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 report here three related patients with a duplication of exons 19-41 of the dystrophin gene, having dissimilar clinical phenotype and dystrophin immunohistochemistry. Two brothers aged six and three years had myalgia, proximal muscular weakness and hypertrophic calves, with 10- 20-fold increase of serum creatine kinase. Muscle biopsy showed dystrophic changes and reduced, patchy binding of dystrophin. The clinical and laboratory findings were consistent with a diagnosis of Becker muscular dystrophy with early onset. Their 14-year-old cousin had only mild hyperCKemia. His muscle biopsy was normal with only mild reduction of dystrophin immunostaining. At follow-up, he is still without symptoms and signs at age 19. All three patients had the same gene duplication and an increased dystrophin size of 507 kDa. Expression of the dystrophin-associated glycoproteins adhalin, alpha-dystroglycan, and beta-dystroglycan were normal in the three patients. An intrafamilial variability in patients carrying a partial duplication of the dystrophin gene may be related to a quantitative difference in mRNA.
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PMID:Duplication of dystrophin gene and dissimilar clinical phenotype in the same family. 858 Jul 29

Limb-girdle muscular dystrophies (LGMDs) represent a clinically heterogeneous group of genetic diseases characterised by progressive weakness of the pelvic and shoulder girdle muscles. An autosomal dominant form (LGMD1A) has been mapped at 5q22.3-31.3, while five genes responsible for the autosomal recessive forms were mapped respectively at: 15q15.1 (LGMD2A), 2p12-p16 (LGMD2B), 13q12 (LGMD2C), 17q12-q21.33 (LGMD2D) and 4q12 (LGMD2E). Among 17 autosomal recessive (AR) LGMD Brazilian families with at least three affected sibs, we were able to exclude four families (one mild and three severe) from all these five known loci as well as from the dystroglycan and syntrophin genes. Therefore, we have performed a genome-wide search in two of the severely affected families, which are alpha-sarcoglycan negative. We demonstrate linkage of these two Duchenne muscular dystrophy-like families to 5q33-34, and propose to classify them as LGMD2F. In addition, linkage analysis in the other two genealogies that are alpha-sarcoglycan positive suggests that there is at least one other gene which causes AR LGMD.
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PMID:Linkage analysis in autosomal recessive limb-girdle muscular dystrophy (AR LGMD) maps a sixth form to 5q33-34 (LGMD2F) and indicates that there is at least one more subtype of AR LGMD. 877 97

"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

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of inherited neuromuscular disorders characterized by proximal muscular weakness of the pelvic and shoulder girdles and a variable progression with symptoms, ranging from very severe to mild. One autosomal dominant (LGMD1A, at chromosome 5q22.3-31.3) (ref. 3) and five autosomal recessive (AR) loci responsible for this phenotype have been identified: LGMD2A at 15q (ref. 4); LGMD2B at 2p (ref. 5), LGMD2C at 13q (ref. 6), LGMD2D at 17q (ref. 7) and LGMD2E at 4q (refs 8,9). In the muscle membrane, dystrophin associates with several proteins and glycoproteins organized in two main subcomplexes: the dystroglycan (DG) and sarcoglycan (SG) complexes. The genes for LGMD2C, LGMD2D and LGMD2E code for proteins of the SG complex. We recently mapped a sixth AR form of LGMD, LGMD2F, to chromosome 5q33-34 in two Brazilian families. In the same chromosomal interval we also mapped the delta SG gene, encoding a novel 35-kD component of the sarcoglycan (SG) complex. We now show that a homozygous mutation in the delta SG gene (a single nucleotide deletion that alters its reading frame) is the cause of LGMD2F.
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PMID:Autosomal recessive limb-girdle muscular dystrophy, LGMD2F, is caused by a mutation in the delta-sarcoglycan gene. 884 Nov 94

beta-Dystroglycan, a 43-kd transmembrane dystrophin-associated glycoprotein, plays an important role in linking dystrophin to the laminin-binding alpha-dystroglycan. alpha-/beta-Dystroglycan is encoded by a single gene on chromosome 3p21 and ubiquitously expressed in muscle and nonmuscle tissues. No known human diseases have been mapped to this locus. Here, we describe the selective deficiency of beta-dystroglycan in a 4-year-old Saudi boy with muscular dystrophy. The patient had a borderline elevation of serum creatine kinase level and early-onset proximal symmetrical muscle weakness and wasting without calf hypertrophy. The milder phenotype may suggest a secondary deficiency of beta-dystroglycan; however, the unique immunofluorescence labeling suggests that the patient may present a novel form of muscular dystrophy.
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PMID:Muscular dystrophy associated with beta-Dystroglycan deficiency. 900

Congenital myasthenic syndromes are a heterogeneous group of conditions in which muscle weakness resulting from impaired neuromuscular transmission is often present from infancy. One form of congenital myasthenic syndrome is due to a reduction of the number of acetylcholine receptors (AChRs) at the neuromuscular junction. We describe four new cases of AChR deficiency, characterized by a reduction in both miniature endplate potential amplitude and AChR abundance accompanied by elongation of the neuromuscular junction and some decrease in postsynaptic folding. A number of cytoplasmic proteins are normally associated with the postsynaptic membrane and may contribute to the clustering of AChRs at the neuromuscular junction. We therefore investigated the expression of several of these proteins in these AChR-deficiency patients. In each patient, immunolabelling of the neuromuscular junction for rapsyn, dystrophin, beta-dystroglycan and a form of beta-spectrin was strong but that for utrophin was markedly reduced or absent. This suggested that a defect in utrophin expression might underlie the congenital AChR deficiency. However, a reduction in utrophin labelling was also seen in three patients with adult acquired autoimmune myasthenia gravis in whom AChR loss results directly from the extracellular binding of autoantibodies. We conclude that the loss of AChRs in AChR deficiency does not result from the absence of rapsyn or beta-dystroglycan and that reduction of utrophin is probably secondary to the loss of AChRs. The possible role of AChRs and/or utrophin in determining the extent of postsynaptic folding is discussed.
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PMID:Utrophin abundance is reduced at neuromuscular junctions of patients with both inherited and acquired acetylcholine receptor deficiencies. 931 36

Abnormalities of dystrophin, the sarcoglycans, and laminin alpha2 are responsible for a subset of the muscular dystrophies. In this study we aim to characterise the nature and frequency of abnormalities of these proteins in an Australian population and to formulate an investigative algorithm to aid in approaching the diagnosis of the muscular dystrophies. To reduce ascertainment bias, biopsies with dystrophic (n=131) and non-dystrophic myopathic (n=71) changes were studied with antibodies to dystrophin, alpha, beta, and gamma sarcoglycan, beta dystroglycan, and laminin alpha2, and results were correlated with clinical phenotype. Abnormalities of dystrophin, the sarcoglycans, or laminin alpha2 were present in 61/131 (47%) dystrophic biopsies and in 0/71 myopathic biopsies, suggesting that immunocytochemical study of dystrophin, the sarcoglycans, and laminin alpha2 may, in general, be restricted to patients with dystrophic biopsies. Two patients with mutations identified in gamma sarcoglycan had abnormal dystrophin (by immunocytochemistry and immunoblot), showing that abnormalities of dystrophin may be a secondary phenomenon. Therefore, biopsies should not be excluded from sarcoglycan analysis on the basis of abnormal dystrophin alone. The diagnostic yield was highest in those with severe, rapidly progressive limb-girdle weakness (92%). Laminin alpha2 deficiency was identified in 5/131 (4%) patients; 215 patients presented after infancy, indicating that abnormalities of laminin alpha2 are not limited to the congenital muscular dystrophy phenotype. Overall patterns of immunocytochemistry and immunoblotting provided a guide to mutation analysis and, on the basis of this study, we have formulated a diagnostic algorithm to guide the investigation of patients with muscular dystrophy.
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PMID:Abnormalities of dystrophin, the sarcoglycans, and laminin alpha2 in the muscular dystrophies. 961 Aug

Abnormalities in the muscle dystrophin-glycoprotein complex are implicated in the molecular pathogenesis of various neuromuscular disorders. Weakening of the trans-sarcolemmal linkage between the actin membrane-cytoskeleton and the extracellular matrix appears to trigger destabilization of the muscle cell periphery. In addition to muscular weakness, one-third of patients suffering from Duchenne muscular dystrophy exhibit mental retardation. Since little is known about the pathophysiology of brain abnormalities in these patients, we investigated the fate of the most abundant dystrophin-associated protein, beta-dystroglycan, in the central nervous system. It was found to be present throughout all normal brain regions studied. In contrast, this glycoprotein was greatly reduced in brain microsomes derived from Duchenne specimens, while it is of normal abundance in the brain from the dystrophic animal model mdx. Deficiency in brain beta-dystroglycan might render nervous tissue more susceptible to cellular disturbances and this may result in cognitive impairment in some Duchenne patients.
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PMID:Decreased expression of brain beta-dystroglycan in Duchenne muscular dystrophy but not in the mdx animal model. 970 63

We report on two brothers (the product of first-degree consanguineous marriage; aged 15 and 12 years) who presented with severe hypotonia at birth, proximal muscle weakness associated with delayed motor milestones but normal cognitive function. Investigations (at 4 years of age) revealed mildly elevated serum creatine kinase (CK) levels (300 and 824 IU/l; N < or = 210). Muscle biopsies showed minimal change myopathy, no neurogenic atrophy but remarkable type-1 fibre predominance (up to 85.5%) without fibre-type disproportion. Clinical examination at 12 and 9 years, respectively, showed mild facial weakness and high-arched palate in both patients. The younger sibling also had ptosis but otherwise normal external ocular muscles. They showed symmetric proximal muscle weakness and wasting associated with calf-muscle hypertrophy. They could walk independently. A repeat muscle biopsy showed advanced dystrophic changes in the younger patient at the age of 10 years. Virtually all the remaining fibres were type 1. Immunohistochemistry revealed normal expression of the dystrophin-glycoprotein complex (DGC), including dystrophin, beta-dystroglycan, alpha-(adhalin), beta-, gamma-, and delta-sarcoglycan, laminin-alpha2 chain (merosin) and syntrophin. Mild dystrophic features and type-1 fibre predominance (92.5%) were seen in the biopsy of the older patient, whereas immunohistochemistry showed normal expression of the DGC. Both cases also showed clear expression of integrin alpha7 at the muscle fibre surface and in the blood vessels. Three years later, they could still walk, but with difficulty, and the older brother showed enlargement of the tongue and echocardiographic features of left ventricular dilated cardiomyopathy.
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PMID:A novel form of familial congenital muscular dystrophy in two adolescents. 1002 46

In humans, mutations in the genes encoding components of the dystrophin-glycoprotein complex cause muscular dystrophy. Specifically, primary mutations in the genes encoding alpha-, beta-, gamma-, and delta-sarcoglycan have been identified in humans with limb-girdle muscular dystrophy. Mice lacking gamma-sarcoglycan develop progressive muscular dystrophy similar to human muscular dystrophy. Without gamma-sarcoglycan, beta- and delta-sarcoglycan are unstable at the muscle membrane and alpha-sarcoglycan is severely reduced. The expression and localization of dystrophin, dystroglycan, and laminin-alpha2, a mechanical link between the actin cytoskeleton and the extracellular matrix, appears unaffected by the loss of sarcoglycan. We assessed the functional integrity of this mechanical link and found that isolated muscles lacking gamma-sarcoglycan showed normal resistance to mechanical strain induced by eccentric muscle contraction. Sarcoglycan-deficient muscles also showed normal peak isometric and tetanic force generation. Furthermore, there was no evidence for contraction-induced injury in mice lacking gamma-sarcoglycan that were subjected to an extended, rigorous exercise regimen. These data demonstrate that mechanical weakness and contraction-induced muscle injury are not required for muscle degeneration and the dystrophic process. Thus, a nonmechanical mechanism, perhaps involving some unknown signaling function, likely is responsible for muscular dystrophy where sarcoglycan is deficient.
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PMID:Muscle degeneration without mechanical injury in sarcoglycan deficiency. 1048 93


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