Duchenne muscular dystrophy
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Duchenne muscular dystrophy (DMD) (also known as muscular dystrophy - Duchenne type) is an eventually fatal disorder that is characterized by rapidly progressive muscle weakness and atrophy of muscle tissue starting in the legs and pelvis and later affecting the whole body. DMD is the most common form of muscular dystrophy.
DMD affects young males, with onset of symptoms occurring usually before the sixth year. Women can be carriers of DMD but usually exhibit no symptoms. Two-thirds of DMD incidences are caused by genetic inheritance from the mother, while the remainder are caused by mutations in the genes of the egg or embryo.
DMD is named after the French neurologist Guillaume Benjamin Amand Duchenne (1806-1875), who first described the disease in the 1860s. It is caused by mutations in the dystrophin gene, which encodes an essential cell membrane protein in myocytes (muscle cells).
Becker's muscular dystrophy (BMD) is also caused by dystrophin mutations and has similar symptoms to Duchenne, but the onset is later and the course is milder.
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[edit] Genetics
Duchenne dystrophy is a type of dystrophinopathy which includes a spectrum of muscle disease caused by mutations in the Xp21 gene, which encodes the protein dystrophin. In Duchenne muscular dystrophy, the dystrophin protein is absent. Becker's muscular dystrophy is a milder type of dystrophinopathy where a mutated form of the protein is present. The large size of the gene means it is more prone to mutation, thus it arises spontaneously in many families without a history of the disease.
Duchenne muscular dystrophy is inherited in an X-linked recessive pattern. Because of random X inactivation, some female carriers can actually be partially affected by this disease, despite its recessive nature. X inactivation leads to women being in a state of X0, not XX as is usually thought (see below). Women who carry the defective gene can pass an abnormal X on to their sons. Since boys have an X from their mother and a Y from father, there is no second X to make up for the defective gene from the carrier mother. The sons of carrier females each have a 50% chance of having the disease, and the daughters each have a 50% chance of being carriers. Daughters of men with Duchenne will always be carriers, since they will inherit an affected X chromosome from their father (note that the diagram only shows the results from an unaffected father). Some females will also have very mild degrees of muscular dystrophy, and this is known as being a manifesting carrier.
Prenatal testing, such as amniocentesis, for pregnancies at risk is possible if the DMD disease-causing mutation has been identified in a family member or if informative linked markers have been identified.
In 1/3 of the cases, the disease is a result of an unspontaneous or new mutation [1].
In some female cases, DMD is caused by skewed x inactivation. In these cases, two copies of the x chromosome exist, but for reasons currently unknown, the flawed x chromosome manifests instead of the unflawed copy. In these cases, a mosaic form of DMD is seen, in which some muscle cells are completely normal while others exhibit classic DMD findings. The effects of a mosaic form of DMD on long-term outlook is not known.
[edit] Patho-mechanism
Duchenne muscular dystrophy is caused by a mutation of the dystrophin gene whose protein product is responsible for the connection of muscle fibres to the extracellular matrix through a protein complex containing many subunits. As a result, the sarcolemma is damaged through shearing forces and muscle fibres undergo necrosis and are ultimately replaced with adipose and connective tissue.
[edit] Symptoms
The main symptom of Duchenne muscular dystrophy is rapidly progressive muscle weakness associated with muscle wasting with the proximal muscles[citation needed] being first affected, especially the pelvis and calf muscles. Muscle weakness also occurs in the arms, neck, and other areas, but not as severely or as early as in the lower half of the body. Symptoms usually appear before age 6 and may appear as early as infancy. Generalized weakness and muscle wasting first affecting the muscles of the hips, pelvic area, thighs and shoulders. Calves are often enlarged. The other physical symptoms are:
- Awkward gait
- Frequent falls
- Difficulty with motor skills (running, hopping, jumping)
- Progressive difficulty walking
- Eventual loss of ability to walk (usually by the age of 12)
- Fatigue
- Mild mental retardation (in approx. 30% of Duchenne's patients)
- Skeletal deformities (including scoliosis in some cases)
- Muscle deformities
- Pseudohypertrophy of tongue and calf muscles. The enlarged muscle tissue is eventually replaced by fat and connective tissue.
- Muscle Contractures of heels and legs, rendering them unusable because the muscle fibers shorten and fibrosis occurs in connective tissue
[edit] Signs and tests
Muscle wasting begins in the legs and pelvis, then progresses to the muscles of the shoulders and neck, followed by loss of arm muscles and respiratory muscles. Calf muscle enlargement (pseudohypertrophy) is quite obvious. Cardiomyopathy may occur, but the development of congestive heart failure or arrhythmias (irregular heartbeats) is rare.
- A positive Gower's sign, which reflects the more severe impairment of the lower extremities muscles. The child helps himself to get up with upper extremities: first by rising to stand on his arms and knees, and then "walking" his hands up his legs to stand upright.
- Creatine kinase (CPK-MM) levels in the bloodstream are extremely high.
- An electromyography (EMG) shows that weakness is caused by destruction of muscle tissue rather than by damage to nerves.
- Genetic testing
- A muscle biopsy (immunohistochemistry or immunoblotting) or genetic test (blood test) confirms the diagnosis.
[edit] Diagnosis
[edit] CPK Test
If a physician suspects DMD after examining the boy they will use a CPK (creatine phosphokinase) test to determine if the muscles are damaged. This test measures the amount of CPK in the blood. In DMD patients CPK leaks out of the muscle cell into the bloodstream, so a high level (nearly 50 to 100 times more) confirms that there is muscle damage.the value is as high as 15,000 to 35,000iu/l (normal = 60iu/l)
[edit] DNA Test
As most patients are missing an exon section from their dystrophin gene, a rapid DNA test can quickly identify the missing exon and confirm the diagnosis.
[edit] Muscle Biopsy
If DNA testing fails to find the mutation, muscle biopsy is carried. The geneticist may either perform fluorescent labeling or find the amount of dystrophin protein in the blood. In DMD patients there is no fluorescence observed and no protein shown in the column as the patients completely lack dystrophin.
[edit] Prenatal Tests
If one or both parents are 'carriers' of a particular condition there is a risk that their unborn child will be affected by that condition. 'Prenatal tests' are carried out during pregnancy, to try to find out if the fetus (unborn child) is affected. The tests are only available for some neuromuscular disorders. Different types of prenatal tests can be carried out after about 10 weeks of pregnancy. Chorion villus sampling (CVS) can be done at 10-12 weeks, and amniocentesis at about 14-16 weeks, while placental biopsy and foetal blood sampling can be done at about 18 weeks. Women and/or couples need to consider carefully which test to have and to discuss this with their genetic counsellor. Earlier testing would allow early termination which would probably be less traumatic for the couple, but it carries a slightly higher risk of miscarriage than later testing (about 2%, as opposed to 0.5%).
[edit] Treatment
There is no known cure for Duchenne muscular dystrophy, though recently, stem-cell reasearch has shown some ways to replace the damaged muscle tissue. Treatment is aimed at control of symptoms to maximize the quality of life.
- Corticosteroids such as prednisone increase energy and strength and defer severity of some symptoms.
- Physical activity is encouraged. Inactivity (such as bed rest) can worsen the muscle disease.
- Physical therapy may be helpful to maintain muscle strength and function.
- Orthopedic appliances (such as braces and wheelchairs) may improve mobility and the ability for self-care.
[edit] Support Groups
Joining a support group where members share common experiences and problems can often help relieve the stress of this illness. See muscular dystrophy - support group. The Muscular Dystrophy Association (http://www.mda.org) is an excellent source of information on this disease. Also, the Parent Project http://www.parentprojectmd.org is an excellent source of support and information. Parent Project national organizations, which focus solely upon the dystrophinopathies (Duchenne and Becker muscular dystrophy), form an international association - United Parent Projects Muscular Dystrophy(UPPMD).[ http://www.uppmd.org/] There are several pertinent Yahoo groups as well.
[edit] Prognosis
Duchenne muscular dystrophy eventually affects all voluntary muscles, and the heart and breathing muscles. Survival is rare beyond the early 30s, [2] although recent advancements in medicine are extending the lives of those afflicted. Death typically occurs from respiratory failure or heart disorders.
[edit] Physiotherapy
Physiotherapists are concerned with enabling children to reach their maximum physical potential. Their aim is to:
- minimize the development of contractures and deformity by developing a programme of stretches and exercises where appropriate
- anticipate and minimise other secondary complications of a physical nature
- monitor respiratory function and advise on techniques to assist with breathing exercises and methods of clearing secretions
[edit] Mechanical Ventilatory Assistance: Volume Ventilators
Modern "volume ventilators," which deliver a preset volume (amount) of air to the person with each breath, are valuable in the treatment of people with muscular dystrophy related respiratory problems. Ventilator treatment usually begins in childhood when the respiratory muscles begin to fail.
When the vital capacity has dropped below 40 percent of normal, a volume ventilator may be used during sleeping hours, a time when the person is most likely to be underventilating ("hypoventilating"). Hypoventilation during sleep is determined by a thorough history of sleep disorder with an oximetry study and a capillary blood gas (See Pulmonary Function Testing). The ventilator requires a nasal or facemask for connection to the airway. The masks are constructed of comfortable plastic with Velcro straps to hold them in place during sleep.
As the vital capacity declines to less than 30 percent of normal, a volume ventilator may also be needed during the day for more assistance. The person gradually will increase the amount of time using the ventilator during the day as needed. A mouthpiece can be used in the daytime and a nasal or facemask can be used during sleep. The machine can easily fit on a ventilator tray on the bottom of a power wheelchair.
There may be times such as during a respiratory infection when a person needs to rest his/her respiratory muscles during the day even when not yet using full-time ventilation. The versatility of the volume ventilator can meet this need, allowing tired breathing muscles to rest and also allowing aerosol medications to be delivered.
[edit] Researching a Cure
Promising research is being conducted around the globe to find a cure, or at minimum a therapy that is able to mitigate some of the devastating effects of the disease.
The research group of Kay Davies works on the upregulation of utrophin as a substitute for dystrophin.
At the Généthon Institute in Evry near Paris under Olivier Danos and Luis García the U7 gene transfer technique is under development. This new technique is a combination of exon skipping and the transfer of a gene that instructs the muscle cells to continuously produce the antisense oligonucleotides (AONs) themselves so that they do not have to be injected repeatedly. The AONs are potential drugs which are able to modify the genetic information in such a way that the fast progressing Duchenne muscular dystrophy is converted into the much slower developing Becker muscular dystrophy. Early research into the effects of U7 Gene Transfer[3] have been very promising. Treated mice have gone on to show very little muscle weakness even after being stressed. Treated monkeys have retained the active AONs 6 years after injection, and treated dogs have developed 80% of the normal muscle mass within 2 months of treatment. First round tests in humans are due to begin soon, but given the need for multiple rounds of testing before a treatment can be released to the public, it will be at least a few years before this cure is widely available (if indeed these results are possible in humans).
The U7 gene transfer technique involves delivery of DNA by viral vector into the patient's cells. Other antisense techniques can also modify splicing of pre-mRNA, similarly converting Duchenne to Becker-like muscular dystrophy but without the need for insertion of DNA by virus into the patient. Especially promising for this application are Morpholino antisense oligos [1][2].
More information on the new PTC124 trials is available at the MDA.org website. This potential treatment addresses a percentage of DMD cases that initiate the production of dystrophin, but an encoded process halts the protein construction before it is complete. The PTC124 treatment skips the "stop" instruction in the genetic sequence, allowing dystrophin to be completed.[4]
Recent research shows losartan, a currently available drug used for treating hypertension, to be effective in halting the progress of the disease in mice that were genetically engineered to have Duchenne's. [5]
Parents of children with Duchenne's are noting reductions of symptomatic severity from a regimen of Protandim, a non-prescription nutritional supplement that increases levels of two specific antioxidant enzymes. DMD mouse-model trials of the therapy are in progress, and human trials are planned.[6]
[edit] Prevention
Genetic counseling is advised if there is a family history of the disorder. Duchenne muscular dystrophy can be detected with about 95% accuracy by genetic studies performed during pregnancy.
[edit] References
- ^ McClorey G, Moulton H, Iversen P, Fletcher S, Wilton S (2006). "Antisense oligonucleotide-induced exon skipping restores dystrophin expression in vitro in a canine model of DMD". Gene Ther 13 (19): 1373-1381. PMID 16724091.
- ^ McClorey G, Fall A, Moulton H, Iversen P, Rasko J, Ryan M, Fletcher S, Wilton S (2006). "Induced dystrophin exon skipping in human muscle explants". Neuromuscul Disord 16 (9-10): 583-590. PMID 16919955.
[edit] External links
- Jesse's Journey - The Foundation for Gene and Cell Therapy
- CDC’s National Center on Birth Defects and Developmental Disabilities (previously listed below as "Duchenne/Becker Muscular Dystrophy, NCBDDD, CDC")
- Muscular Dystrophy Campaign (UK)
- DMD Registry
- Parent Project UK
- Parent Project USA
- MUSCULAR DYSTROPHY Page on NCBI
- Parent Project Australia
- A support group for dads
- Report on U7 gene transfer studies PDF file.
- Duchenne Muscular Dystrophy research at the Cooperative International Neuromuscular Research Group.
- MUSCULAR DYSTROPHIES: DUCHENNE AND BECKER at Royal Children's Hospital in Melbourne, Australia
- NCBI Genes and Disease Page - Duchenne Muscular Dystrophy
- Muscular Dystrophy Association's website in Greece
