Sporadic cases in Duchenne muscular dystrophy

Summary A new estimation of the proportion of sporadic cases in Duchenne muscular dystrophy was attempted by means of segregation analysis in a sample of 988 sibships collected on a world-wide scale by different authors. Maximum likelihood estimates of ascertainment probability (), segregation frequency (p), and frequency of sporadic cases (x) were calculated by Morton's equations under different hypotheses. The best fit was found for p=0.454±0.024 and x=0.235±0.034. The possibility that the proportion of sporadic cases might be lower than the expected 1/3 is suggested.     

Germinal mosaicism in Duchenne muscular dystrophy

Summary We have identified a Duchenne muscular dystrophy (DMD) pedigree where the disease is associated with a molecular deletion within the DMD locus. We have examined the meiotic segregation products of the common female ancestor using marker restriction fragment length polymorphisms (RFLPs) detected by probes that lie within this deletion. These studies show that this female has transmitted three distinet types of X chromosome to her offspring. This observation may be explained by postulating that the mutation arose as a postzygotic deletion within this common ancestor, who was consequently germinally mosaic.     

Plasma lipoproteins in Duchenne muscular dystrophy

Plasma lipoproteins of Duchenne muscular dystrophy patients and carriers of the disease, together with age- and sex-matched controls, were examined by density gradient ultracentrifugation and agarose gel electrophoresis. Analysis of density gradient profiles revealed a significant reduction in absorbance (435 nm) by low density and high density lipoproteins from Duchenne patients when compared with controls. Although no abnormalities were observed on electrophoresis of whole plasma samples, the isolated low density lipoprotein fractions from Duchenne patients and carriers displayed increased electrophoretic mobility compared with controls. The results obtained implicate the plasma lipoproteins, in particular the low density lipoproteins, as the primary site of the lesion in this disease.     

Duchenne型肌营养不良症发病机制

Duchenne型肌营养不良症是我国常见的X连锁隐性遗传性肌病。目前广泛应用的动物模型是mdx小鼠,但其没有很好地模拟人类疾病特点。最近,Sacco等报导了一个新的小鼠模型mdx/mTRG2,它不仅有抗肌萎缩蛋白的缺陷,还有端粒酶的缺失,较好地模拟了人类疾病的症状。通过该模型,人们认识到抗肌萎缩蛋白的缺陷引起肌细胞退化,肌肉干细胞被激活对抗其退化,但干细胞的过度增殖又导致端粒长度下降,引起肌肉干细胞增殖能力的衰竭,最终产生了肌营养不良的表型。该模型使人们对Duchenne型肌营养不良症的发病机制有了进一步的理解,为其治疗提供了新的研究平台。     

Creatine kinase, cell membrane and Duchenne muscular dystrophy

In 1958 Professor Setsuro Ebashi found that serum creatine kinase activity is increased in patients suffering from various muscular dystrophies, especially Duchenne muscular dystrophy (DMD). He and others proposed that creatine kinase passes through the cell membrane as it is released from DMD muscle fibers.Since then, it has been found that dystrophin and dystrophin-associated proteins are connected to several other components, including the basal lamina and subsarcolemmal cytoskeletal networks on the cell membrane, while dystrophin anchors these dystrophin-associated proteins to the actin filaments inside the muscle cell. In DMD muscle, dystrophin has been found to be absent and dystroglycans and sarcoglycans decreased. However, how creatine kinase molecules can pass through the DMD muscle cell membrane still remains unanswered.On the basis of recent findings on the structure of the protein layers which sandwich the lipid bilayer of muscle cell membranes, this essay stresses the importance of these lipid bilayers in protecting creatine kinase release from protoplasma in normal muscle. It further indicates the possibility that the absence of dystrophin in DMD muscle during muscle contraction may result in temporal damage to the lipid bilayer.     

The problem of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a lethal X-linked muscular disorder. The biochemical defect remains unknown, but the gene responsible has been mapped to band Xp21. The gene has now been cloned in two laboratories solely from knowledge of its map location. L. M. Kunkel and his colleagues isolated genomic sequences (PERT 87) from within a large deletion causing DMD, whereas our group isolated genomic sequences (XJ) spanning the junction of an X-autosome translocation causing the disease. Chromosome walking by both groups has led to the isolation of over 400 kilobases of the PERT 87 and XJ region. Subclones of PERT 87 and XJ reveal restriction fragment length polymorphisms that segregate with the DMD gene in 95% of meioses, and fail to hybridize with DNA from about 8% of male patients. Selected subclones of PERT 87 and XJ contain exons that hybridize to muscle-derived complementary DNA (cDNA) clones. The cDNA clones detect a large (16 kilobase) message. Analysis of deletions, mutations and translocations suggests a DMD gene of between two million and three million base pairs. The clones obtained so far are useful for attempts to generate antibody against the gene product and for carrier identification and prenatal diagnosis.     

Segregation analysis of a marker localised Xp21.2-Xp21.3 in Duchenne and Becker muscular dystrophy families

Summary A DNA marker C7, localised Xp21.1-Xp21.3, has been studied in kindreds segregating for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). In DMD families four crossovers were observed in 38 informative meioses between C7 and the DMD locus (=0.12, z _max=+2.72). In BMD families no recombinants were observed in the 16 informative meioses studied. These data are consistent with the localisation of the mutations in these disorders being in the same region of Xp21.Studies in families also segregating for the DNA marker 754 support the previously reported physical order of these loci as X centromere-754-DMD-BMD-C7-X telomere. A recombination fraction of 0.11 (z _max=+5.58) was found between DMD-754 by combining our previously published data with the data presented here. C7 and 754 thus provide good bridging markers for the diagnosis of DMD and BMD.     

Cell therapy prospects in Duchenne muscular dystrophy

Skeletal muscle is made of multinucleated postmitotic fibers which are the agents of contraction. These fibers arise from mononuclear precursor cells which fuse after having migrated from the somites to the site of myogenesis. The cascade of events which result in muscle differentiation is well known nowadays (Sabourin & Rudnicki, 2000). Some precursor cells present in adults muscle are termed satellite cells (Mauro, 1961), because of their location between the plasma membrane and the extracellular matrix of muscle fibers. Since they have a role in muscle growth and regeneration, these cells were the first candidates for treating muscle dystrophies. Despite a large corpus of positive experimental data about transplantation of these cells, no hard clinical result has been obtained to date, However these investigations have led to fruitful thinking about heterogeneity of muscle cell precursors and the possible ways to use them for therapy.     

Muscle adenylate kinase in Duchenne muscular dystrophy

On the basis of electrophoretic and enzyme inhibition studies it was postulated that an aberrant adenylate kinase occurs in muscle and serum of patients with Duchenne muscular dystrophy (Schirmer, R.H. and Thuma, E. (1972) Biochim. Biophys. Acta 268, 92-97; Hamada, M. et al. (1981) Biochim. Biophys. Acta 660, 227-237; Hamada et al. (1985) J. Biol. Chem. 260, 11595-11602). On the basis of the following results we conclude that Duchenne muscular dystrophy patients do not possess an unusual adenylate kinase isoenzyme. In muscle biopsies from five Duchenne patients, the electrophoretic mobility of adenylate kinase and the inhibition of the enzyme by P1, P5-di(adenosine-5')pentaphosphate (Ap5A) was normal. Because of the high SH-group content of the extracts from Duchenne muscle, high concentrations of Ellman's reagent were needed to inhibit adenylate kinase activity in these samples. In Duchenne plasma the adenylate kinase activity was elevated. Like in muscle specimens, the DTNB inhibition curves were shifted to higher reagent concentrations; this was due to a high SH-group content of Duchenne plasma when compared with normal plasma. With respect to inhibition by Ap5A and electrophoretic mobility, Duchenne adenylate kinase in Duchenne plasma behaved like normal muscle adenylate kinase in normal plasma. It was noted that normal muscle adenylate kinase changes its electrophoretic behaviour when mixed with normal or Duchenne plasma. This finding had been considered previously as evidence for the presence of an aberrant adenylate kinase in Duchenne plasma.     

Advances in Duchenne muscular dystrophy gene therapy

Since the initial characterization of the genetic defect for Duchenne muscular dystrophy, much effort has been expended in attempts to develop a therapy for this devastating childhood disease. Gene therapy was the obvious answer but, initially, the dystrophin gene and its product seemed too large and complex for this approach. However, our increasing knowledge of the organization of the gene and the role of dystrophin in muscle function has indicated ways to manipulate them both. Gene therapy for Duchenne muscular dystrophy now seems to be in reach.     

NO vascular control in Duchenne muscular dystrophy

A new investigation into Duchenne muscular dystrophy (DMD) pathogenesis suggests that at least part of the muscle degeneration observed in DMD patients may result from the reduced production of muscle membrane-associated neuronal nitric oxide synthase. This reduction may lead to impaired regulation of the vasoconstrictor response and eventual muscle damage.