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

For Duchenne muscular dystrophy (DMD, dystrophin deficiency) and Thomsen/Becker myotonia (muscular chloride channel deficiency) genetically homologous mouse models are available, the dystrophin-deficient MDX mouse and the myotonic ADR mouse. Whereas the latter shows more severe symptoms than human myotonia patients, the MDX mouse, in contrast to DMD patients, is only mildly affected. We have introduced, by appropriate breeding, the defect leading to myotonia (Clc1 null mutation, adr allele) into MDX mice, thus creating ADR-MDX double mutants. The expectation was that, due to mechanical stress during myotonic cramps, the ADR status should symptomatically aggravate the muscle fibre necrosis caused by the dystrophin deficiency. The overall symptoms of the double mutants were dominated by myotonia. Weight reduction and premature death rate were higher in ADR-MDX than in ADR mice. Sarcolemmal ruptures as indicated by influx into muscle fibres of serum globulins and injected Evans blue were found with great inter-individual variation in MDX and in ADR-MDX muscles. Affected fibres were found mainly in large groups in MDX but single or in small clusters in ADR-MDX leg muscles. The symptoms of myotonia (aftercontractions, shift towards oxidative fibres) were less pronounced in ADR-MDX than in ADR muscles. Conversely, numbers of damaged fibres as well as the percentage of central nuclei (an indicator of fibre regeneration) were significantly lower in ADR-MDX than in MDX skeletal muscles. Thus it appears that, at the level of the muscle fibre, myotonia and muscular dystrophy attenuate each other.
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PMID:Mutual interference of myotonia and muscular dystrophy in the mouse: a study on ADR-MDX double mutants. 1009 61

The integrins are a large family of heterodimeric transmembrane cellular receptors which mediate the association between the extracellular matrix (ECM) and cytoskeletal proteins. The alpha7beta1 integrin is a major laminin binding integrin in skeletal and cardiac muscle and is thought to be involved in myogenic differentiation and migration processes. The main binding partners of the alpha7 integrin are laminin-1 (alpha1-beta1-gamma1), laminin-2 (alpha2-beta1-gamma1) and laminin-4 (alpha2-beta2-gamma1). Targeted deletion of the gene for the alpha7 integrin subunit (ITGA7) in mice leads to a novel form of muscular dystrophy. In the present study we have investigated the expression of two alternative splice variants, the alpha7B and beta1D integrin subunits, in normal human skeletal muscle, as well as in various forms of muscular dystrophy. In normal human skeletal muscle the expression of the alpha7 integrin subunit appeared to be developmentally regulated: it was first detected at 2 years of age. In contrast, the beta1D integrin could be detected in immature and mature muscle in the sarcolemma of normal fetal skeletal muscle at 18 weeks gestation. The expression of alpha7B integrin was significantly reduced at the sarcolemma in six patients with laminin alpha2 chain deficient congenital muscular dystrophy (CMD) (age >2 years). However, this reduction was not correlated with the amount of laminin alpha2 chain expressed. In contrast, the expression of the laminin alpha2 chain was not altered in the skeletal muscle of the alpha7 knock-out mice. These data argue in favor that there is not a tight correlation between the expression of the alpha7 integrin subunit and that of the laminin alpha2 chain in either human or murine dystrophic muscle. Interestingly, in dystrophinopathies (Duchenne and Becker muscular dystrophy; DMD/BMD) expression of alpha7B was upregulated irrespective of the level of dystrophin expression as shown by a strong sarcolemmal staining pattern even in young boys (age <2 years). The expression of the beta1D integrin subunit was not altered in any of our patients with different types of muscular dystrophy. In contrast, sarcolemmal expression of beta1D integrin was significantly reduced in the alpha7 integrin knock-out mice, whereas the expression of the components of the DGC was not altered. The secondary loss of alpha7B in laminin alpha2 chain deficiency defines a biochemical change in the composition of the plasma membrane resulting from a primary protein deficiency in the basal lamina. These findings, in addition to the occurrence of a muscular dystrophy in alpha7 deficient mice, implies that the alpha7B integrin is an important laminin receptor within the plasma membrane which plays a significant role in skeletal muscle function and stability.
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PMID:Secondary reduction of alpha7B integrin in laminin alpha2 deficient congenital muscular dystrophy supports an additional transmembrane link in skeletal muscle. 1037 Oct 75

The clinical and molecular features of 25 Duchenne (DMD), two intermediate (D/BMD) and three Becker (BMD) muscular dystrophy patients from 26 unrelated families were evaluated. Early psychomotor development was normal in patients with D/BMD and BMD. Learning to walk independently after 15 months of age was a risk sign of DMD in nine (36%) patients. Abnormality in crawling was seen in 13 (54%) patients with DMD. These boys demonstrated initial symptoms earlier than those who learned to crawl normally. Mental retardation was established in five (20%) patients with DMD. Deletions in the dystrophin gene were found in 11 families (48%). They were accumulated (9/11, 82%) in the distal region of the gene.
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PMID:Duchenne and Becker muscular dystrophies: an Estonian experience. 1039 46

A cross-sectional study in a cohort of DNA proven carriers of Duchenne (DMD) and Becker (BMD) muscular dystrophy was undertaken with the following objectives: (1) to estimate the frequency of electrocardiographic (ECG) and echocardiographic abnormalities; (2) to establish the proportion of carriers with dilated cardiomyopathy and (3) to assess possible associations between dilated cardiomyopathy and genotype. One hundred and twenty nine DMD and BMD carriers, aged 18-60 years, were traced through the files of the central register kept at the department of Human Genetics in Leiden. Investigations included full medical history, physical examination, ECG and two-dimensional and M-mode echocardiographic examination. Forty-seven percent had ECG changes. Thirty-six percent (DMD 41%, BMD 27%) had at least one abnormality as is usually found in the male patients. Echocardiographic examination was abnormal in 36% (DMD 38%, BMD 34%). Dilated cardiomyopathy was found in seven DMD carriers (8%), and in none of BMD carriers. In addition, 18% had left ventricle dilatation (DMD 19%, BMD 16%). Only 38% had a completely normal investigation of the heart. We found no association between genotype and cardiac manifestations. Our study underlines that cardiac involvement is part of the dystrophinopathies. Carriers should be told about the increased risk of this complication when asking genetic advice. It also implicates that a complete cardiological evaluation should be performed at least once in all carriers. If left ventricle dilatation or dilated cardiomyopathy is present a yearly follow up is needed, in order to start timely therapy.
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PMID:Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy. 1040 58

Mutations in the dystrophin gene (DMD) and in genes encoding several dystrophin-associated proteins result in Duchenne and other forms of muscular dystrophy. alpha-Dystroglycan (Dg) binds to laminins in the basement membrane surrounding each myofibre and docks with beta-Dg, a transmembrane protein, which in turn interacts with dystrophin or utrophin in the subplasmalemmal cytoskeleton. alpha- and beta-Dgs are thought to form the functional core of a larger complex of proteins extending from the basement membrane to the intracellular cytoskeleton, which serves as a superstructure necessary for sarcolemmal integrity. Dgs have also been implicated in the formation of synaptic densities of acetylcholine receptors (AChRs) on skeletal muscle. Here we report that chimaeric mice generated with ES cells targeted for both Dg alleles have skeletal muscles essentially devoid of Dgs and develop a progressive muscle pathology with changes emblematic of muscular dystrophies in humans. In addition, many neuromuscular junctions are disrupted in these mice. The ultrastructure of basement membranes and the deposition of laminin within them, however, appears unaffected in Dg-deficient muscles. We conclude that Dgs are necessary for myofibre survival and synapse differentiation or stability, but not for the formation of the muscle basement membrane, and that Dgs may have more than a purely structural function in maintaining muscle integrity.
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PMID:Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses. 1054 34

Since the identification of dystrophin as the causitive factor in Duchenne muscular dystrophy, there has been substantial progress in understanding the functions and interactions of this protein. Dystrophin has been shown to interact with a group of peripheral- and trans-membrane proteins known as the dystrophin-associated protein complex (DAPC) and mutations in some of the members of this complex have been shown to account for other forms of muscular dystrophy. This review summarizes the experiments using transgenic and knockout mouse models that have defined the roles of dystrophin, and the dystrophin-related protein utrophin at the skeletal muscle membrane and at the neuromuscular junction. These studies are presented in the context of other known interactions at the muscle membrane. Studies of the dystrophin-deficient mdx mouse have lead to a greater understanding of the human disease. Knockouts and transgenics of utrophin have shown this protein to be sufficient to functionally compensate for dystrophin. Dystrophin transgenic mice combined with the mdx mouse have been used to study the function of specific domains of the dystrophin protein. Together these animal models have led to a delineation of protein functions and localization patterns that will be useful for the generation of potential therapies for DMD.
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PMID:Dystrophin and utrophin: genetic analyses of their role in skeletal muscle. 1067 63

Prolonged elevation of the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) is often attributed to hepatic diseases. However, these enzymes are also present in a variety of extrahepatic tissues, including skeletal muscle. Five children (all boys) were referred to the pediatric department of the National Taiwan University Hospital because of persistent elevation of serum aminotransferase activities. The ages of these children were between 4 months and 5.5 years. The neurological findings were all not remarkable. The initial ALT and AST values were 114-581 U/L and 183-700 U/L, respectively. Serum creatine kinase was checked first after 0 to 30 months follow-up and found to be markedly elevated (range, 10,557 U/L to 62,508 U/L). Muscle biopsies in the five cases all showed degenerating and regenerating myofibers with interstitial fibrosis. In Cases 3, 4 and 5, complete absence of dystrophin immunoreactivity was found. Genetic studies showed deletions in the DMD gene (exons 45-48 in case 2 and 49-50 in case 4). This experience indicates that occult muscle diseases should be taken into account in patients with unexplained long-lasting hypertransaminasemia and therefore measurement of serum creatine kinase activity and muscle biopsy should be done early for the correct diagnosis of muscular dystrophy.
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PMID:Persistent hypertransaminasemia as the presenting findings of muscular dystrophy in childhood. 1092 57

Episodes of acute myoglobinuria or cardiac arrest were occasionally complicated in general anesthesia of patients with Duchenne or Becker muscular dystrophy (DMD/BMD). Whether these complications are malignant hyperthermia (MH) or not has several times been discussed. In the present study, we applied the clinical grading scale (CGS) of Larach and modified criteria of caffeine contracture test of the skinned fiber (sIVCT) to solve this problem. When the CGS was applied to reported MH-like episodes of DMD/BMD cases, 9 out of 20 cases were classed as almost certain or very likely MH. According to results of sIVCT in 11 patients with DMD/BMD, 5 patients were judged as MHS (MH-susceptible) and 3 as MHE (MH-equivocal). The diagnostic specificity of present MHS criteria was 100% for the fulminant MH. A possible "false positive" result in European IVCT has been discussed in relation to myopathy such as muscular dystrophy. When we applied our sIVCT to the muscle of mdx mouse, caffeine contracture was rather reduced compared to controls. Present study suggested that a true MH was complicated in some cases of DMD/BMD. In certain stage of muscular degeneration, patients with DMD/BMD become susceptible to MH, probably temporarily, but exact mechanism still awaits clarification.
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PMID:[Malignant hyperthermia of Duchenne muscular dystrophy: application of clinical grading scale and caffeine contracture of skinned muscle fibers]. 1100 22

Muscular dystrophy is a group of genetically determined muscular disorders marked by progressive wasting and weakness of the skeletal muscle, but which often affect cardiac and smooth muscles or other tissues. The patterns of inheritance are either dominant or recessive although the gene may be defective because of a new mutation. Growing evidence revealed the marked heterogeneity of the muscle disorders, and considerable numbers of Japanese scientists and physicians have contributed to the research progress in muscular dystrophy. Among these the discovery of an increased serum creatine kinase activity in muscular dystrophy opened the way for the most reliable laboratory test for muscular dystrophy in 1959, and subsequently accelerated progress in a broad range of research areas in medicine. Progress in modern genetics and molecular pathology provided another breakthrough in muscular dystrophy research and, in 1987, dystrophin was identified, a deficiency of which causes DMD. The present review article highlights contributions of Japanese scientists to muscular dystrophy research.
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PMID:Muscular dystrophy. 1103 85

Previous investigators have suggested that proteolysis by calpain, a Ca2+-dependent protease, causes muscle fiber degradation in Duchenne and Becker muscular dystrophies (DMD/BMD). Recent evidence indicates that the nonlysosomal ATP-ubiquitin-dependent proteolytic complex (proteasomes) participates in muscle wasting during various catabolic states and in muscle fiber degradation in physiological or pathological conditions. To elucidate the possible role of proteasomes in dystrophic muscles, routine histochemistry and immunohistochemistry of 26S proteasomes were performed on muscle biopsy specimens obtained from patients with various neuromuscular disorders including DMD/BMD, polymyositis (PM), amyotrophic lateral sclerosis, and peripheral neuropathies, and on normal human muscle specimens. Immunohistochemically, proteasomes were located in the cytoplasm in normal human muscle, but their staining intensity was faint. Compared to control muscles, abnormal increases in both proteasomes and ubiquitin were demonstrated mainly in the cytoplasm of necrotic fibers and to a lesser extent in regenerative fibers in DMD/BMD and PM. Non-necrotic, atrophic fibers in all diseased muscles showed moderate or weak immunoreactions for the proteins; their staining intensities were stronger than those of control muscle fibers. Both proteins often colocalized well. Not all dystrophin-deficient muscle fibers showed a strong reaction for proteasomes. Our results showed increased proteasomes in necrotic and regenerative muscle fibers in DMD/ PMD, although this may not be disease-specific up-regulation. We suggest that the ATP-ubiquitin-dependent proteolytic pathway as well as the nonlysosomal calpain pathway may participate in muscle fiber degradation in muscular dystrophy.
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PMID:Proteasome expression in the skeletal muscles of patients with muscular dystrophy. 1107 10


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