2011 Group Project 10

From Embryology

2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip

Introduction: What is Duchenne Muscular Dystrophy? (DMD)

Duchenne muscular dystrophy (DMD) is a sex-linked disorder mostly affecting males because it is a recessive X-linked disease. It is caused by a mutation in the gene that produces the important muscle protein, dystrophin. On humans this gene is located on the X-chromosome, thus if a female has one affected X-chromosome then they are said to be a carrier of the disorder and can pass on the altered gene to her offspring. The dystrophin gene is the largest gene in nature on locus Xp21, spanning 1.5% of the X-chromosome which may explain it’s unusually high spontaneous mutation rate [1] In DMD the protein dystrophin is not produced, when it is an important structural component for muscle tissue. Thus it results in muscle degeneration, difficulty in walking, breathing and death. The rate of progression of the disorder is fast and the age of onset is from 2-6yrs of age.[2]


-childhood onset, diagnosed between ages 3-5

-difficulty walking/mobility in first decade of life, respiratory and cardiac problems in second decade. most die in their 30's due to cardiac/respiratory problems

-range of other problems it can cause


Guillaume Benjamin Amand Duchenne first described the disease in 1861.


The incidence rate for DMD is about 1 in 3500 boys. All ethnic groups are equally affected.

Aetiology - Genetics

The largest gene of the human genome is called the dystrophin gene. This codes for the dystrophin protein which plays a very important role in the structural stability of muscle fibres. In DMD, there is a mutation in this gene causing an absence or severe reduction in the production of dystrophin.

Duchenne Muscular Dystrophy is an inherited X-linked diseased caused by inactivating mutations of the DMD gene. This particular mutation results in the production of a non-functional protein that causes the degeneration of skeletal muscle. [3].

DMD, also known as BMD or dystrophin, is a gene located on the short arm of the X chromosome at position 21.2. To be more specific, this particular gene is located from base pair 31,137,344 to base pair 33,357,725 on the X chromosome. [4] In its normal functional form, DMD produces a protein called dystrophin. There a multiple forms of dystrophin, however it is mostly common found in both skeletal and cardiac muscles. Together with other proteins, dystrophin acts to strengthen and protect muscle fibers, connecting muscle cell components and can also be involved in cell signalling. [5]


Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscle and cardiac muscle. The exact function of dystrophin is unknown - it is thought to secure the sarcolemma to the actin cytoskeleton of the muscle cell. This adds strength and rigidity, protecting the muscle when it contracts[6].

Without dystrophin, the muscle cells can be easily damaged during contraction- the cell membrane becomes very permeable and allows extracellular material in. This causes swelling, until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated necrosis and regeneration[7]. Necrosis often occurs in zones within the muscle fibres, a characteristic feature of Duchenne disease. The rate at which necrosis occurs is faster than the rate at which the tissue can regenerate, so the muscle fibres progressively disappear. [8].

Within the extracellular material are calcium ions, which cause serious damage when there is an influx into the muscle. Calcium activates the enzyme protease, an enzyme that breaks down proteins and peptides. In the muscle, this results in necrosis of myocytes and inflammation[9]. In the heart, increased intracellular calcium activates another protease called calpain, which deteriorates the contractile muscle[10]. This increases the stress placed on the remaining functional heart muscle.

A key part of the pathogenesis is the replacement of dead muscle fibres with connective tissue (fibrosis) and adipose tissue. Although components of connective tissue, such as collagen, have high tensile strength, it does not and cannot function like muscle. Significant amounts of fibroid material weaken and hinder normal muscle contraction. In the heart, this is known as cardiomyopathy.

Clinical manifestations and complications

*Skeletal muscle:

The degeneration of skeletal muscle causes many problems with mobility. In early childhood, a child affected with DMD may take longer than other children to sit or begin standing and walking. Young children may develop a waddling gait, a characteristic feature of DMD [11]. As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by between the ages of 8 and 11[12]. Other indicators of the disease include pseudohypertrophy, fatigue, leg cramps and Gower's Sign[13]. Gower's Sign is particularly characteristic of DMD - it is where the child, from a kneeling position, will push their arms up along their legs to help them stand. A person with DMD may also suffer from joint contractures in the ankle, knees and hips[14]

In addition to effects on body movement, DMD can cause problems with the spine. If the muscles around the spine (such as latissimus dorsi, erector spinae and trapezius muscles) weaken or atrophy, scoliosis can develop. As high as 90% of people affected by DMD will develop clinically significant scoliosis[15]. If the muscles degenerate unevenly, kyphosis[16] can occur - excessive outward curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis[17] - excessive inward curvature of the lumbar spine (resulting in a pushed forward abdomen and backwards extending hips).

Pictures: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047897/

*Cardiac muscle:

A very common and serious complication of DMD is cardiomyopathy- on average, 20% of DMD sufferers will die from cardiac failure[18]. Cardiac muscle is affected in a similar way to skeletal muscle, in which the sarcolemma loses integrity and necrotic tissue is replaced by fat and connective tissue. This severely compromises the strength and ability of the heart to contract properly and circulate blood around the body. If the heart cannot pump blood properly, cells will not receive enough oxygen for normal function. The area of the heart that is most affected is the lateral postero-basal side of the left ventricle, as this area takes the greatest strain as the heart beats[19]. Currently, there is no evidence to suggest that DMD affects the conduction system of the heart, however [20][21], in the late stages of the disease, the large quantities of fibroid material in the heart can cause systolic dysfunction and ventricular arrhythmias.

*Respiratory problems:

Problems relating to respiratory function become most prevalent when the person requires a wheelchair or assistance in moving. By this stage of the disease, overall muscle strength is low, and so the person may have difficulties breathing, or may not be able to inspire or expire to their maximum capacity. The degree of muscle strength may be (indirectly) measured by a Forced Vital Capacity (FVC) - the volume of air that can be forcibly expelled after a full inspiration. If the FVC is low, this is indicative of poor muscle strength and therefore possible respiratory failure. As a result, hypercapnia may develop (abnormally high levels of CO2 in the bloodstream) and can affect energy levels, weight management, cause bad headaches and disturb sleep[22]. [Effects of high CO2 and the problems it can cause]. Combined, these symptoms increase susceptibility or predispose the patient to a range of pulmonary infections, such as pneumonia. Approximately 80% of Duchenne sufferers will die from respiratory failure or a related illness[23]

*Smooth muscle:

DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea&&&. Muscles in the oesophagus can weaken, and cause difficulties swallowing food (leading to under-nutrition) or aspiration&&&.

*Cognitive Impairment:


In a study done by S. Cyrulink & R. Fee et al., it was found that results of paired t tests indicate that children with DMD are rated as delayed relative to familial controls on measures of adaptive functioning, as assessed by the Vineland Adaptive Behavior Scales. Furthermore, children with DMD exhibit impairments on multiple measures of cognition, including measures of receptive language, expressive language, visuo-spatial skills, fine-motor skills, attention, and memory skills. Across all domains examined, the young children with DMD performed more poorly than their familial controls[25].


  • Clinical Diagnosis - in males: progressive symmetrical muscle weakness, symptoms present before age 5, elevated kinase blood levels.
  • Muscle biopsy - a sample of muscle can be taken to look for abnormal levels of dystrophin in the muscle. A special stain is used to detect the dystrophin protein. In a unaffected patient, dystrophin will appear as though there is caulking around the individual muscles cells and it is holding them together like window panes. A patient suffering from DMD will have an absence of the dystrophin.
  • Genetic Testing - this is achieved through a blood sample analysis. Changes in the DMD gene can be detected through various methods. E.g. Large changes in gene (deletion/duplication) or smaller components that spell out the instructions found within the DMD gene (sequencing). However, results may not be conclusive since changes in the genetic code by go undetected by the methods used.

A combination of these components along with family history confirms the diagnosis. [26]

Treatment: Current and Future Prospects

Currently, there is no known cure for DMD. However, there a variety of treatments available which are aimed at managing the symptoms, protecting muscle mass and maximising the quality of life for those who suffer from DMD. Treatments includes:

  • Physical Therapy: in order to maintain muscle strength and function. (Inactivity leads to weakened muscles and can worsen the condition)
  • Orthopedic appliances such as braces and wheelchairs are available to improve mobility
  • Aggressive management of dilated cardiomyopathy with anti-congestive medications
  • The medication prednisone — a corticosteroid — is given to improve the strength and function of individuals with DMD (However there are side affects associated with this medication)

Future Therapies

  • Poloxamer 188
  • Idebenone
  • Gene Therapy
  • Stem Cell transplant
  • Exon Skipping therapy


2 case studies

Glossary of terms

  • Arrhythmias: abnormal heart contractions/irregular heart beat.
  • Atrophy: wasting away, degeneration of
  • Creatine kinase: an enzyme normally highly concentrated within muscle cells. As muscle cells degenerate, their contents are released into the bloodstream. Therefore elevated levels of creatine kinase can be detected by a blood test and is a measure of muscle damage.
  • Dystrophy: the weakening of
  • Macrophage: lymphatic cell found throughout the body; clears dead cells and debris.
  • Necrosis: cell death in a particular region of tissue
  • Protease:
  • Pseudohypertrophy: enlarged muscles due to large amounts of fat and connective tissue; characteristic of DMD. Usually of the calves but may be found in other muscles such as the deltoids and serratus anterior.
  • Scoliosis: curvature of the spine
  • Systolic: blood pressure during contraction of the heart (???Check)


  1. (http://hstalks.com.wwwproxy0.library.unsw.edu.au/main/citation_info.php?c=252)
  2. (http://dystrophy.com/muscular-dystrophy/Types+of+Muscular+Dystrophies)
  3. <pubmed>21810612</pubmed>
  4. Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD
  5. Genetics Home Reference. 2011. “Genes: DMD” Author anonymous. Accessed via. http://ghr.nlm.nih.gov/gene/DMD
  6. Chamberlain, J. (2007), "Duchenne Muscular Dystrophy", in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).
  7. S Carpenter, G Karpati. Duchenne Muscular Dystrophy: Plasma Membrane Loss Initiates Muscle Cell Necrosis Unless it is Repaired. Brain: 1979, 102(1): 147-161 doi:10.1093/brain/102.1.147.
  8. Sarnat, H.B. (1983) Muscle Pathology and Histochemistry, American Society of Clinical Pathologists, USA: 114.
  9. <pubmed>21674516</pubmed>
  10. <pubmed>21674516</pubmed>
  11. http://emedicine.medscape.com/article/1173204-clinical
  12. Chamberlain, J. (2007), "Duchenne Muscular Dystrophy", in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).
  13. http://books.google.com.au/books?id=HEUZnAd4L98C&printsec=frontcover&dq=duchenne+muscular+dystrophy&hl=en&ei=xiRkTsC5B-vzmAXx8r2sCg&sa=X&oi=book_result&ct=result&resnum=1&ved=0CCsQ6AEwAA#v=onepage&q&f=false
  14. Stone, K., Tester, C., Howarth, A., Blakeney, J., Traynor, N., McAndrew, H., McCutcheon, M.(2007)Occupational Therapy and Duchenne Muscular Dystrophy. John Wiley & Sons, England.
  15. http://www.enmc.org/uploaded/publicatie/manage.DMD.pdf
  16. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002220/
  17. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003762/
  18. Chamberlain, J. (2007), "Duchenne Muscular Dystrophy", in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio).
  19. K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. The multidisciplinary management of Duchenne muscular dystrophy.Elsevier Current Paediatrics: 2005, 15(4); 293-300. doi:10.1016/j.cupe.2005.04.001.
  20. Bushby K, Muntoni F, Bourke JP. 107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003; 13:166-172
  21. Finsterer J, Stollberger C. The heart in human dystrophinopathies. Cardiology 2003; 99:1-19.
  22. K. Bushby; J. Bourke; R. Bullock; M. Eagle; M. Gibson; J. Quinby. The multidisciplinary management of Duchenne muscular dystrophy.Elsevier Current Paediatrics: 2005, 15(4); 293-300. doi:10.1016/j.cupe.2005.04.001.
  23. Chamberlain, J. (2007), "Duchenne Muscular Dystrophy", in Dunn, B. (ed.), Protein Epidemiology: Diseases at the Level of Protein Structure and Function, The Biomedical & Life Sciences Collection, London (online at http://hstalks.com/bio)
  24. J. Anderson, S. Head, C. Rae, J. Morley.Brain Function in Duchenne Muscular Dystrophy. Brain: 2002, 125 (1): 4-13. doi: 10.1093/brain/awf012
  25. S. Cyrulink, R. Fee, A. Batchelder, J. Kiefel, E. Goldstein, V.J. Hinton. Cognitive and adaptive deficits in young children with Duchenne muscular dystrophy (DMD). Journal of the International Neuropsychological Society (2008), 14, 853–861. doi:10.10170S135561770808106X
  26. http://www.genome.gov/19518854
  27. <pubmed>21674516</pubmed>

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