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

It has recently been shown that merosin, an extracellular matrix protein linked to the dystrophin-associated glycoproteins, is deficient in a proportion of patients with classical congenital muscular dystrophy (CMD). We have undertaken a detailed study of the clinical features and brain imaging in 24 cases of CMD in relation to the merosin status. Immunocytochemistry showed that merosin was present in 13 cases and markedly deficient in 11. In the merosin-positive cases, the maximum motor achievement was independent walking in 11, walking with support in one and sitting unsupported in one (currently 18 months old). In contrast, none of the merosin-deficient cases achieved independent ambulation. Two achieved walking with support, nine standing with support. In addition, nine of the 11 merosin-deficient cases had a creatine kinase level greater than 2000 whereas only one merosin-positive case had this degree of elevation. Magnetic resonance imaging of the brain was carried out on 15 of the children. All eight merosin-positive cases had normal scans whereas all seven of the merosin-deficient cases had significant changes in the white matter. This study has demonstrated that children with merosin-deficient CMD have a more severe clinical phenotype and associated white matter changes on brain imaging.
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PMID:Clinical phenotype in congenital muscular dystrophy: correlation with expression of merosin in skeletal muscle. 758 Feb 43

The mdx mouse has a mutated dystrophin gene and is used as a model for the study of Duchenne muscular dystrophy (DMD). We investigated whether regenerating mdx skeletal muscle contains the extracellular matrix protein tenascin-C (TN-C), which is expressed in wound healing and nerve regeneration. Prior to the initiation of muscle degeneration, both normal and mdx mice displayed similar weak staining for TN-C in skeletal muscle, but by 3 weeks of age the mice differed substantially. TN-C was undetectable in normal muscle except at the myotendinous junction, while in dystrophic muscle, TN-C was prominent in degenerating/regenerating areas, but absent from undegenerated muscle. With increasing age, TN-C staining declined around stable regenerated mdx myofibers. TN-C was also observed in muscle from dogs with muscular dystrophy and in human boys with DMD. Therefore, in dystrophic muscle, TN-C expression may be stimulated by the degenerative process and remain upregulated unless the tissue undergoes successful regeneration.
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PMID:Tenascin-C expression in dystrophin-related muscular dystrophy. 855 62

"Classic" congenital muscular dystrophy is a heterogeneous group of disorders, characterized by early-onset muscle weakness and hypotonia, absence of overt cerebral or ocular symptoms, and muscle pathology consistent with a dystrophic process. A subset of patients with congenital muscular dystrophy have recently been found to be deficient in the extracellular matrix protein merosin. Consequently, we reviewed the clinical, pathologic, and immunohistochemical features of 12 patients (six males and six females) with classic congenital muscular dystrophy who have been seen at the Children's Hospital, Boston, over the past 15 years. There was marked clinical heterogeneity within this patient population, with age of independent ambulation ranging from 13 months to 6 years. Immunocytochemical analysis using antibodies to merosin, dystrophin, 43-kDa dystroglycan, adhalin, and laminin was normal in 11 of 12 patients. One patient had markedly abnormal staining for merosin; the majority of fibers were negative, although occasional fibers demonstrated patchy staining. Immunoblot analysis in this patient demonstrated markedly reduced levels of merosin (< 10% compared to controls and other patient), of apparently normal size. Clinically, this patient could be differentiated from the others by a marked elevation of serum creatine kinase (> 1000 U/L) and the presence of early white-matter changes on magnetic resonance imaging. The results of this study support the observation that abnormalities of merosin are present in a subgroup of patients with classic congenital muscular dystrophy. Although marked elevation of serum creatine kinase and white-matter changes on magnetic resonance imaging may serve to distinguish these patients from other patients with congenital muscular dystrophy, there remains a large proportion of patients in whom the underlying pathogenesis remains to be elucidated.
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PMID:Congenital muscular dystrophy associated with merosin deficiency. 880 18

A subset of patients with congenital muscular dystrophy (CMD) are deficient for the extracellular matrix protein, merosin. Although the aetiology of merosin-positive CMD is as yet unknown, abnormalities of other structural muscle-specific proteins are likely to be involved. The alpha-actinins are actin-binding proteins related to dystrophin. We studied expression of the skeletal muscle isoforms of alpha-actinin (alpha-actinin-2 and alpha-actinin-3) in muscle biopsies from 12 patients with pure CMD (including one with a merosin abnormality), two with unclassified CMD and central nervous system (CNS) involvement, and three with other neuromuscular disorders. Four specimens exhibited deficient alpha-actinin-3 staining by immunofluorescence and/or Western blot analysis. In one, this pattern may be a secondary consequence of marked type 1 fibre predominance, but the other three biopsies contained abundant type 2 fibres where alpha-actinin-3 is normally expressed. Three alpha-actinin-3-deficient patients had pure CMD and presented in the newborn period with muscle weakness, hypotonia and arthrogryposis. The fourth had a dystrophic muscle biopsy and CNS involvement. These results suggest that deficiency of alpha-actinin-3 may be a marker for a subset of patients with CMD. It remains to be determined whether the deficiency of alpha-actinin-3 reflects ACTN3 gene mutations or is a secondary phenomenon.
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PMID:Deficiency of a skeletal muscle isoform of alpha-actinin (alpha-actinin-3) in merosin-positive congenital muscular dystrophy. 888 51

About half of the children with classical congenital muscular dystrophy (CMD) show an absence in their skeletal muscle of laminin alpha2 chain, one of the components of the extracellular matrix protein, merosin. Linkage analysis implicated the laminin alpha2 chain gene (LAMA2) on chromosome 6q2, now confirmed by the discovery of mutations in the laminin alpha2 chain gene. We have further investigated the location of the LAMA2 locus on chromosome 6q2, using both linkage analysis in nine informative families and homozygosity mapping in 13 consanguineous families. Four of these families only had mild or moderate down regulation of laminin alpha2 chain expression and a milder phenotype; the rest had no protein or only a trace. Haplotype analysis in all the informative families, including those with partial laminin alpha2 expression, was compatible with linkage to chromosome 6q2. This observation expands the spectrum of the phenotype secondary to laminin alpha2 chain deficiency. Our results suggest that the LAMA2 locus is more centromeric than previously proposed. Recombinant events place the locus between markers D6S470 and D6S1620 in an interval of less than 3 cM.
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PMID:Refinement of the laminin alpha2 chain locus to human chromosome 6q2 in severe and mild merosin deficient congenital muscular dystrophy. 903 83

One recently described form of congenital muscular dystrophy (CMD) is associated with deficiency of the alpha 2-chain of laminin, an extracellular matrix protein that is specifically located in the basement membrane of placental villi, Schwann cells and skeletal muscle in healthy humans. This laminin is also normally present in the skin, kidney and basement membrane of blood vessels of the CNS, though it is absent from the blood vessel walls in other tissues. In this immunohistochemical study, we have explored the presence of the alpha 1, alpha 2, beta 1 and gamma 1 chains of laminin in the normal human retina, which are all localized in the basement membrane of blood vessels. This study adds to the growing evidence that the alpha 2-chain of laminin is selectively expressed in certain tissues, and suggests that CMD associated with a lack of this protein may be a multisystem disorder, with possible direct involvement of the visual system.
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PMID:Localization of laminin chains in the human retina: possible implications for congenital muscular dystrophy associated with alpha 2-chain of laminin deficiency. 913 36

Recent advances in molecular genetics research have revolutionised our understanding of the childhood muscular dystrophies. The first breakthrough came in 1987 with the identification of the gene for dystrophin, the protein that is abnormal in X-linked Duchenne muscular dystrophy. Dystrophin is bound to a complex of proteins in the muscle membrane, and primary abnormalities of these proteins have now been identified as the cause of some autosomally inherited forms of muscular dystrophy. A group of transmembrane proteins known as alpha- (adhalin) beta-, gamma- and delta-sarcoglycan are deficient in autosomal recessive limb-girdle muscular dystrophy, and the extracellular matrix protein merosin (alpha2-laminin), is deficient in a subset of patients with congenital muscular dystrophy. Identification of primary deficiencies in these 'dystrophin associated proteins' will result in improved diagnostic accuracy, more accurate genetic counselling and, in some cases, the availability of prenatal diagnosis.
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PMID:Recent advances in diagnosis of the childhood muscular dystrophies. 925 92

We have identified a new pathogenic mechanism for an inherited muscular dystrophy in which functional haploinsufficiency of the extracellular matrix protein collagen VI causes Bethlem myopathy. The heterozygous COL6A1 mutation results in a single base deletion from the mRNA and a premature stop codon. The mutant mRNA is unstable, subject to nonsense-mediated mRNA decay, and is almost completely absent both from patient fibroblasts and skeletal muscle, resulting in haploinsufficiency of the alpha1(VI) subunit and reduced production of structurally normal collagen VI. This is the first example of a muscular dystrophy caused by haploinsufficiency of a structural protein or member of the dystrophin-glycoprotein complex, and identifies collagen VI as a critical contributor to cell-matrix adhesion in skeletal muscle.
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PMID:Reduced collagen VI causes Bethlem myopathy: a heterozygous COL6A1 nonsense mutation results in mRNA decay and functional haploinsufficiency. 958 Jun 62

Merosin alpha 2 chain, an extracellular matrix protein, is deficient in a proportion of patients with classical congenital muscular dystrophy (CMD). A study of clinical, laboratory and histopathological features of 18 patients with CMD was performed in relation to the merosin expression in muscle biopsy. Immunohistochemistry study showed that merosin was deficient in 11 patients and present in 7. None of the 9 merosin-deficient patients evaluated achieved walking. In contrast, 4 of 7 merosin-positive patients achieved independent ambulation. Creatine kinase levels were higher in merosin-deficient patients, but this difference was not statistically significant. Motor nerve conduction study was carried out on 12 children. All 4 merosin-positive patients had normal exams whereas 2 out 8 merosin-deficient patients presented decreased motor nerve conduction velocity. Among 69 histopathological features studied, we did not find any significant difference between merosin-deficient and merosin-positive patients. These results suggest that merosin status evaluation is important in the determination of the prognostic, since merosin-positive patients can achieve independent walking. This study also suggests that there is no relation between absence of merosin and histopathological features.
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PMID:[Congenital muscular dystrophy and merosin deficiency]. 962 38

This lecture traces recent advances in knowledge of the muscular dystrophies, as well as their increasing complexity. They are described through the eyes of the author from his first exposure to and complete ignorance of the disease in the late 1950s, through the advent of modern techniques, to the molecular genetic revolution, with the recognition of individual genes and proteins for disorders within the muscular dystrophy umbrella. There initially seemed to be a logical sequence of linked membrane proteins from dystrophin in Duchenne and Becker dystrophy, through the dystrophin-associated glycoproteins (sarcoglycans) in some of the limb girdle muscular dystrophies (LGMD), to the extracellular matrix protein merosin (alpha-2 laminin) in congenital muscular dystrophy (CMD). The first spoke in the wheel came with the discovery of a calcium activated protease enzyme, calpain 3, in one form of LGMD, and subsequently another novel non-membrane protein, dysferlin, in another. There are currently at least eight distinct genetic forms of LGMD alone, and another eight separate genetic entities in the CMD group. This has highlighted our ignorance of the pathogenesis of the muscular dystrophies in relation to a diverse array of protein deficiencies. To compound things further, the X-linked and dominant forms of Emery-Dreifuss muscular dystrophy have recently been linked to emerin and lamin A/C, respectively, two proteins of the nuclear membrane, opening up yet another new ballpark of discovery.
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PMID:What is muscular dystrophy? Forty years of progressive ignorance. 1107 61


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