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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by the lack of expression of the dystrophin protein in muscle tissues. We genetically engineered a mouse model (mdx) of DMD that allowed for the high level and inducible transcription of a dystrophin mini-gene. This was achieved via the tetracycline-responsive transactivator (tTA) system. Multiple analyses confirmed that dystrophin expression in the mice was: (i) tTA dependent; (ii) correctly localized to the sarcolemmal membranes; (iii) capable of preventing the onset of dystrophy; and (iv) effectively blocked by the oral administration of tetracyclines. The model allowed us to somatically extinguish or induce dystrophin gene transcription. Somatic induction of dystrophin transcription prevented the onset of muscular dystrophy in some muscle groups. The levels of phenotypic rescue were influenced, however, by the age of the animals at the time of dystrophin induction. We also found that despite somatic termination of dystrophin gene transcription, the dystrophin protein was found to be associated with the sarcolemmal membrane for at least 26 weeks. Persistent detection of dystrophin was also accompanied by a prolonged protection of the muscle cells from the onset of dystrophy. The findings demonstrated that somatic transfer of the dystrophin gene not only may allow for the prevention of muscular dystrophy in multiple muscle groups, but also may be accompanied by persistent efficacy, secondary to the long-term functional stability of the dystrophin protein in vivo. This model should be useful in future studies concerning the potential of genetic therapy for DMD, as well as other muscle disorders.
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PMID:Mdx mice inducibly expressing dystrophin provide insights into the potential of gene therapy for duchenne muscular dystrophy. 1103 Jul 55

The experience of DNA-diagnosis of X-linked recessive Emery-Dreifuss muscular dystrophy for the first time made in Russia is presented. A search for mutations in emerin gene responsible for the disease has been conducted in 13 blood samples of male patients with clinical diagnosis of various muscular dystrophy. Mutations were found in 2 patients. In one of them clinical diagnosis of Emery-Dreifuss muscular dystrophy was confirmed. In the other, a novel mutation was described that allowed to change a clinical diagnosis of limb girdle muscular dystrophy. X-linked and clinically identical autosomal-dominant forms of Emery-Dreifuss muscular dystrophy are characterized by pronounced clinical polymorphism complicating clinical diagnosis. DNA-diagnosis principally extends possibilities for early diagnosis of this disorder that is extremely important for prevention of severe and frequently lethal heart diseases.
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PMID:[DNA-diagnosis of Emery-Dreifuss muscular dystrophy]. 1287 22

1. Duchenne muscular dystrophy (DMD) is a severe disease of skeletal muscle, characterized by an X-linked recessive inheritance and a lack of dystrophin in muscle fibres. It is associated with progressive and severe wasting and weakness of nearly all muscles and premature death by cardiorespiratory failure. 2. Studies investigating the susceptibility of dystrophic skeletal muscles to contraction-mediated damage, especially after lengthening actions where activated muscles are stretched forcibly, have concluded that dystrophin may confer protection to muscle fibres by providing a mechanical link between the contractile apparatus and the plasma membrane. In the absence of dystrophin, there is disruption to normal force transmission and greater stress placed upon myofibrillar and membrane proteins, leading to muscle damage. 3. Contraction protocols (involving activation and stretch of isolated muscles or muscle fibres) have been developed to assess the relative susceptibility of dystrophic (and otherwise healthy) muscles to contraction-induced injury. These protocols have been used successfully to determine the relative efficacy of different (gene, cell or pharmacological) interventions designed to ameliorate or cure the dystrophic pathology. More research is needed to develop specific 'contraction assays' that will assist in the evaluation of the clinical significance of different therapeutic strategies for muscular dystrophy.
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PMID:Role of contraction-induced injury in the mechanisms of muscle damage in muscular dystrophy. 1529 51

Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy type 1B (LGMD1B) are characterized by cardiac dysrhythmias, late-onset cardiomyopathy, slowly progressive skeletal myopathy and contractures of the neck, elbows and ankles. The causative mutation is either in the emerin gene (X-linked recessive EDMD) or lamin A/C gene (autosomal dominant EDMD2 or LGMD1B). We report three cases of EDMD, EDMD2 and LGMD1B. A 14-yr-old boy showed limitation of cervical flexion and contractures of both elbows and ankles. Sinus arrest with junctional escape beats was noted. He was diagnosed as X-linked recessive EDMD (MIM 310300). A 28-yr-old female showed severe wasting and weakness of humeroperoneal muscles. Marked limitation of cervical flexion and contractures of both elbows and ankles were noted. Varying degrees of AV block were noted. She was diagnosed as autosomal dominant EDMD2 (MIM 181350). A 41-yr-old female had contractures of both ankles and limb-girdle type muscular dystrophy. ECG revealed atrial tachycardia with high grade AV block. She was diagnosed as autosomal dominant LGMD1B (MIM 159001). Cardiac dysrhythmias in EDMD and LGMD1B include AV block, bradycardia, atrial tachycardia, atrial fibrillation, and atrial standstill, causing sudden death necessitating pacemaker implantation. Cardiologists should know about these unusual genetic diseases with conduction defects, especially in young adults.
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PMID:Cardiac dysrhythmias,cardiomyopathy and muscular dystrophy in patients with Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B. 1583 2

Mutations of lamin A/C (LMNA) cause a wide range of human disorders, including progeria, lipodystrophy, neuropathies and autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD). EDMD is also caused by X-linked recessive loss-of-function mutations of emerin, another component of the inner nuclear lamina that directly interacts with LMNA. One model for disease pathogenesis of LMNA and emerin mutations is cell-specific perturbations of the mRNA transcriptome in terminally differentiated cells. To test this model, we studied 125 human muscle biopsies from 13 diagnostic groups (125 U133A, 125 U133B microarrays), including EDMD patients with LMNA and emerin mutations. A Visual and Statistical Data Analyzer (VISDA) algorithm was used to statistically model cluster hierarchy, resulting in a tree of phenotypic classifications. Validations of the diagnostic tree included permutations of U133A and U133B arrays, and use of two probe set algorithms (MAS5.0 and MBEI). This showed that the two nuclear envelope defects (EDMD LMNA, EDMD emerin) were highly related disorders and were also related to fascioscapulohumeral muscular dystrophy (FSHD). FSHD has recently been hypothesized to involve abnormal interactions of chromatin with the nuclear envelope. To identify disease-specific transcripts for EDMD, we applied a leave-one-out (LOO) cross-validation approach using LMNA patient muscle as a test data set, with reverse transcription-polymerase chain reaction (RT-PCR) validations in both LMNA and emerin patient muscle. A high proportion of top-ranked and validated transcripts were components of the same transcriptional regulatory pathway involving Rb1 and MyoD during muscle regeneration (CRI-1, CREBBP, Nap1L1, ECREBBP/p300), where each was specifically upregulated in EDMD. Using a muscle regeneration time series (27 time points) we develop a transcriptional model for downstream consequences of LMNA and emerin mutations. We propose that key interactions between the nuclear envelope and Rb and MyoD fail in EDMD at the point of myoblast exit from the cell cycle, leading to poorly coordinated phosphorylation and acetylation steps. Our data is consistent with mutations of nuclear lamina components leading to destabilization of the transcriptome in differentiated cells.
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PMID:Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration. 1647 98

Emery-Dreifuss muscular dystrophy (EDMD) is an inherited muscular disorder clinically characterized by slowly progressive weakness affecting humero-peroneal muscles, early joint contractures and cardiomyopathy with conduction defects. Autosomal dominant and recessive forms are caused by mutations in lamin A/C gene. Lamin A/C is a major component of nuclear lamina, and its gene mutations cause several human disorders including muscular dystrophy, cardiomyopathy, lipodystrophy, neuropathy, and progeria syndrome. X-linked recessive form of EDMD is caused by mutation in EMD (or STA) gene encoding an integral protein of the inner nuclear membrane. Emerin expresses ubiquitously, but its deficiency affects only limited tissues of skeletal and cardiac muscles and joints. In this paper, I will focus on clinical and pathological aspects of X-EDMD and possible functions of emerin.
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PMID:X-linked form of Emery-Dreifuss muscular dystrophy. 1655 Sep 25

Cardiomyopathy is a frequent occurrence in muscular dystrophy, and heart disease in muscular dystrophy can contribute to both morbidity and mortality. A number of novel therapies are being developed for muscular dystrophy, and the efficacy of these therapies for heart disease is unknown. The most common X-linked recessive disease is Duchenne muscular dystrophy (DMD), which arises from defects in the dystrophin gene. Therapy specifically aimed at DMD is reviewed in the context of its projected effect on cardiomyopathy associated with DMD. Additionally, novel therapies are being pursued to treat specifically the cardiomyopathy of DMD. There is substantial genetic heterogeneity underlying the muscular dystrophies, and not all muscular dystrophy patients develop cardiomyopathy. A subset of muscular dystrophies may place patients at significantly greater risk of developing cardiomyopathy and cardiac rhythm disturbances. These disorders are discussed, highlighting recent studies and recommendations for therapy.
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PMID:New approaches in the therapy of cardiomyopathy in muscular dystrophy. 1721 26

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy. There is no effective treatment and patients typically die in approximately the third decade. DMD is an X-linked recessive disease caused by mutations in the dystrophin gene. There are three mammalian models of DMD that have been used to understand better the pathogenesis of disease and develop therapeutic strategies. The mdx mouse is the most widely used model of DMD that displays some features of muscle degeneration, but the pathogenesis of disease is comparatively mild. The severity of disease in mice lacking both dystrophin and utrophin is similar to DMD, but one has to account for the discrete functions of utrophin. Canine X-linked muscular dystrophy (cxmd) is the best representation of DMD, but the phenotype of the most widely used golden retriever (GRMD) model is variable, making functional endpoints difficult to ascertain. Although each mammalian model has its limitations, together they have been essential for the development of several treatment strategies for DMD that target dystrophin replacement, disease progression, and muscle regeneration.
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PMID:The value of mammalian models for duchenne muscular dystrophy in developing therapeutic strategies. 1918 50

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disease caused by mutations in the gene coding for the protein dystrophin. Recent work demonstrates that dystrophin is also found in the vasculature and its absence results in vascular deficiency and abnormal blood flow. This induces a state of ischemia further aggravating the muscular dystrophy pathogenesis. For an effective form of therapy of DMD, both the muscle and the vasculature need to be addressed. To reveal the developmental relationship between muscular dystrophy and vasculature, mdx mice, an animal model for DMD, were crossed with Flt-1 gene knockout mice to create a model with increased vasculature. Flt-1 is a decoy receptor for vascular endothelial growth factor, and therefore both homozygous (Flt-1(-/-)) and heterozygous (Flt-1(+/-)) Flt-1 gene knockout mice display increased endothelial cell proliferation and vascular density during embryogenesis. Here, we show that Flt-1(+/-) and mdx:Flt-1(+/-) adult mice also display a developmentally increased vascular density in skeletal muscle compared with the wild-type and mdx mice, respectively. The mdx:Flt-1(+/-) mice show improved muscle histology compared with the mdx mice with decreased fibrosis, calcification and membrane permeability. Functionally, the mdx:Flt-1(+/-) mice have an increase in muscle blood flow and force production, compared with the mdx mice. Consequently, the mdx:utrophin(-/-):Flt-1(+/-) mice display improved muscle histology and significantly higher survival rates compared with the mdx:utrophin(-/-) mice, which show more severe muscle phenotypes than the mdx mice. These data suggest that increasing the vasculature in DMD may ameliorate the histological and functional phenotypes associated with this disease.
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PMID:Flt-1 haploinsufficiency ameliorates muscular dystrophy phenotype by developmentally increased vasculature in mdx mice. 2070 34

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder and is the most common form of muscular dystrophy. Affected children develop muscle weakness in early childhood. Only steroids have been shown with evidence to improve muscle function in patients with DMD. We report the long-term effects of prednisolone treatment in patients with DMD, comparing the age at which 14 treated patients and 15 control patients lost their ability to walk. The prednisolone-treated patients were assigned to one of five regimens: 0.5 mg/kg/day given for the first 10 days of every month (n = 6), 0.75 mg/kg/day given for the first 10 days of every month (n = 3), 0.5 mg/kg on alternate days (n = 1), 0.75 mg/kg on alternate days (n = 1), or 5 mg/kg twice a week (n = 3). No significant difference in age of losing ambulation ability was observed between the treated group and the untreated group (mean age; 10 years and 6 months in both groups). However, 13 of the 14 patients showed an improvement in their activity of daily living other than ambulation in the treated group. The results of this study showed that the prednisolone treatment regimens used in this study did not prolong the period of ambulation.
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PMID:[Prednisolone treatment for Duchenne muscular dystrophy]. 2140 Sep 28


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