Duchenne muscular dystrophy models show their age

The lack of appropriate animal models has hampered efforts to develop therapies for Duchenne muscular dystrophy (DMD). A new mouse model lacking both dystrophin and telomerase (Sacco et?al., 2010) closely mimics the pathological progression of human DMD and shows that muscle stem cell activity is a key determinant of disease severity.     

Duchenne muscular dystrophy

Summary By a general survey in the hospitals of northeast Italy, Duchenne cases have been located and identified over a 20-year period.In a more restricted area screening for Duchenne carriers has been carried out in affected families. This procedure made possible an exact estimate of the incidence rate, prevalence rate, and mutation rate in a large sample of population. Prevalence rate was found to be 34x10^-6, incidence rate about 28x10^-5, while mutation rate was found lower than 50x10^-6 by the direct method.The discrepancy between the results obtained by the Haldane formula and those obtained by the direct method for the estimate of the mutation rate is discussed.     

Duchenne muscular dystrophy

Summary In an extensive epidemiological survey of Duchenne muscular dystrophy carried out in Venetia (Italy) the incidence was found to be 28.2×10^-5 and female gamete mutation rate was estimated by the direct method between 61 and 35×10^-6. The percentage of isolated cases was 0.54. Indirect and direct estimates of this proportion suggest, however, that only a minor fraction arises from maternal mutation (from 0.11 to 0.18 of the total number of cases). Studies on pedigrees collected in the course of the survey indicate that there is a higher frequency of Duchenne carrier females than normal females in affected sibships. Additional evidence supporting the hypothesis of a reproductive heterozygote advantage and gametic selection is reported.This work was supported by an MDA grant and by funds from the Italian Muscular Dystrophy Assoc. (UILDM)     

Duchenne muscular dystrophy

Summary A segregation analysis on 135 Duchenne families from Venetia (Italy) suggests that the proportion of sporadic cases might be less than expected. Support for this view is also given by an analysis of a pooled sample including 284 additional sibships from comparable studies published previously. Several hypotheses were tested: the maximum likelihood was obtained for a segregation frequency p=0.46 and for a proportion of sporadic cases x=0.227±0.048.Dedicated to Professor G. Montalenti in the occasion of his 80th birthday     

Duchenne muscular dystrophy.

Progress in understanding the role of dystrophin raises promising hopes for a treatment for Duchenne muscular dystrophy. In addition, great improvements have been made in the ability to diagnose this disease using simple molecular methods.     

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.     

Hypokalemia complicating Duchenne muscular dystrophy

Although patients with Duchenne muscular dystrophy (DMD) have been shown to have decreased total body potassium levels, serum potassium levels have generally been though to be within normal limits. We report two siblings with DMD noted to be hypokalemic in conjunction with a respiratory illness. Hypokalemia may have exacerbated the pre-existing pulmonary insufficiency in these patients. The literature concerning hypokalemia and DMD is reviewed, and recommendations for the closer monitoring of serum potassium levels in patients with DMD are presented.     

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.     

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。     

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.