Muscular dystrophies, Becker

Duchenne and Becker muscular dystrophies (DMD and BMD) are X-linked, allelic, neuromuscular diseases. DMD/BMD are characterized by progressive muscular weakness and degeneration of skeletal muscle. DMD is the most common recessive lethal disease, with an incidence of approximately 1 in 3500 newborns, and according to estimates, one-third of the cases are linked with new mutations (M3). Clinical symptoms of the disease appear earlier, by 2 to 3 years of age, in the form of retarded motor development. Progressive symptomatic children show weakness and wasting of muscle and are usually wheelchair bound approximately by the age of 11-12 years. It has been reported that most patients die at about the age of 20 due to pneumonia, which is related to chronic respiratory insufficiency. BMD—being the rarer allelic disorder—has a milder clinical course with slower disease progression. The BMD-affected patients usually survive beyond the age of 30. 

The DMD gene was identified before the protein named dystrophin. The gene was first identified as localized to the short arm of the X chromosome (xp21). The isolated DMD gene, spanning more than 2000 kb of genomic DNA, is composed of approximately 75 exons that encode a 14-kb transcript which is 

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LGMD, limb girdle muscular dystrophy DMD, Duchenne muscular dystrophies BMD, Becker muscular dystrophies... 

Figure 1. Immunofluorescent labeling of dystrophin in the Xp21 muscular dystrophies. In normal muscle, clear uniform labeling is present at the membrane of each muscle fiber. In Becker muscular dystrophy (BMD), there is inter- and intrafiber variation in labeling intensity. In Duchenne muscular dystrophy (DMD), most fibers are devoid of labeling (note, however, that in most biopsies occasional fibers exhibit weak labeling). In the biopsy from a manifesting carrier, some fibers show normal labeling and others are negative. In the former, the normal X-chromosome is active while in the latter the abnormal X-chromosome is active.

Bushby, K., Gardner-Medwin, D. (1993). The clinical, genetic and dystrophin characteristics of Becker muscular dystrophy. I. Natural History. J. Neurol. 240. 98-104. 

Hoffrnan, E.P., Kunkel, L.M. (1989). Dystrophin abnormalities in Duchenne/Becker muscular dystrophy. Neuron 2, 1019-1029. 

Duchenne and Becker Muscular Dystrophy Current Diagnostics. 55... 

PI. Prior, T. W., Friedman, K. J., Highsmith, W. E., Perry, T. R., and Silverman, L. M., Molecular probe protocol for determining carrier status in Duchenne and Becker muscular dystrophies. Clin. Chem. (Winston-Salem. NC) 36, 441-445 (1990). 

The clinical progression of Becker muscular dystrophy is typically much slower than that of Duchenne muscular dystrophy. This is usually the result of... 

Answer B. In-frame deletions or insertions typically produce an altered protein product (dystrophin), but the alteration is mild enough so that Becker muscular dystrophy results. Frame-shifts usually produce a truncated protein because a stop codon is eventually encountered. The truncated protein is degraded, resulting in an absence of dystrophin and a more severe disease phenotype. 

Muscular dystrophies are characterised by variable degrees of muscle weakness and degeneration. The most common forms are Duchenne (severe) and Becker (benign), both caused by mutation in the same gene in the X chromosome. In Duchenne muscular dystrophy, the first symptom is muscle weakness in early years of life which gradually worsens so that patients are unable to walk by the age of 10. Death from cardiac or respiratory insufficiency usually occurs before the age of 25. In Becker muscular dystrophy, weakness and wasting become apparent between 5 and 25 years but, although severely disabled, patients can have a normal lifespan. 

An X-linked disease of boys, it may not be recognized until two to three years of age, but victims are usually in a wheelchair by age 12 and die around age 20. Individual muscle fibers disintegrate, die, and are replaced by fibrous or fatty tissue.a d The disease strikes about 1 out of 3500 boys born. The less serious Becker muscular dystrophy arises from defects in the same gene but affects only 1 in 30,000 males, some of whom have a normal life span. Because of its frequency and the knowledge that the gene must lie in the X-chromosome, an intensive search for the gene was made. It was found in 1986 after a five-year search.a e This was the first attempt to find a faulty gene whose protein product was totally unknown. 

Schematic model of the dystrophin-glycoprotein complex. Courtesy of Kevin P. Campbell. See Lim and Campbell1 Abbreviations LGMD, Limb Girdle muscular dystrophy CMD, congenital muscular dystrophy DMD / BMD, Duchenne / Becker muscular dystrophies.

Adrenal hypoplasia Glycerol kinase deficiency Chronic granulomatous disease Retinitis pigmentosa-3 Duchenne muscular dystrophy Becker muscular dystrophy... 

Thanh, L T, Nguyen thi Man, Hori, S, Sewry, C A, Dubowitz V., and Morris, G E. (1995) Characterization of genetic deletions in Becker Muscular Dystrophy using monoclonal antibodies against a deletion-prone region of dystrophin. Am J Med Genet 58, 177-186. 

DMD is a severe X-linked recessive, progressive muscle wasting disease that affects approximately 1 in 3500 newborn males (Emery, 1991). An allelic variant of DMD is also known, referred to as Becker muscular dystrophy (BMD). It has a later onset and lesser phenotype than DMD, resulting in longer life expectancy (reviewed in O Brien and Kunkel, 2001). DMD is caused by mutations in the DMD gene that encodes the cytoskeletal linker protein dystrophin. The vast majority of DMD mutations result in the... 

Love, D. R., Flint, T. J., Genet, S. A., Middleton-Price, H. R., and Davies, K. E. (1991). Becker muscular dystrophy patient with a large intragenic dystrophin deletion Implications for functional minigenes and gene therapy. /. Med. Genet. 28, 860-864. 

Norwood, F. L., Sutherland-Smith, A. J., Keep, N. H., and Kendrickjones, J. (2000). The structure of the N-terminal ac tin-binding domain of human dystrophin and how mutations in this domain may cause Duchenne or Becker muscular dystrophy. Structure Fold Des. 8, 481—491. 

Vainzof, M., Takata, R. I., Passos-Bueno, M. R., Pavanello, R. C., and Zatz, M. (1993). Is the maintenance of the G-terminus domain of dystrophin enough to ensure a milder Becker muscular dystrophy phenotype Hum. Mol. Genet. 2, 39-42. 

Basset, O., Boittin, F.X., Dorchies, O.M., Chatton, J.Y., van Breemen, C., and Ruegg, U.T., 2004, Involvement of inositol 1,4,5-trisphosphate in nicotinic calcium responses in dystrophic myotubes assessed by near-plasma membrane calcium measurement, J Biol Chem, 279, pp 47092 17100. Baumbach, L.L., Chamberlain, J.S., Ward, P.A., Farwell, N.J., and Caskey, C.T., 1989, Molecular and clinical correlations of deletions leading to Duchenne and Becker muscular dystrophies, Neurology, 39, pp 465 174. 

Beggs, A.H., and Kunkel, L.M., 1990, Improved diagnosis of Duchenne/Becker muscular dystrophy, J Clin Invest, 85, pp 613-619. 

Koenig, M., Beggs, A.H., Moyer, M., Scherpf, S., Heindrich, K., Bettecken, T., Meng, G., Muller, C.R., Lindlof, M., Kaariainen, H., and et al., 1989, The molecular basis for Duchenne versus Becker muscular dystrophy correlation of severity with type of deletion, Am J Hum Genet, 45, pp 498-506. 

Dmd DGC-associated, sarcolemmal integrity Sp, ENU, KO Duchenne and Becker muscular dystrophy... 

Genetic errors in or damage to cytoskeletal components can play a central role in disease including many forms of hemolytic anemia and the Duchenne and Becker muscular dystrophies. Appropriate cell-cell contact (regulated through the cytoskeleton) appears to be critical in preventing cells from becoming cancerous and, indeed, many types of cancerous cell exhibit abnormal cytoskeletons. 

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