Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We described two patients, a mother and daughter, of Stormorken's syndrome. The syndrome is characterized clinically by autosomal dominant inheritance, congenital miosis, thrombocytopenia, asplenia and muscle weakness. Both patients had bleeding tendency, ichthyosis of arms, and muscle weakness. The daughter additionally had short stature (146 cm), low body weight (32 kg) and muscle cramp. Neurological findings of the patients included migraine-like headache, cognitive dysfunction, limitation of upward and lateral gaze, and amydriasis. Femoral muscle MRI of the daughter demonstrated decreased volume with patchy high intensity areas in the hamstrings. A muscle biopsy from the daughter showed myogenic changes with muscle fiber necrosis and regeneration, variation in fiber size, tubular aggregates in approximately 5% of fibers, and fibrous tissue proliferation. Dystrophin, dystrophin-associated proteins and dysferlin were normally expressed. Although both patients had elevated creatine kinase levels and generalized muscle wasting, muscle weakness was mild with slow progression. A certain membrane defect in the platelet and muscle fiber might be responsible for the pathogenesis of this syndrome.
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PMID:[Muscle involvement of Stormorken's syndrome]. 1125 89

Abnormalities of dystrophin are a common cause of muscular dystrophy and testing for dystrophin gene or protein has become a part of routine diagnostic evaluation of patients who present with progressive proximal muscle weakness, high serum creatine kinase concentrations, and histopathological evidence of a dystrophic process. Patients who have no dystrophin abnormalities are assumed to have autosomal recessive muscular dystrophy. In a family consisting of 5 sibs, 2 mentally normal brothers presented with abnormal gait and protrusion of chest and hips. Muscle biopsy from one of them showed dystrophic changes and reduced patchy binding of dystrophin. No detectable deletion was observed in the patient's DNA and his brother with cDMD probes. Dystrophin associated proteins, beta-dystroglycan showed discontinuous immunostaining in the sarcolemma and alpha-sarcoglycan (adhalin) was totally absent, while beta-, gamma-, and delta-sarcoglycans were highly reduced. Immunoblot analysis showed dystrophin of normal molecular weight but of decreased quantity, beta-dystroglycan was reduced by about 37% while alpha-sarcoglycan was completely absent. This study is a first attempt for a systematic clinical, genetic and molecular investigation of the autosomal recessive LGMD in India.
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PMID:Deficiency of the 50 kDa dystrophin-associated-glycoprotein (adhalin) in an Indian autosomal recessive limb girdle muscular dystrophy patient : immunochemical analysis and clinical aspects. 1130 36

A 48-year-old female carrier of Duchenne muscular dystrophy had developed congestive heart failure but had no skeletal muscle symptoms. She was admitted to our hospital complaining of palpitation in December 1998. Her three sons had Duchenne muscular dystrophy. Neurological examination was unremarkable with no evidence of muscle weakness. Serum creatine kinase level was slightly increased. Echocardiography showed severe left ventricular dysfunction. Coronary angiography showed no abnormalities. Left ventriculography showed generalized hypokinesis and left ventricular ejection fraction was 28%. Dystrophin immunostaining of the skeletal muscle biopsy specimen showed a mosaic pattern. The dystrophin negative fibers were scattered among positive fibers. Cardiomyopathy is the only clinical manifestation of dystrophin gene mutation in carriers. Beta-blocker therapy(carvedilol 5 mg/day) was effective in this patient.
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PMID:[Female carrier of Duchenne muscular dystrophy presenting with secondary dilated cardiomyopathy: a case report]. 1149 34

Duchenne and Becker muscular dystrophy (DMD and BMD) are progressive disorders, which almost exclusively affect males. DMD is the more severe type with an onset at 2-3 years of age. Patients become wheelchair-bound before the age of 13 and often die due to cardiac arrest or respiratory insufficiency. BMD, a more varying phenotype which may overlap with limb girdle muscular dystrophy (LGMD), has a less severe muscle weakness which starts later than in DMD patients. DMD carriers may show some muscle weakness. The dystrophin gene (2.4 Mb), known to be involved in DMD/BMD, codes for a 427 kilodalton muscle-specific protein named dystrophin as well as several tissue-specific isoforms. Dystrophin, as part of a membrane-bound complex of proteins, connects the cytoskeleton of the muscle cell to the extracellular matrix. Since 1985, when highly reliable carrier detection and prenatal diagnosis at the DNA level became possible, over 250 prenatal tests have been performed. Molecular genetic analysis, highlighted a phenomenon called germinal mosaicism, which explains the recurrence of de novo mutations and led to the discovery of the so-called reading-frame rule, which helps to discriminate between DMD and BMD. Fifteen years after the discovery of the dystrophin gene, mutations can be detected in 95% of the patients, while the remaining 5% are still hiding within this very large gene.
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PMID:[From gene to disease; the dystrophin gene involved in Duchenne and Becker muscular dystrophy]. 1188 23

An 8-year-old boy was referred for recent onset of easy fatigue. He showed hyperCKemia and mild scapular winging. Muscle biopsy on the quadriceps muscle demonstrated slight fibre size variability. Dystrophin was normally distributed, carnitine palmitoyl transferase and glycolytic enzymes had normal activities. In the following years the patient developed exercise intolerance and myoglobinuria. Immunohistochemistry showed marked reduction of alpha-sarcoglycan, confirmed by Western blotting. Molecular analysis revealed compound heterozygosity with Arg284Cys and Glu137Lys substitutions, corresponding to nucleotide changes C850 T and G409 A in the gene. At present the patient, 20 years old, shows mild proximal weakness with prominent involvement of the paraspinal muscles, dorsal kyphosis and lumbar hyperlordosis. Exercise intolerance and myoglobinuria, already described in Becker muscular dystrophy, should be also considered among the possible presentations of sarcoglycan deficiencies.
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PMID:Alpha-sarcoglycan deficiency featuring exercise intolerance and myoglobinuria. 1207 95

Duchenne/Becker and limb-girdle muscular dystrophies share clinical symptoms like muscle weakness and wasting but differ in clinical presentation and severity. To get a closer view on the differentiating molecular events responsible for the muscular dystrophies, we have carried out a comparative gene expression profiling of hindlimb muscles of the following mouse models: dystrophin-deficient (mdx, mdx(3cv)), sarcoglycan-deficient (Sgca null, Sgcb null, Sgcg null, Sgcd null), dysferlin-deficient (Dysf null, SJL(Dysf)), sarcospan-deficient (Sspn null), and wild-type (C57Bl/6, C57Bl/10) mice. The expression profiles clearly discriminated between severely affected (dystrophinopathies and sarcoglycanopathies) and mildly or nonaffected models (dysferlinopathies, sarcospan-deficiency, wild-type). Dystrophin-deficient and sarcoglycan-deficient profiles were remarkably similar, sharing inflammatory and structural remodeling processes. These processes were also ongoing in dysferlin-deficient animals, albeit at lower levels, in agreement with the later age of onset of this muscular dystrophy. The inflammatory proteins Spp1 and S100a9 were up-regulated in all models, including sarcospan-deficient mice, which points, for the first time, at a subtle phenotype for Sspn null mice. In conclusion, we identified biomarker genes for which expression correlates with the severity of the disease, which can be used for monitoring disease progression. This comparative study is an integrating step toward the development of an expression profiling-based diagnostic approach for muscular dystrophies in humans.
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PMID:Common pathological mechanisms in mouse models for muscular dystrophies. 1630 63

Dystrophin deficiency leads to the progressive muscle wasting disease Duchenne muscular dystrophy (DMD). Dystrophin-deficient mdx mice are characterized by skeletal muscle weakness and degeneration but they appear outwardly normal in contrast to DMD patients. Mice lacking both dystrophin and the dystrophin homolog utrophin [double knockout (dko)] have muscle degeneration similar to mdx mice, but they display clinical features similar to DMD patients. Dko limb muscles also lack postsynaptic membrane folding and display fiber-type abnormalities including an abundance of phenotypically oxidative muscle fibers. Extraocular muscles, which are spared in mdx mice, show a significant pathology in dko mice. In this study, microarray analysis was used to characterize gene expression differences between mdx and dko tibialis anterior and extraocular skeletal muscles in an effort to understand the phenotypic differences between these two dystrophic mouse models. Analysis of gene expression differences showed that upregulation of slow muscle genes specifically characterizes dko limb muscle and suggests that upregulation of these genes may directly account for the more severe phenotype of dko mice. To investigate whether any upregulation of slow genes is retained in vitro, independent of postsynaptic membrane abnormalities, we derived mdx and dko primary myogenic cultures and analyzed the expression of Myh7 and Myl2. Real-time reverse transcriptase-polymerase chain reaction analysis demonstrates that transcription of these slow genes is also upregulated in dko vs mdx myotubes. This data suggests that at least part of the fiber-type abnormality is due directly to the combined absence of utrophin and dystrophin and is not an indirect effect of the postsynaptic membrane abnormalities.
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PMID:Analysis of gene expression differences between utrophin/dystrophin-deficient vs mdx skeletal muscles reveals a specific upregulation of slow muscle genes in limb muscles. 1652 50

This report describes three males from a single kinship, ages 7, 8, and 67 years with clinically asymptomatic dystrophinopathy. The index case was an 8-year-old male evaluated for asymptomatic but persistently elevated serum creatine kinase levels. Muscle biopsy demonstrated a mild myopathy, without necrotic fibers. Immunostaining for dystrophin revealed a slight reduction in sarcolemmal reactivity for the amino terminus of dystrophin. Dystrophin gene analysis revealed a deletion of exon 45 to exon 51. Genetic analysis identified two other affected males (age 7 years and 67 years), as well as four female carriers in the same family. The 7-year-old male had mildly increased creatine kinase levels with normal muscle strength. The 67-year-old grandfather had normal neuromuscular examination and serum creatine kinase levels. Asymptomatic dystrophinopathy in late adulthood is exceptionally rare, and highlights the importance of consideration of dystrophin mutation analysis in patients with hyperCKemia, even in the absence of muscle weakness.
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PMID:Grandpa and I have dystrophinopathy?: approach to asymptomatic hyperCKemia. 1743 17

Duchenne muscular dystrophy (DMD) is one of the most severe X-linked, inherited diseases of childhood, characterized by progressive muscle wasting and weakness as the consequence of mutations in the dystrophin gene. The protein encoded by dystrophin is a huge cytosolic protein that links the intracellular F-actin filaments to the members of the dystrophin-glycoprotein-complex (DGC). Dystrophin deficiency results in the absence or reduction of complex components that are degraded through an unknown pathway. We show here that muscle degeneration in a Caenorhabditis elegans DMD model is efficiently reduced by downregulation of chn-1, encoding the homologue of the human E3/E4 ubiquitylation enzyme CHIP. A deletion mutant of chn-1 delays the cell death of body-wall muscle cells and improves the motility of animals carrying mutations in dystrophin and MyoD. Elimination of chn-1 function in the musculature, but not in the nervous system, is sufficient for this effect, and can be phenocopied by proteasome inhibitor treatment. This suggests a critical role of CHIP/CHN-1-mediated ubiquitylation in the control of muscle wasting and degeneration and identifies a potential new drug target for the treatment of this disease.
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PMID:A mutation in CHN-1/CHIP suppresses muscle degeneration in Caenorhabditis elegans. 1796 35

The neuromuscular disorders are a heterogeneous group of genetic diseases, caused by mutations in genes coding sarcolemmal, sarcomeric, and citosolic muscle proteins. Deficiencies or loss of function of these proteins leads to variable degree of progressive loss of motor ability. Several animal models, manifesting phenotypes observed in neuromuscular diseases, have been identified in nature or generated in laboratory. These models generally present physiological alterations observed in human patients and can be used as important tools for genetic, clinic, and histopathological studies. The mdx mouse is the most widely used animal model for Duchenne muscular dystrophy (DMD). Although it is a good genetic and biochemical model, presenting total deficiency of the protein dystrophin in the muscle, this mouse is not useful for clinical trials because of its very mild phenotype. The canine golden retriever MD model represents a more clinically similar model of DMD due to its larger size and significant muscle weakness. Autosomal recessive limb-girdle MD forms models include the SJL/J mice, which develop a spontaneous myopathy resulting from a mutation in the Dysferlin gene, being a model for LGMD2B. For the human sarcoglycanopahties (SG), the BIO14.6 hamster is the spontaneous animal model for delta-SG deficiency, whereas some canine models with deficiency of SG proteins have also been identified. More recently, using the homologous recombination technique in embryonic stem cell, several mouse models have been developed with null mutations in each one of the four SG genes. All sarcoglycan-null animals display a progressive muscular dystrophy of variable severity and share the property of a significant secondary reduction in the expression of the other members of the sarcoglycan subcomplex and other components of the Dystrophin-glycoprotein complex. Mouse models for congenital MD include the dy/dy (dystrophia-muscularis) mouse and the allelic mutant dy(2J)/dy(2J) mouse, both presenting significant reduction of alpha2-laminin in the muscle and a severe phenotype. The myodystrophy mouse (Large(myd)) harbors a mutation in the glycosyltransferase Large, which leads to altered glycosylation of alpha-DG, and also a severe phenotype. Other informative models for muscle proteins include the knockout mouse for myostatin, which demonstrated that this protein is a negative regulator of muscle growth. Additionally, the stress syndrome in pigs, caused by mutations in the porcine RYR1 gene, helped to localize the gene causing malignant hypertermia and Central Core myopathy in humans. The study of animal models for genetic diseases, in spite of the existence of differences in some phenotypes, can provide important clues to the understanding of the pathogenesis of these disorders and are also very valuable for testing strategies for therapeutic approaches.
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PMID:Animal models for genetic neuromuscular diseases. 1820 36


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