AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Background

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy affecting 1 in 3500 boys born worldwide. Although Duchenne's name is inextricably linked to the most common childhood muscular dystrophy, it was Gowers who recognized Sir Charles Bell for providing the first clinical description of Duchenne dystrophy in his 1830 publication, The Nervous System of the Human Body. Others, including Edward Meryon in 1852 and John Little in 1853, described families of boys with delayed motor milestones, calf enlargement, progressive inability to ambulate, heel cord contractures, and death at an early age.

In a 1868 publication, Duchenne established the diagnostic criteria that are still used. These criteria include (1) weakness with onset in the legs; (2) hyperlordosis with wide-based gait; (3) hypertrophy of weak muscles; (4) progressive course over time; (5) reduced muscle contractility on electrical stimulation in advanced stages of the disease; and (6) absence of bladder or bowel dysfunction, sensory disturbance, or febrile illness.

Gowers was the first to deduce the genetic basis for the disease and the first to describe patients with delayed onset of disease. However, it was Becker who proposed that the less symptomatic patients reflected milder mutations in the same gene. These patients are now classified as having Becker muscular dystrophy.

In 1986, exactly 100 years after Gowers' keen observations, Kunkel identified the DMD gene located at band Xp21 and provided molecular genetic confirmation of the X-linked inheritance pattern. The DMD gene was named dystrophin. It is the largest recorded human gene encoding a 427-kd protein, dystrophin. Dystrophin plays an integral role in sarcolemmal stability. Research by Ervasti as well as Yoshida and Ozawa in the 1990s shed further light on the complex association of the dystrophin protein with a number of transmembrane proteins and glycoproteins, referred to as sarcoglycans and dystroglycans.

Another similar 395-kd protein, known as utrophin, has also been identified. This protein has a similar structure to dystrophin and seems able to perform some of the same functions. Despite there being no cure for the dystrophinopathies, knowing the genetic cause and related functions of dystrophin has been invaluable in creating new molecular and pharmacologic techniques for diagnosis and treatment.

Pathophysiology

Dystrophin is integral to the structural stability of the myofiber. Without dystrophin, muscles are susceptible to mechanical injury and will undergo repeated cycles of necrosis and regeneration. In the 1850s, Edward Meryon used a harpoonlike device to perform muscle biopsies and described the tissue from an affected patient: "The striped elementary primitive fibers were completely destroyed. The sarcous element being diffused, and in many places, converted into oil globules and granular matter, whilst the sarcolemma or tunic of the elementary fibre was broken down and destroyed." In order to understand how a mutation in the gene can cause such devastation, accurate conceptualization of the structure of dystrophin is necessary.

Dystrophin is encoded by the largest gene described to date. It occupies almost 2% of the X chromosome and nearly 0.05% of the entire genome. The gene consists of 79 exons and 8 promoters spread over 2.2 million base pairs of genomic DNA. It is expressed mainly in smooth, cardiac, and skeletal muscle, with lower levels in the brain.

In muscle, it is expressed as a 427-kd protein that consists of 2 apposed globular heads with a flexible rod-shaped center that links the intracellular actin cytoskeleton to the extracellular matrix via the dystroglycan complex. The protein is organized into 4 structural domains including the amino-terminal actin-binding domain, a central rod domain, a cysteine-rich domain, and a carboxy-terminal domain. Its amino terminal end insinuates with the subsarcolemmal actin filaments of myofibrils, while cysteine-rich domains of the carboxy-terminal end associate with beta-dystroglycan as well as elements of the sarcoglycan complex, all of which are contained within the sarcolemmal membrane (see Images 1-2). Beta-dystroglycan in turn anchors the entire complex to the basal lamina via laminin.

Deletions or duplications of the gene that do not disturb the reading frame generally lead to minor alterations in the structure, and by extension, the function of dystrophin, particularly if they are located within the amino-terminal or central regions. In contrast, mutations that disturb the reading frame or that prematurely generate stop codons either produce a severely truncated, completely dysfunctional protein product or do not produce the protein at all (see Image 3).

The functional loss of dystrophin initiates a cascade of events, including loss of other components of the dystrophin-associated glycoprotein complex, sarcolemmal breakdown with attendant calcium ion influx, phospholipase activation, oxidative cellular injury, and, ultimately, myonecrosis.

Microscopic evaluation in the early stages of the disease reveals widespread myonecrosis with fiber splitting (see Image 4). Interspersed between the dying myocytes are ghost cells, the shells of formerly healthy tissue. Inflammatory cell infiltration of the necrotic fibers may be observed in particularly aggressive disease. Fibers that survive exhibit considerable variability and often demonstrate internal nuclei. As the disease progresses, dead muscle fibers are cleared away by macrophages and replaced by fatty and connective tissue elements, conveying a deceptively healthy appearance to the muscle (pseudohypertrophy).

Frequency

United States

DMD is by far the most common childhood-onset muscular dystrophy, afflicting 1 in 3300 boys with an overall prevalence of 63 cases per million. The prevalence of the Becker phenotype is 24 cases per million. One third of these cases are due to spontaneous mutations, while the rest are inherited in an X-linked dominant manner. Gonadal mosaicism accounts for approximately 20% of new DMD cases.

Mortality/Morbidity

DMD is much more than a disease of skeletal muscles. Dystrophin is also found in the heart, brain, and smooth muscle. Cardiac fibrosis can lead to output failure and pulmonary congestion, a common cause of death. Additionally, cardiac fibrosis can also lead to conduction abnormalities, which can induce fatal arrhythmias.

Weakness of skeletal muscle can contribute to cardiopulmonary complications. Scoliotic deformity from paraspinal muscle atrophy impairs pulmonary function, predisposing individuals to pneumonia and respiratory failure. Smooth muscle dysfunction as a result of abnormal or absent dystrophin leads to gastrointestinal dysmotility, causing constipation and diarrhea.

In general, patients with Becker muscular dystrophy (BMD) have much greater phenotypic variability; patients may become wheelchair bound as early as age 20 years or as late as age 70 years. Motor dysfunction usually is at least a decade later than in DMD. Once wheelchair bound, patients with dystrophy become much more susceptible to the scourges of the sedentary, which include scoliosis, contractures, and impaired pulmonary function. While cardiomyopathy is less frequent in patients with BMD, conduction abnormalities occasionally may dominate the clinical picture, necessitating implantation of a defibrillator or even heart transplant.

Although significant advances have been made in understanding the molecular underpinnings of the disorder, DMD remains an incurable illness with a mortality rate of 100%. Like its clinical presentation, the prognosis of patients with BMD is variable, with patients who are less affected ultimately dying of other diseases after a near-normal life span.

Sex

• DMD and BMD almost exclusively afflict males because of their X-linked inheritance patterns.
• Rarely, skewed random inactivation of healthy copies of the X chromosome leads to the Becker phenotype in females.
• Females with Turner syndrome (XO) or uniparental disomy or those who have translocations between the X and autosomal chromosomes may similarly manifest the Duchenne phenotype. Elevations of creatine phosphokinase (CPK) level are found in two thirds of female carriers, the vast majority of whom are clinically asymptomatic.

Age

• DMD clinically manifests in patients aged 3-7 years, with development of lordosis, a waddling gait, and the Gower sign. Calf pseudohypertrophy follows 1-2 years later. Most patients are wheelchair bound by age 12 years.
• BMD follows a much more variable course, manifesting any time from age 3 years to adulthood.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

History

• Waddling gait, manifesting in children aged 3-6 years, often is the first symptom in patients with DMD and is secondary to girdle muscle weakness.
• Because of this proximal lower back and extremity weakness, parents often note that the boy pushes on his knees in order to stand; this is known as the Gower sign (see Image 5).
• The calf enlargement imparts the illusory appearance of strength, but, in fact, the enlarged calf muscles are caused by fatty and fibrotic infiltration of already necrotic muscles. However, another explanation may relate to compensatory hypertrophy of the calves secondary to weak tibialis anterior muscles, which tend to be affected earlier and more prominently.
• Inexorable progressive weakness is seen in the proximal musculature, initially in the lower extremities but later involving the neck, shoulders, and arms.
• Around the age of 8 years, most patients notice difficulty with ascending stairs, and respiratory muscle strength begins a slow but steady decline.
• The forced vital capacity gradually wanes, leading to symptoms of nocturnal hypoxemia such as lethargy and early morning headaches.
• Already wheelchair bound and profoundly weak, patients develop terminal respiratory or cardiac failure, usually by the early 20s, if not sooner.

Physical

• Generally, neck flexors, wrist extensors, quadriceps, tibialis anterior, biceps, and triceps muscles are affected more than the neck extensors, wrist flexors, deltoids, hamstrings, gastrocnemii, and solei.
• Deep tendon reflexes, which tend to parallel muscle fiber loss, slowly diminish and ultimately disappear.
• By age 10 years, 70% of children are hobbled by contractures of the iliotibial bands, hip flexors, and heel cords. Most are wheelchair bound by this time, creating a vicious cycle of immobility and further formation of contractures.
• Asymmetric weakening of the paraspinal muscles leads to kyphoscoliosis, which in turn further compromises pulmonary function.
• Inability to generate a forceful cough underlies the development of atelectasis with attendant episodes of pneumonia.
• Compared to DMD, the Becker phenotype manifests later (ie, in those aged 10-20 y) and evolves over a longer period of time. Muscle weakness is milder than in DMD, and calf pseudohypertrophy and contractures are not invariant features.
• In contrast to patients with DMD who are wheelchair bound by age 10 years, many patients with BMD are able to ambulate independently until the fourth decade of life; some are able to ambulate into the seventh decade of life.
• While average life expectancy of patients with mild BMD (ie, ~40s) is diminished compared to that of the general population, survival of these individuals into the seventh or eighth decade of their lives is not unusual.

Causes

DMD and BMD are caused by mutations in the gene encoding dystrophin.

• Mutations that result in the absence or severe reduction of the dystrophin protein result in DMD, while those that lead to a less severe reduction and/or expression of an internally truncated, semifunctional protein result in BMD.
• The size of the mutation is not a determining factor of severity. There are correlations with the type of mutation and severity. Deletions, duplications, and frame-shift mutations resulting in the absence or truncation of the protein cause the most severe phenotypes seen in DMD, while in-frame mutations lead to a less severe phenotype seen in BMD.
• Analysis of the location of deletions has shown that the amino-terminal, cysteine-rich, and carboxy-terminal domains are essential for dystrophin function, while the central rod domain can accommodate large in-frame deletions.
• Larger deletions of one or more exons cause approximately 59% of DMD and 65% of BMD cases. Premature stop codon mutations are found in 15%, duplications in 5%, and the rest are caused by frameshifting insertions/deletions, splice site, or missense mutations.
• Despite the fact that most of the cases of DMD/BMD are transmitted in an X-linked manner, one third are the result of a spontaneous mutation with no family history.

DIFFERENTIALS

Section 4 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Severe childhood autosomal recessive muscular dystrophy
Congenital muscular dystrophy (eg, Fukuyama)
Acid maltase deficiency
Progressive spinal muscular atrophy
Lipid myopathy due to carnitine deficiency
Myotonic dystrophy
Polymyositis of childhood

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Lab Studies

• Serum creatine phosphokinase
• • This level is always increased in patients with DMD or BMD, probably from birth. It often is increased to levels that are 50-100 times the reference range (ie, as high as 20,000 mU/mL).
  • A child or adult with a CPK level within the reference range does not have a dystrophinopathy.
  • Strongly suspect DMD in a child with proximal weakness and very elevated levels of CPK. Perform further testing to confirm the diagnosis (see Other Tests).

Imaging Studies

• Scoliosis frequently ensues in patients with DMD, particularly after they are wheelchair dependent. Radiographs of the spine are important for screening and evaluating the degree of scoliotic deformity.
• As the disease progresses and dyspnea becomes a complaint, chest x-ray also is likely to become a part of the evaluation.
• Beyond imaging for scoliosis and dyspnea, imaging studies are of little help in making the diagnosis.
• Imaging studies of the brain usually are unremarkable.

Other Tests

• Electromyography
• • Electromyography (EMG), even though not diagnostic, narrows the differential diagnosis by effectively excluding primarily neurogenic processes such as spinal muscular atrophy.
  • In general, the proximal muscles of the lower extremities may exhibit the more prominent EMG findings. A sufficient number of muscles need to be sampled to establish the presence of a diffuse process such as a dystrophy. The more revealing findings will be obtained in muscles of intermediate involvement with respect to weakness.
  • The motor unit action potentials (MUAPs) in patients with DMD or BMD are typically of short duration, particularly the simple (ie, nonpolyphasic) MUAPs. MUAP amplitudes are variable (normal to reduced) and they are typically polyphasic from the variability in muscle fiber diameters, resulting in longer MUAP durations. Early recruitment of MUAPs may be seen. If muscle fiber loss is severe, then what appears to be a loss of motor units may be seen with fast firing individual spikes. The latter are distinguished from neurogenic processes by their generally lower-than-normal amplitudes and reduced area of spikes.
  • Fibrillation potentials and positive sharp waves, which represent spontaneously depolarizing muscle fibers bereft of nervous innervation, are encountered in active disease as necrosis engulfs the motor endplate or separates the endplate from other portions of the muscle fiber. These may be difficult to see in some muscles, requiring higher-than-usual sensitivity settings on the amplifier.
• Molecular diagnosis
• • DMD, BMD, and carrier states can be reliably and accurately detected from peripheral blood samples in almost all cases. These methods can also be used in prenatal diagnosis. Direct sequencing of this large gene is not a viable option because it is too costly and time consuming. As a result, other innovative methods have been devised so that accurate noninvasive diagnosis is possible.
    • Currently, most laboratories use multiplex PCR amplification to examine deletion "hotspots," which account for approximately 59% of all mutations. This method has a 98% detection rate for deletions.
    • Duplications, which account for 5% of mutations, can be detected by several different quantitative techniques, including Southern blot, quantitative PCR, multiplex amplifiable probe hybridization (MAPH), and multiplex ligation-dependent probe (MLPA). These techniques are also highly sensitive for detecting deletions.
    • The remaining one third of the mutations are composed of subexonic sequences of which 34% are nonsensemutations, 33% are frameshifts, 29% are splice site mutations, and 4% are missense mutations. These mutations can be screened for by using techniques such as denaturing high-performance liquid chromatography (dHPLC); single- stranded conformational polymorphism analysis with single condition amplification internal primers (SCAIP) or DOVAM (detection of virtually all mutations), a robotically enhanced multiplexed method; or denaturing gradient gel electrophoresis.
  • It has recently been shown that 96% of mutations in patients with DMD can be noninvasively identified by using these techniques in a 3-tiered approach. Tier one is PCR amplification to detect large deletions, tier two would utilize DOVAM to rapidly scan for point mutations, and tier three would use MAPH to define duplications. Other similar techniques can be substituted for any of the tiers. For example, MAPH can be substituted with Southern blot. This same approach can also be applied to the patient with BMD. While most of these techniques were originally used for research purposes, many are now available clinically.
  • In patients without detectable mutations of the dystrophin gene, diagnosis requires muscle biopsy for dystrophin protein quantification (see muscle biopsy in Procedures below).
• Electrocardiogram and echocardiogram
• • Electrocardiogram (ECG) provides a simple means for uncovering sinus arrhythmias and also may demonstrate deep Q waves and elevated right precordial R waves.
  • Transthoracic echocardiography yields a clearer and more dynamic view of the heart, often revealing small ventricles with prolonged diastolic relaxation.
• Carrier detection
• • Carrier detection is an important aspect of the care and evaluation of patients with DMD and BMD and their family members.
  • A small minority of female carriers are symptomatic, but even in these symptomatic patients, correct diagnosis requires appropriate testing.
  • For many years, CPK testing was the best method for carrier detection; however, it is elevated in only two thirds of female carriers and the results can be difficult to interpret in ethnic and racial groups with normally elevated CPK levels. For example, blacks have a higher reference range than whites; CPK levels of blacks may exceed the laboratory-stated normal limits without the presence of any pathology.
  • In families in which an affected male has a known deletion or duplication of the dystrophin gene, testing for carrier status is performed accurately by testing possible carriers for the same deletion or duplication, the absence of which would exclude them as a carrier.
  • If the affected males in the family are unavailable for deletion or duplication testing, the female still can be tested, but the absence of an abnormality does not exclude them as carriers. Obviously, the presence of a deletion or duplication in a female always conveys carrier status.
  • In families in which the affected male has no detectable deletion or duplication, muscle immunofluorescence for dystrophin can be used. Carrier females should exhibit a mosaic pattern, with some myofibers being normal and some being abnormal. This is subject to sampling error, and again, normal biopsy findings do not exclude carrier status.
  • Unfortunately, dystrophin immunoblot quantitation, which is very useful in affected males, is not helpful in carrier detection as even female carriers manifesting the disease may have levels within the reference range.
• If all else fails, linkage analysis comparing polymorphic DNA markers on the X chromosome of an affected patient with those of his mother or sister permits detection of asymptomatic carriers. This can be performed using PCR techniques but requires blood from at least one affected male in the family. On occasion, the results are uninformative (eg, if the mother is homozygous for all markers, discerning which X chromosome harbors the defective gene is impossible).

Procedures

• Muscle biopsy
• • Despite the specificity of molecular genetic diagnosis, one third of boys with dystrophinopathies have no detectable deletions on DNA testing. Therefore, muscle biopsy, while supplanted as the criterion standard, remains an important adjunctive tool, both for quantifying the amount of muscle dystrophin as well as for detecting asymptomatic female carriers. Depending on the purpose of the biopsy, proper site selection is crucial.
  • For detection of female carriers, strong muscles may exhibit no pathology, and very weak muscles may be too devoid of fibers for adequate analysis. For affected males, a very weak muscle may have inadequate tissue for immunoblot and immunofluorescent testing. In addition, the acquisition of muscle tissue from a muscle already severely weak may precipitate further weakness. Therefore, the ideal muscle to biopsy is one that is easily accessible and exhibits moderate weakness (ie, has 80% strength).
  • Two methods are available for assessing dystrophin in muscle tissue.
    • Immunostaining of the muscle using antibodies directed against the rod domain and carboxy and amino terminals of dystrophin shows absence of the usual sarcolemmal staining in boys with DMD (see Image 6C). Patients with BMD show more fragmented and patchy staining of sarcolemmal regions (see Image 6B).
    • The most accurate method for differentiating DMD from BMD is by immunoblot of muscle homogenates. Patients with DMD have greatly decreased or absent amounts of truncated dystrophin, whereas patients with BMD reveal more moderately reduced amounts of dystrophin, which may be smaller (ie, deletion of the dystrophin gene) or larger (ie, duplications of the dystrophin gene) than normal.

Histologic Findings

Few muscle biopsies are as instantly recognizable as those of patients with DMD. Features of DMD are reminiscent of a battlefield the morning after a major conflict, with necrotic muscle fibers like corpses littering the landscape. Widespread muscle necrosis leads to angulated fibers, central nuclei, and considerable fiber size variation, with regenerating cells in different stages of atrophy and regrowth.

Fibers that are too damaged to regenerate may become empty skeletal remnants or ghost cells. Actively regenerating fibers often display cytoplasmic basophilia, with large nuclei and prominent nucleoli. Damaged fibers exhibit reduced histochemical staining for oxidative enzymes. Initially, macrophages and cluster of differentiation 8-positive (CD8+) T lymphocytes invade necrosing muscle fibers. In time, this cellular response is supplanted by endomysial and perimysial fibrosis and fatty tissue replacement, which convey the macroscopic appearance of pseudohypertrophy.

Aside from linkage analysis, fluorescent immunostaining for dystrophin is the only way to diagnose carrier status in a family with no known gene deletion or duplication. Antibody staining for portions of the dystrophin molecule at the sarcolemmal membrane reveals the conspicuous absence of various portions of the dystrophin complex.

In boys with DMD, the sarcolemma is virtually devoid of staining (see Image 6C). In contrast, carrier females exhibit a more variable mosaic pattern consisting of normal and abnormal fibers.

Immunoblot analysis of muscle tissue, available through commercial laboratories, can determine the size and quantity of the dystrophin molecule. Patients with DMD exhibit no dystrophin. In patients with BMD, variable amounts of dystrophin are present but with an altered molecular size. Carriers of DMD exhibit mosaicism for dystrophin expression and usually have enough functional dystrophin to be within normal limits on Western blot testing, making this a generally poor method for carrier detection.

TREATMENT

Section 6 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Medical Care

Therapeutic strategies for the dystrophinopathies can be categorized into 3 groups based on their approach: (1) gene, (2) cell, and (3) pharmacologic 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 DMD with the thought that benefits can be extrapolated to BMD. The gene and cell approaches are more likely to be curative, but they are still under investigation. Until these therapies become clinically available, pharmacologic therapies can be used to protect muscle mass and function and to help improve quality of life.

Gene therapy

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 mini-dystrophin and micro-dystrophin genes that have the advantage of being within viral/plasmid cloning capacities. These mini-dystrophins or micro-dystrophins can be directly inserted into muscle. Use of naked plasmid DNA does not provoke the vigorous antigenic response that viral vectors do. 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 systematically.The first US trial testing the effectiveness of minidystrophins in humans began in late March 2006 at Columbus Children's Hospital in Ohio.

Modification of endogenous dystrophin is another gene therapy technique under investigation. Most mutations in DMD 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 reestablish 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 DMD 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 one or two 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 DMD patients, when a comprehensive panel of specific AOs or cocktails of AOs to treat all of the different dystrophin mutations becomes available.

Several pharmaceutical compounds are also under investigation for their ability to possibly modify the endogenous dystrophin gene. These compounds are most effective in suppressing nonsense mutations, a mutation which affects approximately 15% of DMD cases and most BMD cases. The most promising compounds are the aminoglycosides. These compounds induce ribosomes to readthrough stop codons, resulting from nonsense mutations, thus hopefully increasing dystrophin expression. Although promising results were achieved in the mdx mice, human trials with gentamicin failed to show an increase in the expression of dystrophin. It is possible that the induction of readthrough depends on the sequence context, the aminoglycoside used, and the dose.

Cellular therapies

Unfortunately, clinical trials have not shown favorable results with the use of myoblast transplantation or stem cell transplantation into DMD patients. Myoblasts (normal muscle precursor cells) can be introduced into dystrophic muscles and incorporated into the myofibers. The newly formed myofiber carries 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.

Although shown to be promising in the mdx mouse, human trials did not show any objective benefit and levels of expression were low. These same disappointing results also occurred with the use of stem cell transplantation. Currently, neither therapy is recommended for clinical use.

Pharmacologic therapies

While unlikely to provide a cure for the Duchenne or Becker muscular dystrophy, pharmacologic therapies can help to protect muscle mass and function and ameliorate some of the secondary aspects of this disease, thus improving quality of life.

Inflammation plays a key role in the pathogenesis of the dystrophinopathies despite the fact that most biopsies in patients with DMD do not show inflammatory cells. Steroids have been used for over 40 years with some success to treat DMD patients. 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.

To date, prednisone is the only medication that has demonstrated even a modest benefit in modifying the course of the disease. Clinical improvement is seen as early as 1 month after starting treatment and lasts as long as 3 years. Children who discontinue steroids 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.

Prednisone may also increase the expression of untrophin, a dystrophin homologue, by stimulating the utrophin promoter. Unfortunately, chronic daily use of prednisone causes weight gain, cataracts, osteoporosis, hypertension, diabetes, and behavioral changes. Alternate-day dosing of prednisone (0.75-1.5 mg/kg/d) may help to delay the onset of some of these side effects.

Oxandrolone (Deflazacort) is another steroid approved for use in Europe but not the United States; it has been used in DMD and may have a more favorable side effect profile. Other immunosuppressants such as azathioprine have not demonstrated the same clinical benefit.

Anabolic steroids have been used with varying levels of success to preserve muscle mass by increasing protein synthesis. Studies with norethandrolone and methandrostenolone showed only modest improvement in muscle strength with the unfortunate androgenic side effects of priapism, acne, and growth of pubic hair. Even worse, when these medications were withdrawn, there was a rapid and severe deterioration in muscle mass and function.

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 HIV patients and burn victims, increasing lean body mass, and it remains onboard for 6 months after cessation of treatment. Additionally, this medication produces only minor androgenic side effects in children.

Clinical testing in DMD patients 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 is that the growth of the subjects was not slowed.

Growth factors have also been tried as a strategy to increase protein production in dystrophic muscles. In a clinical trial with 7 DMD patients, 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 DMD cardiomyopathy. Given these mixed results, the usefulness of GH in treating DMD remains in doubt.

Insulin-like growth factor (IGF-1), on the other hand, 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 DMD patients.

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 a2-adrenergic agonists.

A 12-week trial in boys with DMD 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.

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 causes muscle cell hypertrophy.

Anti-myostatin antibodies injected into the mdx mouse has resulted in improvement in the muscles injected. No human clinical trials have begun in DMD or BMD, but they are underway in facioscapulohumeral muscular dystrophy. However, 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.

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. Most treatments, including the ones discussed here, have not shown a benefit as significant as that of prednisone.

• Supportive care plays a crucial role in maximizing functional status and tone, as well as in delaying dependence upon a wheelchair.
  • Daily joint-stretching exercises prevent the debilitating onset of contractures.
  • 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, are important 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 the wheelchair dependency becomes inevitable, 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, particularly the forced vital capacity (FVC), provides a rational means for deciding when the patient would benefit from assisted ventilation.
  • 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.
• Dietary modifications can prevent excessive weight gain with its attendant strain on transfers and pulmonary function.
• As the disease continues to progress, more invasive options include tracheostomy with or without mechanical ventilation.
• 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.
• To date, 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 she 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, as occurs about 30% of the time.
  • While major dystrophin deletions can be detected in carrier females, 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.
• As with so many other incurable diseases, much hope resides in molecular genetic advancements.

Consultations

• Psychologists
• Genetic counseling

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

To date, prednisone is the only medication that has demonstrated even a modest benefit in modifying the course of the disease. Clinical improvement is seen as early as 1 month after starting treatment and lasts as long as 3 years. Children who discontinue steroids for various reasons soon revert to natural downward progression of the disease.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Special Concerns

• The dystrophinopathies are chronically progressive, and a disciplined, multispecialty care plan is critical for these patients. This is important not only to improve both the length and quality of life but also for the safety of these patients, since falls and accidents become more likely as the disease progresses and the burden on caregivers increases.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Media file 1:  Dystrophinopathies. Structure of the dystroglycan complex (adapted from Ozawa et al).
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Media file 2:  The molecular organization of integral and peripheral components of the dystrophin-glycoprotein complex and novel proteins involved in muscular dystrophy in skeletal muscle.
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Media file 3:  Dystrophinopathies. Point vs frameshift mutations. In contrast to most point mutations, which generally preserve the reading frame, frameshift mutations often lead to truncated protein products.
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Media file 4:  Dystrophinopathies. Dystrophic muscle (A = Gomori trichrome; B = hematoxylin and eosin [H&E] stain).
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Media file 5:  Dystrophinopathies. Gower sign.
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Media file 6:  Dystrophinopathies. (A) Normal dystrophin staining; (B) intermediate dystrophin staining in a patient with Becker muscular dystrophy; (C) absent dystrophin staining in a patient with Duchenne dystrophy.
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Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

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Article Last Updated: Jul 10, 2006