Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biglycan and decorin are small extracellular proteoglycans that interact with cytokines, whose activity they may modulate, and with matrix proteins, particularly collagens. To better understand their role in muscle fibrosis, we investigated expression of decorin and biglycan transcripts and protein in muscle of several forms of muscular dystrophy, and also expression of perlecan, an extracellular proteoglycan unrelated to collagen deposition. In Duchenne muscular dystrophy (DMD) and LAMA2-mutated congenital muscular dystrophy (MDC1A) we also quantitated transcript levels of the profibrotic cytokine TGF-beta1. We examined muscle biopsies from nine DMD patients, aged 2-8 years; 14 BMD (Becker muscular dystrophy) patients (nine aged 1-5 years; five aged 30-37 years); four MDC1A patients (aged 2-7 years); six dysferlin-deficient patients (aged 19-53 years) with mutation ascertained in two, and normal expression of proteins related to limb girdle muscular dystrophies in the others; 10 sarcoglycan-deficient patients: seven with alpha-sarcoglycan mutation, two with beta-sarcoglycan mutation and one with gamma-sarcoglycan mutation (five aged 8-15 years; five aged 26-43 years); and nine children (aged 1-6 years) and 12 adults (aged 16-61 years) suspected of neuromuscular disease, but who had normal muscle on biopsy. Biglycan mRNA levels varied in DMD and MDC1A depending on the quantitation method, but were upregulated in BMD, sarcoglycanopathies and dysferlinopathy. Decorin mRNA was significantly downregulated in DMD and MDC1A, whereas TGF-beta1 was significantly upregulated. Decorin mRNA was normal in paediatric BMD, but upregulated in adult BMD, sarcoglycanopathies and dysferlinopathy. Perlecan transcript levels were similar to those of age-matched controls in all disease groups. By immunohistochemistry, decorin and biglycan were mainly localized in muscle connective tissue; their presence increased in relation to increased fibrosis in all dystrophic muscle. By visual inspection, decorin bands on immunoblot did not differ from those of age-matched controls in all patient groups. However, when the intensity of the bands was quantitated against vimentin and normalized against sarcomeric actin, in DMD and MDC1A the ratio of band intensities was significantly lower than in age-matched controls. Variations in the transcript and protein levels of these proteoglycans in different muscular dystrophies probably reflect the variable disruption of extracellular matrix organization that occurs in these diseases. The significantly lowered decorin levels in DMD and MDC1A may be related to the increased TGF-beta1 levels, suggesting a therapeutic role of decorin in these severe dystrophies.
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PMID:Decorin and biglycan expression is differentially altered in several muscular dystrophies. 1618 58

Myotonic dystrophies, the most common form of adult muscular dystrophy, comprise at least two forms, clinically and genetically heterogeneous. Myotonic dystrophy type 1 and type 2 are both caused by unstable repetitions in untranslated gene regions: a [CTG]n expansion in the 3' region of the DMPK gene on chromosome 19q13 (DM1) and [CCTG]n tetranucleotide repeat located in the first intron of the ZNF9 gene on chromosome 3q21 (DM2). DM clinical features are caused by a gain of functions RNA mechanism in which the CUG and CCUG repeats alter nuclear functions, including alternative splicing of shared genes. Southern blot and/or polymerase chain reaction PCR-based approaches allow the detection of DM mutations in almost 100% of cases, however, the expansion size and the elevated grade of somatic instability make molecular testing for DM a diagnostic challenge. The increased use of DNA testing for DM generates many questions regarding the indications and interpretations of the test which require standardized methods, routinely available in molecular genetic laboratories. Here, we propose Guidelines for the molecular diagnosis of DM1 and DM2 approved by the Italian Ministry of Health in 2005 (Piano Nazionale Linee Guida, PNLG). Best practice for DM molecular analysis in diagnostic application, presymptomatic and prenatal testing, using direct and indirect approaches are described, with particular attention focused on ethical, legal and social issues. Overviews of materials used in the molecular diagnosis, as well as internet resources, are also included.
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PMID:Italian guidelines for molecular analysis in myotonic dystrophies. 1703 77

There exists much phenotypic heterogeneity in Duchenne muscular dystrophy and its allelic variant, Becker muscular dystrophy. The molecular findings on 53 patients with Duchenne and 15 patients with Becker type muscular dystrophy in KwaZulu Natal, South Africa are reported. Multiplex PCR was performed using primers targeting 18 hot-spot exons throughout the dystrophin gene. Analysis of the multiplex PCR data revealed that 39/68 (57.0%) patients included in the study showed a deletion (33 DMD and 6 BMD patients). Twenty-five patients were Black, 4 were White and 10 were Indian. Using the Chamberlain and Beggs multiplex PCR assays, the region of the genome most frequently affected by a deletion includes exons 47-51. The distal region of the dystrophin gene was most frequently affected by the deletion in both Black and Indian patients. There were too few White patients for conclusions to be drawn concerning the most frequently affected part of the gene. Although the numbers are insufficient to determine whether ethnic differences are present, the Chamberlain and Beggs multiplex PCR assays detect deletions with the same frequency in South African DMD/BMD patients as that reported in the literature.
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PMID:Molecular deletion patterns in Duchenne and Becker muscular dystrophy patients from KwaZulu Natal. 1714 Dec 73

Chronic painful muscle conditions include non-inflammatory and inflammatory illnesses. This review is focused on chronic non-inflammatory pain conditions such as myofascial pain syndrome (MPS) and fibromyalgia syndrome (FM), and will not discuss metabolic, genetic or inflammatory muscle diseases such as McArdle's disease, muscular dystrophy, polymyositis, dermatomyositis, or inclusion body myositis.
Best Pract Res Clin Rheumatol 2007 Jun
PMID:Future perspectives: pathogenesis of chronic muscle pain. 1760 1

Adverse reactions to genral anesthesia, which partly resembled malignant hyperthermia (MH), were more frequent in muscular dystrophy than in controls. In the present study, 35 cases so far reported in Duchenne or Becker muscular dystrophy (DMD or BMD) were analyzed and their pathogenesis was discussed. Cardiac involvements were sole manifestations in 7 cases. In other 28 cases, the acute rhabdomyolysis was the most prevailing manifestation. About 60% of myolysis cases were associated with muscle contracture (rigidity) or other hypermetabolic signs such as hypercapnia, hyperthermia and metabolic acidosis. Cases with BMD were more hyperthermic than with DMD. These results suggest Ca ion-induced hypermetabolic reactions are also present in dystrophinopathy, which have been assumed as core syndromes of the classical (gene-defined) MH. However, question whether the abnormal Ca ion is from the extracellular or intracellular stores is still unclear. Circumstancial evidences suggest that the Ca-induced Ca release (CICR) mechanism might also be involved. Endogenous redox modulators such as nitric oxide or reactive oxygen species in the dystrophic muscle might contribute to the perturbed Ca ion homeostasis.
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PMID:[Malignant hyperthermia-like reactions in Duchenne or Becker muscular dystrophy: review and hypothesis]. 1832 2

The purpose of this study was to examine the prevalence and characteristics of pain in children with Duchenne (DMD) or Becker (BMD) muscular dystrophy, including the nature of disagreements concerning pain symptoms among children, parents, and physicians, and limitations in daily activities. Male children (age 8-18 y, n=53) and parents (n=53) completed questionnaires assessing pain intensity (visual analogue scale), pain frequency (Likert scale [LS]), pain duration (LS), emotional distress due to pain (LS), and pain location (body outline markings). The Child Activity Limitations Interview was also completed by both raters to assess daily activities that are limited by recurrent pain. Physicians completed a form indicating medical history and pain symptoms. The majority of children with DMD (mean age 13 y 11 mo [SD 3.38]; range 8-18 y) or BMD (mean 14 y 10 mo [SD 1.48]; range 12-17 y) were non-ambulatory (79 and 50% respectively) and experienced pain according to self (54-80%) and parent reports (70-90%). Pain typically occurred at least once per week and was of mild to moderate intensity. Most children experienced pain for less than a few hours and little to moderate levels of emotional distress due to pain. Pain occurred in the lower back, spine, and legs, and was described as 'aching'. Children and parents indicated significantly more intense pain than the physician. Actual agreement between parent and child report on pain symptoms was poor to fair. Pain is a common occurrence in children with DMD or BMD, yet may be under-recognized. Pain assessment needs to be a standard part of care and may identify difficulties faced by these children to be targeted by interventions.
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PMID:Pain and activity limitations in children with Duchenne or Becker muscular dystrophy. 1861 Dec 7

While the function of dystrophin in muscle disease has been thoroughly investigated, dystrophin and associated proteins also have important roles in the central nervous system. Many patients with Duchenne and Becker muscular dystrophies (D/BMD) have cognitive impairment, learning disability, and an increased incidence of some neuropsychiatric disorders. Accordingly, dystrophin and members of the dystrophin-associated glycoprotein complex (DGC) are found in the brain where they participate in macromolecular assemblies that anchor receptors to specialized sites within the membrane. In neurons, dystrophin and the DGC participate in the postsynaptic clustering and stabilization of some inhibitory GABAergic synapses. During development, alpha-dystroglycan functions as an extracellular matrix receptor controlling, amongst other things, neuronal migration in the developing cortex and cerebellum. Several types of congenital muscular dystrophy caused by impaired alpha-dystroglycan glycosylation cause neuronal migration abnormalities and mental retardation. In glial cells, the DGC is involved in the organization of protein complexes that target water-channels to the plasma membrane. Finally, mutations in the gene encoding epsilon-sarcoglycan cause the neurogenic movement disorder, myoclonus-dystonia syndrome implicating epsilon-sarcoglycan in dopaminergic neurotransmission. In this review we describe the recent progress in defining the role of the DGC and associated proteins in the brain.
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PMID:The neurobiology of the dystrophin-associated glycoprotein complex. 1917 27

Duchenne muscular dystrophy (DMD) is X-linked disorder caused by mutations in the dystrophin gene. To investigate mutation types and distribution characteristics of dystrophin gene in Chinese DMD patients, we used Multiplex Ligation-Dependent Probe Amplification (MLPA) to analyze the dystrophin gene in 720 DMD patients, their mothers, and 20 normal adult males. Results showed that detection rate was 64.9% (467/720) in all the patients, gene deletion rate was 54.3% (391/720), and gene duplication rate was 10.6% (76/720). The rate of deletion mutant occurred in Exon 45-54 was 71.9% (281/391) in all gene deletion patients; meanwhile, the rate of gene duplication occurred in Exon 1-40 was 82.9% (63/76) in all gene duplication ones. In all the patients with gene deletion and duplication, the rate of DMD and IMD was 90.6% (423/467), and BMD, 9.4% (44/467). This indicates that the main reason of duchenne muscular dystrophy is dystrophin gene deletion mutation, which would occur in any gene unevenly with hot spots of mutation. The location and fragment length of gene deletion and duplication cannot decide the severity of clinical symptoms directly.
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PMID:[Association of mutation types and distribution characteristics of dystrophin gene with clinical symptoms in Chinese population]. 2140 33

The muscular dystrophies collectively represent a major health challenge, as few significant treatment options currently exist for any of these disorders. Recent years have witnessed a proliferation of novel approaches to therapy, spanning increased testing of existing and new pharmaceuticals, DNA delivery (both anti-sense oligonucleotides and plasmid DNA), gene therapies and stem cell technologies. While none of these has reached the point of being used in clinical practice, all show promise for being able to impact different types of muscular dystrophies. Our group has focused on developing direct gene replacement strategies to treat recessively inherited forms of muscular dystrophy, particularly Duchenne and Becker muscular dystrophy (DMD/BMD). Both forms of dystrophy are caused by mutations in the dystrophin gene and all cases can in theory be treated by gene replacement using synthetic forms of the dystrophin gene. The major challenges for success of this approach are the development of a suitable gene delivery shuttle, generating a suitable gene expression cassette able to be carried by such a shuttle, and achieving safe and effective delivery without elicitation of a destructive immune response. This review summarizes the current state of the art in terms of using adeno-associated viral vectors to deliver synthetic dystrophin genes for the purpose of developing gene therapy for DMD.
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PMID:Gene replacement therapies for duchenne muscular dystrophy using adeno-associated viral vectors. 2253 79

Dystrophin-deficient muscular dystrophies (dystrophinopathies) are the most common form of muscular dystrophy, with variable clinical phenotypes ranging from the severe Duchenne (DMD) to the milder Becker (BMD) forms. In this study, we investigated the relationship between clinical characteristics, findings at immunohistochemistry (IHC) and Western blot, and the pattern of exon deletions in 24 male patients with dystrophinopathies. We retrospectively reviewed findings from clinical and laboratory examinations, IHC for dystrophin of muscle biopsy tissue, Western blot analysis, and multiplex polymerase chain reaction (PCR) examination of genomic DNA. All tests were performed in every patient. PCR examination revealed exon deletions in 13 patients (54.2%). At Western blot analysis, 15 patients (62.5%) were negative at all three dystrophin domains. Most of these patients had a clinical presentation consistent with the DMD phenotype. Nine (37.5%) others were weakly positive at one or more domains. Most of these patients presented clinically as BMD phenotype. One patient whose clinical presentation was consistent with BMD phenotype had normal findings at IHC and was weakly positive at all three domains on Western blot analysis; however, with the exception of this patient, the findings at IHC and Western blot were consistent for individual patients. Based on these findings, we conclude that Western blot analysis appears useful for confirmation of dystrophinopathy in BMD patients with normal staining on IHC. Exon deletion analysis by multiplex PCR using peripheral blood is also a simple and useful test for the diagnosis of dystrophinopathy, although it has limited sensitivity.
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PMID:Clinical, immunohistochemical, Western blot, and genetic analysis in dystrophinopathy. 2379 Jun 20


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