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Weekly UpdatesProgress in science is generally marked in slow incremental steps. It's also true that there are times when the pace accelerates, leading to fundamental changes in our understanding and treatment of a disease. We are at just such a crossroads for muscular dystrophy. Although it's unlikely that any single therapy will cure this devastating disease, in the next 5-10 years we are likely to see a major shift in terms of the therapeutic options for children with muscular dystrophies.
There are several forms of muscular dystrophy (MD) that affect children including Duchenne, facioscapulohumeral, limb-girdle, and myotonic muscular dystrophy. Duchenne muscular dystrophy (DMD) is the most common and severe form. Untreated, children lose ambulation by age 13, and even when treated usually die in young adulthood. The disease is rare in girls, while 1 out of every 3,500 boys born worldwide have a mutation in the gene for dystrophin, located on the X chromosome at Xp21. Between 2 and 4 years of age, children may begin to show signs of leg weakness or have some mildly delayed motor milestones. Parents may notice they have difficulty running or jumping or keeping up with their peers.
Diagnosing, Treating MD
When muscular dystrophy is suspected, the goal is a quick and accurate diagnosis to try to avoid the diagnostic odyssey that many families still go through. Unfortunately, we continue to see children getting extensive work-ups for liver disease, including a liver biopsy for elevated transaminases that originate from muscle and not liver disease. A referral to a neuromuscular specialist can be extremely helpful in this regard. In most cases, a diagnosis can be made by commercially available genetic blood testing. If genetic testing is unrevealing, a muscle biopsy is indicated.
Care of both pediatric and adult muscular dystrophy patients is highly variable across the United States. The optimal management of MD is multidisciplinary, as the disease affects so many systems and aspects of a child's life. Even though we think of muscular dystrophies as muscular disorders, there can be a cognitive component, respiratory and cardiac issues, and social issues that are important to address early on. Getting one health care provider to coordinate care is particularly helpful to families and patients. Diagnostic and management considerations for DMD are expected to be published later this year by the Centers for Disease Control and Prevention.
There are no drugs currently approved for use in MD. Prednisone has proven efficacy in DMD, with a dose of 0.75 mg/kg per day considered an appropriate starting dose. Because of the substantial side effects associated with longterm prednisone use, different dosing paradigms have been examined. The National Institutes of Health is sponsoring an international, randomized trial comparing daily prednisone, daily deflazacort, and intermittent prednisone with 10 days on and 10 days off. Deflazacort is available in Canada and throughout Europe, and has attracted attention among patients with MD, some of whom are petitioning for its approval in the United States. Evidence suggests it has comparable efficacy to prednisone and a different side effect profile: notably less weight gain, but earlier cataract development.
Ideas about when to begin and when to stop corticosteroids in DMD also vary. The consensus is to avoid prednisone in a child who is still making gains or getting stronger, even if genetic testing is positive, and to start therapy when the child plateaus or gets weak, usually at 5-6 years. The most accepted benefit of corticosteroid use is the prolongation of ambulation. Multiple trials have shown that boys treated early and for several years with corticosteroids will walk for a longer time, which has benefits in terms of maintaining muscle strength and mass, bone density, and social interactions, while reducing contractures and scoliosis. Limited evidence suggests that early and long-term steroid therapy may preserve cardiac function, when used alone or in combination with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II-type receptor blockers. This is an additional reason to consider long-term steroid use, but further study is needed.
Physical therapy is widely used today in children with MD, but less than a decade ago, patients were advised not to exercise to preserve limited muscle function. Children with MD may stop walking because of contractures at the hips, knees, and ankles. When they become weaker, they also can develop contractures in the wrists and hands, limiting their ability to operate a wheelchair or computer. Stretching should be performed on a daily basis, but eccentric contractions, in which the muscle bears an external load and simultaneously lengthens, are discouraged. Orthotics and braces are sometimes needed to reduce contractures.
Respiratory muscle weakness not only reduces effective gas exchange, but results in a weak cough and an inability to effectively clear secretions. Bringing a pulmonologist onto the team early is critical to address these issues with noninvasive ventilation and cough-assist devices. Simple precautions such as yearly influenza and pneumococcal immunizations every 5 years also reduce the risk of infection and respiratory complications. Early and more aggressive respiratory care may be the single most important element in longevity beyond the teen years.
Novel Therapeutics
Several novel therapeutic approaches are being investigated including agents that modify gene and protein expression or increase muscle growth and regeneration. Researchers recently announced that intravenous injection of exon-skipping compounds in a dog model of DMD resulted in bodywide production of significant levels of dystrophin and functional improvement (Ann. Neurol. 2009 March 13 [doi: 10.1002 / ana.21627]).
The first gene therapy to show promise beyond safety alone also was reported earlier this year. Injections of the alphasarcoglycan gene in the foot muscles of three patients with limb-girdle muscular dystrophy type 2D produced 4-5 times the amount of the alpha-sarcoglycan protein, compared with saline injections. Investigators are also investigating nonsense suppression, a strategy that attempts to stabilize the ribosome to "read through'" the nonsense mutation that causes premature termination of the translation of the dystrophin gene in up to 15% of patients with DMD, as well as a subset of other MD patients. A phase II trial of the oral agent PTC124 is ongoing to assess dystrophin expression and function of patients with DMD due to nonsense mutations.
Our group at the Johns Hopkins University and the Kennedy Krieger Institute works to stimulate muscle generation and reduce muscle fibrosis in a range of muscular dystrophies. Blocking myostatin, a negative regulator of muscle growth, with the novel drug MYO-029 was demonstrated to be safe in 116 patients with various muscular dystrophies (Ann. Neurol. 2008;63:561-71).
Maintaining Hope
For many families, a diagnosis of MD is devastating. One of the most important roles for the pediatrician is to impart a message of hope to patients and their families. The current reality is that with aggressive respiratory and cardiac care and long-term corticosteroid use, these children are living into adulthood. The coming decade holds even greater promise for improving the lives of patients with muscular dystrophy.
BY KATHRYN WAGNER, M.D., PH.D.
DR. WAGNER is a neuromuscular clinician scientist and director of the Center for Inherited Muscle Disorders at the Kennedy Krieger Institute. To respond to this column, e-mail Dr. Wagner at pdnews@elsevier.com.
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