2011 Group Project 10

--Mark Hill 12:44, 5 August 2011 (EST) This belongs on your discussion page.

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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 said to be 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 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.

-Severe

-childhood onset

-difficulty walking/mobility, breathing. most die in their 30's

-range of other problems it can cause

History/timeline

Guillaume Benjamin Amand Duchenne first described the disease in 1861.

Epidemiology

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.

Pathogenesis

Dystrophin is needed in all muscle cells of the body - this includes skeletal muscles, smooth muscles (like in organs and blood vessels) and cardiac muscle. Without dystrophin, the muscle cells can be easily damaged - the cell membrane becomes very permeable and allows extracellular material in. This causes the cell to swell until the pressure causes it to burst. Muscle fibres can also split, or begin a detrimental cycle of repeated necrosis and regeneration. Any dead muscle material is removed by macrophages, and then replaced by fatty or connective tissue. As a result, the muscle cells become extremely weak and atrophies.

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 . As the disease progresses, walking (especially up stairs) can become extremely difficult, and many children are confined to a wheelchair by the time they are 10.

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. If the muscles degenerate unevenly, kyphoscoliosis can occur - this is a curving of the spine in both a coronal and sagittal direction. Weakness in spine muscles can also have an effect on pulmonary and gastrointestinal function.

Smooth muscle:

DMD in the gastrointestinal tract means the muscles cannot contract properly, resulting in constipation or diarrhoea.

Cardiac muscle:

Diagnosis

• 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.

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

Glossary of terms

• 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

• Scoliosis: curvature of the spine

References

Kornberg, R. (2007), "Chromatin and Transcription", in Tsonis, P. (ed.), From DNA to Proteins: The Multiple Levels of Regulation, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://www.hstalks.com/bio)