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

The most significant pathologic finding in muscular dystrophy(MD) is muscle fiber necrosis followed by regeneration. A membrane hypothesis to explain fiber necrosis seems to be confirmed by the discovery of dystrophin and dystrophin-associated glycoprotein (DAG); both are located along the muscle surface membrane. However the mechanism of muscle fiber degeneration cannot be fully explained by the membrane theory itself, because the gene product of Emery-Dreifuss MD is present in the nuclear membrane. Heterogeneous clinical expressions of mitochondrial diseases are also puzzling and have been explained by "tissue specificity" due to different population of wild and mutant mitochondrial DNA from tissue to tissue. The tissue with higher percentage of mutant mitochondrial DNA may not function in an "all-or-none" manner.
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PMID:[Molecular pathology of muscle diseases]. 943 18

Three patients with Emery Dreifuss muscular dystrophy are reported. Emery Dreifuss muscular dystrophy is an X linked muscular dystrophy, in which locomotor involvement is characteristically mild and slowly progressive. The effect on the heart becomes apparent in the teenage years and is characterised by cardiac conduction defects and infiltration of the myocardium by fibrous and adipose tissue. It first affects the atria, which results in atrial paralysis; treatment with ventricular pacing is usually needed. Female carriers can develop heart problems and are at risk of sudden death. Relatives of affected patients should be offered screening with electrocardiography and echocardiography.
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PMID:Cardiac involvement in Emery Dreifuss muscular dystrophy: a case series. 1037 22

Using immunohistochemical methods, we assessed the distribution of all 10 known laminin chains (alpha1-5, beta1-3, gamma1 and gamma2) in skeletal muscles from patients with Duchenne, congenital, limb girdle, or Emery-Dreifuss muscular dystrophies. The alpha2, beta1 and gamma1 chains were abundant in the basal lamina surrounding muscle fibers in normal controls; alpha1, alpha3-alpha5, beta3, and gamma2 were undetectable; and beta2 was present at a low level. Compared to controls, levels of the alpha5 chain were increased in muscles from many dystrophic patients; levels of beta1 were reduced and/or levels of beta2 were increased in a minority. However, these changes were neither specific for, nor consistent within, diagnostic categories. In contrast, levels of alpha4 were increased in muscles from all patients with alpha2 laminin (merosin)-deficient congenital muscular dystrophy. Loss of alpha2 laminin in congenital dystrophy is disease-specific but some other changes in laminin isoform expression in dystrophic muscles could be secondary consequences of myopathy, denervation, regeneration or immaturity. To distinguish among these possibilities, we compared the laminins of embryonic, denervated, regenerating, and mutant mouse muscles with those in normal adult muscle. Embryonic muscle basal lamina contained alpha4 and alpha5 along with alpha2, and regenerating muscle re-expressed alpha5 but not alpha4. Levels of alpha5 but not alpha4 were increased in dystrophin (mdx) mutants and in dystrophin/utrophin double mutants (mdx:utrn -/-), models for Duchenne dystrophy. In contrast, laminin alpha4 was upregulated more than alpha5 in muscles of laminin alpha2 mutant mice (dy/dy; a model for alpha2-deficient congenital dystrophy). Based on these results, we hypothesize that the expression of alpha5 in many dystrophies reflects the regenerative process, whereas the selective expression of alpha4 in alpha2-deficient muscle is a specific compensatory response to loss of alpha2.
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PMID:Distribution of ten laminin chains in dystrophic and regenerating muscles. 1054 49

The lipodystrophies are a group of disorders characterized by the absence or reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660) is an inherited condition in which a regional (trunk and limbs) loss of fat occurs during the peri-pubertal phase. Additionally, variable degrees of resistance to insulin action, together with a hyperlipidaemic state, may occur and simulate the metabolic features commonly associated with predisposition to atherosclerotic disease. The PLD locus has been mapped to chromosome 1q with no evidence of genetic heterogeneity. We, and others, have refined the location to a 5.3-cM interval between markers D1S305 and D1S1600 (refs 5, 6). Through a positional cloning approach we have identified five different missense mutations in LMNA among ten kindreds and three individuals with PLD. The protein product of LMNA is lamin A/C, which is a component of the nuclear envelope. Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD-AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A). As LMNA is ubiquitously expressed, the finding of site-specific amino acid substitutions in PLD, EDMD-AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.
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PMID:LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. 1065 47

To fully understand genome function, the linear genome map must be integrated with a spatial map of chromosomes in the nucleus. Distinct nuclear addresses for a few human chromosomes have been described. Previously we have demonstrated that the gene-rich human chromosome 19 is located in a more central position in the nucleus than the similarly sized, but gene-poor, chromosome 18. To determine whether these two chromosomes are a paradigm for the organization of chromatin in the human nucleus, we have now analysed the nuclear organization of every human chromosome in diploid lymphoblasts and primary fibroblasts. We find that the most gene-rich chromosomes concentrate at the centre of the nucleus, whereas the more gene-poor chromosomes are located towards the nuclear periphery. In contrast, we find no significant relationship between chromosome size and position within the nucleus. Proteins of the nuclear membrane or lamina are candidates for molecules that might anchor regions of the genome at the nuclear periphery and it has been suggested that disruption of this organization may play a role in some disease pathologies. We show that the intranuclear organization of chromosomes is not altered in cells that lack the integral nuclear membrane protein emerin, from an individual with X-linked Emery--Dreifuss muscular dystrophy. This suggests that emerin is not necessary for localizing chromosomes at the nuclear periphery and that the muscular dystrophy phenotype in such individuals is not due to grossly altered nuclear organization of chromatin.
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PMID:The spatial organization of human chromosomes within the nuclei of normal and emerin-mutant cells. 1115 39

We report a case of fully transvenous single-unit biventricular implantable cardioverter defibrillator (ICD) use in a 43-year-old woman with a manifesting carrier form of muscular dystrophy (Emery-Dreifuss syndrome). The indication for biventricular ICD use was progressive heart failure with ventricular arrhythmia, permanent atrial fibrillation and previous VVIR pacemaker insertion. Single-unit transvenous biventricular ICD implantation was undertaken without complication. No potentially serious device malfunction was noted during subsequent follow-up. We conclude that single-unit biventricular ICD implantation is feasible for pacing and ventricular tachyarrhythmia control in patients with underlying atrial fibrillation.
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PMID:Biventricular implantable cardioverter defibrillator use in a patient with heart failure and ventricular tachycardia secondary to Emery-Dreifuss syndrome. 1122 1

The muscular dystrophies are characterised by progressive muscle weakness and wasting. Pathologically the hallmarks are muscle fibre degeneration and fibrosis. Several recessive forms of muscular dystrophy are caused by defects in proteins localised to the sarcolemma. However, it is now apparent that others are due to defects in a wide range of proteins including those which are either nuclear-related (Emery-Dreifuss type muscular dystrophies, oculopharyngeal muscular dystrophy), enzymatic (limb-girdle muscular dystrophy 2A, myotonic dystrophy) or sarcomeric (limb-girdle muscular dystrophies 1A and 2G). Although the clinical and molecular basis of these disorders is heterogeneous all display myopathic morphological features. These include variation in fibre size, an increase in internal nuclei, and some myofibrillar distortion. Degeneration and fibrosis occur, but usually not to the same extent as in muscular dystrophies associated with sarcolemmal protein defects. This review outlines the genetic basis of these "non-sarcolemmal" forms of dystrophy and discusses current ideas on their pathogenesis.
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PMID:Non-sarcolemmal muscular dystrophies. 1130 95

In the past decade, advances in molecular genetics have shown that many familial neuromuscular and cardiovascular diseases share a common pathophysiology. They are caused by inherited mutations in the cellular cytoskeleton of cardiac and skeletal muscle cells. The clinical manifestation of cardiac disease in neuromuscular disorders is common and their management should include both periodic cardiac assessment and appropriate symptomatic and definitive therapy. Dilated cardiomyopathy is a common complication of neuromuscular diseases. Cardiac function may decline progressively as part of the natural history of the disease, but current medical therapy, including angiotensin-converting enzyme inhibitors, beta-blockers, and diuretics, can be used to alleviate symptoms of left ventricular dysfunction. Conduction disturbances may be an important cause of mortality, especially in patients with Emery Dreifuss muscular dystrophy, Kearns-Sayre syndrome, and myotonic dystrophy, and thus pacemaker implantation can be life-saving. Rhythm disturbances, such as atrial fibrillation and ventricular tachyarrhythmias, have been reported in patients with neuromuscular diseases. Treatment is based on preventing sudden death and embolic phenomena and cardioverting or controlling atrial fibrillation. In these patients, problems may arise with anticoagulation and antiarrhythmic therapy due to the inherent locomotor instability associated with the disease, and the presence of concomitant atrioventricular disease. Although uncommon, hypertrophic cardiomyopathy may be a feature of some neuromuscular disorders. Patients should undergo regular risk stratification for sudden cardiac death and symptoms such as heart failure can be treated with medical therapy.
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PMID:Cardiovascular Complications of Neuromuscular Disorders. 1185 79

Charcot-Marie-Tooth disease constitutes a genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. The axonal type of Charcot-Marie-Tooth is designated type 2. Six loci for autosomal dominant and three for recessive Charcot-Marie-Tooth type 2 have been reported so far. In this study we report the phenotype of autosomal recessive axonal Charcot-Marie-Tooth type 2 due to a recently-described mutation (c.892C>T-p.R298C) in a gene encoding Lamin A/C nuclear envelope proteins and the first gene in which a mutation leads to autosomal recessive Charcot-Marie-Tooth type 2. We have explored eight patients from four Algerian families. The onset is usually in the second decade and the course is rapid, involving upper limbs and proximal muscles, leading to a severe condition in less than 4 years. Many different mutations in Lamin A/C have been identified as causing variable phenotypes, such as limb girdle muscular dystrophy type 1B, autosomal dominant and recessive Emery-Dreyfuss muscular dystrophy, dilated cardiomyopathy with atrioventricular conduction defect, and Dunnigan-type familial partial lipodystrophy should prompt us to fully investigate the skeletal and cardiac muscles in patients affected with autosomal recessive Charcot-Marie-Tooth type 2 carrying a mutation in LMNA.
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PMID:The phenotypic manifestations of autosomal recessive axonal Charcot-Marie-Tooth due to a mutation in Lamin A/C gene. 1246 34

Emery Dreifuss muscular dystrophy is a genetically heterogeneous disorder characterized by the clinical triad of early onset contractures, progressive muscular wasting and weakness with humeroperoneal distribution and cardiac conduction defects. Mutations in the Lamin A/C (LMNA) gene are responsible for the autosomal dominant and the autosomal recessive forms. Familiar and sporadic patients carrying mutations in the LMNA gene show high variability in the clinical symptomatology and age of onset. In this report, we describe four families harboring missense mutations in the LMNA gene and we show that the effect of mutations ranges from silent to fully penetrant. We suggest that incomplete penetrance of dominant mutations in the LMNA gene is a common feature and we emphasize the significance of mutational analysis in relatives of sporadic cases of laminopathies, as asymptomatic carriers face high risk of sudden cardiac death.
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PMID:Frequent low penetrance mutations in the Lamin A/C gene, causing Emery Dreifuss muscular dystrophy. 1246 52


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