Duchenne Muscular DystrophyThe Search for New Treatments Races against the Clock

[caption id="" align="alignright" width="225"] 2012 MDA National Goodwill Ambassador, Bryson Foster, age 11. Foster was diagnosed with Duchenne muscular dystrophy at the age of five. Photograph courtesy of the Muscular Dystrophy Association.[/caption] One out of about every 3,500 boys worldwide is born with Duchenne muscular dystrophy (DMD). DMD is the most common as well as the most severe of the more than 30 types of muscular dystrophies, comprising about 50 percent of all cases. Young men with DMD face a difficult life, but they do not face a life without hope. Researchers around the world are working on promising treatments, including drug- and cell-based therapies, to prolong life expectancy, improve quality of life, and even cure the disease. Joining previous research on improving care and quality of life for DMD patients is a landmark international consensus document, "The Diagnosis and Management of Duchenne Muscular Dystrophy." The document is the result of an extensive review process by 84 international experts in DMD and provides best-practice diagnosis and care standards. It was published in two parts in The Lancet Neurology: part 1, published in January 2010, covers diagnosis and pharmacological and psychological management; and part 2, published in February 2010, covers the implementation of multidisciplinary care. ( Author's note: The full document, including parts 1 and 2, can be accessed at www.oandp.com/link/144 ) Previously, there had not been any consensus about how best to care for DMD patients, with care standards differing not only from country to country but also within individual countries, notes CARE-NMD, a three-year project to implement best-practice standards of DMD care across Europe ( en.care-nmd.eu ). The disparity of care approaches has impacted quality of life for boys and young men with DMD, and-because treatments vary from center to center, making it difficult to compare results across multiple centers-it has hindered clinical trials of promising new treatments. "By producing consensus guidelines agreed [upon] by doctors and patient groups across the world, it is possible to...make best-practice care more widespread across the world," CARE-NMD points out. What Is DMD? [caption id="" align="alignright" width="400"] A young DMD patient undergoes an echocardiogram. Photograph courtesy of the Muscular Dystrophy Association.[/caption] An inherited X-linked recessive disease affecting males, DMD is characterized by a lack of the protein dystrophin, which causes muscles to deteriorate and break down. About two-thirds of DMD patients inherited the defective gene from their mothers; the remaining one-third of DMD patients have the defective gene because of a spontaneous mutation. (Since females have two X chromosomes, they can be carriers but rarely experience any symptoms.) DMD usually becomes apparent when the child begins to walk, according to the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH). Degenerating muscle fibers produce progressive weakness and muscle wasting beginning in the upper legs and pelvis and spreading into the upper arms. Children experience some loss of reflexes, a waddling gait, difficulty in rising from a sitting or lying position, overall posture changes, lung weakness, and cardiomyopathy. Some children may have mild cognitive impairment. According to several sources, life expectancy is usually from the late teens into the 20s. On a happier note, however, many young men live into their 30s and 40s, pursue and earn higher education degrees, get married, and achieve personal and professional goals. The 2010 international consensus document paints a brighter picture for patients with DMD. "Although specific treatments for DMD [currently being researched] have not yet reached the clinic, the natural history of the disease can be changed by the targeting of interventions to known manifestations and complications. Diagnosis can be swiftly reached; the family and child can be well supported, and individuals who have DMD can reach their full potential in education and employment." The consensus report continues, "Corticosteroid, respiratory, cardiac, orthopedic, and rehabilitative interventions have led to improvements in function, quality of life, health, and longevity, with children who are diagnosed today having the possibility of a life expectancy into their fourth decade." For instance, corticosteroids can extend the ability of patients to walk by up to two years, according to the NIH. Orthotist's Role in High-Quality Care DMD follows a progressive, predictable pattern of independent walking, then assisted walking, followed by wheelchair mobility. Orthotists and physical therapists play a vital role in helping to extend the ambulatory periods. [caption id="" align="alignright" width="300"] Nighttime AFOs. Photograph courtesy of Phil Stevens.[/caption] "I believe every human being cherishes the opportunity of being independent and mobile," says Mark Taylor, MLS, CPO, FAAOP, who works in the Department of Physical Medicine & Rehabilitation at the University of Michigan Orthotics and Prosthetics Center (UMOPC), Ann Arbor. "It is devastating to patients and parents alike when this independence starts to disappear in small increments. Proper orthotic intervention can prolong this independence for a short while and provide assistance with mobility and help prevent/delay complications that come with muscles weakening." Phil Stevens, MEd, CPO, FAAOP, Hanger Clinic, Salt Lake City, Utah, notes that physicians frequently rely on the orthotist's in-depth knowledge of orthotic technologies and materials for specific orthotic devices to implement a somewhat generalized prescription, thus placing a responsibility on the orthotist to be knowledgeable about the orthotic management of DMD. [caption id="" align="alignright" width="250"] Photograph of DMD patient Julian Soto courtesy of the Muscular Dystrophy Association.[/caption] In 2006, Stevens, a board member of the American Academy of Orthotists and Prosthetists (the Academy) and a member of the Academy's Research Council, published a literature review, " Lower Limb Orthotic Management of Duchenne Muscular Dystrophy ," in the Journal of Prosthetics and Orthotics (JPO) . In the article, Stevens outlines orthotic interventions during the three functional stages of DMD: independent ambulation, assisted ambulation, and wheelchair mobility. He discusses the mechanics of gait and stance and the progression of the disease as it affects mobility. He points out that daytime AFO use places excessive demands on increasingly weakening quadriceps and should generally be avoided. Although proximal weakness is primarily responsible for the end of a child's independent ambulation, extreme equinus contractures contribute to this, and Stevens cites evidence that compliant use of nighttime AFOs can slow the progression of equinovarus deformities. Nighttime AFOs are often prescribed along with passive stretching regimens. "We have to be very careful in bracing Duchenne patients while they are still ambulatory," Stevens says in an interview with The O&P EDGE. "I think there is a potential to do more harm than good. There is literature that clearly shows that bracing can make walking much more difficult. For most ambulatory cases, the best approach is to use nighttime orthoses so as to not affect their gait kinematics and kinetics during waking hours." He continues, "Children with Duchenne muscular dystrophy stop walking due to a combination of lower-limb weakness and increasing contractures. A little bit of plantarflexion contracture can help these children because it helps position the ground reaction forces anterior to the knee, making the children more stable. However, as the contracture becomes more severe, stability is reduced, and patients start walking higher on their toes, finally reaching a point where independent walking is impossible. Many experts recommend nighttime orthoses and/or aggressive physical therapy to control plantarflexion contractures and...prolong the ambulatory period." Taylor says he has used AFOs for nighttime stretching but has found good compliance a limiting factor and that often orthoses are not used to their fullest potential, a problem Stevens also mentions. "Many parents who are trying to provide comfort for their child have a hard time applying the orthoses when the child complains of pain and discomfort when muscles and tendons are being stretched," Taylor says. [caption id="" align="alignright" width="350"] Photograph of DMD patient Christopher Rhoades courtesy of the Muscular Dystrophy Association.[/caption] Prolonging Ambulation When asked about a 1985 study showing a prolonged ambulatory period with related benefits, Stevens says that treatment regimens including aggressive surgeries to release contractures, KAFO application, and standing the first day postoperative, along with studies reporting on the results, were quite common in the 1970s and 1980s in the United States, but he has not seen current reiterations of these studies. He notes that these aggressive regimens are costly and require close coordination and timing among the healthcare team to carry them out successfully; therefore, following these treatment protocols in any setting other than an institutional one is difficult, and the results may not justify the effort and expense, factors that could explain the decline in these procedures in the United States. More information about these protocols is available in the international practice standards consensus document. In his JPO literature review, Stevens discusses findings that show the benefits of prolonging ambulation, such as preventing or postponing problems associated with wheelchair use in the DMD population, including scoliosis, obesity, disuse atrophy, osteoporosis, pathologic fracture, severe contractures of hip and knee flexors, and further foot and ankle deformity, along with benefits to gastrointestinal and pulmonary function and psychological well-being. Regarding KAFO use, Taylor says, "I have seen both positive and negative results in providing KAFOs to Duchenne patients. Modern technology has allowed the orthotist to use stronger and lighter materials in designing and providing orthotic intervention to these patients. However, the orthotist needs to understand in detail the effects of biomechanical control and how it can affect the control of lever arms in the lower-extremities position of the lower trunk. Too much control can limit the dystrophy patient in the ability to stay upright and stable." He adds, "I believe our technical staff has now worked with carbon fiber long enough to understand how to use it and keep the function of the orthosis strong and yet lightweight, which is necessary when applying KAFOs and AFOs to muscles that are continuing getting weaker." In the third stage, wheelchair mobility, Stevens notes that some authors point out the value of postoperative nighttime AFOs to prevent reoccurrence of deformity after corrective surgery. In describing the value of nighttime AFOs in controlling equinus contractures for pain management, he says, "Severe equinus plantarflexion contractures can be painful, and in extreme cases the foot can actually sublux." Taylor adds, "There are strong benefits when applying orthotic intervention properly. It needs to start early, and close follow-up needs to be a part of the total medical plan. Even though muscles are getting weaker, there is still bone growth, and whatever orthotic plan is initiated, adjustment needs to be made to accommodate for growth and continued comfort. "Orthotists need to become very familiar with the pathology of Duchenne muscular dystrophy and the pathway it takes," he continues. "They need to be available for their patients and have the ability to communicate with other members of the healthcare team as to what is needed and at what time it is needed. Waiting too long to make a decision can void an opportunity for enhanced stability and quality of ambulation." International Consensus The international consensus document on DMD best-practice standards includes the following findings on orthotic management: Prevention of contractures also relies on resting orthoses, joint positioning, and standing programs. Resting AFOs used at night can help to prevent or minimize progressive equinus contractures and are appropriate throughout life. AFOs should be custom-molded and fabricated for comfort and optimum foot and ankle alignment. KAFOs for prevention of contracture and deformity can be of value in the late ambulatory and early non-ambulatory stages to allow standing and limited ambulation for therapeutic purposes but might not be well tolerated at night. Use of AFOs during the daytime can be appropriate for full-time wheelchair users. A passive standing device for patients with either no or mild hip, knee, or ankle contractures is necessary for late ambulatory and early non-ambulatory stages. Many advocate continued use of passive standing devices or a power standing wheelchair into the late non-ambulatory stage if contractures are not too severe to restrict positioning and if devices are tolerable. Research Moves Forward Just as following best-practice care standards when working with patients with DMD enhances function and quality of life, ongoing research offers hope for better therapies and even possibly a cure. Initiatives, among others, include the following: "Exon skipping," which employs synthetic DNA-like molecules that function as a "Band-Aid" to skip over the parts of the gene that block the effective creation of dystrophin. In 2009, genetic researchers at Children's National Medical Center, Washington DC, and the National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan, achieved the first successful application of multiple exon skipping in dogs with muscular dystrophy. A Children's National Medical Center press release states, "By skipping more than a single exon, this so-called DNA Band-Aid becomes applicable to between 80 and 90 percent of Duchenne muscular dystrophy patients, including the mutation found in dogs." ( Author's note: To read the full press release, visit www.oandp.com/link/148 ) There are a number of other treatments and therapies being studied, according to NINDS: The nutritional supplement coenzyme Q10, which has been found to protect cell membranes from oxidative injury and may be essential for proper mitochondrial function and cellular energy production. Creatine, a protein produced naturally and absorbed through food intake, has been shown in animal models to increase energy in nerve cells and improve muscle strength. Oxatomide, a steroid that interferes with the release of histamine from mast cells (involved with inflammatory diseases), is being clinically tested for safety and efficacy in increasing strength among DMD patients. The combination of glutamine, an amino acid essential for muscle strength, and creatine monohydrate is being tested as a possible therapy. Enhancing natural muscle repair mechanisms. "Understanding the repair mechanisms may provide new therapies to slow, and possibly stabilize, muscle degeneration," NINDS notes. Gene replacement therapy-replacing a defective gene with a functional one-could provide a true cure for Duchenne and some other types of muscular dystrophy. Researchers are making important progress in this area, according to NINDS. Developing drugs that increase the muscle production of the protein utrophin, which is similar to dystrophin and can help compensate for its loss. Genetic modification therapy to bypass inherited mutations. "By manipulating the protein synthesis process, production of a gene that 'reads through' the genetic mutation that stops production can result in functional dystrophin," according to NINDS. Two strategies being studied include using gentamicin , an antibiotic that can cause the synthesis machinery to ignore the premature stop signal and produce functional dystrophin, and splicing technology , which skips past the mutations in the dystrophin gene to where genetic information is complete and can produce a functional protein. Resources for Patients, Families A well-known English proverb states, "A trouble shared is a trouble halved." Although a DMD diagnosis can leave parents feeling alone and overwhelmed, there is an abundance of resources and support mechanisms available to help parents-and the young patient himself when he is old enough to understand his condition: The Diagnosis and Management of Duchenne Muscular Dystrophy: A Guide for Families (en.care-nmd.eu/international/family-guide/), based on the findings of the international study on best-practice standards of care. Parent Project Muscular Dystrophy ( www.parentprojectmd.org ), founded by Pat Furlong, whose two sons lost their fight against DMD in their teens, provides a wealth of information on such subjects as caring for the child with DMD, how family members are affected and what they can do, current research, information for medical professionals, and support and outreach. In addition to funding worldwide research to cure muscular dystrophy, amyotrophic lateral sclerosis (ALS), and related diseases, the Muscular Dystrophy Association ( www.mda.org ) provides healthcare support services, advocacy, and education. Friends of Man ( www.friendsofman.org ) provides aid to a variety of persons and families in need, including mobility equipment such as wheelchairs, van lifts and modifications, ramps, and home modifications. First Hand Foundation ( www.firsthandfoundation.org ) provides funding for healthcare access for children in need, including clinical care, therapy, wheelchairs, and assistive technology equipment. Abraham Lincoln (1809-1865) said, "In the end, it's not the years in your life that count. It's the life in your years." Although most of us want as many years of life as possible, improved therapies, treatment standards, and promising research are not only adding years to the lives of patients with DMD, they are improving the quality of those years. Miki Fairley is a freelance writer based in southwest Colorado.

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Duchenne Muscular Dystrophy
The Search for New Treatments Races against the Clock