Germinal mosaicism from grand-paternal origin in a family with Duchenne muscular dystrophy

Summary We have identified a Duchenne muscular dystrophy (DMD) pedigree with an unexpected pattern of inheritance. Using marker restriction fragment length polymorphisms detected by probes that lie within and outside the DMD gene, we could demonstrate that the maternal grandfather has transmitted two distinct types of X chromosomes to his offspring. This original observation may be explained by postulating that the DMD mutation must have occurred during mitosis in early germline proliferation, leading to a germline mosaicism within this male ancestor.     

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     

Germline and somatic mosaicism in a female carrier of Duchenne muscular dystrophy

The family of a male with Duchenne muscular dystrophy (DMD) and a deletion within the dystrophin gene has been studied. Polymerase chain reaction analysis of ectopic mRNA from peripheral blood T+B lymphocytes and the use of (CA) _n repeat polymorphisms in and around the deleted region showed the proband's mother to be both a germline mosaic and a somatic mosaic for the deletion seen in her son. The mutation therefore occurred as a mitotic event early in embryogenesis.     

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.     

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.     

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.     

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.     

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.     

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。