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

Muscular dystrophies include a diverse group of genetically heterogeneous disorders that together affect 1 in 2000 births worldwide. The diseases are characterized by progressive muscle weakness and wasting that lead to severe disability and often premature death. Rostrocaudal muscular dystrophy (rmd) is a new recessive mouse mutation that causes a rapidly progressive muscular dystrophy and a neonatal forelimb bone deformity. The rmd mutation is a 1.6-kb intragenic deletion within the choline kinase beta (Chkb) gene, resulting in a complete loss of CHKB protein and enzymatic activity. CHKB is one of two mammalian choline kinase (CHK) enzymes (alpha and beta) that catalyze the phosphorylation of choline to phosphocholine in the biosynthesis of the major membrane phospholipid phosphatidylcholine. While mutant rmd mice show a dramatic decrease of CHK activity in all tissues, the dystrophy is only evident in skeletal muscle tissues in an unusual rostral-to-caudal gradient. Minor membrane disruption similar to dysferlinopathies suggest that membrane fusion defects may underlie this dystrophy, because severe membrane disruptions are not evident as determined by creatine kinase levels, Evans Blue infiltration, and unaltered levels of proteins in the dystrophin-glycoprotein complex. The rmd mutant mouse offers the first demonstration of a defect in a phospholipid biosynthetic enzyme causing muscular dystrophy, representing a unique model for understanding mechanisms of muscle degeneration.
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PMID:A rostrocaudal muscular dystrophy caused by a defect in choline kinase beta, the first enzyme in phosphatidylcholine biosynthesis. 1637 53

The dystrophin-glycoprotein complex (DGC) can be considered as a specialized adhesion complex, linking the extracellular matrix to the actin cytoskeleton, primarily in muscle cells. Mutations in several components of the DGC lead to its partial or total loss, resulting in various forms of muscular dystrophy. These typically manifest as progressive wasting diseases with loss of muscle integrity. Debate is ongoing about the precise function of the DGC: initially a strictly mechanical role was proposed but it has been suggested that there is aberrant calcium handling in muscular dystrophy and, more recently, changes in MAP kinase and GTPase signalling have been implicated in the aetiology of the disease. Here, we discuss new and interesting developments in these aspects of DGC function and attempt to rationalize the mechanical, calcium and signalling hypotheses to provide a unifying hypothesis of the underlying process of muscular dystrophy.
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PMID:Sparks, signals and shock absorbers: how dystrophin loss causes muscular dystrophy. 1651 61

While much is known about the clinical course of adult FSHD, the third most common inherited muscular dystrophy, data on the "infantile phenotype" and especially on the progression of the disease in children are limited. We have followed a cohort of 7 patients with infantile FSHD for 9-25 years and here report the clinical and genetic findings in this group. Infantile FSHD is relatively rare, amounting to 4% of all of our FSHD patients. Despite some variability in the progression, infantile FSHD has a more consistent phenotype than adult FSHD. Although they had normal motor milestones, all patients showed facial weakness from early childhood, and subsequently were severely affected with rapid progression of the disease, marked muscular wasting, weakness, and hyperlordosis. None of the patients have shown signs of nocturnal hypoventilation or cardiomyopathy so far. No correlation was found between sex and the severity of phenotype whereas all but one patient had very short fragment sizes of the D4Z4 repeat. Only two patients had a de novo mutation: 3 patients inherited the mutation from a parent with somatic mosaicism, and one was inherited from a parent with classical adult FSHD. One patient was unusual in having one allele inherited from his father who showed somatic mosaicism and one allele with an additional de novo mutation. We conclude that infantile FSHD is a severe and rapidly progressive disease, and this needs to be taken into account in the advice given to patients diagnosed in early childhood. However, our data also suggest that the risk to an individual with classical FSHD of having a child with the infantile form is low.
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PMID:Severe phenotype in infantile facioscapulohumeral muscular dystrophy. 1693 68

Here, we present the first study of a human neuromuscular disorder at transcriptional and proteomic level. Autosomal dominant facio-scapulo-humeral muscular dystrophy (FSHD) is caused by a deletion of an integral number of 3.3-kb KpnI repeats inside the telomeric region D4Z4 at the 4q35 locus. We combined a muscle-specific cDNA microarray platform with a proteomic investigation to analyse muscle biopsies of patients carrying a variable number of KpnI repeats. Unsupervised cluster analysis divides patients into three classes, according to their KpnI repeat number. Expression data reveal a transition from fast-glycolytic to slow-oxidative phenotype in FSHD muscle, which is accompanied by a deficit of proteins involved in response to oxidative stress. Besides, FSHD individuals show a disruption in the MyoD-dependent gene network suggesting a coregulation at transcriptional level during myogenesis. We also discuss the hypothesis that D4Z4 contraction may affect in trans the expression of a set of genes involved in myogenesis, as well as in the regeneration pathway of satellite cells in adult tissue. Muscular wasting could result from the inability of satellite cells to successfully differentiate into mature fibres and from the accumulation of structural damages caused by a reactive oxygen species (ROS) imbalance induced by an increased oxidative metabolism in fibres.
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PMID:Parallel protein and transcript profiles of FSHD patient muscles correlate to the D4Z4 arrangement and reveal a common impairment of slow to fast fibre differentiation and a general deregulation of MyoD-dependent genes. 1701 91

Much progress has been made over the past decade elucidating the molecular basis for a variety of muscular dystrophies (MDs). Accordingly, there are examples of mouse models of MD whose disease progression has been halted in large part with the use of viral vector technology. Even so, we must acknowledge significant limitations of present vector systems that must be overcome prior to successful treatment of humans with such approaches. This review will present a variety of viral-mediated therapeutic strategies aimed at counteracting the muscle-wasting symptoms associated with muscular dystrophy. We include viral vector systems used for muscle gene transfer, with a particular emphasis on adeno-associated virus. Findings of several encouraging studies focusing on repair of the mutant dystrophin gene are also included. Lastly, we present a discussion of muscle compensatory therapeutics being considered that include pathways involved in the up-regulation of utrophin, promotion of cellular adhesion, enhancement of muscle mass, and antagonism of the inflammatory response. Considering the complexity of the muscular dystrophies, it appears likely that a multilayered approach tailored to a patient sub-group may be warranted in order to effectively contest the progression of this devastating disease.
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PMID:Viral-mediated gene therapy for the muscular dystrophies: successes, limitations and recent advances. 1706 82

Skeletal muscles become atrophied by muscular disorders such as muscular dystrophy, wasting and even aging. In addition to muscle atrophy, progressive muscle damage, inflammation and replacement of muscle fibers with fibrous and fatty tissues are observed in muscular dystrophy. Neuronal innervation is required for skeletal muscle, and muscles become atrophic when motor neurons are affected by neurodegenerative disorders such as amyotrophic lateral sclerosis. Restoring muscle mass and function lost by diseases such as muscular dystrophy and neurodegenerative disorders is important. There are three rational therapies for muscular dystrophy and related diseases: gene therapy, cell therapy and drug therapy. Gene therapies to replace the defective genes have been tried with various degrees of effectiveness. Multiple myogenic stem cells including satellite cells, bone marrow cells, muscle side population cells, muscle-derived stem cells and mesoangioblast have been characterized. Cell therapies using these stem cells are one of the promising therapies for neuromuscular diseases causing muscle atrophy. As pharmacological drug therapies, increasing skeletal muscle mass by myostatin inhibition is quite promising and will be applied clinically in the near future.
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PMID:[Development of therapies against neuromuscular diseases causing muscle atrophy]. 1724 Aug 49

Muscular dystrophy is characterized by skeletal muscle weakness and wasting, but little is known about possible alterations to the vasculature. Many muscular dystrophies are caused by a defective dystrophin-glycoprotein complex (DGC), which plays an important role in mechanotransduction and maintenance of structural integrity in muscle cells. The DGC is a group of membrane-associated proteins, including dystrophin and sarcoglycan-delta, that helps connect the cytoskeleton of muscle cells to the extracellular matrix. In this paper, mice lacking genes encoding dystrophin (mdx) or sarcoglycan-delta (sgcd-/-) were studied to detect possible alterations to vascular wall mechanics. Pressure-diameter and axial force-length tests were performed on common carotid arteries from mdx, sgcd-/-, and wild-type mice in active (basal) and passive smooth muscle states, and functional responses to three vasoactive compounds were determined at constant pressure and length. Apparent biomechanical differences included the following: mdx and sgcd-/- arteries had decreased distensibilities in pressure-diameter tests, with mdx arteries exhibiting elevated circumferential stresses, and mdx and sgcd-/- arteries generated elevated axial loads and stresses in axial force-length tests. Interestingly, however, mdx and sgcd-/- arteries also had significantly lower in vivo axial stretches than did the wild type. Accounting for this possible adaptation largely eliminated the apparent differences in circumferential and axial stiffness, thus suggesting that loss of DGC proteins may induce adaptive biomechanical changes that can maintain overall wall mechanics in response to normal loads. Nevertheless, there remains a need to understand better possible vascular adaptations in response to sustained altered loads in patients with muscular dystrophy.
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PMID:Altered biomechanical properties of carotid arteries in two mouse models of muscular dystrophy. 1752 97

A unique sib pair afflicted by limb girdle muscular dystrophy type 2A (LGMD2A) is described showing a slowly progressive autosomal recessive type of muscular dystrophy with onset in the third and fourth decades. The patients had early asymmetric muscle involvement characterized by prominent biceps brachii atrophy with sparing of the knee extensors. Additional findings included elevation of serum creatine kinase level, myopathic EMG changes and dystrophic type of pathology on muscle biopsy. Asymmetrical wasting of muscles in the extremities exhibited uniform and highly selective CT imaging patterns. RNA and DNA analyses confirmed novel compound heterozygous mutations (R147X/L212F) in the human CAPN3 gene.
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PMID:A unique case of limb-girdle muscular dystrophy type 2A carrying novel compound heterozygous mutations in the human CAPN3 gene. 1759 42

1. Duchenne muscular dystrophy (DMD), a severe muscle wasting disease of young boys with an incidence of one in every 3000, results from a mutation in the gene that encodes dystrophin. The absence of dystrophin expression in skeletal muscles and heart results in the degeneration of muscle fibres and, consequently, severe muscle weakness and wasting. The mdx mouse discovered in 1984, with some adjustments for differences, has proven to be an invaluable model for scientific investigations of dystrophy. 2. The development of the diaphagm strip preparation provided an ideal experimental model for investigations of skeletal muscle impairments in structure and function induced by interactions of disease- and age-related factors. Unlike the limb muscles of the mdx mouse, which show adaptive changes in structure and function, the diaphragm strip preparation reflects accurately the deterioration in muscle structure and function observed in boys with DMD. 3. The advent of sophisticated servo motors and force transducers interfaced with state-of-the-art software packages to drive complex experimental designs during the 1990s greatly enhanced the capability of the mdx mouse and the diaphragm strip preparation to evaluate more accurately the impact of the disease on the structure-function relationships throughout the life span of the mouse. 4. Finally, during the 1990s and through the early years of the 21st century, many promising, sophisticated genetic techniques have been designed to ameliorate the devastating impact of muscular dystrophy on the structure and function of skeletal muscles. During this period of rapid development of promising genetic therapies, the combination of the mdx mouse and the diaphragm strip preparation has provided an ideal model for the evaluation of the success, or failure, of these genetic techniques to improve dystrophic muscle structure, function or both. With the 2 year life span of the mdx mouse, the impact of age-related effects can be studied in this model.
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PMID:Diaphragm muscle strip preparation for evaluation of gene therapies in mdx mice. 1821 82

Restoring dystrophin expression in the muscles of patients with Duchenne muscular dystrophy (DMD) may halt or reverse the degenerative wasting and weakness that causes premature death. However, the therapeutic efficacy of an intervention may be limited by the extent of disease progression prior to treatment. In this study, we considered the potential for ameliorating the pathology in a mouse model of advanced-stage muscular dystrophy by systemic administration of recombinant adeno-associated viral (rAAV6) vectors encoding a microdystrophin expression construct. The treatment of 20-month-old mdx mice restored body-wide expression of a dystrophin-based protein in striated musculature. In aged mice that received treatment, the resultant dystrophin expression was associated with improved hindlimb and respiratory muscle morphology and function, concomitant with reduced muscle fiber degeneration. The findings demonstrate that an established dystrophic state remains amenable to improvement with appropriate intervention and, by some measures, may even achieve benefits similar to those observed with intervention early in disease progression. The capacity to ameliorate the pathology in an animal model of advanced-stage muscular dystrophy suggests that interventions ultimately proven to exert a therapeutic effect in young patients may offer benefits to older patients or those with advanced conditions of progressive muscular dystrophy.
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PMID:Systemic microdystrophin gene delivery improves skeletal muscle structure and function in old dystrophic mdx mice. 1833 86


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