Therapeutic Approaches to Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a progressive form of muscular dystrophy that occurs primarily in males, though in rare cases may affect females. DMD causes progressive weakness and loss of skeletal and heart muscles. Early signs of DMD may include delayed ability to sit, stand, or walk and difficulties learning to speak. Muscle weakness is usually noticeable by 3 or 4 years of age and begins in the hips, pelvic area, upper legs, and shoulders. The calves may be enlarged. Children with DMD may have an unusual walk and difficulty running, climbing stairs, and getting up from the floor. DMD may also affect learning and memory, as well as communication and certain social emotional skills. Muscle weakness worsens with age and progresses to the arms, legs and trunk. Most children with DMD use a wheelchair full time by age 13. Heart and respiratory muscle problems begin in the teen years and lead to serious, life threatening complications.

DMD is caused by changes (mutations) in the DMD gene. The DMD gene codes for the protein dystrophin. Dystrophin is mainly made in skeletal and heart muscle cells, but a small amount is also made in nerve cells (neurons) in specific parts of the brain. DMD is inherited in an X-linked recessive pattern; however, it may also occur in people who do not have a family history of DMD.  While there is no known cure for DMD, there are treatments that can help control symptoms. Due to the advancement of medical treatment, boys with DMD may now live into young adulthood.

Becker muscular dystrophy (BMD) is also caused by mutations in the DMD gene. People with BMD have less severe symptoms than DMD. In addition, symptoms start later in childhood or in adolescence and progress more slowly.

Causes of DMD:

DMD was first described by the French neurologist Guillaume Benjamin Amand Duchenne in the 1860s, but until the 1980s, little was known about the cause of any kind of muscular dystrophy. In 1986, MDA-supported researchers identified a particular gene on the X chromosome that, when mutated, leads to DMD. In 1987, the protein associated with this gene was identified and named dystrophin. Lack of the dystrophin protein in muscle cells causes them to be fragile and easily damaged.

• The main function of dystrophin in muscle cells is to link the thin filaments of the sarcomere to integral membrane proteins in the sarcolemma, which are attached in turn to proteins in the connective tissue matrix that surrounds muscle fibers.
• When dystrophin is missing, the muscle cells become damaged more easily. Over time, the muscle cells without dystrophin weaken and die, leading to the muscle weakness and heart problems seen in DMD.
• Small amounts of dystrophin are also made in nerve cells (neurons) in specific parts of the brain, including the hippocampus, but its function is unknown.

Symptoms of DMD:

• Muscle weakness is the principal symptom of DMD.
• It can begin as early as age 2 or 3, first affecting the proximal muscles and later affecting the distal limb muscles. Usually, the lower external muscles are affected before the upper external muscles.
• The affected child might have difficulty jumping, running, and walking.
• Other symptoms include enlargement of the calves, a waddling gait, and lumbar lordosis (an inward curve of the spine).
• Later on, the heart and respiratory muscles are affected as well. Progressive weakness and scoliosis result in impaired pulmonary function, which can eventually cause acute respiratory failure.

Inheritance:

Since females have two X chromosomes, they have two copies of the DMD gene. Having two changed copies of the DMD gene that can cause DMD is unlikely, but would cause DMD in females. A female with only one changed copy of the DMD gene is called a 'carrier'. She can pass on the changed gene, but usually does not have symptoms of DMD. Carriers of changes in the DMD gene that can cause DMD are at an increased risk of developing heart problems, including cardiomyopathy. In addition, due to a process called X-inactivation, in rare cases, female carriers may have mild, moderate, or severe DMD.

If a man with DMD has children, all of his daughters will be carriers. Since boys inherit the Y chromosome from their father, sons will not inherit DMD from their fathers, even if the father has DMD. Women who are carriers of a change in the DMD gene that can cause DMD have a 50% chance of passing it on to each child, whether the child is a boy or a girl. In other words, each daughter will have a 50% risk of being a carrier. Each son will have a 50% risk of having DMD.

Diagnosis & treatment:

A child's doctor may suspect Duchenne muscular dystrophy (DMD) in young boys who have the signs and symptoms of DMD, including progressive muscle weakness. Family history is also important. Blood tests can be used to check for increased levels of certain special proteins called muscle enzymes in the blood which can leak from damaged muscles. Most commonly, the blood level of the enzyme creatine phosphokinase (CPK or CK) is checked, but a doctor may also check the blood levels of transaminases such as aspartate transaminase and alanine transaminase. Finding a change in the DMD gene that can cause DMD through genetic testing confirms the diagnosis of DMD.  

Testing for DMD may include: 

• Blood test which measures the levels of serum creatine phosphokinase (CK or CPK). Very high CK levels indicate muscle damage is causing the muscle weakness, rather than nerve damage.
• Molecular genetic testing  (usually blood cells are used) to see whether there is a change or mutation in the DMD gene that can cause DMD or one of the related dystrophinopathies.
• Electromyography can be used to distinguish conditions that only impact the muscles (myotonic) from those that involve that brain and muscles (neurogenic).
• Muscle biopsy is rarely used to diagnose DMD due to the decreased cost and higher accuracy of genetic testing.

Conclusion

There is no known cure for Duchenne muscular dystrophy (DMD) but research is ongoing. The goal of treatment is to control the symptoms of DMD and related complications caused by severe progressive muscle weakness and loss in order to maximize the quality of life. An enlarged, weakened heart (dilated cardiomyopathy) may be treated with medications, but in severe cases a heart transplant may be necessary.