准确的心律失常鉴定方法,对于致死性心律失常所致心源性猝死的鉴定尤为重要。本文将就上述问题,从致死性心律失常的定义、分类、产生原因、致死机制、形态学所见及死后生化检测指标等方面进行综述,以期为心源性猝死致死原因的法医病理学分析、鉴定提供帮助。     

肥厚型心肌病分子机制及法医病理学意义

肥厚型心肌病(hypertrophic cardiomyopathy,HCM)被证实是引发35岁以下青年人(尤其是运动员心源性猝死(sudden cardiac death,SCD)的首要原因。约60%的HCM患者由编码肌小节蛋白的基因突变导致,呈常染色体显性遗传模式。β肌球蛋白重链基因、肌球蛋白结合蛋白C基因、肌钙蛋白T基因、肌钙蛋白I基因被认为是引起HCM最常见的突变基因。基因检测在HCM的临床诊断中已趋于常态化,但在法医工作中应用较少,如果基因检测技术能够应用于法医病理学诊断,将会给HCM猝死案件的死亡原因确认工作提供便利。更重要的是,通过猝死者的基因检测结果尽早进行家庭成员的危险评估才能降低猝死的发生率。本文主要综述了HCM的分子机制进展以及该疾病在法医病理学诊断中的应用价值。     

常用心脏标志物的生化检测及法医学应用

在法医病理学鉴定工作中,由早期缺血性心肌病变及致死性心律失常引起的心源性猝死常常缺乏典型的病理组织学改变,如何准确、客观地诊断、查明死因是法医病理学亟待解决的问题。近来研究发现的一些心肌特异性指标对心源性猝死的诊断有很好的应用前景。本文介绍几种常见心肌特异性标志物的生化特点、实验室检验方法以及临床和法医学应用前景,以期为心源性猝死的法医病理学鉴定提供依据。     

Sudden cardiac death in young adults: environmental risk factors and genetic aspects of premature atherosclerosis

Familial hypercholesterolemia (FH) is a genetic disorder that may lead to premature coronary heart disease (CHD) and sudden cardiac death (SCD). Mutations in the LDLR or APOB genes cause FH. We have screened the LDLR and the ligand-binding region of APOB genes in 52 cases of SCD. Deceased patients were younger than 40 years of age and were suspected of having FH. The LDLR and APOB genes were examined via PCR, high-resolution melting, and DNA sequencing. Therein, it was observed that 7.7% of the screened patients exhibited a rare sequence variant in the LDLR gene, with 5.7% suspected of being pathogenic mutations. Lipid profiles and genetic testing for FH could be considered when autopsy reveals significant atherosclerosis of the coronary arteries in young adults. First-degree family members are advised to seek medical advice and testing to determine their own risks of atherosclerosis to prevent premature CHD and SCD.     

Presence of psychoactive substances in oral fluid from randomly selected drivers in Denmark

The aim of this investigation was to identify and characterise pathogenic mutations in a sudden cardiac death (SCD) cohort suspected of cardiomyopathy in persons aged 0-40 years. The study material for the genetic screening of cardiomyopathies consisted of 41 cases and was selected from the case database at the Institute of Forensic Medicine. Mutational screening by DNA sequencing was performed to detect mutations in DNA samples from deceased persons suspected of suffering from hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricle cardiomyopathy (ARVC). A total of 9 of the examined 41 cases had a rare sequence variant in the MYBPC3, MYH7, LMNA, PKP2 or TMEM43 genes, of which 4 cases (9.8%) were presumed to be pathogenic mutations. The presumed pathogenic mutations were distributed with one case of suspected HCM and DCM (MYH7; p.R442H), one case of suspected DCM (LMNA; p.R471H), and two cases of suspected ARVC (PKP2; p.R79X and LMNA; p.R644C). The presented data adds important information on the genetic elements of SCD in the young, and calls for expert pathological evaluation and molecular autopsy in the post-mortem examination of SCD victims with structural anomalies of the heart.     

Study by next generation sequencing of sudden cardiac death (SCD)

Sudden cardiac death (SCD) is one of the most common causes of death; most SCD are related to secondary arrhythmias, to structural heart disease, or to primary electrical abnormalities of the heart.A significant number of SCD, especially among young people, are due to genetic heart disorders, both with structural and arrhythmogenic abnormalities. However SCD occurs also in patients with negative clinical history, autopsy is not always conclusive for a diagnosis.Recent technological advances in DNA sequencing, have led to the commercialization of genetic testing now widely available in clinical practice. In particular, next generation sequencing, allows the large-scale and rapid assessment of entire genomes.Analysis of SCD with a NGS panel of 174 genes was performed in our laboratory in order to identify the genetic causes and thus to direct the clinician to an accurate clinical and genetic screening of relatives.Two SDC were studied:Case 1: female, 57, without story of syncope and no previously highlighted cardiac alteration, died post cardiac arrest; negative family history. Autopsy was apparently negative.Case 2: male, 52, who died during a football game; negative family history, neurological episodes occurred before death was reported by close relative. Autopsy was positive for ventricular hypertrophic.In both cases we made a genetic diagnosis.     

新生儿呼吸系统疾病死亡的法医病理学分析

目的分析和探讨呼吸系统疾病引起新生儿死亡的病理学特点,为法医学死亡原因鉴定和相关医疗纠纷鉴定提供科学依据。方法回顾性总结分析1993～2008年16年间攀枝花市公安局尸检档案中85例新生儿死亡案例。结果呼吸系统疾病是引起新生儿死亡的首要因素（共56例,占65.88%）,其中新生儿吸入性肺炎20例（23.53%）、新生儿感染性肺炎14例（16.47%）、新生儿窒息12例（14.12%）、新生儿肺透明膜病6例（7.59%）、新生儿肺出血4例（4.71%）。结论新生儿尸检应重视呼吸系统的检查,根据新生儿发病特点和肺部病理变化明确临床诊断和死亡原因。     

Is there progress in the autopsy diagnosis of sudden unexpected death in adults?

Sudden death is now currently described as natural unexpected death occurring within 1h of new symptoms. Most studies on the subject focused on cardiac causes of death because most of the cases are related to cardiovascular disease, especially coronary artery disease. The incidence of sudden death varies largely as a function of coronary heart disease prevalence and is underestimated. Although cardiac causes are the leading cause of sudden death, the exact incidence of the other causes is not well established because in some countries, many sudden deaths are not autopsied. Many risk factors of sudden cardiac death are identified: age, gender, heredity factors such as malignant mutations, left ventricular hypertrophy and left ventricle function impairment. The role of the police surgeon in the investigation of sudden death is very important. This investigation requires the interrogation of witnesses and of the family members of the deceased. The interrogation of physicians of the rescue team who attempted resuscitation is also useful. Recent symptoms before death and past medical history must be searched. Other sudden deaths in the family must be noted. The distinction between sudden death at rest and during effort is very important because some lethal arrhythmia are triggered by catecholamines during stressful activity. The type of drugs taken by the deceased may indicate a particular disease linked with sudden death. Sudden death in the young always requires systematic forensic autopsy performed by at least one forensic pathologist. According to recent autopsy studies, coronary artery disease is still the major cause of death in people aged more than 35 years. Cardiomyopathies are more frequently encountered in people aged less than 35 years. The most frequent cardiomyopathy revealed by sudden death is now arrhythmogenic right ventricular cardiomyopathy also known simply as right ventricular cardiomyopathy (RVC). The postmortem diagnosis of cardiomyopathies is very important because the family of the deceased will need counseling and the first-degree relatives may undergo a possible screening to prevent other sudden deaths. In each case of sudden death, one important duty of the forensic pathologist is to inform the family of all autopsy results within 1 month after the autopsy. Most of the recent progress in autopsy diagnosis of sudden unexpected death in the adults comes from molecular biology, especially in case of sudden death without significant morphological anomalies. Searching mutations linked with functional cardiac pathology such as long-QT syndrome, Brugada syndrome or idiopathic ventricular fibrillation is now the best way in order to explain such sudden death. Moreover, new syndromes have been described by cardiologists, such as short-QT syndrome and revealed in some cases by a sudden death. Molecular biology is now needed when limits of morphological diagnosis have been reached.