Becker Muscular Dystrophy

Article Author:
Pawan Thada
Article Author:
Jenish Bhandari
Article Editor:
Krishna Kishore Umapathi
Updated:
6/22/2020 7:05:48 PM
PubMed Link:
Becker Muscular Dystrophy

Introduction

Becker muscular dystrophy (BMD) is an X-linked recessive disorder due to mutation in the Dystrophin gene that results in progressive muscle degeneration and proximal muscle weakness.[1][2] This condition is less common and less severe than Duchenne muscular dystrophy (DMD). The onset of symptoms is late compared to Duchenne muscular dystrophy, although it varies widely between 5 to 60 years of age. In an investigation done in 67 patients exercising a standard protocol, the milder group had been found ambulant till their forties or beyond and more severe group with the earlier loss of ambulation.[3]

Etiology

Becker muscular dystrophy is caused by a mutation in a protein called "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 pattern of inheritance may have defects in other genes, affecting the dystrophin-associated glycoproteins. 

Epidemiology

BMD is a rare disease almost exclusively in males due to X-linked inheritance. Worldwide prevalence of Duchenne and Becker muscular dystrophy ranges from 0.1 to 1.8 per 10000 male individuals. According to research conducted in the United States in 2010, the prevalence of BMD for all age groups was 0.26 per 10000 male individuals, and it was found more common among non-Hispanic whites than non-Hispanic black. The study of Becker muscular dystrophy (per 10000 males) suggests the prevalence of 0.01 in South Africa, 0.1 to 0.2 in Asia, 0.1 to 0.7 in European countries. Isolated data shows Becker muscular dystrophy is three times less common than Duchenne muscular dystrophy.[4]

Pathophysiology

Dystrophin is a rod-shaped protein present in the cytoplasmic side of muscle fibers cell membrane as a part of a glycoprotein complex that connects the cytoskeleton to the extracellular matrix. It provides mechanical reinforcement and stabilizes the cell membrane.[2] Becker muscular dystrophy is caused by mutation in the dystrophin gene more commonly deletions (65% to 70%) or duplications (5% to 10%), which results in nonfunctional or less production of dystrophin.[5] The dystrophin gene consists of 79 exons[6] in Xp21 spans more than 2200 kb.[7] There are more chances of mutation during meiosis due to a large number of base pairs (around 2 million base pairs). Other forms of mutations, like small deletions and insertions, small site variants, are also present in small numbers.[8] Disruption of the dystrophin-glycoprotein complex leads to loss of cell membrane and degeneration of myofibers.

Neuronal nitric oxide (nNOS) is secured as a part of the dystrophin-glycoprotein complex produces nitric oxide, which regulates the vasodilation and increases blood flow to the muscle. The absence of dystrophin causes loss of neuronal nitric oxide associated with exercise-induced muscle weakness and fatigue.[9][10]

Damage to the cell membrane causes the outflow of creatine kinase from inside the cell, and the influx of calcium ions into the cell due to markedly increased open probability of leak channels.[11] Inflammatory mediators aids in overexpression of inducible Nitric oxide synthase (iNOS), increased production of nitric oxide. Nitrosylation destabilizes the ryanodine receptor (RyR1) of the sarcoplasmic reticulum, followed by calcium leakage in the cytosol. Increased cellular calcium ion concentration activates calpains that mediate protein degradation.[12][13]

Histopathology

On microscopic examination, the hallmark of Becker muscular dystrophy is ongoing myofiber necrosis and regeneration. Active muscle fiber necrosis and cluster of basophilic regenerating fibers are more prominent in younger age. In contrast, myofiber splitting with necrosis, increased internal nuclei, fiber hypertrophy, fatty replacement, and endomysia fibrosis are conspicuous in older age.[14][15]

History and Physical

There is a significant variation in clinical presentation and the onset of symptoms. Some patients retain ambulation till the old age and some present earlier. Growth is slower, leading to short stature. Obtaining a complete family history assists in genetic counseling. Becker muscular dystrophy has a milder clinical course and later onset than Duchenne muscular dystrophy. Suspicion of BMD is made when a child presents with muscle weakness selectively affecting proximal earlier than distal limb muscles and lower limbs before upper limbs with positive family history. Patients may present with symptoms like cramping with strenuous activity, the delayed ability of jumping, running, stair climbing, and cognitive impairment.[16] The intelligence quotient (IQ) of around 20% to 25% of patients is less than 70. Elbow fractures, cardiomyopathies, toe walking may be seen later in life as BMD is a progressive disease. Cardiomyopathy is characterized by fibrosis of the wall of the left ventricle, which can further lead to the development of life-threatening arrhythmias.

On physical examination, atrophy with pseudohypertrophy of calf muscles and occasionally quadriceps, hypotonia, hyporeflexia, fasciculations, Gower sign (use their hands and arms support to push them upright from squatting position), lumbar lordosis, shortening of Achilles tendons along with contractures of joints like knee, elbows, and hips are the common findings.[16][17] Pseudohypertrophy is due to the fibrosis and fatty replacement of atrophic muscles, which is a classical feature. Besides calf muscle hypertrophy of forearm muscle and tongue is also found in rare instances.

Female carriers may only present with cardiomyopathy. Sometimes carrier females may have mild muscle weakness. Approximately 22 percent of carriers become symptomatic with a high degree of variability. Genetic analysis is required for proper investigation of a mutation in case of suspicion.

Evaluation

When muscular dystrophy is suspected after history and examination, creatinine kinase level followed by dystrophin gene deletion analysis or muscle biopsy with dystrophin antibody staining is the mainstay of the laboratory studies to confirm the diagnosis.[16] However, in most instances, muscle biopsy is avoided, and genetic testing is confirmatory.

Creatinine kinase (CK) level

Raised creatinine kinase level indicates muscle degeneration, attaining a maximum of around 10 to 15 yrs of age.[6] Creatinine level is raised five times or more above the normal.

Genetic analysis

Genetic analysis is usually sufficient for diagnosis and commonly used in the modern era. This is performed for the detection of deletions and duplications by several methods such as Multiplex ligation-dependant probe amplification(MLPA)[18], fluorescence in situ hybridization(FISH), and polymerase chain reaction(PCR).[18][19] Among them, MLPA is the mainstay of methods that are mostly used for diagnosis. However, muscle biopsy with dystrophin can still be useful in cases of negative genetic analysis. In sporadic cases, the genetic analysis should be performed first for diagnosis. In familial cases in which gene mutation has already been revealed, diagnosis is straightforward.

Electromyography

Electromyography may be indicated to differentiate between primary nerve process disease and myopathy, identifying the muscle group for optimal biopsy. However, electromyography is almost never used in diagnosis.

Muscle Biopsy

Muscle histology reveals necrosis, regeneration, fatty replacement, endomysial fibrosis but is not specific for diagnosis.[20][15]

Electrocardiograms (ECG)

Electrocardiograms are an important part of surveillance for supraventricular and ventricular arrhythmias in cardiomyopathies or symptomatic patients.

Other tests

Liver function tests for transaminases, pulmonary function tests, and spinal radiographs to follow the progression of scoliosis are also important but less important.

Treatment / Management

Becker muscular dystrophy has no curative treatment, and supportive therapy, along with rehabilitation, is the mainstay of treatment. Many clinical trials for gene therapy are still under progress.

Pharmacological 

Corticosteroid (prednisolone at a dose of 0.75 mg/kg/day or deflazacort at a dose of 0.9mg/kg/day) has been the mainstay of treatment.[16][21][22] Corticosteroids should be started before physical disability and continue even after the loss of ambulation and in more severe cases.[16] It is beneficial for improving pulmonary function, delays scoliosis (decreases the need for surgery), delaying the onset of cardiomyopathy, and prolongs survival.[23][24] Corticosteroid dose should be reduced by 25% to 33% in case of side effects.[16] Nitric oxide has become the drug of treatment in some cases to increase the blood supply to muscles through vasodilation.

Medical Treatment

Tracheostomy and assisted ventilation are needed for patients with respiratory failure, and treatment of cardiomyopathy with ACE inhibitors and beta-blockers can help prolong survival.[25]

Rehabilitation 

Interprofessional care is provided to facilitate multiple specialized assessment and intervention to improve the quality of life. Interprofessional care includes physical therapy to strengthen the motor activity along with speech therapy, occupational therapy, and recreational therapy.

Endocrine Management

In case of impaired growth and delayed puberty, advice from endocrinologists plays a crucial role in the development of the child.[16]

Surgical Management

Progressive scoliosis and contracture require surgical intervention to prolong ambulation.[25]

Differential Diagnosis

Becker muscular dystrophy has to be distinguished from other myopathies with muscle weakness as presenting symptoms.

Duchenne muscular dystrophy: More severe and early onset than BMD. The patient becomes wheelchair-bound earlier, and the length of survival is shorter. Patients usually have lower dystrophin concentration.[26]

Polymyositis: This is the idiopathic inflammatory myopathy characterized by bilateral proximal muscle weakness may confuse this condition with BMD, but the absence of distal pseudohypertrophy helps in differentiating it from BMD.[27]

Spinal muscular atrophy: This is an autosomal-recessive inherited disorder with hyporeflexia, tongue fasciculations, weakness in bulbar, or brainstem muscles are more common but have less cognitive impairment. The absence of dystrophin gene mutation in a DNA probe provokes spinal muscular atrophy as an alternative diagnosis.[28]

Limb-girdle muscular dystrophy: This condition is hard to differentiate from BMD; however, calf muscle pseudohypertrophy is absent.[29]

Dilated cardiomyopathy: Muscular dystrophy results in cardiomyopathy, which is one of the most serious complications and the leading cause of mortality. But dilated cardiomyopathy can be a separate entity with a different genetic etiology or from other causes apart from muscular dystrophy.[30]

Emery-Dreyfuss muscular dystrophy: Early contractures and cardiac defects help to distinguish it from BMD. Humeroperineal muscle weakness and wasting that begins in the first and second decades of life.[31]

Myasthenia gravis: Fluctuating skeletal muscle weakness simulate the clinical presentation of BMD, but facial weakness, ptosis, and diplopia are common. However, infrequent proximal muscle weakness alone may occur.[32]

Metabolic myopathies: Metabolic myopathies are the storage diseases caused by the deficiency of enzymes required for the metabolism of glycogen, lipids, and mitochondrial diseases. Most patients complain about muscle weakness and pain during physical activity rather than during rest.[33]

Prognosis

Patients with Becker muscular dystrophy have less severe and milder clinical course than Duchenne muscular dystrophy. Chances of survival decrease with time as the disease progresses. Thus supportive interventions help prolong life. The average life expectancy of the patient with Becker muscular dystrophy is about 40 to 50 years. Death is most commonly due to dilated cardiomyopathy.[34]

Complications

Progressive deterioration of the disease process is complicated by cardiomyopathy, progressive loss of pulmonary and liver functions, loss of ambulation, cognitive impairment, and bone fractures. All patients have a high chance of postoperative chest infections.[25] Rhabdomyolysis leads to myoglobinuria and subsequent kidney failure. The use of corticosteroids causes adrenal insufficiency and immunosuppression.

Deterrence and Patient Education

Late medical, rehabilitative, and surgical interventions worsen this condition. So patients and families should be made aware of the disease and encouraged to approach the healthcare facilities as soon as possible. Prolonged use of corticosteroids increases the toxicity, so an initial discussion should be done with family before the use of steroids. The family should be educated about the signs and symptoms of toxicity.[16] The patient must have access to complete information about treatment options and tests. Consultations should be done if the carrier mother wants to have a child. Genetic counseling and specialist clinical genetic advice are vital. Patients should be educated early about the disease and should be provided with truthful expectations about the disease process and outcomes. Guide them with the need for regular follow up and physical therapy.

Enhancing Healthcare Team Outcomes

Although Becker muscular dystrophy is a rare condition, the clinical presentation gives high suspicion of the disease. But, a wide range of symptoms necessitates the efforts of an interprofessional healthcare team. Especially the patients having more severe conditions should care under the intervention of physiotherapists, vocational trainers, nurses, clinicians, nutritionists, radiologists, pharmacists, speech therapists, recreational therapists, cardiologists, pulmonologists, neurologists, genetic experts. Genetic analysis needs precise evaluation to get accurate results for diagnosis. Pharmacists should make sure that the patient is receiving glucocorticoids, working with other health professionals on dosing, administration, and side effects. The interaction between health professionals is essential to improving patient outcomes.


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