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The author: Professor Yasser Metwally

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INTRODUCTION

Background: While Duchenne’s name inextricably is linked to the most common childhood muscular dystrophy (ie, Duchenne muscular dystrophy [DMD]), Gowers recognized Sir Charles Bell with 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. However, in an 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 a febrile illness.

Figure 1. (Click to magnify figure)

Gowers was the first to deduce the genetic basis for the disease, as described in his 1886 text: “The disease is thus transmitted by women who are not themselves its subjects, thus the congenital tendency is exclusively due to the maternal element in the embryo. This is also shown by another fact that the children of the same women, by different husbands, have been affected.” In the same book, Gowers describes patients with delayed onset of disease and correctly postulates that they represent cases with milder muscle fiber involvement: “Very rarely, the patient is conscious of no symptoms until after puberty, and he has reached the age of 18 or 20. It is therefore probable that, in such late cases, it is rather the influence of the disease on the muscle fibers, than its development, which is delayed.” In a 1953 paper, Becker proposed that these less symptomatic patients reflected milder mutations in the same gene.

In 1986, exactly 100 years after Gowers’ keen observations, Kunkel identified the DMD gene and provided molecular genetic confirmation of the inheritance pattern. The DMD gene was named dystrophin; it constituted the largest recorded human gene at that time. Encoding for a 427-kilodalton protein, dystrophin was found to play 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. Today, the techniques of polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism (RFLP) analysis permit not only the diagnosis of asymptomatic female carriers but also allow fetal diagnosis as early as 8 weeks’ gestation.

Pathophysiology: Dystrophin is integral to the structural stability of the myofiber, as is evidenced by the widespread destruction that occurs when it is defective or absent. As early as the 1850s, Edward Meryon, using a harpoonlike device to perform muscle biopsies, described the tissue from an afflicted 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, it is necessary to better conceptualize the structure of dystrophin.

Dystrophin is 427 kilodalton (kd) in size and consists of 2 apposed globular heads with a flexible rod-shaped center. 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. 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 produce either severely truncated, completely dysfunctional protein product or absent protein product.

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. 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 and the dead muscle fibers are cleared away by macrophages, fatty and connective tissue elements fill the void, conveying a deceptively healthy appearance to the muscle (pseudohypertrophy).

Figure 2. DMD: Hypertrophic leg muscle (Click to magnify figure)

Frequency:

• In the US: 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 muscles. Since dystrophin is found in the heart and brain, these organs are affected as well. Cardiac fibrosis may lead to output failure and pulmonary congestion, a common cause of death, and cardiac conduction abnormalities may induce fatal arrhythmias as well. The intelligence quotient distribution shows an overall leftward shift, with a mean intelligence quotient of 83.

• Scoliotic deformity from paraspinal muscle atrophy impairs pulmonary function, predisposing individuals to pneumonia and respiratory failure.

• Gastrointestinal dysmotility leads to constipation and diarrhea.

• In general, patients with Becker muscular dystrophy (BMD) have much greater phenotypic variability; patients may become wheelchair bound as early as 20 years of age or as late as 70 years of age. However, motor dysfunction usually is offset by a decade or more compared to 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 the implantation of a defibrillator or even requiring a heart transplant.

Figure 3. A, Toe walking. B, Enlarged calves in a case with Becker muscular dystrophy (Click to magnify figure) 

• Although significant advances have been made in understanding the molecular underpinnings of the disorder, DMD remains an incurable illness with a 100% mortality rate. Like its clinical presentation, the prognosis of patients with BMD is variable, with patients who are less affected ultimately succumbing to 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. Creatine kinase elevations 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 the development of lordosis, a waddling gait, and the Gower sign. Calf pseudohypertrophy follows 1-2 years later. Most patients are wheelchair bound by the time they are aged 12 years.

Video 1. Duchenne muscular dystrophy. Standing from supine position (Gower sign)

Figure 4. Duchenne muscular dystrophy. Standing from supine position (Gower sign) (Click to magnify figure)

• BMD follows a much more variable course, manifesting anytime from age 3 years to adulthood.

CLINICAL PICTURE

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.

• Due to this proximal lower back and extremity weakness, parents often note that the boy pushes on his knees in order to stand, the Gower sign.

• 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, terminal respiratory or cardiac failure usually intercedes by the early 20s, if not sooner.

Physical:

• Generally, neck flexors, wrist extensors, quadriceps, tibialis anterior, biceps, and triceps muscles are more affected 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 the age of 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 contracture formation.

• 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. Milder muscle weakness is present, and calf pseudohypertrophy and contractures are not invariant features.

• In contrast to patients with DMD who are wheelchair bound by the time they are aged 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 the general population, it is not uncommon for these individuals to survive into the seventh and eighth decade of their lives.

Causes: Advances in molecular genetics have revealed the importance of the dystrophin complex in maintaining muscle membrane integrity.

• Mutations or deletions that significantly disrupt large or critical segments of the dystrophin gene produce the Duchenne phenotype. The most significant mutations tend to be located within larger introns as well as at the amino-terminal end of the dystrophin gene, which encodes for the actin-binding region of the protein.

• The Becker phenotype correlates with point mutations that preserve the reading frame or gene deletions that cause less structural compromise, such as the central rod domain.

WORK-UP

Lab Studies:

• Serum creatine kinase level

  • This level is always increased in patients with DMD or BMD, probably from birth. It is often increased to levels that are 50-100 times the reference range (ie, up to 20,000 mU/mL).

  • A child or adult with a creatine kinase level within the reference range does not have a dystrophinopathy.

  • Strongly suspect DMD in a child with proximal weakness and very elevated levels of creatine kinase. 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 DMD or BMD patients are typically of short duration, particularly the simple (i.e. non-polyphasic) 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 the 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.

• Polymerase chain reaction technique

  • Several advances in molecular genetics over the last 15 years have revolutionized the diagnosis of DMD. Gene amplification through the PCR technique detects gene deletions in two thirds of patients affected with DMD. This can be performed on a blood sample using DNA gleaned from lymphocytes.

  • Unfortunately, not all commercial laboratories test for the full spectrum of duplications, point mutations, or deletions. In patients without detectable deletions or duplications of the dystrophin gene, diagnosis requires muscle biopsy for dystrophin protein quantification (see muscle biopsy in Procedures).

• 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, creatine phosphokinase (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 accurately performed by testing possible carriers for the same deletion or duplication, the absence of which would exclude them as a carrier.

  • If the affected male(s) in the family is unavailable for deletion or duplication testing, the female can still 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, a normal biopsy does 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.

• Lastly, 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 the 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, it is impossible to discern which X chromosome harbors the defective gene).

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).

  • There are 2 methods to assess dystrophin using 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. Patients with BMD show more fragmented and patchy staining of sarcolemmal regions.

    • 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 (deletion of the dystrophin gene) or larger (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. 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.

MANAGEMENT

Medical Care: Despite the stunning advances in molecular biology, DMD remains an incurable illness, but fortunately, not an altogether untreatable one. Recognition and palliation of the multisystemic and debilitating symptoms of the disease significantly can improve not only the duration but also the quality of life.

• To date, prednisone is the only medication that has demonstrated a modest benefit in modifying the course of the disease.

  • Alternate-day dosing of prednisone (0.75-1.5 mg/kg/d) retards muscle wasting; clinical improvement is seen as early as 1 month and lasts up to 3 years. This benefit is tempered by the frequently encountered sequelae of steroid use, including stomach ulcers, cushingoid habitus, weight gain, rashes, osteopenia, and glucose intolerance. Children who discontinue steroids for these reasons soon revert to the natural downward progression of the disease.

  • The synthetic steroid, deflazacort, which is presently available only in Europe and South America, appears to delay clinical progression and has a more favorable profile of adverse effects.

• 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.

  • The judicious use of tendon release surgeries may prolong ambulation by up to 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 carefully chosen 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 the 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 dynamics.

  • Educating the family about the natural course of the disease and informing them about the availability of support groups remains an important task 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, in cases of more subtle point mutations, it occasionally becomes necessary to prove that both mother and son share the same X chromosome by linkage analysis.

  • Chorionic villus sampling and amniotic cell analysis permit prenatal diagnosis either by testing for a known deletion or duplication, or by linkage analysis. Only perform these procedures 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.

  • One proposed therapy involves upregulating the expression of utrophin, an endogenous protein that has dystrophinlike characteristics.

  • Despite attempts to transfer myoblasts into dystrophic muscle with the hope that these embryonal cells would differentiate into healthy tissue, such efforts have so far proven ineffective.

  • Another promising approach employs genetically reengineered viruses as vectors to infect dystrophin-deficient cells with healthy (although truncated) copies of the dystrophin gene. It is somewhat ironic that viruses, which have long plagued mankind, may ultimately serve as vehicles for a therapeutic payload.

Consultations:

• Psychologists

• Genetic counseling

Special Concerns:

• The dystrophinopathies are chronically progressive and a disciplined, multispecialty care plan is critical for these patients. This is not only important 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.

MEDICATIONS

Prednisone is the only medication that has shown modest benefit in delaying the progression of the disease.

References

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