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 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. 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. Without dystrophin, the muscle cells can be easily damaged during contraction- 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 between the ages of 8 and 11. Other indicators of the disease include pseudohypertrophy, fatigue, leg cramps and Gower's Sign. 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 contractions in the ankle, knees and hips.

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. If the muscles degenerate unevenly, kyphosis can occur - excessive outward curvature of the thoracic spine (resulting in a hunched or rounded back), or lordosis - excessive inward curvature of the lumbar spine (resulting in a pushed forward abdomen and hips).

• 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.

• Cardiac muscle:

• 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 the maximum capacity. The degree of muscle strength may be 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 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. Combined, these symptoms increases the susceptibility to a range of pulmonary infections.

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

• Pseudohypertrophy: enlarged muscles due to large amounts of fat and connective tissue. Usually of the calves but may be found in other muscles.

• 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)