Recombinant DNA study of Duchenne muscular dystrophy occurring in a myotonic dystrophy family

A recombinant DNA study was performed in a three-generation family with 8 typical cases of late onset myotonic dystrophy (DM) and with one case of Duchenne muscular dystrophy (DMD). The study with DNA markers for chromosome 19 showed linkage of DM locus to the 3.8 Kb allele of apolipoprotein C2 (APOC2) probe and to 9 Kb allele of pSC11 probe (APOC2 lod score = 0.69 at theta = 0). The 21-year-old DMD patient showed no myotonic signs. His clinical history revealed onset with weakness around 4 years of age, progressive course with wheelchair confinement at 11, and cardiomyopathy. His karyotype was normal (46, XY). The study with 10 DNA markers for the chromosome X found a deletion limited to XJ 1.1, XJ 1.2, and XJ 2.3 probes. His 22-year-old sister with typical clinical, EMG and recombinant DNA findings characteristic for myotonic dystrophy was also a carrier of DMD deletion.     

Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule

The severe Duchenne and milder Becker muscular dystrophy are both caused by mutations in the DMD gene. This gene codes for dystrophin, a protein important for maintaining the stability of muscle-fiber membranes. In 1988, Monaco and colleagues postulated an explanation for the phenotypic difference between Duchenne and Becker patients in the reading-frame rule: In Duchenne patients, mutations induce a shift in the reading frame leading to prematurely truncated, dysfunctional dystrophins. In Becker patients, in-frame mutations allow the synthesis of internally deleted, but largely functional dystrophins. Currently, over 4700 mutations have been reported in the Leiden DMD mutation database, of which 91% are in agreement with this rule. In this study we provide an update of the mutational variability in the DMD gene, particularly focusing on genotype-phenotype correlations and mutations that appear to be exceptions to the reading-frame rule.     

Duchenne型肌营养不良症肌肉超微病理研究

目的:观察Duchenne型肌营养不良症(DMD)患者病变肌肉超微病理特征,从亚细胞水平上探讨其发病机制。方法:对临床确诊的7例DMD患者,通过肌肉活检进行超薄切片和冷冻复型透射电镜观察。结果:超薄切片电镜观察显示:(1)肌原纤维"Z"线模糊不清,肌原纤维过收缩、肌丝排列紊乱等变性、坏死。(2)肌纤维内线粒体空泡样变;糖原累积;肌浆网有程度不等的病变。(3)间质毛细血管内皮细胞肿胀、闭塞,血流瘀滞。冷冻复型电镜观察显示:粗细肌丝排列紊乱,膜蛋白颗粒大小不等的变化。结论:DMD时,肌细胞膜结构缺陷除可导致肌纤维变性、坏死外,还可致线粒体、糖原、肌浆网及肌原纤维板层体膜内颗粒等一系列亚细胞水平的变化;另外,血液循环障碍可导致肌细胞继发变性、坏死,推测在本病的发病中也起着重要作用。     

Medulloblastoma in a child with Duchenne muscular dystrophy

Materials and methods A 7-year-old boy diagnosed with Duchenne muscular dystrophy (DMD) presented with clinical features of raised intracranial tension. A CT scan revealed an enhancing vermian mass extending on to the fourth ventricle, which was excised and reported to be medulloblastoma. The patient was treated with craniospinal radiotherapy but progressed after 6 months. Discussion Neoplasms associated with DMD are rare and the present case may well be the first one with medulloblastoma. Interestingly, all neoplasms associated with DMD reported so far have been round cell tumors, which may lead to insights into their possible molecular associations.     

Assessment of locomotor function in young boys with Duchenne muscular dystrophy

Thirty-three young boys (mean age 3.42 years) with Duchenne muscular dystrophy (DMD) and 21 normal control boys (mean age 3.51 years) were studied prospectively to determine whether it is possible to objectively assess locomotor function in young boys with DMD so that they can be included in treatment trials. An initial reproducibility study using a hand-held myometer demonstrated that this method was not useful. The Hammersmith Motor Ability Score demonstrated an increase in developmental abilities with age which was markedly different from normal. The locomotor quotient of the Griffiths' Scales demonstrated a deterioration of quotient scores and is a useful method of assessment that could be used in treatment trials involving young boys with DMD. Sample size planning for treatment trials is discussed.     

自噬在Duchenne型肌营养不良中的研究

目的检测Duchenne型肌营养不良症(DMD)患者骨骼肌中LC3和p62的表达情况,分析自噬在DMD骨骼肌细胞坏死中的作用。方法收集2008年1月~2015年5月在我院就诊的病理确诊为DMD的患者(DMD组,81例),另以怀疑为肌病,但肌肉病理未见明显病变者为对照组(6例)。所有入选者均行心肌酶学、肌电图、骨骼肌活检常规组织学和酶学染色、抗dystrophin-N,-C,-R和抗dysferlin免疫组织化学染色。检测其中6例DMD患者及对照组骨骼肌中LC3和p62的表达。结果 81例DMD患者均为男性,起病年龄(4.60±2.35)岁,首发症状多以双下肢起病为主。血清肌酸激酶值的高峰出现在患者年龄的6~8岁,随着肌细胞明显坏死,肌酸激酶水平下降,但仍高于正常。在DMD患者骨骼肌中,组织病理均示典型肌营养不良改变。半定量Western blot提示DMD患者骨骼肌中LC3-II的表达降低,而p62表达显著升高。结论自噬功能障碍可能参与了DMD骨骼肌细胞坏死的病理生理过程。     

Scoliosis in Duchenne muscular dystrophy (DMD)

Scoliosis is a frequent complication in the non-ambulant patient with Duchenne muscular dystrophy (DMD). Weakness of the paraspinal muscles leads to trunk and body positional changes facilitating the development of a progressive collapsing scoliosis which inevitably interferes with comfortable sitting and may exacerbate deteriorating respiratory function. The recommended international standard of care for management of DMD includes strategies to prolong ambulation which may delay the onset of scoliosis. In the non-ambulant child there should be regular monitoring for scoliosis and, when present, surgical treatment should undertaken at an early stage. Careful multi-disciplinary pre-operative assessment and peri-operative care are essential.     

Functional evaluation of Duchenne muscular dystrophy: proposal for a protocol

A protocol for the evaluation of functional activities in subjects with Duchenne muscular dystrophy (DMD) was designed. The aim of our study was to define objective clinical criteria for the evaluation both of the clinical status of the patient and of the natural history of the illness itself. A protocol with such criteria is particularly necessary when testing the efficacy of treatment. 43 still-ambulant children with DMD between the ages of 3.10 yr and 10.4 yr were examined. Of this number 19 children were evaluated every 4 months over a period of 12 months; of these 14 formed part of a randomized double blind trial with L-carnitine (1.2–1.8 g/day) versus placebo.This work has been in part supported by a grant from the Dino and Enzo Ferrari Foundation for Muscular Dystrophy Research.     

IQ, prognosis and Duchenne muscular dystrophy

The verbal scales (VS-IQ) of the IQs of 25 boys with Duchenne muscular dystrophy, the total population in Western Australia older than five yrs, were recorded. All the results of those 20 yrs of age and older lay within the normal range. The mean VS-IQ of those less than 20 yrs and less than 18 yrs is compared with the mean VS-IQ of those 20 yrs and older, and 18 yrs and older, respectively. The differences between the groups are statistically significant, and it is postulated that an active management programme has revealed a population of boys with normal intelligence who have an increased chance of prolonged survival.     

Heterogeneity of dystrophin expression in patients with Duchenne and Becker muscular dystrophy

Summary This report documents the results of an integrated biochemical and immunocytochemical investigation into the expression of dystrophin (the protein product of the Duchenne muscular dystrophy gene) in muscle biopsies from 226 patients. It is the first study in which dystrophin has been analysed on blots and on tissue sections in such a large number of patients using the same (monoclonal) antibody. The 140 patients with Xp21 muscular dystrophy who were included in this study represent a continuous spectrum of disease severity and this range was reflected in the heterogeneity of dystrophin expression which was observed with respect to abundance, size and the pattern of tissue localisation. Approximately 40% of biopsies obtained from patients diagnosed as having Duchenne muscular, dystrophy (DMD) contained isolated clearly positive fibres and a further 20% had very weak labelling on a large number of fibres. Biopsies from patients with Becker muscular dystrophy (BMD) showed labelling patterns which varied from weak labelling on the majority of fibres to clear labelling on all fibres. Typically, however, there was inter-and intra-fibre variation in labelling intensity. Approximately 85% of the 52 BMD and 54 DMD patients who had unequivocal labelling on blots demonstrated a protein of abnormal size. The remaining 15% had a protein of normal size but reduced abundance. Overall, the estimated abundance of dystrophin correlated well with clinical assessments of the disease severity expressed in patients: We conclude that dystrophin analysis is an essential and dependable technique for the differential diagnosis of patients with Xp21 muscular dystrophy.Supported by the University of Newcastle-upon-Tyne Research Committee, the Muscular Dystropy Group of Great Britain and the Medical Research Council     

假肥大型肌营养不良症患者及携带者的致病基因突变检测

目的 检测假肥大型肌营养不良症患者及携带者的dystrophin基因致病突变类型,为防止假肥大型肌营养不良症的再发提供信息.方法 利用多重引物连接依赖式扩增技术和变性高效液相色谱技术检测临床研究发现的20例假肥大型肌营养不良症患者的DMD基因突变.结果 缺失突变10例,重复突变1例,终止密码子突变4例,5例未发现致病突变.结论 通过致病突变的检测可以为防止患者家庭假肥大型肌营养不良症的再发提供优生优育指导.     

Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy

Background

One of the main complications in patients with muscular dystrophies is cardiac dysfunction. The literature on cardiac involvement in patients with Fukuyama congenital muscular dystrophy (FCMD) is limited.

肌营养不良蛋白在假肥大肌营养不良症肌组织中的表达研究

目的检测假肥大肌营养不良症肌组织中肌营养不良蛋白（ｄｙｓｔｒｏｐｈｉｎ）的表达。方法用针对ｄｙｓｔｒｏｐｈｉｎ棒状区第１５～１８重复区域的多克隆抗血清Ａｎｔｉ５～７，对２２例Ｄｕｃｈｅｎｎｅ型（ＤＭＤ）和４例Ｂｅｃｋｅｒ型肌营养不良症（ＢＭＤ）患者及１１例无神经肌肉疾病的急诊外伤患者（作为对照）的肌组织进行免疫组化分析。结果在对照组肌细胞中ｄｙｓｔｒｏｐｈｉｎ存在着可达检测水平的表达，并特异地定位于肌细胞膜上。１９例ＤＭＤ没有可达检测水平的ｄｙｓｔｒｏｐｈｉｎ表达，３例ＤＭＤ存在着ｄｙｓｔｒｏｐｈｉｎ表达。４例ＢＭＤ肌细胞膜上则呈现出斑片状、不连续ｄｙｓｔｒｏｐｈｉｎ弱阳性表达。结论ｄｙｓ－ｔｒｏｐｈｉｎ的缺乏是造成ＤＭＤ／ＢＭＤ表型的基本生化因素，此方法为临床上对ＤＭＤ／ＢＭＤ患者作出确诊提供了直接的特异生化测试指标。     

A manifesting carrier of Duchenne muscular dystrophy with severe myocardial symptoms

Summary A 42-year-old so-called manifesting carrier of Duchenne muscular dystrophy (DMD), whose first complaints were severe myocardial symptoms, is described. Immunohistochemical study using anti-dystrophin antiserum and analysis of cloned segments of X chromosome DNA were performed. Her two sons and one of her brothers appear to have had the same disease. She was admitted to hospital complaining of dyspnoea, back pain and palpitations and was first diagnosed as having myocardial infarction. However, this diagnosis was excluded. The echocardiogram showed diffuse abnormalities of myocardial function. Serum enzymes were increased. Minimal weakness and decreased deep tendon reflexes were detected in her left lower extremity. Muscle biopsy revealed a small number of necrotic fibres. Immunohistochemical study using anti-dystrophin antiserum showed a mosaic pattern of the surface membrane. Analysis of cloned segments of X chromosome DNA from the patient and her son showed the XmnI(Asp) alleles of pERT 87-15 and the TaqI alleles of pERT 87-8 in both patients.     

Reliability of the Performance of Upper Limb assessment in Duchenne muscular dystrophy

The Performance of Upper Limb was specifically designed to assess upper limb function in Duchenne muscular dystrophy. The aim of this study was to assess (1) a cohort of typically developing children from the age of 3 years onwards in order to identify the age when the activities assessed in the individual items are consistently achieved, and (2) a cohort of 322 Duchenne children and young adults to establish the range of findings at different ages. We collected normative data for the scale validation on 277 typically developing subjects from 3 to 25 years old. A full score was consistently achieved by the age of 5 years. In the Duchenne cohort there was early involvement of the proximal muscles and a proximal to distal progressive involvement. The scale was capable of measuring small distal movements, related to activities of daily living, even in the oldest and weakest patients. Our data suggest that the assessment can be reliably used in both ambulant and non ambulant Duchenne patients in a multicentric setting and could therefore be considered as an outcome measure for future trials.     

干细胞移植治疗Duchenne型肌营养不良症的研究进展

Duchenne型肌营养不良症（duchenne muscular dystrophy，DMD）是最常见的X连锁隐性遗传性肌病，由位于Xp21的抗肌萎缩蛋白（dystrophy）基因突变引起dystrophy完全或部分缺失所致。该病主要见于男孩，发病率约3／10万活男婴。女性为致病基因携带者，所生男孩50％发病。患者一般3～5岁发病，主要表现为全身骨骼肌进行性无力、萎缩和小腿腓肠肌假性肥大。随着病情逐渐加重，12岁丧失行走能力，20岁左右因呼吸肌萎缩、无力，呼吸循环衰竭而死亡，迄今尚无有效的治疗方法。对症治疗、支持治疗、药物治疗、物理疗法和矫形治疗虽可预防及适度改善关节的畸形和挛缩，却未能有效的阻止病程的进展。对进行性肌营养不良患者而言，基因治疗和干细胞移植可望成为有效的治疗方法。近年来不少学者用骨髓或脐血干细胞移植治疗DMD模型鼠，其病理、生理、生化、抗肌萎缩蛋白表达和运动功能均有改善。     

Origins and early descriptions of "Duchenne muscular dystrophy"

One of the seminal events in the history of neurology was the identification of primary diseases of muscle and their separation from diseases in which muscle weakness was secondary to injury involving the anterior horns of the spinal cord ("progressive muscular atrophy"). Not surprisingly, one of the first groups of primary muscle diseases to be satisfactorily characterized belonged to what would today be classified as muscular dystrophies. Pride of place in this group belongs to Duchenne muscular dystrophy (DMD). DMD's primacy as the first well-characterized muscular dystrophy was due both to the fact that it is relatively common, as well as to the clinically striking feature, apparent in many cases, of apparent paradoxical enlargement of severely weakened muscles ("pseudo-hypertrophy"). This review traces the historical roots of DMD in the 19th century, from the early papers by Conte, Bell, Partridge, and Meryon through the classic monographs by Duchenne and Gowers. In addition, the first American contributions to DMD are reviewed, including those by Pepper, Hammond, and S. Weir Mitchell. Many of the original papers describing this disease are now unavailable outside of major medical libraries, and several important contributions, excepting those of Duchenne, which are recognized eponymously, are now virtually forgotten.     

Muscle hypertrophy in Duchenne muscular dystrophy

Summary In order to investigate the pathological basis of muscle hypertrophy in Duchenne dystrophy, 9 biopsy specimens of the lateral gastrocnemius and 7 of the vastus lateralis were compared. All patients had calf hypertrophy and normal strength in gastrocnemius-soleus, whereas the quadriceps biopsied were all atrophied and weak. The patients' ages ranged from 4 to 11 years. The pathological and histochemical changes were assessed semi-quantitatively. Comparison of the gastrocnemius and quadriceps groups showed that the number of hypercontracted fibres, the degree of endomysial fibrosis and the degree of fat infiltration were significantly higher in the quadriceps. The fibre type differentiation was better in the gastrocnemius group. The mean fibre diameter was above normal in all gastrocnemius biopsies and showed no increase with age. In the quadriceps, fibre hypertrophy was found early in the disease but had changed into fibre atrophy in the three oldest patients. When present, fibre hypertrophy involved both fibre types. The amount of fat-fibrosis per unit area was increased in both groups, but more severely so in the quadriceps. These results indicate that there is no true muscle hypertrophy in the gastrocnemius, in which the fat-fibrosis component was increased in all patients and that the dystrophic process is more active in the quadriceps. The finding of persistent fibre hypertrophy in the gastrocnemius is discussed with respect to the postural abnormalities observed in the lower limbs in Duchenne dystrophy.