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The Disease

         Duchenne muscular dystrophy (DMD) is the most common and most severe form of muscular dystrophy.  DMD is characterized symptomatically by rapidly progressing wasting of skeletal and cardiac muscles [2].  Compared to other types of muscular dystrophy, DMD results in the earliest onset of symptoms and shortest average lifespan [3].  DMD is caused by the complete absence of functional dystrophin (a protein involved in connecting muscle cells to each other) [1].  Other forms of muscular dystrophy, such as Becker’s muscular dystrophy, result from decreased concentrations—not a complete deficiency—of functional dystrophin [1].  DMD is a genetic disorder linked to the X-chromosome, and according to the Muscular Dystrophy Association, about one in 3,600 male children in the US are born with the disease [3].  Because of the pattern of inheritance, females are far less likely to be afflicted with the recessive disease, but can become carriers with no symptoms if they receive one copy of the mutant x chromosome.

        Diagnosis of Duchenne Muscular Dystrophy can be made a number of ways.  Muscle weakness, as exhibited by below average physical mobility and the tendency of the child to rely on their arms to stand up (Gower’s sign), is often the first visible symptom of DMD[2].  Enlargement of the calves or the infraspinatus and deltoid muscles (as shown below) can further indicate the presence of DMD [5].  The first laboratory test done on an child exhibiting muscle weakness and/or wasting is usually the creatine kinase test (CKT), which tests for muscle damage as evidenced by an increased concentration of the creatine kinase enzyme (normally constrained to muscle cells) in the blood [2].  After a positive CKT result, muscle tissue biopsies are often performed.  Technicians observe these tissues for the presence of dystrophyn.  An absence of visible dystrophin can give a relatively certain diagnosis for Duchenne muscular dystrophy, but the most definitive answer can be obtained through genetic analysis of the patient’s blood [2].  


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This image shows the common enlargement of the infraspinatus and deltoid muscles (arrow heads) and wasting of the posterior axillary muscles (arrow) in a DMD affected individual [1].
http://www.neurologyindia.com/articles/2002/50/2/images/ni_2002_50_2_184_1398_1.jpg

        Most individuals afflicted with DMD first show signs of the disease—usually starting with muscle weakness—before turning six, are confined to wheelchairs by age twelve, and often die by age 25 [3].  About one in three individuals afflicted with DMD show some form of learning disability, although this is usually mild [1].  Other possible complications include: scoliosis of the chest and back, irregular heart rhythm, and abnormally weak heart muscle (cardiomyopathy) [1]. Death is often caused by complications to the cardiopulmonary system, including congestive heart failure, respiratory failure, and pneumonia (due to inability to effectively cough) [3].  Currently, treatment options for individuals with DMD are limited to slowing the progression of the symptoms through physical therapy, but future promise lies in genetic manipulation of muscle cells to express functional dystrophin [6].

 

Below is a video made by an individual withDMD.  He explains his perspectiveon the disease and how he copes with the debilitating nature of DMD.

 

From: YouTube, 2010.  “Conner’s Story - A Jeans for Genes Film”.  Retrieved from http://www.youtube.com/watch?v=tMfKDNLCnXM&feature=related

The Gene

Thegene (named DMD) coding for the dystrophin proteinmeasures 2.4Mb long, making it the largest gene known to exist in nature [entrez].  TheDMD gene is located on the X chromosome in humans [Pozzoli](as shown below) and has 79 exons that account foronly 0.6% of the sequence.

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DuchenneMuscular Dystrophy is caused by severe loss-of-function mutations that resultin premature translational termination of the protein dystrophin [4].  This leads to skeletal muscle cells,and some nerve cells in the brain, that are devoid of functional dystrophin[entrez].  In normal skeletalmuscle tissue, dystrophin anchors the cytoskeleton of muscle cells to theextracellular matrix, as shown in the figure below [1]. Without functionaldystrophin, skeletal and cardiac muscle cells become damaged after repeatedcontraction and eventually die. This massive muscle cell death results in the debilitating symptomspresent in people afflicted with DMD.


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References

     1) Duchenne muscular dystrophy: MedlinePlusMedical Encyclopedia. (2008, December 17). National Library of Medicine -National Institutes of Health. Retrieved February 3, 2010, from http://www.nlm.nih.gov/medlineplus/ency/article/000705.htm

      

     2)'Duchenne's Muscular Dystrophy | Health | Patient UK.' Health Information and Advice | MedicinesGuide | Patient.co.uk. Web. 22 Mar. 2010..

 

      

     3) Facts About Duchenne and Becker Muscular Dystrophies | MDAPublications. (n.d.). Muscular Dystrophy Association. Retrieved February1, 2010, from http://www.mda.org/publications/fa-dmdbmd.html

      

     4) Gillard, E. F., Chamberlain, J. S., Ray, P. N., Worton, R. G.,Murphy, E. G., Smith, B., et al. (1989). Molecular and Phenotypic Analysis ofPatients with Deletions within the Deletion-rich Region of the DuchenneMuscular Dystrophy (DMD) Gene. American Journal of Human Genetics, 45,507-520.

 

      

     5) Pradhan S.Valley sign in duchenne muscular dystrophy : importance in patients withinconspicuous calves. Neurol India [serial online] 2002 [cited 2010 Mar21];50:184. Available from: http://www.neurologyindia.com/text.asp?2002/50/2/184/1398

      

     6) Skuk, D., Goulet, M.,Senay, H., Jacques, P., Brigitte, R., Chapdelaine, P., et al. (2006). DystrophinExpression in Muscles of Duchenne Muscular Dystrophy Patients AfterHigh-Density Injections of Normal Myogenic Cells. rnal of Neuropathology andExperimental Neurology, 64(4), 371-386.

 

The purpose of this research is to perform an analysis of the human dystrophin gene and gene product using genomic, proteomic, and interactomic data.  I will also propose further research using the model organism  M. musculis.


This site was created by Anthony Parendo for an undergraduate Genetics 677 course at the University of Wisconsin-Madison.