杜氏进行性肌营养不良的临床实践指南

杜氏进行性肌营养不良(Duchenne muscular dystrophy,DMD)是最常见的X连锁隐性遗传性肌肉变性疾病,在男性新生儿中的发病率约为1/3500。DMD是由于Xp21.2区的抗肌萎缩蛋白基因(dystrophin,DMD)突变所致,患者的主要临床表现包括进行性、对称性肌无力。由于呼吸肌和心肌受累,通常在30岁前死亡。通过基因检测,可以为93.1%的患者找到遗传学病因,为早期治疗和指导家庭成员的生育奠定基础,有利于改善患者的生存质量,预防这些家庭再次生育DMD患儿。本指南结合了国内外的相关研究和指南共识,总结了DMD相关的医学遗传学知识和临床处置要点,期望能给予临床工作者帮助,为DMD患者及其家庭提供规范的诊断、治疗和预防。     

毛细管电泳多重PCR诊断杜氏/贝氏进行性肌营养不良

目的用毛细管电泳技术结合多重PCR方法分析DMD基因缺失位点,以建立一种快速、准确、适用于临床的DMD的诊断技术.方法将对缺失热区18对引物分成两套,用毛细管电泳分析7个DMD/BMD家系中的7名患者的二步多重PCR产物.结果毛细管电泳能快速、准确分离18对引物多重PCR产物,判断出DMD基因缺失位点.结论毛细管电泳定量PCR方法能高效、准确、快速诊断缺失型DMD患者,具有很好临床应用价值.     

基因移植与进行性肌营养不良

进行性肌营养不良（ｐｒｏｇｒｅｓｉｖｅｍｕｓｃｕｌａｒｄｙｓ－ｔｒｏｐｈｙ）是一组原发性肌肉的遗传性病变，临床主要表现为进行性肌力减退和萎缩。根据其临床特点又可分为Ｄｕｃｈｅｎｎｅ型（ＤＭＤ）及Ｂｅｃｋｅｒ型（ＢＭＤ）两类。ＤＭＤ属性连锁隐性遗传性肌...     

进行性肌营养不良4例家系分析

进行性肌营养不良４例家系分析杭州市妇幼保健院（３１０００１）周兆梅进行性肌营养不良症是一种遗传性、进行性肌肉变性疾病。本资料收集４例均为Ｘ－连锁遗传Ｄｕｃｈｅｎｎｅ肌营养不良症（简称ＤＭＤ）。分别对其遗传因素的家系作一分析。病例与家系例１：男，３岁，...     

缺失型杜氏肌营养不良症缺失热区内含子断裂点分子结构特点的对比分析

目的 对比分析缺失型杜氏肌营养不良症(Duchenne muscular dystrophy，DMD)缺失热区第46号和51号外显子缺失后形成的连接片段的断裂点的分子结构特点，以研究DMD基因外显子的缺失机理。方法 多重引物PCR法鉴定缺失型DMD患者，分别克隆第46、51号外显子缺失后形成的连接片段，测定断裂点侧翼的核苷酸序列。结果第46号外显子缺失后，5’端断裂点位于45号内含子的AT富含区内。3’端断裂点位于46号内含子的中等重复序列(medium reiteration repeats，MERl)内。连接片段有两个bp的连接同源序列ta，局部无小的缺失、插入和碱基的置换。第51号外显子缺失后，5’端断裂点位于50号内含子的人类类转座因子(transposon-like human elements，THEl)序列内。3’端短裂点位于51号内含子L2序列内。连接片段有3个bp的连接同源序列cta，局部无小的缺失、插入和碱基的置换。第46、51号外显子缺失后连接片段的断裂点的二级结构分析示断裂点均位于单链发夹环的非匹配区。结论 对比第46、51号外显子缺失后形成的连接片段，其断裂点的共同特征是均位于重复序列，这些重复序列形成的单链发夹结构，使DNA结构具有不稳定性，易于断裂并导致外显子缺失。     

蓝山地区进行性肌营养不良3例报告

进行性肌营养不良 (ｐｒｏｇｒｅｓｉｖｅｍｕｓｃｕｌａｒｄｙｓｔｒｏｐｈｙ) ,这是一种原发性肌肉遗传性病变 ,是进行性发展 ,遗传方式为Ｘ连锁隐性遗传。根据其临床特点又分为Ｄｕｃｈｅｎｎｅ型肌营养不良 (ＤＭＤ)和Ｂｅｃｋｅｒ型肌营养不良 (ＢＭＤ)两类。病例　家系 1:先证者 ,男 6岁 ,足月顺产 ,2岁前与正常儿无异 ,2岁后呈进行性肌萎缩 ,鸡胸进行性加重 ,5岁时出现双下肢乏力 ,下蹲后不能起来 ,易跌倒 ,逐渐加重 ,双亲非近亲婚配 ,女方舅舅有类似病史 ,18岁死亡 ,查 :神清 ,无明显假性肥大 ,双下肢肌力ＩＶ级 ,Ｇｏｗｅｒ征 ( ) …     

遗传性进行性肌营养不良的临床分析

本文对12例进行性肌营养不良症进行临床、病理、肌电图分析,与遗传有关的探讨,其中10例做活检,肌束内有脂肪的准聚的肌纤维增粗、肥大、变性。     

杜氏肌营养不良新生儿筛查及诊断策略研究

目的:探究将肌型肌酸激酶同工酶(MM isoenzyme of creatine kinase,CK-MM)检测用于筛查新生儿杜氏肌营养不良症(Duchenne muscular dystrophy,DMD)的可行性。方法:对10 252例男性新生儿干血斑的CK-MM含量进行测定,将结果按孕周、采血时间、实验间隔时间分...     

进行性肌营养不良39例临床及肌电图分析

进行性肌营养不良是一组原发于肌肉的遗传性疾病。主要临床特征为进行性加重的肌肉萎缩和无力。现将我院1993年至 2 0 0 1年收治的 3 9例进行性肌营养不良患者的临床及肌电图特点分析如下。1　病例资料一般资料 :3 9例中男 2 8例 ,女 11例 ,男女比例为 2 .5比1,年龄 2～ 3 1岁 ,平均 8岁 ,其中≤ 5岁 8例 ,6～ 10岁 2 3例 ,11～ 2 0岁 6例 ,≥ 2 1岁 2例。病程 1个月至 15年 ,平均 3 .5年。有阳性家族史的 6例中 ,1例仅其兄患同样疾病 ,1例母系三代人中有 9名男性 ,已有 5例患病。临床表现 :2 6例先有下肢肌无力 ,上楼困难 ,易摔跤 ,行走如…     

Duchenne型肌营养不良的治疗进展

进行性肌营养不良是一组遗传性肌肉变性疾病,以Duchenne型肌营养（DMD）不良最常见,目前尚无有效的治疗方法,本文从药物疗法、成肌细胞移植疗法以及基因移植疗法3方面介绍了国外近几年关于DMD的治疗进展。     

第二代测序技术在假肥大型肌营养不良基因诊断中的应用

目的 对假肥大型肌营养不良患者进行基因检测.方法 采用目标区序列捕获及第2代高通量测序技术对6例假肥大型肌营养不良患者进行检测;采用第1代测序技术、多重连接依赖的探针扩增技术(multiplex ligation-dependent probe amplification,MLPA)对患者及其母亲的基因型进行验证.结果 1例为第10和11外显子缺失,1例为第16和17外显子重复,4例为点突变.共发现10种变异:c.2776C＞T、c.5475delA、c.6391_ 6392delCA、IVS64+1G＞A、c.2645A＞G、c.5244G＞A、c.7728T＞C、c.8729A＞T、e.8734A＞G和c.8810G＞A,前4种为可疑致病性变异,后6种为人群中的多态.其中3例为首次发现的新突变(IVS64+1G＞A、c.6391_6392delCA(p.Q2131NfsX3)和p.Q926X(CAG＞TAG).结论 通过第2代测序技术可以在一个反应中准确检测出DMD基因的缺失、重复和点突变,具有一定的临床应用价值.     

脊髓性肌萎缩症的临床实践指南

脊髓性肌萎缩症(spinal muscular atrophy,SMA)为最常见的婴幼儿致死性常染色体隐性遗传病之一,由运动神经元存活基因1(SMN1)突变所致,新生儿发病率为1/10000〜1/6000,人群携带率约为1/72〜1/47,且具有种族差异性。临床表现为进行性、对称性、以肢体近端为主的肌无力和肌萎缩,根据发病时间与临床表型又分为Ⅰ〜Ⅳ型。约95%的SMA患者是由于SMN1基因第7外显子的纯合缺失所致。患者表型差异大、SMN1基因拷贝数变化多、存在假基因干扰、人群携带率高等因素,给SMA的早期诊断、遗传咨询、治疗和预防造成了较大的闲难。本指南总结了国内外的相关研究和指南共识,并结合中国人群的实际情况,介绍了SMA患者的临床表现和发病机制,总结了诊断与遗传咨询等方面的相关经验,期望对临床医师及相关工作者有所帮助,以促进SMA的规范诊治,降低患儿的出生率。     

A study of possible heterogeneity in Duchenne muscular dystrophy

One possible explanation for the apparently high birth incidence of Duchenne muscular dystrophy (DMD), a lethal X-linked disorder, is genetic heterogeneity. As a first step in possibly demonstrating genetic heterogeneity, affected boys were sub-divided into those with and without severe mental handicap. In those with severe mental handicap, ages at onset and of becoming confined to a wheelchair were later, the fall in SCK level with age was less marked, and the urinary excretion of certain aminoacids was greater than in affected boys with normal intelligence. Though the number of subjects investigated was relatively small (15 in each group) and further studies are therefore needed, the results suggest that DMD may not be a single disease entity.     

外显子跳跃治疗Duchenne型肌营养不良症的研究进展

Duchenne型肌营养不良症是一种致死性肌肉疾病,抗肌萎缩蛋白基因缺陷是导致本病的原因,目前本病尚无特效的疗法.反义寡核苷酸(antisense oligonucleotides,AOs)诱导的外显子跳跃作为一种新的治疗手段具有良好的应用前景.本文主要从外显子跳跃治疗的原理、基础研究及临床研究进行综述.     

Genetic epidemiology of Duchenne and Becker muscular dystrophy in Slovenia

Most population studies on Duchenne (DMD) and Becker (BMD) muscular dystrophies predated the discovery of the gene and its product dystrophin. The diagnosis of these conditions and consequent epidemiological estimates were therefore limited to clinical criteria. In our study of the Slovene population the prevalence and cumulative incidence of DMD and BMD were calculated by including additional diagnostic tests: deletion screening in the dystrophin gene as well as dystrophin immunocytochemistry. The minimal prevalence rates, 2.9/100000 for DMD, 1.2/100000 for BMD, and the minimal cumulative DMD incidence rate of 13.8/100000 are in the range of lower estimates compared to studies world-wide. However, we found a high BMD cumulative incidence rate of 5.7/100000 and a high proportion of BMD versus DMD cumulative incidence rate (41.3%). Our results imply that the epidemiological figures for BMD might have been underestimated in the past.     

DGGE-based whole-gene mutation scanning of the dystrophin gene in Duchenne and Becker muscular dystrophy patients

Duchenne and Becker muscular dystrophy (DMD and BMD) are caused by mutations in the dystrophin gene. Large rearrangements in the gene are found in about two-thirds of DMD patients, with approximately 60% carrying deletions and 5-10% carrying duplications. Most of the remaining 30-35% of patients are expected to have small nucleotide substitutions, insertions, or deletions. To detect these subtle changes within the coding and splice site determining sequences of the dystrophin gene, we established a semiautomated denaturing gradient gel electrophoresis (DGGE) mutation scanning system. The DGGE scan covers the dystrophin gene with 95 amplicons, PCRed either individually or in a multiplex setup. PCR and pooling were performed semiautomatically, using a pipetting robot and 384-well plates, enabling concurrent amplification of DNA of four patients in one run. Amplification of individual fragments was performed using one PCR program. The products were pooled just before gel loading; DGGE requires only a single gel condition. Validation was performed using DNA samples harboring 39 known DMD variants, all of which could be readily detected. DGGE mutation scanning was applied to analyze 135 DMD/BMD patients and potential DMD carriers without large deletions or duplications. In DNA from 25 out of 44 DMD patients (57%) and from 5 out of 39 BMD patients (13%), we identified clear pathogenic changes. All mutations were different, with the exception of one DMD mutation, which occurred twice. In DNA from 10 out of 44 potential DMD carriers, including four obligate carriers, we detected causative changes, including one pathogenic change in every obligate carrier. In addition to these pathogenic changes, we detected 15 unique unclassified variants, i.e., changes for which a pathogenic nature is uncertain.     

Molecular deletions in the Duchenne/Becker muscular dystrophy gene

To gain further information relating to the frequency, position and size of DNA deletions in the Duchenne/Becker muscular dystrophy (D/BMD) gene region, and to detect any correlation of these deletions with phenotype, a large clinic-based population of DMD and BMD patients has been investigated using 13 cloned intragenic sequences. Our of 263 separate patients studied, 75 showed a deletion of at least one locus (28.5%). These represented 25.6% (55/215) of DMD patients and 41.7% (20/48) of BMD patients, suggesting that the milder phenotype is more often likely to be due to a deletion. The deletions range from 6 kilobases (kb) to greater than 1000 kb in size. The distribution of deletions across the gene region shows at least one region (detected by P20) prone to deletion mutations in both DMD and BMD patients. There is no simple correlation of position or extent of deletions with DMD or BMD, although deletion of a specific region towards the 5' end of the gene may be more often associated with a milder phenotype. Apparently similar deletions can give rise to phenotypes differing significantly in severity, presumably indicating further complexities in the molecular or cellular pathology.     

Theoretic applicability of antisense‐mediated exon skipping for Duchenne muscular dystrophy mutations

Antisense‐mediated exon skipping aiming for reading frame restoration is currently a promising therapeutic application for Duchenne muscular dystrophy (DMD). This approach is mutation specific, but as the majority of DMD patients have deletions that cluster in hotspot regions, the skipping of a small number of exons is applicable to relatively large numbers of patients. To assess the actual applicability of the exon skipping approach, we here determined for deletions, duplications and point mutations reported in the Leiden DMD mutation database, which exon(s) should be skipped to restore the open reading frame. In theory, single and double exon skipping would be applicable to 79% of deletions, 91% of small mutations, and 73% of duplications, amounting to 83% of all DMD mutations. Exon 51 skipping, which is being tested in clinical trials, would be applicable to the largest group (13%) of all DMD patients. Further research is needed to determine the functionality of different in‐frame dystrophins and a number of hurdles has to be overcome before this approach can be applied clinically. Hum Mutat 0, 1–7, 2009. © 2009 Wiley‐Liss, Inc.     

应用DNA微阵列技术检测缺失型DMD/BMD患者的研究

目的研究Duchenne型肌营养不良（DMD）/Becker型肌营养不良（BMD）患者基因缺失检测的可行技术。方法应用分子克隆的方法扩增DMD基因18个常见易缺失外显予片段，以此作为探针制备出简易DNA微阵列，对30例DMD/BMD患者和5例健康对照的基因进行检测分析。部分结果与PCR方法比较结果一致性。结果应用简易DNA微阵列检测出21例DMD/BMD患者具有不同程度的外显予缺失，10例经PCR检测得到了完全验证。结论DNA微阵列技术检测缺失型DMD/BMD患者简便、准确、灵敏，具有临床应用价值。     

Duchenne muscular dystrophy and myotonic dystrophy in the same patient

We report on the first patient identified with myotonic dystrophy and Duchenne muscular dystrophy (DMD). The family of the propositus had a strong history of myotonic dystrophy, and there was an intrafamilial pathological expansion of the responsible CTG repeat between the mildly affected mother (160 repeats; normal 27 repeats) and her more severely affected son (650 repeats), and his sister (650 repeats). The propositus was an isolated case of Duchenne muscular dystrophy with marked dystrophin deficiency in muscle biopsy. The patient was still ambulatory post age 16. Myotonic dystrophy could interfere to some extent with the progression of Duchenne dystrophy. However, other interpretations are possible. Twelve percent of dystrophin revertant fibers as observed by immunohistochemistry could be sufficient to ameliorate typical DMD clinical severity, or the patient may present a somatic mosaic. The pathophysiological interactions of these two unlinked disorders are discussed at the clinical and histopathological levels. © 1995 Wiley-Liss, Inc.