Becker Muscular Dystrophy

Etiology

BMD arises from a mutation in the subsarcolemmal protein dystrophin. The defective gene is located in the Xp21.2 chromosome, and the defect is inherited as an X-linked recessive trait. Patients without a clear X-linked inheritance pattern may have defects in the genes encoding dystrophin-associated glycoproteins rather than dystrophin.

The dystrophin gene consists of 79 exons in Xp21 and spans more than 2200 kb.[6][7] Mutation is more likely during meiosis due to a large number of base pairs—around 2 million—involved. Other mutations, like small deletions, insertions, and small site variants, also occur less frequently.[8]

DMD mutations are often different from those involved in BMD. DMD arises mainly from out-of-frame mutations of the dystrophin open reading frame, resulting in a lack of dystrophin expression. BMD results from in-frame mutations, leading to dystrophin deficiency or dysfunction. Consequently, BMD has a much broader phenotypic presentation.

Immunohistoanalysis shows a complete absence of dystrophin in patients with DMD. Individuals with BMD have 10% to 40% of the normal dystrophin amount or have a partially functional form of the subsarcolemmal protein.[9]

Epidemiology

BMD is a rare disease almost exclusively in male individuals due to X-linked inheritance. The condition is less common and less severe than DMD and is considered a milder allelic form of DMD. The worldwide prevalence of DMD and BMD ranges from 0.1 to 1.8 per 10,000 male individuals. A 2010 U.S. research revealed that BMD's prevalence for all age groups was 0.26 per 10,000 male individuals. Additionally, the condition was found to be more common among non-Hispanic white persons than non-Hispanic black persons.

A study of people with BMD suggests a prevalence of 0.01 in South Africa, 0.1 to 0.2 in Asia, and 0.1 to 0.7 in European countries per 10,000 male individuals. Isolated data shows BMD is 3 times less common than DMD.[10] However, sequencing studies show that BMD is underdiagnosed. Better dystrophin gene sequencing has allowed the identification of more patients with BMD and female carriers of dystrophin gene mutation.[11]

Pathophysiology

Dystrophin gene deletions (65% to 70%) or duplications (5% to 10%) result in dystrophin dysfunction or deficiency.[12] Disruption of the dystrophin-glycoprotein complex leads to cell membrane damage and myofiber degeneration. Sarcolemmal damage causes the outflow of CK and the influx of calcium ions in the myocytes.[13] Inflammatory mediators stimulate inducible nitric oxide synthase overexpression, increasing nitric oxide production. Nitrosylation destabilizes the ryanodine receptor of the sarcoplasmic reticulum, followed by calcium leakage in the cytosol. Increased cellular calcium ion concentration activates calpains that mediate protein degradation and progressive muscle weakness.[14][15] Complications like cardiomyopathy, joint contractures, and respiratory failure may arise from severe muscle wasting in the late stages of this illness.

BMD often presents with exercise-induced muscle weakness and fatigue. During exercise, the dystrophin-glycoprotein complex normally recruits neuronal nitric oxide synthase into the sarcolemma. This enzyme produces the vasodilator nitric oxide, which increases blood flow to the muscles to prevent fatigue. Dystrophin deficiency or dysfunction disrupts neuronal nitric oxide synthase recruitment and produces nitric oxide during intense physical activity.[16][17]

Histopathology

The hallmark of BMD on microscopic examination is ongoing myofiber necrosis and regeneration. Active muscle fiber necrosis and clusters of basophilic regenerating fibers are more prominent in younger patients. In contrast, myofiber splitting with necrosis, increased internal nuclei, fiber hypertrophy, fatty replacement, and endomysial fibrosis are more often found in older patients.[18][19]

History and Physical

BMD presents variably. When taking the clinical history, the onset of symptoms, precipitating and palliative factors, body areas affected, and symptom severity must be established. Family and developmental history must likewise be documented.

Children may present with proximal muscle weakness earlier than distal limb muscles. Lower limbs are affected earlier than upper limbs. Cramping with strenuous activity and gross motor milestone delays may also be reported. Growth can be slower, leading to short stature. Some patients may have cognitive impairment. The intelligence quotient of 20% to 25% of patients is less than 70. A positive family history may be elicited.

Some patients experience a late onset and retain ambulation until adulthood. Elbow fractures, cardiomyopathy, breathing difficulty, joint contractures, and toe-walking may be seen as the condition progresses. Cardiomyopathy is due to left ventricular wall fibrosis, which can cause life-threatening arrhythmias.

Rarely patients have elevated CK levels without any weakness. Other individuals may manifest neurologic symptoms instead of skeletal muscle involvement. Female carriers may only present with cardiomyopathy, though some may also have mild skeletal muscle weakness. Approximately 22% of carriers become symptomatic with a high degree of variability. Genetic analysis is required for proper diagnosis. 

Physical examination may reveal the following:[20][21][43]

• Atrophy with pseudohypertrophy of the calf muscles
• Quadriceps hypotonia, hyporeflexia, and fasciculations
• Gowers sign or using the hands and arms to push the body upright from a squatting position
• Lumbar lordosis
• Achilles tendon shortening
• Knee, elbow, or hip joint contractures
• Macroglossia
• Forearm muscle enlargement
• Scoliosis due to progressive thoracic muscle weakness
• Signs of cardiac involvement, such as jugular venous distension, cardiac impulse displacement, peripheral edema, S3 gallop, and mitral or tricuspid regurgitation murmurs 
• Signs of respiratory failure in advanced cases, such as crackles, cyanosis, and low oxygen saturation

Muscle pseudohypertrophy is due to the fibrosis and fatty replacement of atrophic muscles, which are classical features of BMD.

All individuals with suspected BMD must have a detailed head and neck, musculoskeletal, and neurologic examination. Since patients have an increased risk of cardiorespiratory failure, a complete cardiovascular and respiratory examination should be performed during every consultation.

Evaluation

Proximal limb muscle weakness and distal limb hypertrophy in a male individual should increase suspicion of BMD, especially if family history is positive for the same condition. The mainstays of BMD diagnostic testing are CK level and dystrophin gene deletion analysis or muscle biopsy with dystrophin antibody staining. However, an invasive procedure like muscle biopsy is avoided in most instances, and genetic testing suffices for BMD confirmation.

CK Levels

High blood CK levels indicate muscle degeneration. CK levels peak at ages 10 to 15 years. Creatinine levels are likewise elevated five times or more than normal.

Genetic Analysis

Genetic analysis is usually sufficient for diagnosis and is thus commonly used in the modern era. This modality detects deletions and duplications by methods like multiplex ligation-dependent probe amplification, fluorescence in situ hybridization, and polymerase chain reaction.[22][23] Of these tests, multiplex ligation-dependent probe amplification is most frequently used for diagnosis. Muscle biopsy with dystrophin antibody staining may be useful if the result of genetic analysis is negative.

Genetic analysis should be performed first for diagnosis in patients with sporadic illness. Meanwhile, the diagnosis is straightforward in familial cases since gene mutation has already been determined.

Electromyography

Electromyography may help differentiate between a primary nerve disease process and myopathy. This diagnostic modality can identify the best muscle group for obtaining a biopsy specimen. However, electromyography is rarely used in diagnosis.

Muscle Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) can aid in the diagnosis and progress assessment of all dystrophinopathies (see Image. Cross-sectional Magnetic Resonance Images at Baseline and on Follow-Up of a Patient with Becker Muscular Dystrophy). MRI is especially helpful in outcome measure analysis in clinical trials. This modality is a non-invasive means of visualizing fatty infiltration, muscle loss, edema from ongoing muscle damage, and fibrosis. The pattern of muscle involvement can help define different types of muscle diseases. Dystrophinopathies are characterized by glutei and adductor magnus involvement while sparing the sartorius and gracilis.[24]

Muscle Biopsy

Muscle histology reveals muscle necrosis and regeneration, fatty replacement, and endomysial fibrosis. However, these findings are not specific to BMD. Genetic analysis is still preferred for confirming the diagnosis.[25]

Electrocardiography

BMD predisposes patients to cardiac disease. Electrocardiography is an excellent test for initial cardiac function evaluation in affected individuals. This modality can help detect supraventricular and ventricular arrhythmias early in symptomatic patients.

MiscellaneousTests

Transaminases may be elevated in the presence of muscle pathology. Pulmonary function tests may be obtained since BMD can cause respiratory muscle dysfunction. Spinal radiographs can help follow scoliosis progression, which may result from progressive trunk muscle weakness. These modalities are unnecessary for BMD diagnosis but may be recommended depending on patient presentation.

Treatment / Management

BMD has no cure. Gene therapy for restoring normal levels of functional dystrophin is a promising approach, but clinical trials are still in progress. Currently, supportive therapy and rehabilitation are the cornerstones of BMD treatment.

Pharmacological Therapy of Muscle Dystrophy

There is no approved BMD treatment to date. However, the management approach to this condition is often similar to that for milder DMD cases. Corticosteroids have been the mainstay of treatment for patients with significant muscle weakness. Prednisolone at a dose of 0.75 mg/kg/day or deflazacort at a dose of 0.9 mg/kg/day may be given initially.[26][27]

Corticosteroids should be started before physical disability develops and must continue even after losing ambulation. Glucocorticoid treatment helps prolong survival by delaying the onset of cardiomyopathy, improving pulmonary function, retarding scoliosis, and reducing the need for spinal surgery.[28][29] The steroid dose should be reduced by 25% to 33% if adverse effects develop. Nitric oxide is occasionally prescribed to improve muscular circulation.(A1)

Dilated cardiomyopathy with heart failure is a common cause of morbidity and mortality in patients with BMD. Early cardiac evaluation and treatment are thus vital. Angiotensin-converting enzyme inhibitors with or without β-blockers are the main treatments for patients with BMD who have developed cardiac complications.[30]

Rehabilitation 

Rehabilitative care helps preserve muscle and overall function for as long as possible. An interprofessional approach addresses various aspects of this part of BMD management. Combining physical, speech, recreational, and occupational therapy is the best way to optimize patient outcomes. 

Surgical Management

Muscle weakness may produce progressive scoliosis and joint contractures in patients with BMD, though less frequently than in people with DMD. Monitoring and physical rehabilitation may benefit individuals with slowly evolving symptoms. Surgery may be considered in patients experiencing rapid symptom progression to help maintain ambulation for a longer period.

Combined Therapy

Individuals with severe respiratory failure may be managed with tracheostomy and assisted ventilation. Angiotensin-converting enzyme inhibitors and β-blockers may be given for associated cardiomyopathy. Home mechanical ventilation may reduce pulmonary pressure and protect the heart in patients with BMD when combined with cardioprotective medical therapy.[31][44]

Endocrine Management

Some children may experience impaired growth and delayed puberty. An endocrinology consultation may benefit these individuals. Low-dose testosterone can help promote normal bone development and prevent osteoporosis in boys with BMD.

Evolving Treatments

Previous clinical trials have shown no clear benefit from metformin treatment with or without L-citrulline.[32] Meanwhile, the synthetic glucocorticoid-like drug vamorolone has demonstrated potent anti-inflammatory activity through nuclear factor inhibition, improving sarcolemmal stability. This agent has shown early positive trial results. More randomized controlled trials are being conducted to find support for vamorolone's use in BMD management.[33](A1)

Differential Diagnosis

BMD has to be distinguished from other myopathies with muscle weakness as presenting symptoms, which include the following:

• DMD: more severe and earlier onset than BMD. The patient becomes wheelchair-bound earlier, and the length of survival is shorter. Patients usually have much lower dystrophin concentrations.[34]
• Polymyositis: an idiopathic inflammatory myopathy characterized by bilateral proximal muscle weakness. However, unlike BMD, polymyositis is not associated with distal pseudohypertrophy.[35]
• Spinal muscular atrophy: an autosomal-recessive inherited disorder commonly presenting with hyporeflexia, tongue fasciculations, and weakness in the bulbar or brainstem muscles. Cognitive impairment is less frequent. Consider spinal muscular atrophy as an alternative diagnosis in the absence of dystrophin gene mutation.[36]
• Limb-girdle muscular dystrophy: symptoms are similar to BMD, though calf muscle pseudohypertrophy is absent.[37]
• Dilated cardiomyopathy: can arise from a mechanism other than muscular dystrophy.[38]
• Emery-Dreyfuss muscular dystrophy: early contractures and cardiac defects help to distinguish this condition from BMD. Humeroperoneal muscle weakness and wasting begin in the 1st and 2nd decades of life.[39]
• Myasthenia gravis: fluctuating skeletal muscle weakness can be the initial or only symptom of this condition, which can make it difficult to distinguish clinically from BMD. However, facial weakness, ptosis, and diplopia commonly occur in myasthenia gravis but not in BMD.[40]
• Metabolic myopathies: mitochondrial disorders and glycogen and lipid storage diseases may manifest with generalized muscle weakness. However, many patients with these conditions develop symptoms as early as infancy. Hepatomegaly, hypotonia, and hypoglycemia are also common. Patients who reach adolescence or adulthood may experience exercise-induced muscle fatigue.[41]

A thorough clinical evaluation and the appropriate diagnostic exams can help distinguish these conditions from BMD.

Prognosis

BMD generally has a milder clinical course than DMD. However, the chances of survival decrease with time as the disease progresses. Patients become dependent on supportive interventions to prolong life. The average life expectancy of individuals with BMD is about 40 to 50 years. Death is most commonly due to dilated cardiomyopathy.[42]

Complications

BMD's potential complications include the following:

• Loss of ambulation
• Cognitive dysfunction
• Growth impairment
• Fractures
• Cardiomyopathy
• Joint contractures
• Scoliosis
• Postoperative chest infections
• Progressive hepatic and pulmonary failure
• Kidney failure from rhabdomyolysis and myoglobinuria
• Adrenal insufficiency and immunosuppression from long-term corticosteroid use

Early intervention and comprehensive care can help manage symptoms and improve the quality of life for people affected by BMD.