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Duchenne muscular dystrophy

2007 Schools Wikipedia Selection. Related subjects: Health and medicine

   Duchenne muscular dystrophy (DMD) (also known as muscular dystrophy -
   Duchenne type) is an inherited disorder characterized by rapidly
   progressive muscle weakness which starts in the legs and pelvis and
   later affects the whole body. Duchenne muscular dystrophy (DMD) is the
   most common form of muscular dystrophy. It usually affects only males,
   but in rare cases it can also affect females. It is an X-linked
   recessive inherited disease. A milder form of this disease is known as
   Becker's muscular dystrophy (BMD). In Becker muscular dystrophy, most
   of the symptoms are similar to Duchenne, but the onset is later and the
   course is milder.

   DMD is named after the French neurologist Guillaume Benjamin Amand
   Duchenne (1806-1875), who first described the disease in the 1860s. It
   is due to mutations in the dystrophin gene, which encodes a cell
   membrane protein in myocytes (muscle cells). One third of the cases are
   known to be caused by development of spontaneous mutations in the gene,
   while the remainder are inherited. Boys with DMD develop weak muscles
   because the muscle fibers that were present at birth are destroyed.
   Symptoms result in death by age 30 and respiratory failure usually
   results in a life expectancy of 20 years. A 1996 study found that early
   detection of the disease does not improve life-expectancy, and the most
   common cause of death is respiratory failure.

Genetics

   X-linked recessive inheritance

   Duchenne dystrophy is a type of dystrophinopathy which includes a
   spectrum of muscle disease caused by mutations in the DMD gene, which
   encodes the protein dystrophin. Becker's muscular dystrophy is a milder
   type of dystrophinopathy. Although it is caused by a defective gene, it
   often occurs in people from families without a known family history of
   the condition.

   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 unnaffected father) but since affected males are
   infertile they do not have children. Also, affected males 2/3 of the
   time inherited the mutation from the mother while 1/3 of the time the
   mutation is de novo, or new. 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 a spontaneous or new
   mutation .

   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.

Patho-mechanism

   Duchenne muscular dystrophy is caused by a mutation of the dystrophin
   gene whose protein product is responsible for linking the actin
   filaments 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.

Symptoms

   The main symptom of Duchenne muscular dystrophy is rapidly progressive
   muscle weakness associated with muscle wasting with the proximal
   muscles 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. The
   other physical symptoms are:
     * Awkward Gait
     * Rapidly progressive
     * Frequent falls
     * Difficulty with motor skills (running, hopping, jumping)
     * Progressive difficulty walking
     * Ability to walk is usually lost 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

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.
     * The ability to walk is usually lost by the age of 12.
     * 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.

Treatment

   There is no known cure for Duchenne muscular dystrophy. Treatment is
   aimed at control of symptoms to maximize the quality of life. Physical
   activity is encouraged. Inactivity (such as bed rest) can worsen the
   muscle disease. Physical and occupational therapy may be helpful to
   maintain muscle strength and function. Orthopaedic appliances (such as
   braces and wheelchairs) may improve mobility and the ability for
   self-care.

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
   (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. There are several pertinent Yahoo
   groups as well.

Prognosis

   Duchenne muscular dystrophy eventually affects all voluntary muscles,
   and the heart and breathing muscles. Survival is rare beyond the early
   30s. Death typically occurs from respiratory failure (suffocation) or
   heart disorders.

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
     * prescribe equipment such as orthoses, callipers, wheelchairs and
       standing frames
     * advise on moving and handling issues and equipment
     * monitor respiratory function and advise on techniques to assist
       with breathing exercises and methods of clearing secretions

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.

Researching a Cure

   Promising research is being conducted around the globe to find a cure,
   or at the least a therapy that is able to mitigate some of the
   devastating effects of the disease.

   The research group of Kay Davies work 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 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 , .

   More information on the new PTC124 trials is available at the MDA.org
   website. http://www.mda.org/research/061021dmd_trial_prem_results.html

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.
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