Dystrophinopathies Treatment & Management
- Author: Dinesh G Nair, MD, PhD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE more...
Therapeutic strategies for the dystrophinopathies can be categorized into 3 groups based on their approach: (1) Supportive pharmacologic therapy, (2) research gene therapy, and (3) research cellular therapy. Gene therapy involves viral, plasmid, and oligonucleotide-based approaches. Cell therapy uses myoblast and stem cell techniques. The therapeutic strategies are usually applied first to Duchenne muscular dystrophy with the thought that benefits can be extrapolated to Becker muscular dystrophy. The gene and cell approaches are more likely to be curative, but they are still under investigation. Until these molecular therapies become clinically available, supportive therapies can be used to protect muscle mass and function and to help improve quality of life.
The one proven medical treatment for Duchenne muscular dystrophy is corticosteroids, which are known to help to protect muscle mass and function and ameliorate some of the secondary aspects of this disease, thus improving quality of life. Independent ambulation may be preserved for a period of time. Inflammation is implicated in the pathogenesis of the dystrophinopathies despite the fact that most biopsies in patients with Duchenne muscular dystrophy do not show inflammatory cells. Corticosteroids have been used for more than 40 years with some success to treat patients with Duchenne muscular dystrophy. The central role of inflammation in the pathogenesis of the dystrophinopathies is suggested by the fact that use of corticosteroids, such as prednisone, results in prolongation of ambulation, maintenance of strength and function, and delay in the development of scoliosis.
The adverse effects are well-known and do temper many clinicians enthusiasm to recommend steroid use in small children, patients with behavior or learning issues, or any patient for long-term use. A detailed understanding of the mechanism of action for corticosteroids on the body is still a large mystery.
To date, corticosteroids are the only medication that has demonstrated a modest benefit in modifying the course of the disease. Clinical improvement is seen as early as 1 month after starting treatment and can last as long as 3 years. Children who discontinue corticosteroids for various reasons soon revert to natural downward progression of the disease. It is hypothesized that prednisone reduces tissue inflammation, suppresses cytotoxic cells, improves calcium homeostasis, and stimulates myoblasts.
One challenge is to know if a young boy with elevated serum CK levels is likely to have Duchenne versus Becker muscular dystrophy and if corticosteroids should be initiated in either situation. The muscle biopsy with protein analysis can be valuable in this determination. Some clinicians recommend waiting to start corticosteroids and others believe if Gowers sign is visible then treatment of a low-dose, intermittent regimen should be initiated. The genotype-phenotype correlations in cases of dystrophinopathy have shown "outliers" or exceptions to the rules. Biopsy protein studies in young boys are thought to provide further evidence to help predict Duchenne versus Becker muscular dystrophy phenotype but that has not been conclusively demonstrated and again, there are a small proportion of outliers.
In retrospective and prospective studies, corticosteroids (prednisone and deflazacort) have been found to be favorably associated with 2-3 years more of independent ambulation, reduced or delayed need for scoliosis surgery, reduced or stabilized ventricular dysfunction, and improved respiratory function. These associated favorable measures in Duchenne muscular dystrophy certainly implicate the positive benefits of corticosteroids in improving quality of life and reducing morbidity and mortality. However, clearly significant side effects must be addressed and monitored.
Unfortunately, chronic daily use of corticosteroids can cause weight gain, cataracts, osteoporosis, hypertension, diabetes, delayed puberty, stunted vertical growth, and behavioral/sleep issues. Alternate-day dosing of prednisone (0.75-1.5 mg/kg/d) may help reduce the risk and severity of these side effects. Currently, an international trial of steroid dosing regimens is evaluating prednisone 0.75 mg/kg/d versus deflazacort 0.9 mg/kg/d versus prednisone 0.75 mg/kg/d (10 days on, followed by 10 days off). Prednisone may also increase the expression of utrophin, a dystrophin homologue, by stimulating the utrophin promoter.
Oxandrolone (Anavar or Bonavar) is an anabolic steroid first approved for use in Europe and FDA approved in the United States in 2006; it has been used in Duchenne muscular dystrophy and may have a more favorable side effect profile including less excess weight gain. Oxandrolone has shown greater promise than other anabolic steroids because of its action not only on androgen receptors but also by antagonizing cortisol binding to glucocorticoid receptors to decrease catabolic pathways. It has been used with success in patients with HIV and burn victims, increasing lean body mass, and it remains onboard for 6 months after cessation of treatment. Despite its prior use in some patients, it is no longer considered to be appropriate for treatment in patients with dystrophinopathies.
Additionally, this medication produces only minor androgenic side effects in children. Preliminary clinical testing in patients with Duchenne muscular dystrophy who are receiving daily oxandrolone showed improvement in muscle strength testing but not in functional testing as compared with controls. No significant adverse effects occurred over the 6-month trial. Additionally, an advantage over corticosteroid use may be that the growth of the subjects was not slowed.
While most clinicians acknowledge that corticosteroids have a valuable role, controversies exist with respect to the age at which to start corticosteroids, clinical criteria to start corticosteroids, which corticosteroid, which dose and which regimen (continuous daily or intermittent regimens), and when to discontinue corticosteroids. Immunization schedule is generally thought to be a reason to hold off initiating corticosteroids until age 4 years, but there is no question that serum CKs are already elevated in the first year of life. Some ongoing clinical trials may clarify these issues.
A recent clinical trial of early alternate-day dosing of corticosteroids with a 14-year follow-up showed that initiation of corticosteroids (age 2-4 y) in 5 Duchenne muscular dystrophy patients preserved ambulation in 4 patients, 3 of whom retained the ability to climb stairs. Although this small observational trial seems promising, larger randomized controlled trials are necessary to clarify optimal treatment with steroids.
In addition to skeletal muscle abnormalities, cardiomyopathy is also a significant problem in individuals with dystrophinopathy. The extent of cardiac involvement and resultant cardiomyopathy is often a significant determinant of clinical status and long-term outcome, especially for patients with a dystrophinopathy.
Corticosteroids have been shown to have favorable effects on cardiac function in Duchenne muscular dystrophy.
Studies have shown that afterload reduction with ACE inhibitors in patients with and without ventricular dysfunction leads to better preservation of the myocardium and improvement in ventricular function and geometry. In addition, angiotensin II is a potent stimulator of transforming growth factor β (TGF-β), which promotes fibrosis. Hence, by inhibiting conversion of angiotensin I to angiotensin II, ACE inhibitors limit fibrosis and scarring in the myocardium. Perindopril, an ACE inhibitor, has been reported to have a positive influence on cardiac function in a cohort of patients in France.
In mdx mouse models, angiotensinogen receptor-blocking agents may have a favorable role in both skeletal and cardiac muscle function. Some advocate concomitant use of a beta-blocker with ACE inhibitors to improve cardiac outcome.
Future therapeutic options may be promising. P188 (Poloxamer 188) is a nonionic triblock copolymer that inserts into artificial lipid monolayers and thus repairs damaged biological membranes. Significant decrease in cardiac fibrosis and prevention of ventricular dilation were observed in mdx mouse and Golden retriever muscular dystrophy (GRMD) dogs. Losartan, an angiotensin II receptor blocker, also has shown significant decrease in fibrosis of skeletal and cardiac muscle in mdx mice, and its efficacy in humans is currently being investigated. A synthetic analog of coenzyme Q10, Idebenone, through its antioxidant properties, has shown similar benefits in mdx mice. Encouraged by results in a phase IIa study in a small group of Duchenne muscular dystrophy boys, a phase III, double-blind, randomized, placebo-controlled, multicentric trial recruiting Duchenne muscular dystrophypatients in Europe and North America is currently underway.
Osteoporosis and fractures are also significant problems. A small case series of 3 boys with Duchenne muscular dystrophy and known osteoporosis were treated for 1 year with weekly alendronate and daily calcium with vitamin D. Dual-energy x-ray absorptiometry was followed from baseline to 6 months and 1 year. This treatment regimen was found to be effective in improving bone mineral density; however, the study did not address the impact of this treatment on the prevention of long-bone or vertebral fractures. Other bone mass—enhancing drugs may be worthy of further investigation, but research is lacking in this area.
A 12-week trial in boys with Duchenne muscular dystrophy with daily administration of the a2-adrenergic agonist, albuterol, showed an increase in muscle strength on knee extension testing, but no significant difference in muscle function. Clinical trials with calcium channel blockers have shown no benefit. However, dantrolene, a medication that prevents calcium release from the sarcoplasmic reticulum, has shown a mild beneficial effect.
Pentoxifylline, a phosphodiesterase inhibitor that improves calcium homeostasis and reduces inflammation, fibrosis, and oxidative stress, was previously shown to reduce muscle strength deterioration by 51% in mdx mice. However, a multicenter, double-blinded, randomized controlled trial using slow-release pentoxifylline (20 mg/kg/day) in 64 corticosteroid-treated boys failed to show an improvement in muscle strength or function (using quantitative muscle testing score) over 12 months.
Other pharmacologic treatments, such as cyclosporine, cytokine modulation with TNF-a, nitrous oxide regulation, and mitogens, are currently being investigated, but current evidence does not show any significant benefit. One study showed that combining prednisone with cyclosporine A, or using cyclosporine A as a monotherapy, while safe and well tolerated, did not show improved muscle strength or functional abilities. Most treatments have not shown a benefit as significant as that of prednisone.
There is very little evidence supporting the use of supplements such as coenzyme Q10, carnitine, amino acids (glutamine, arginine), and anti-inflammatories/antioxidants (fish oil, vitamin E, greet-tea extract).
While no cure yet exists for Duchenne or Becker muscular dystrophy, medical and supportive treatments can have a positive impact to reduce morbidity, improve quality of life, and prolong lifespan. Please see Treat-NMD recommendations for Standards of care for Duchenne muscular dystrophy. Comprehensive care for patients with dystrophinopathy is pivotal. Some centers offer multidisciplinary (different pediatric specialties) and interdisciplinary (coordinated) approaches. Fragmented and limited care has been shown to be suboptimal, not only for those who have a dystrophinopathy, but also their families.
Muscular dystrophy is not just a muscle disease. The interdisciplinary approach incorporating the expertise of the primary care physician, neurologist, pulmonologist, cardiologist, endocrinologist, physical therapist, orthotist, mobility expert, nutritionist, orthopedic surgeon, social worker, genetic counselor, psychologist/psychiatrist, palliative care team, and school staff (including teacher, counselors, and nurses) is invaluable to both patients and their families. Care guidelines have been published that detail multidisciplinary management, including the role of corticosteroids, dedicated cardiac surveillance, and respiratory expertise.[1, 21, 22]
Maximizing functional status and tone, as well as in delaying wheelchair dependence, is desirable. Daily joint-stretching exercises prevent the debilitating onset of contractures. Night splints can have a favorable influence. Judicious use of tendon release surgeries may prolong ambulation by as long as 2 years. Braces, such as ankle-foot orthoses and knee-ankle-foot orthoses, can be adjuncts in prolonging the period of mobility and delaying wheelchair dependency. Maintaining the ability to stand, even without mobility, delays the onset of many contractures and scoliosis. This may require elaborate bracing mechanisms and often is poorly tolerated and expensive. Because bracing delays but does not prevent the eventual outcome, this option is less frequently pursued now than in the past.
Once wheelchair dependency becomes more prominent, attention shifts to prophylaxis against the deleterious consequences of immobility. The chair itself must be chosen carefully and customized to the patient's needs. Strategic cushioning reduces the incidence of pressure sores with attendant skin breakdown, which often occur in the sacral and coccygeal regions.
Adaptive devices, such as specially designed wheelchair tables and ball-bearing splints, maximize upper extremity mobility in muscles that cannot resist gravity.
Careful monitoring of pulmonary function is necessary. The forced vital capacity (FVC), provides a rational means for deciding when the patient would benefit from assisted ventilation.
Insufflator, exsufflator, or cough assist devices, are believed to greatly reduce the risk of pneumonias/hospitalizations and improve pulmonary health.
Continuous positive airway pressure (CPAP) and the more physiologic bilevel positive airway pressure (BiPAP) are the 2 major options in this regard, both of which are minimally invasive and easy to use. Daily use of incentive spirometer reduces atelectasis and pneumonia. X-rays are used to monitor spinal curvature because scoliosis adversely affects respiratory capacity. Spinal instrumentation or even fusion may become necessary if serial x-rays reveal worsening of spinal curvature. As the disease continues to progress, more technology for noninvasive ventilatory support and invasive options include tracheostomy with or without mechanical ventilation.
Dietary modifications can prevent excessive weight gain with its attendant strain on transfers and pulmonary function. Great interest in nutraceuticals with antioxidant and antifibrotic properties have been highly sought after by Duchenne muscular dystrophy families. The appeal of avoiding FDA regulatory issues in nutraceuticals is limited by the less stringent and relatively unregulated marketplace of dietary supplements where claims/labels are not held to the standards and inspections of FDA-approved drugs. Issues in this realm include impurity of compounds sold as nutraceuticals. Sometimes nutraceutical labels may claim to have an active compound in it that is actually not included, and, in other cases the concern may be what other extra compounds (contaminants) may be included that are not mentioned in the labeling.
Ultimately, sensitive yet candid and thorough discussions with patients and their families are important in making decisions about prolonging life while maximizing quality of life.
Family support is an important but complex and underappreciated element in any therapeutic strategy. Psychologists have observed development of an unusually close relationship between mothers and afflicted sons, often at the expense of siblings and spouses. Family counseling, by fostering open communication and addressing unresolved issues of jealousy, guilt, and anger, may improve this social dynamic. Educating the family about the natural course of the disease and informing them about the availability of support groups remain important tasks of the neurologist. Note the following:
BrainPOP, Duchenne Muscular Dystrophy
Transitional care and special care primary care providers
Transitional care is vital so that patients with dystrophinopathy, especially Duchenne muscular dystrophy, will grow up to have dedicated medical care as they achieve benefit from comprehensive care. Unfortunately, one challenge will be for adult care providers to take on patients with Duchenne or Becker muscular dystrophy as this is historically considered a pediatric disorder and few patients with Duchenne muscular dystrophy survive into adulthood.
New comprehensive approaches will continue to improve the natural history of Duchenne muscular dystrophy and improve health for all touched by dystrophinopathies. As with so many other genetic diseases, much hope resides in molecular genetic advancements, and improving treatments will aim to shift this disorder into a chronic disorder instead of a life-limiting one.
Research gene therapy
Information about Duchenne and Becker clinical trials can be explored by searching for Duchenne or Becker muscular dystrophy on ClinicalTrials.gov for eligibility criteria.
One key component to position this field for clinical trials is for individuals with Duchenne or Becker muscular dystrophy to register in patient databases so that streamlined accessibility can better link clinicians, scientists, and patients with research opportunities. Some invaluable Duchenne and Becker muscular dystrophy registries on which individuals may register are as follows.
The DuchenneConnect Profile allows all those living with Duchenne or Becker muscular dystrophy to join the DuchenneConnect patient registry, offering them access to information about new treatments and trials, as well as regional and local resources. Registering with DuchenneConnect also connects members to the global international database (TREAT-NMD Neuromuscular Network).
The United Dystrophinopathy Project (UDP) Patient Registry directed by Dr. Kevin Flanigan gathers basic information about patients with Duchenne, Becker, and intermediate muscular dystrophy and invites families to join the UDP registry. Registering with UDP also enrolls participants in the global international database (TREAT-NMD Neuromuscular Network).
Action Duchenne, DMD registry
For families outside the United States, visit the TREAT-NMD Neuromuscular Network. The TREAT-NMD Neuromuscular Network (TREAT-NMD) is a registry network focused on advancing diagnosis, care, and treatment for people with neuromuscular diseases around the world. TREAT-NMD maintains data submitted from all member registries. Click on the link to your country's DMD registry and then you will be registered with TREAT-NMD. Having this information in one place should make it easier for researchers to perform clinical trials to study these diseases. Individuals with Duchenne/Becker muscular dystrophy can become a participant of TREAT-NMD by joining their respective national registry.
The aim of gene therapy is to deliver DNA encoding dystrophin or other therapeutic genes, such as utrophin, to muscle. This strategy is complicated because of the enormous size of the dystrophin gene and difficulty engineering an effective delivery system. Currently, the delivery vectors available cannot accommodate the gene in its native form.
Functional studies of the gene in mdx mice have shown that multiple regions of the protein can be deleted in various combinations to generate highly functional minidystrophin and microdystrophin genes that have the advantage of being within viral/plasmid cloning capacities. These minidystrophins or microdystrophins can be directly inserted into muscle. Use of naked plasmid DNA does not provoke the vigorous antigenic response that viral vectors do. Recombinant adeno-associated virus (rAAV) vectors carrying minidystrophins arrest further muscle degeneration and have been shown to correctly localize to the sarcolemma, restore the missing dystrophin-associated protein complex to the cell membrane, ameliorate dystrophic pathology in mdx muscle, and even normalize myofiber morphology and cell membrane integrity.
However, the success of this approach depends on the development of a suitable gene delivery shuttle, generating a suitable gene expression cassette able to be carried, and achieving effective delivery without eliciting a detrimental immune response (for a review see ). Current research focuses on optimizing the gene delivery technique. In a randomized, double-blind, phase I clinical trial in Duchenne muscular dystrophy boys, Bowles et al reported the safety of a chimeric adeno-associated virus (AAV) capsid variant that evoked no cellular immune response.
The problem with directly inserting the DNA into muscle is knowing the exact dose to produce a clinical response and having to insert the DNA into several different muscles separately rather than being able to give it systemically. Additionally, evidence shows that the contractile properties of the muscles are not restored despite significant correction of the underlying membrane defect. The first US trial testing the effectiveness of minidystrophins in humans began in late March 2006 at Columbus Children's Hospital in Ohio.
"Booster" genes are beginning to be studied to augment the possible therapeutic effect of these mini- or microdystrophins. Dual gene therapy of the small dystrophins with genes that create an environment for muscle growth or regeneration (including insulin growth factor-1 or genes such as follistatin that inhibit the negative muscle growth regulatory factor myostatin) have been shown to protect muscle against contraction-induced injury and to increase muscle mass in animal models, respectively.[7, 27] Additionally, overexpression of the enzyme Galgt2 has been shown in animal models to be useful in maintaining membrane stability by creating a utrophin-glycoprotein complex. Clinical trials are planned to assess the possible effectiveness of these adjunctive treatments.
Modification of endogenous dystrophin is another gene therapy technique under investigation. Most mutations in Duchenne muscular dystrophy cause a disruption of the open reading frame during transcription, which effectively aborts translation to a functional dystrophin protein. Several different techniques can be used to re-establish an open reading frame mutant, resulting in a functional dystrophin mRNA. Targeted exon skipping can restore an open reading frame by modulating the splicing of the Duchenne muscular dystrophy gene.
In the case of single or multiple deletions and point mutations, a slightly shorter, but in-frame transcript, would be produced by skipping over a particular exon sequence. This therapy may be even more effective in duplications because of the possible generation of a true wild-type dystrophin from skipping 1 or 2 exons. The mechanism of exon skipping is based on the use of antisense oligonucleotides (AO). AO are small synthetic RNA molecules that can bind to specific sequences within the dystrophin pre-mRNA.
This technique could possibly benefit 70-80% of patients with Duchenne muscular dystrophy when a comprehensive panel of specific AOs or cocktails of AOs to treat all of the different dystrophin mutations becomes available. Clinical trials are currently underway to evaluate the safety and tolerability of this treatment.
Approximately 10% of Duchenne muscular dystrophy cases and most Becker muscular dystrophy cases are caused by nonsense mutations that induce premature stop codons causing premature translational termination. The most promising compounds capable of suppressing premature termination are the aminoglycosides and PTC-124 (Ataluren). These compounds induce ribosomes to readthrough premature stop codons, resulting from nonsense mutations, thus, increasing dystrophin protein expression. The oral agent Ataluren dose and the efficiency of upregulated dystrophin protein expression, which may equate to human functional motor benefit, remains to be proven as do any long-term side effects.
Although promising results were achieved in the mdx mice, human trials with gentamicin failed to show an increase in the expression of dystrophin. PTC-124/Ataluren has been shown to be superior to gentamicin at ribosomal read through in vitro. Despite these results, clinical trials were prematurely stopped because of lack of efficacy.
Growth factors have also been tried as a strategy to increase protein production in dystrophic muscles. In a clinical trial with 7 patients with Duchenne muscular dystrophy, exogenous growth hormone (GH) produced undesired, catabolic effects likely secondary to a positive nitrogen balance induced by the hormone. While GH has this effect on skeletal muscle, it has been shown to have a potential beneficial effect on Duchenne muscular dystrophy cardiomyopathy. Given these mixed results, the usefulness of GH in treating Duchenne muscular dystrophy remains in doubt.
On the other hand, insulin like growth factor (IGF-1) may be helpful in protecting muscle mass and function. IGF-1 is a positive regulator of muscle growth and has a profound effect on muscle precursor activation and proliferation. Upregulation of IGF-1 in the mdx mouse showed functional improvement, restoration of muscle strength, and reduced fibrosis. While promising, other studies have shown that IGF-1 can play a key role in proliferation and metastasis of cancer cell and also the occurrence of cancer in humans. IGF-1 has not been clinically tested in patients with Duchenne muscular dystrophy, but such trials may be on the near horizon.
Inhibition of calcium-dependent proteases (calpains) can also protect muscle mass. It has been long postulated that calcium homeostasis is disrupted in dystrophic muscle. This disruption in calcium homeostasis is caused by the activity of muscle, which can lead to microlesions of the dystrophic membrane, allowing an abnormal calcium influx that could promote cell death by activating proteases. The actions of these proteases can be aborted by calpastatin, an endogenous inhibitor of calpains. The expression of calpastatins can be increased with α2-adrenergic agonists.
Regulation of myostatin may also be another alternative to preserving muscle mass and function. Myostatin is a member of the transforming growth factor (TGF), a superfamily of growth/developmental factors, and is a potent, negative regulator of functional muscle mass. Deletions of the myostatin gene cause muscle cell hypertrophy. One case report exists in the literature of a 4 and a half-year-old boy born with no detectable myostatin in his sera. He had unusually large muscle at birth, with no other detectable abnormalities, including cardiac abnormalities. A phase I study with antimyostatin antibodies injected into patients with muscular dystrophy resulted in no improvement in the muscles.
Unfortunately, clinical trials to date have not shown favorable results with the use of myoblast transplantation or stem cell transplantation into patients with Duchenne muscular dystrophy. Myoblasts (normal muscle precursor cells) can be introduced into dystrophic muscles and incorporated into the myofibers but efficiency of transfer and immunorejection remain problematic. The newly formed myofiber can carry a functional form of the dystrophin gene which, with the help of reverse transcriptase, can result in the production of a normal dystrophin protein that can be incorporated into the sarcolemma.
However, the success of myoblast transplantation depends on the activity of myostatin, a negative regulator of skeletal muscle development, and its binding to activin type IIB receptor (ActRIIB). Blocking the myostatin signal in transplanted human myoblasts with expression of a dominant negative mutant of ActRIIB enhanced the number of muscle fibers expressing human dystrophin in the muscles of Rag/mdx mice. A recent in vivo study further reported that systemic inhibition of ActRIIB signaling by delivery of a soluble form of the extracellular domain of ActRIIB increased body weight, increased skeletal muscle mass, and improved myoblast transplantation in mice; and its effects were enhanced when combined with exercise.
Although shown to be promising in the mdx mouse, human trials did not show any objective benefit and levels of expression of dystrophin were low. These same disappointing results also occurred with the use of stem cell transplantation. Currently, neither therapy is recommended for clinical use.
Future molecular therapies
Given breakthroughs shown in animal models of Duchenne muscular dystrophy (mdx mouse and GRMD dog) and now human Duchenne muscular dystrophy clinical trials, it stands to reason that the ultimate cure, dystrophin gene replacement/repair will be realized. Scientific challenges to surmount include the following: age to intervene, efficiency of gene repair in high percentage skeletal and cardiac muscle cells, clinical efficacy to functionally normalize a boy with Duchenne muscular dystrophy, immune rejection issues, long-term side-effects, short-term toxicity.
Given the time necessary to establish dosing, safety, and efficacy of new molecular medicine techniques for regulatory approvals (ie, FDA), bridging therapies are needed to slow down the pathogenesis of dystrophin-deficiency. Some critical areas to prioritize include attenuating the fibrotic accumulation, maintaining the overall health of affected individuals, using favorable medicines and nutraceuticals, avoiding deleterious medications or regimens.
Some in the field believe that a combination treatment or Duchenne muscular dystrophy cocktail will be necessary to offer an optimum multifaceted approach to slow down muscular dystrophy.
See the list below:
- Genetic counseling remains the sole intervention for preventing the disease.
- Initiate genetic counseling soon after the diagnosis has been made.
- Maternal genetic testing can assess whether the mother is a carrier (carrier state conveys a 50% risk for any future male progeny) or whether the patient's disease arose from a de novo mutation, which occurs about 30% of the time.
- While major dystrophin deletions can be detected in female carriers, linkage analysis occasionally becomes necessary in cases of more subtle point mutations to prove that mother and son share the same X chromosome.
- Chorionic villus sampling and amniotic cell analysis permit prenatal diagnosis either by testing for a known deletion or duplication, or by linkage analysis. These procedures should be performed only after extensive counseling that involves discussing the implications of a positive test result as well as the available options.
Overzealous exercise or training can speed up muscular dystrophy, but gentle sports or activities (eg, swimming, tricycle/bicycles) may be encouraged. With the supervision of an experienced physical therapist, stretching is also important for parents to incorporate into the home regimen. However, no guidelines exist regarding the type, intensity, and frequency of exercise to be prescribed to patients.
Animal studies, especially using the mdx mouse model, have shown that appropriate exercise regimens may promote cellular and molecular pathways in a manner that limits further muscle damage. How specifically tailored exercise regimens modulate the pathophysiological mechanisms of muscular dystrophy such as mechanical weakening of sarcolemma, inappropriate calcium influx, aberrant cell signaling, increased oxidative stress, and recurrent muscle ischemia is discussed in a recent review. The primary mechanism seems to be exercise-induced reduction in oxidative stress, as measured by increased reactive oxygen species and antioxidants in blood and increased skeletal superoxide dismutase.
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