Duchenne Muscular Dystrophy

1. What is Duchenne Muscular Dystrophy? Muscular dystrophy (MD) is a group of inherited muscle diseases in which muscle fibers are unusually susceptible to damage. Muscles, primarily voluntary muscles, become progressively weaker. In the late stages of muscular dystrophy, fat and connective tissue often replace muscle fibers. Some types of muscular dystrophy affect heart muscles, other involuntary muscles and other organs. There's no cure for muscular dystrophy, but medications and therapy can slow the course of the disease. Signs and symptoms Signs and symptoms vary according to the type of muscular dystrophy. In general, muscular dystrophy symptoms may include: • • •

Muscle weakness Apparent lack of coordination Progressive crippling, resulting in fixations (contractures) of the muscles around your joints and loss of mobility

Duchenne's muscular dystrophy is the most severe form of dystrophinopathy. It occurs mostly in young boys and is the most common form of MD that affects children. Signs and symptoms of Duchenne's MD may include: • • • • • •

Frequent falls Large calf muscles Difficulty getting up from a lying or sitting position Weakness in lower leg muscles, resulting in difficulty running and jumping Waddling gait Mild mental retardation, in some cases Signs and symptoms of Duchenne's usually appear between the ages of 2 and 6. It first affects the muscles of the pelvis, upper arms and upper legs. By late childhood, most children with this form of muscular dystrophy are unable to walk. Most die by their late teens or early 20s, often from pneumonia, respiratory muscle weakness or cardiac complications. Some people with Duchenne's MD may exhibit curvature of their spine (scoliosis).

2. Provide an explanation for the symptoms experienced by this patient. Give the significance of the elevated Creatinine Kinase levels. 3. Discuss how mutation in the dystrophin gene can lead to the development symptoms characteristic of DMD. Muscular dystrophy is a general term for a group of inherited diseases involving a defective gene. Each form of muscular dystrophy is caused by a genetic mutation that's particular to that type of the disease. The most common types of muscular dystrophy appear to be due to a genetic deficiency of the muscle protein dystrophin.

Inheriting Duchenne's or Becker's MD Duchenne's and Becker's muscular dystrophies are passed from mother to son through one of the mother's genes in a pattern called X-linked recessive inheritance. Boys inherit an X chromosome from their mothers and a Y chromosome from their fathers. The X-Y combination makes them male. Girls inherit two X chromosomes, one from their mothers and one from their fathers. The X-X combination determines that they are female. The defective gene that causes Duchenne's and Becker's muscular dystrophies is located on the X-chromosome. Women who have only one X-chromosome with the defective gene that causes these muscular dystrophies are carriers and sometimes develop heart muscle problems (cardiomyopathy) and mild muscle weakness. The disease can skip a generation until another son inherits the defective gene on the Xchromosome. In some cases of Duchenne's and Becker's muscular dystrophies, the disease arises from a new mutation in a gene rather than from an inherited defective gene. Duchenne's muscular dystrophy occurs almost exclusively in boys, although it can occur in girls. Your young child may have difficulty walking, running, rising from the floor or climbing the stairs, or may appear clumsy and fall often. These may be early indications of muscular dystrophy. A child with MD may learn to walk later than other children do and may exhibit signs of muscle weakness between the ages of 2 and 6. By school age, a child with MD may walk unsteadily and on the toes or balls of the feet. Duchenne's MD usually results in children losing the ability to walk by age 12. Mutations in the human dystrophin gene cause the Duchenne and Becker muscular dystrophies. The Dystrophin protein provides a structural link between the muscle cytoskeleton and extracellular matrix to maintain muscle integrity. Recently, Dystrophin has also been found to act as a scaffold for several signaling molecules, but the roles of dystrophin-mediated signaling pathways remain unknown. To further an understanding of this aspect of the function of dystrophin, Drosophila mutants that lack the large dystrophin isoforms were generated and their role in synapse function at the neuromuscular junction was analyzed. In expression and rescue studies, lack of the large dystrophin isoforms in the postsynaptic muscle cell were shown to lead to elevated evoked neurotransmitter release from the presynaptic apparatus. Overall synapse size, the size of the readily releasable vesicle pool as assessed with hypertonic shock, and the number of presynaptic neurotransmitter release sites (active zones) are not changed in the mutants. Short-term synaptic facilitation of evoked transmitter release is decreased in the mutants, suggesting that the absence of dystrophin results in increased probability of release. Absence of the large dystrophin isoforms does not lead to changes in muscle cell morphology or alterations in the postsynaptic electrical response to spontaneously released neurotransmitter. Therefore, postsynaptic glutamate receptor function does not appear to be affected. These results indicate that the postsynaptically localized scaffolding protein Dystrophin is required for appropriate control of neuromuscular synaptic homeostasis (van der Plas, 2006). Muscular dystrophy (MD) refers to a group of genetic disorders whose major symptom is muscle wasting. There are two major forms of MD, differing in severity and age of onset. In Duchenne muscular dystrophy, symptoms are noticeable in early childhood and quickly become debilitating. Becker muscular dystrophy, on the other hand, is of later onset and less severe. Both forms of MD are caused by mutations in the

dystrophin gene, a large (2.6Mb) gene comprised of 97 exons. The dystrophin protein plays an important structural role as part of a large complex in muscle fiber membranes. When dystrophin is missing or non-functional, the entire complex is compromised, leading to degeneration of muscle tissue. When the ability to regenerate the muscle is exhausted, muscle wasting occurs.

Once it was discovered that Duchenne MD and Becker MD were both forms of the same disease, researchers attempted to determine which regions of the dystrophin gene were most important by correlating genotype and phenotype. It was mystifying that several large deletions were present in patients with the mild, Becker, form, while smaller deletions were sometimes found in patients with Duchenne MD[1-4]. What seemed to be more important than the amount of coding sequence that was deleted was whether or not the offending mutation resulted in a frameshift or not. Researchers working on the mouse model of Duchenne MD, mdx mouse, found a similarly puzzling result: a C-terminally truncated version of dystrophin was competent to rescue the MD phenotype in these mice[5]. In 1988, it was entirely unclear how to explain the apparent disconnect between genotype and phenotype. In light of NMD, these findings are comprehensible. Becker MD patients have a partially functional version of dystrophin that leads to less severe symptoms. Duchenne MD patients, however, have mutations that prevent any functional dystrophin production. Because of NMD, this includes mutations that introduce premature termination codons. Appreciation of the role of NMD in MD has led to improved diagnostics and promising new treatment strategies. For example, the drug gentamicin, which causes translational read-through of stop codons, has shown some effectiveness for restoring dystrophin expression in cultured cells from mdx-mice[6]. Human clinical trials are currently underway. 4. The term muscular dystrophy encompasses a number of diseases characterized by progressive muscle wasting. How is DMD different from Becker’s muscular dystrophy (BMD) in terms of symptamology and prognosis? Becker's muscular dystrophy (Benign pseudohypertrophic muscular dystrophy) is a milder form of dystrophinopathy. Becker's muscular dystrophy is an inherited disorder that involves slowly progressive muscle weakness of the legs and pelvis. It generally affects older boys and young men, and progresses more slowly, usually over several decades. Signs and symptoms of Becker's MD are similar to those of Duchenne's. The onset of the signs and symptoms is generally around age 11, but may not occur until the

mid-20s or even later. Those affected by Becker's MD usually are able to walk through their teens, and often well into adulthood. Rarely, infants have this form of muscular dystrophy, in which case it's called congenital myotonic dystrophy. The infant form is more severe, although infants with myotonic dystrophy don't experience myotonia. Signs in infants may include: • • • •

Severe muscle weakness Difficulty sucking and swallowing Difficulty breathing Cognitive impairment

Causes, incidence, and risk factors: Becker's muscular dystrophy is very similar to Duchenne's muscular dystrophy , except that it progresses at a much slower rate. The disorder is inherited with an X-linked recessive inheritance pattern -- the gene is located on the X chromosome. Since women have two X chromosomes, if one X chromosome has the defective gene, the second X chromosome will have a working copy of the gene to compensate. In these cases, some women have much milder symptoms because of this ability to compensate. Men have an X and a Y and because they don't have another X to compensate for the defective gene, they will develop symptoms if they inherit the defective gene. People with this disorder experience progressive muscle weakness of the legs and pelvis, which is associated with a loss of muscle mass ( wasting ). Muscle weakness also occurs in the arms, neck, and other areas, but not as severely as in the lower half of the body. Calf muscles initially enlarge (an attempt by the body to compensate for loss of muscle strength), but the enlarged muscle tissue is eventually replaced by fat and connective tissue (pseudohypertrophy). Muscle contractures occur in the legs and heels, causing inability to use the muscles because of shortening of muscle fibers and fibrosis of connective tissue. Bones develop abnormally, causing skeletal deformities of the chest and other areas. Cardiomyopathy (damage to the heart) does not occur as commonly with this disorder as it does with Duchenne's muscular dystrophy. Cognitive problems may accompany the disorder, but they are not inevitable and do not worsen as the disorder progresses. Becker's muscular dystrophy occurs in approximately 3-6 in 100,000 male births. Symptoms usually appear in men at about age 12, but may sometimes begin later. The average age of becoming unable to walk is 25-30. Women rarely develop symptoms. 5. What treatment modalities may be offered in this case?

Treatment There's currently no cure for any form of muscular dystrophy. Research into gene therapy may eventually provide treatment to stop the progression of some types of muscular dystrophy. Current treatment is designed to help prevent or reduce deformities in the joints and the spine and to allow people with MD to remain mobile as long as possible. Treatments may include various types of physical therapy, medications, assistive devices and surgery. Physical therapy As muscular dystrophy progresses and muscles weaken, fixations (contractures) can develop in joints. Tendons can shorten, restricting the flexibility and mobility of joints. Contractures are uncomfortable and may affect the joints of your hands, feet, elbows, knees and hips. One goal of physical therapy is to provide regular range-of-motion exercises to keep your joints as flexible as possible, delaying the progression of contractures, and reducing or delaying curvature of your spine. Using hot baths (hydrotherapy) also can help maintain range of motion in joints. Medications Doctors prescribe medications to treat some forms of muscular dystrophy: •

Duchenne's muscular dystrophy. The anti-inflammatory corticosteroid medication prednisone may help improve muscle strength and delay the progression of Duchenne's MD.

Braces can both provide support for weakened muscles of your hands and lower legs and help keep muscles and tendons stretched and flexible, slowing the progression of contractures. Other devices such as canes, walkers and wheelchairs can help maintain mobility and independence. If respiratory muscles become weakened, using a ventilator may become necessary. Surgery To release the contractures that may develop and that can position joints in painful ways, doctors can perform a tendon release surgery. This may be done to relieve tendons of your hip and knee and on the Achilles tendon at the back of your foot. Surgery may also be needed to correct curvature of the spine. Other treatments Because respiratory infections may become a problem in later stages of muscular dystrophy, it's important to be vaccinated for pneumonia and to keep up-to-date with influenza shots.