Becker Muscular Dystrophy

Advancements in the diagnosis of genetic conditions have revealed that BMD is a type of recessive, X-linked dystrophinopathy. Exon deletions exist in the dystrophin gene Xp21 (X-chromosome, short arm p, region 2, band 1). Affected males in approximately 30% of known cases of BMD phenotype do not have a demonstrable mutation/deletion. A reading frame or in-frame mutation hypothesis has been proposed to explain abnormal translation of the dystrophin gene. Abnormal but functional dystrophin may be produced, in contrast to the pathology in DMD, in which a frame-shift mutation essentially leads to failure to produce dystrophin.[9, 10, 11, 12] Dystrophin levels in BMD are generally 30-80% of normal, while in DMD, the levels are less than 5%.[6]

Dilated cardiomyopathy with congestive heart failure presents in males between age 20 and 40 years, but in carrier female carriers it is found later in life.[6, 13] This possibly explains why, in comparison with females, males suffer a rapid progression to death.

A study by Nicolas et al suggested that clinical variations in patients with BMD are related to differences in dystrophin mutations, as derived from different in-frame exon deletions. For example, delayed onset of dilated cardiomyopathy seemed to be related to specific exon deletions, as did earlier wheelchair dependency.[14]

See also the following related Medscape Drugs & Diseases articles:

Dilated Cardiomyopathy [Cardiology]

Dilated Cardiomyopathy [Emergency Medicine]

Pediatric Dilated Cardiomyopathy [Pediatrics: Cardiac Disease and Critical Care Medicine]

Imaging in Dilated Cardiomyopathy [Radiology]

Frequency

United States

The incidence and prevalence of BMD are lower than those of DMD. The estimated incidence of BMD is 1 individual per 30,000 male births, compared with 1 individual per 3500 male births for DMD.[15] The prevalence of BMD is 17-27 cases per 1 million population.

International

The international incidence is probably similar to that in the United States.

Mortality/Morbidity

A series by Emery and Skinner showed the mean age for symptom onset to be 11 years, with the age range for onset being 2-21 years.[16] The mean age at which affected patients described in the studies became nonambulatory was 27 years, with an age range of 12-30 years. Death usually resulted from respiratory or cardiac failure at a mean age of 42 years, with the age range being 23-63 years.[17]

Ambulatory status and age may differentiate DMD from BMD. In general, an ambulatory patient who is older than 16 years may be classified as not having the Duchenne phenotype, although some subjects with BMD stop walking between ages 13-16 years. Atypical clinical presentations include cramps with exercise, focal myopathy, and isolated cardiomyopathy. Unaffected patients with no evidence of skeletal muscle disease have been classified as having subclinical BMD.[18]

A study by De Wel et al indicated that in persons with BMD, loss of ambulation leads to more rapid respiratory deterioration, with a deeper annual decline in forced vital capacity. The investigators also reported that body mass index (BMI) increase in nonambulatory patients is associated with even greater respiratory impairment.[19]

Sex

BMD is an X-linked disorder. Given the transmission pattern, the disease affects primarily males. Translocations may allow the possibility of a female presentation of the BMD phenotype.

Age

The onset of symptoms occurs at a mean age of 11 years, with the age range for onset being 2-21 years.

A typical developmental history of a patient with BMD may include the following:

• Delayed gross motor milestones (eg, late walking, running, jumping, difficulty with stair climbing) may be reported.

• Initially, some children who are later diagnosed with BMD may be called clumsy.

• Increasing numbers of falls, toe walking, and difficulty rising from the floor may be later features.

• Proximal muscle weakness is reported.

• Subclinical cases may manifest later in life; dilated cardiomyopathy can be the first sign of BMD.

• Elbow contractures may be seen later in life.

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• The Gowers sign is not a specific finding for muscular dystrophy, but it does point to proximal weakness in the hip extensors, leading to the pattern of movement seen when patients rise from the floor.

• A weakness pattern limited to specific muscle groups may help to differentiate BMD from other muscular dystrophies (such as limb-girdle and Emery-Dreifuss muscular dystrophies).

• Progressive, symmetrical muscle weakness and atrophy with pseudohypertrophic calves may be seen.

• Cases have been described of patients presenting without weakness but with symptoms of cardiomyopathy or cramps as the only indication of a myopathic process. Isolated weakness to the quadriceps femoris may be the only symptom noted.

• Fasciculation or sensory modality abnormalities can exclude the diagnosis of a dystrophinopathy.

• Preservation of neck flexor muscle strength may differentiate BMD from DMD.

BMD is an X-linked, recessive, inherited disorder. A family history of similarly affected maternal uncles assists the clinician in confirming a diagnosis of BMD.

• A woman is an obligate heterozygote if she has an affected son and one other affected relative in the maternal line.

• A woman with more than 1 affected child and no family history in the maternal line may have a germline mutation or a germline mosaicism.

• An isolated proband without a family history may be explained by a mutation occurring in the egg at or following conception in which only some cells were affected (mosaicism). On the other hand, the proband's mother may have inherited the gene mutation if (1) her mother was a carrier or (2) her mother or father had somatic or germline mosaicism.

• Siblings of the proband are at risk of transmitting the gene defect based on the carrier status of the mother.

  • A carrier mother has a 50% transmission rate for the mutation, per pregnancy; daughters inheriting the mutation will be carriers, and sons with the mutation will be affected.

  • Mothers with germline and/or somatic mosaicism have a higher risk of transmitting the mutation.

After a thorough history has been taken and a physical examination has been performed, a diagnosis of BMD may be confirmed with the following lab study sequence:

• Serum creatine kinase shows moderate to severe elevation (that is, 5-100 times the normal level)
• Dystrophin gene deletion analysis shows specific exon deletions in about 98% of cases; test methods include the multiplex polymerase chain reaction assay, southern blot analysis, and fluorescent in situ hybridization
• Muscle biopsy with dystrophin antibody staining demonstrates the presence of dystrophin in variable percentages; this may be helpful in the young child with no maternal history

A study by Zhang et al indicated that serum creatinine levels are significantly higher in patients with BMD than in those with DMD. The study was conducted using biochemical and genetic data, as well as Vignos scale scores (used to assess motor function), from 212 boys with dystrophinopathy.[20]

Laboratory evaluation is generally confirmatory of BMD if the patient possesses a phenotype that is consistent with muscular dystrophy and has a family history of the Becker form of the disease. Laboratory and phenotypic expression confirm sporadic cases. A clinical picture of muscular dystrophy, coupled with a preserved ambulatory status beyond age 16 years, is consistent with a diagnosis of BMD.

Genetic testing and next-generation sequencing technology may aid in diagnosis.[21, 22]  Other laboratory studies that may be indicated include the following:

• Liver function screen for aspartate transaminase and alanine transaminase
• Muscle biopsy
• Standard histology

Spinal radiographs may be performed to follow the progression of scoliosis, particularly during adolescence.

A report by Marty et al indicated that quantitative cardiac magnetic resonance imaging (MRI) is an effective means of assessing structural and functional myocardial impairments in patients with BMD, with 26% of patients in the study demonstrating a significant reduction in the left ventricular ejection fraction, as well as a greater dyssynchrony index than controls. Moreover, native T1, T2, and extracellular volume fraction were significantly higher in patients with BMD than in controls, serving as quantitative biomarkers associated with inflammation and fibrosis.[23]

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• Electromyography may be indicated.[24]

  • Expect normal nerve conduction with possible borderline-to-low motor evoked responses.

  • Expect increased insertional activity with myopathic motor unit action potentials (ie, short duration, low-to-normal amplitude, rapid recruitment, decreased units).

  • An electrodiagnostic study will facilitate a distinction between a muscular and a primary nerve process (eg, anterior horn cell disease, hereditary polyneuropathies).

  • Electromyography also may assist in identifying which muscle groups would be optimal for biopsy.

• An electrocardiogram/echocardiogram may show cardiomyopathy and/or arrhythmia. Dilated cardiomyopathy manifests after age 20 years; the risk progressively increases with age.

• Pulmonary function testing may reveal bellows failure caused by progressive weakness.

• Associated restrictive disease may be seen with scoliosis or a poorly compliant chest.

Standard muscle biopsy alone does not support a diagnosis of BMD. Histologic changes — specifically, findings of degenerating muscle fibers, a variation in fiber size, focal necrosis, regeneration, and a proliferation of connective tissue, as well as fatty replacement of degenerated muscles — point to a muscular dystrophy.

Physical Therapy

The role of physical therapy services is to address the functional needs of the patient as the disease progresses. Early interventions may focus on stretching tight muscles (which may initially be the only therapy goal). As the patient's weakness progresses, appropriate equipment and assistive devices will be required to enable the individual to maintain functional mobility and independence in daily living activities. Educational objectives include teaching the patient techniques for energy conservation, joint protection, and the prevention of overuse fatigue.

The greatest physical therapy benefits for patients with BMD may be derived from twice-weekly sessions of 30-45 minutes each (although the patient’s capacity, fatigability, and availability must be taken into account). Greater exercise precautions, including limitation of intense contractions and eccentric stresses and promotion of aerobic metabolism, are needed for the muscles that have been most affected (ie, those with a score of less than four on the Medical Research Council Scale for Muscle Strength). In addition, evaluation for and monitoring of BMD-associated disorders, including pain (rest and stress myalgia), respiratory or cardiac involvement, and swallowing or cognitive dysfunction (executive disorders), is required.[25]

Occupational Therapy

Activities of daily living skills are addressed, depending on the level of impairments, in occupational therapy. Specific adaptations (to aid, for instance, dressing and bathroom skills) may be provided. Such adaptations range from methods of buttoning and zippering clothes to grab bars and raised toilet seats in the bathroom. Mobility concerns are addressed, including the need for devices to assist with mobility, such as a scooter or a fully adapted wheelchair with a custom seat and back, custom supports, and electric power.[26]

Speech Therapy

Dysphagia concerns may be evaluated by a speech therapist. Progressive weakness toward the end of the disease process may lead to dysphagia and an increased risk of aspiration pneumonia. Clinical evaluation may result in the recommendation to avoid specific food textures and liquid viscosities, as well as to avoid certain positions during feeding. Videofluoroscopic evaluation may be performed to demonstrate the risk of aspiration.

Recreational Therapy

Specific planning for avocational needs and desires may be coordinated with a recreational therapist. Resources within the community, such as activity programs with the local parks and recreation department, may be explored. Educational institutions, from public schools to community colleges and universities, may have resources that can be utilized. Adaptive physical education programs and disabled student services are generally available for qualified individuals. Access and mobility concerns in the community invariably touch upon the adjustment issues faced by individuals with a progressive disability.

Potential complications of BMD include progressive weakness that results in orthopedic deformity and medical emergencies for cardiac and respiratory symptoms. Swallowing-related complications, from difficulties with mastication to problems in the pharyngeal phases, may arise with progressive weakness of the swallow mechanism.

A study by Yamada et al found that when patients with BMD were matched by physical function status to patients with DMD, both groups had similar swallowing problems. The investigators reported that BMD patients did not differ from those with DMD with regard to the rate of aspiration or scores on the penetration-aspiration scale or total videofluorographic dysphagia scale.[27]

Recurrent aspiration pneumonias from progressive dysphagia may eventually cause mortality in BMD. The progressive loss of safe swallowing may result in the need for gastrostomy tube placement. Constipation may be an associated problem, given poor fluid intake and progressive difficulty with commode transfers. Overuse syndromes may lead to complaints of muscle pain, prolonged fatigue, and myoglobinuria.

Progressive scoliosis and contracture formation may require surgical intervention. Spinal fusion to correct scoliosis may be scheduled based on the progression of spinal deformity and the age of the patient. Ankle contractures may be corrected with appropriate heel cord release and lengthening. Muscle transfers, such as with the posterior tibialis muscle, also may be considered to preserve functional mobility.

Subspecialty consultations depend on the patient's specific needs as related to the disorder. Appropriate consultations may include the following:

• Anesthesiologist - Preoperative management and planning for appropriate anesthesia are key reasons for consultation with an anesthesiologist. The risk of malignant hyperthermia is significant, given the intrinsic muscle disorder. Appropriate cautions must be taken to avoid medications that may precipitate malignant hyperthermia.[28, 29] Dantrolene sodium is probably the best medication to use if malignant hyperthermia arises.

• Cardiologist - Cardiac function requires ongoing follow-up care. Symptomatic patients with significant cardiomyopathy have undergone transplantation procedures.

• Pulmonologist - The need for management of pulmonary problems associated with muscle weakness and restrictive disease is a typical indication.[30] Formal pulmonary function testing may be used for preoperative care, as well as for the determination of need for ventilatory support.

• Orthopedist - The need for management of scoliosis and joint contractures are major indications for consultation with an orthopedist.[31] The period around puberty is generally the time for significant change in scoliosis, especially if the patient's ambulatory status is limited. Heel cord release is a commonly performed joint contracture procedure.

• Geneticist - Consultation regarding the carrier status of the patient's mother and siblings is important. Transmission risk to offspring should be discussed. Identifying mosaicism in the mother or father, as well as determining the risk of transmission, is another topic to consider in nonheterozygote carrier families or in isolated cases.

Because no cure exists for BMD, treatment is focused on controlling a patient's symptoms. Weakness progresses, and emergencies related to cardiac and respiratory symptoms are hallmarks of advance in the disease process. Possible future treatments for BMD include the following:

• Gene therapy may eventually lead to effective treatment, given proper identification of the gene defect and effective administration of the corrective gene to the muscle targets.[32, 33]

• Myoblast treatment, as well as the use of stem cells, also may be alternative modalities if proven successful.

• Steroids have been reported to show benefit in patients with DMD, but there are conflicting reports. No definitive evidence demonstrates that steroids are effective against BMD.

No medications are provided to patients for the specific treatment of BMD. Medications are administered to treat symptoms that are commonly are associated with BMD (such as cardiac medications for heart disease).

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• Rehabilitation management coordinates the administration of appropriate therapeutic modalities.

  • The physiatrist initiates and coordinates diagnostic studies, because muscular dystrophy may not have been diagnosed in these patients prior to the initial visit.

  • Routine health care issues include the recommendation of yearly influenza vaccinations, as well as the administration of pneumococcal vaccine.

  • Given the progressive nature of the BMD, anticipatory guidance is ongoing. The physiatrist provides recommendations for classroom accommodations and activity during a patient's school years. Work-related concerns during the patient's adult years of employment are primary issues, with work modification scenarios and the use of assistive devices being prominent concerns.

• Cardiopulmonary evaluations include pulmonary function and electrocardiographic testing.

  • Pulmonary evaluations are important in tracking the progression of muscular weakness affecting ventilation.

  • A simple clinical test with a spirometer may be employed to measure maximal expiratory volume during routine clinic visits.

  • A pattern of falling maximal expiratory volumes over time may indicates the need for formal pulmonary function to determine the need for ventilatory support.

  • Nighttime ventilatory support with a mask or nasal bilevel positive airway pressure is commonly used if a rising pCO2 is noted. The results from sleep studies also may suggest progressive difficulty in nighttime ventilation.

  • Cardiovascular health supervision guidelines are available[15]

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• Prenatal diagnosis is available for a woman with an at-risk pregnancy who has been identified as having a family history of muscular dystrophy. Identification of dystrophin gene exon deletions in a male fetus points to the risk of a child with muscular dystrophy. Couples may elect to terminate the pregnancy if the fetus is affected.

• Carrier status may be determined in the mother and siblings of a proband.

See the list below:

• Progressive disability

• Dilated cardiomyopathy

• Respiratory symptoms, with a potential need for ventilatory support

• Joint contractures

• Scoliosis

• Dysphagia

• Functional constipation

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• See Mortality/Morbidity.

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• Well in advance of the projected necessity, discuss the decision, with the occurrence of pulmonary failure, to place a tracheostomy tube for positive-pressure ventilation, as well as for airway and secretion management. Inform the patient, family members, and/or caregivers of the implications of placing the patient on a ventilator. Early education can help the patient and his/her family to determine advanced directives.