Becker's muscular dystrophy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo, M.D.

Overview[edit | edit source]

Former "pseudohypertrophic muscular dystrophy", now Becker's muscular dystrophy, is a genetic neuromuscular condition characterized by slowly progresive weakness and atrophy of skeletal (mostly legs and pelvis) and cardiac muscles.

Historical Perspective[edit | edit source]

Becker's muscular dystrophy was first described by Peter Emil Becker, a German neurologist, psychiatrist and geneticist, in 1953 with his thesis called ‘‘Dystrophia Musculorum Progessiva: A Genetic and Clinical Investigation of the Muscular Dystrophies’’, after his work was interrumpted in 1942 due to WWII recruitment.

Before Becker, in the 1860's, French neurologist Guillaume Benjamin Amand Duchenne described in detail a slowly progessive muscular weakness in a boy, later known as Duchenne muscular dystrophy.

The association between genetic mutations and Duchenne muscular dystrophy was made in 1986.

In 1987, dystrophin gene on X chromosome were first implicated in the pathogenesis of Becker's muscular dystrophy.

Pathophysiology[edit | edit source]

The pathogenesis of Becker's muscular dystrophy is characterized by muscle weakness and pseudohypertrophy (mostly proximal), cardiomyopathy, elevated CK and skelletal deformities.

Becker's muscular dystrophy is inherited in an X-linked recessive fashion.

Becker's muscular dystrophy is caused by a mutation in the gene DMD, one of the largest genes in humans. This gene encodes for the 3685Y aminoacid protein called dystrophin, wich can be found in skeletal and cardiac muscle, among other tisues. This mutation produces a truncated dystrophin protein that will translate into a decreased but not incomplete functionality (difference from Duchenne). Around 33% of patients with Becker's muscular dystrophy have de novo mutations. Point mutations and duplications appear mostly from spermatogenesis while deletions arise from oogenesis in most of te cases.   

On microscopic histopathological analysis, endomysial fibrosis with fatty replacement of muscle in later stages, inflammation, increased internal nuclei, myofiber cleavage with necrosis, and phagocytosis are characteristic findings of Becker's muscular dystrophy.

Clinical Features[edit | edit source]

Unlike Duchenne muscular dystrophy, Becker's muscular dystrophy (BMD) phenotype presents at a later age, widely variable onset from early childhood to late adulthood, most of them falling in puberty range. Most of the patients will requiere a wheelchair after age 16.

Clinical presentation Becker's muscular dystrophy include:

• Progressive symmetric muscle weakness, with a predilection in proximal muscles (eg. pelvic, legs, shoulders)
• Congestive heart failure
• Calf hypertrophy
• Cramping and muscle pain after exercise
• Flexion contractures
• Normal neck flexor muscle strength (differenting factor of BMD from DMD)

There is an abcense of fasciculations, and this finding may exclude BMD

CNS is rarely afected in Becker's muscular dystrophy, for this reason, intelligence is usually spared.

Most of women are asymptomatic carriers, with very rare cases presenting the classic symptoms.

Differentiating [disease name] from other Diseases[edit | edit source]

Becker's muscular dystrophy must be differentiated from other diseases that cause skelletal and cardiac muscle afection, such as:

• Duchenne muscular dystrophy. Presents with most of the symptoms of Beckers muscular dystrophy but with an earlier and more severe onset, most of them having symptoms from age 3 (Gower's sign); by convention, if a patient with a suspected dystrophinopathy stops walking before 12 years of age, he has DMD. Another diferentiating factor is the normal strength of neck flexor muscles in BMD
• Limb-girdle muscular dystrophy (LGMD). Is a group of inherited autosomal conditions that are clinically similar to dystrophynopathies (muscle weakness and wasting) but occur in both sexes. They are caused by a gene mutation that encodes sarcoglycans.
• Emery-Dreifuss muscular dystrophy (EDMD). Is a neuromuscular disorder that may be inherited in an autosomal or X-linked mode. The classic clinical triad encompasses incidious muscle weakness and wasting with predilection in the humero-peroneal distribution, joint contractures in childhood, and cardiac afection that includes palpitations, and syncope.
• Spinal muscular atrophy (SMA). Presents with muscle atrophy, delayed weight and height gain, restrictive lung disease, scoliosis, joint contractures, and sleep difficulties. Is inherited in an autosomal recessive mode.
• Dilated cardiomyopathy (DCM). Familial variants may be inherited in an autosomal (dominant or recessive), or an X-linked fashion. Presents with symptoms of dyspnea and poor exercise tolerance.
• Barth syndrome. Is an X-linked disorder characterized by prepubertal growth delay followed by a growth spurt, muscle weakness, cardiomyopathy, neutropenia, and facial gestalt.
  

Screening

It is appropriate to evaluate at-risk female family members (i.e., the sisters or maternal female relatives of an affected male and first-degree relatives of a known or possible heterozygous female) in order to identify as early as possible heterozygous females who would benefit from cardiac surveillance (see Surveillance).

Evaluations can include the following:

• Molecular genetic testing if the DMD pathogenic variant in the family is known
• Serum CK testing if the pathogenic variant in the family is not known. Although serum CK concentration can be normal in carrier females, if elevated, it will support heterozygosity status in a female relative.
• Molecular genetic testing of the at-risk female if an affected male is not available for testing:
  • By deletion/duplication analysis first
  • If no pathogenic variant is identified, by sequence analysis
• Linkage analysis to determine carrier status in at-risk females if (1) the DMD pathogenic variant in the proband is not known, (2) no DMD pathogenic variant or serum CK elevation is identified in a carrier female, and (3) the family has more than one affected male with the unequivocal diagnosis of DMD/BMD/DMD-associated DCM
  • Linkage studies are based on accurate clinical diagnosis of DMD/BMD/DMD-associated DCM in the affected family members and accurate understanding of the genetic relationships in the family.
  • Linkage analysis relies on the availability and willingness of family members to be tested.
  • Because the markers used for linkage in DMD/BMD/DMD-associated DCM are highly informative and lie both within and flanking the DMD locus, they can be used in most families with DMD/BMD/DMD-associated DCM [Kim et al 2002]. Note: (1) The large size of DMD leads to an appreciable risk of recombination. It has been estimated that the gene itself spans a genetic distance of 12 centimorgans [Abbs et al 1990]; thus, multiple recombination events among different members of a family may complicate the interpretation of a linkage study. (2)Testing by linkage analysis is not possible for families in which there is a single affected male. (3) Testing by linkage analysis may not be widely available on a clinical basis.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the DMD pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for a dystrophinopathy are possible.

Fetal muscle biopsy. In utero fetal muscle biopsy has been used in the prenatal diagnosis of DMD in families with DMD in which the DMD pathogenic variant is not known [Ladwig et al 2002].

The history of molecular diagnostic testing in DMD and the impact of new techniques including chromosome microarray (CMA) analysis and noninvasive prenatal diagnosis methods are reviewed in various publications [Raymond et al 2010, Xu et al 2015, Parks et al 2016].

Epidemiology and Demographics[edit | edit source]

• The prevalence of Becker's muscular dystrophy is approximately 3-6 per 100,000 individuals worldwide.
• In [year], the incidence of [disease name] was estimated to be [number or range] cases per 100,000 individuals in [location].

Age[edit | edit source]

• Patients of all age groups may develop [disease name].

• [Disease name] is more commonly observed among patients aged [age range] years old.
• [Disease name] is more commonly observed among [elderly patients/young patients/children].

Gender[edit | edit source]

Becker's muscular dystrophy affects men almost exclusively.

• [Gender 1] are more commonly affected with [disease name] than [gender 2].
• The [gender 1] to [Gender 2] ratio is approximately [number > 1] to 1.

Race[edit | edit source]

• There is no racial predilection for [disease name].

• [Disease name] usually affects individuals of the [race 1] race.
• [Race 2] individuals are less likely to develop [disease name].

Risk Factors[edit | edit source]

• Common risk factors in the development of [disease name] are [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].

Natural History, Complications and Prognosis[edit | edit source]

• The majority of patients with [disease name] remain asymptomatic for [duration/years].
• Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
• If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
• Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
• Prognosis is generally [excellent/good/poor], and the [1/5/10­year mortality/survival rate] of patients with [disease name] is approximately [#%].

In the early stages, Duchenne and Becker MD affect the shoulder and upper arm muscles and the muscles of the hips and thighs. These weaknesses lead to difficulty in rising from the floor, climbing stairs, maintaining balance and raising the arms.

The clinical course and natural history of MDs have dramatically changed over the recent years since advances in medical management and care of patients have been made, with treatment of complications, in particular cardiac, respiratory and orthopedic, as well as enhancement of quality of life, timely supply of aids, adaptations and access to independent living (Worman and Bonne, 2007; Bushby et al., 2010a). The same clinical care should be offered to patients independently by their geographic location and nihilistic approach should not be accepted. Use of steroids have been introduced in the treatment of DMD about a decade ago and currently represent the gold standard in DMD care, being the only currently available medication able to slow down the disease progression in terms of muscle strength and function. This also reduces risk of scoliosis, stabilizes respiratory function and improves cardiac function.

Becker muscular dystrophy (BMD) is characterized by later-onset skeletal muscle weakness. With improved diagnostic techniques, it has been recognized that the mild end of the spectrum includes men with onset of symptoms after age 30 years who remain ambulatory even into their 60s. Despite the milder skeletal muscle involvement, heart failure from DCM is a common cause of morbidity and the most common cause of death in BMD. Mean age of death is in the mid-40s.

Diagnosis[edit | edit source]

Diagnostic Criteria[edit | edit source]

• The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met:

• [criterion 1]
• [criterion 2]
• [criterion 3]
• [criterion 4]

Symptoms[edit | edit source]

• [Disease name] is usually asymptomatic.
• Symptoms of [disease name] may include the following:

• [symptom 1]
• [symptom 2]
• [symptom 3]
• [symptom 4]
• [symptom 5]
• [symptom 6]

Physical Examination[edit | edit source]

• Patients with [disease name] usually appear [general appearance].
• Physical examination may be remarkable for:

• [finding 1]
• [finding 2]
• [finding 3]
• [finding 4]
• [finding 5]
• [finding 6]

Laboratory Findings[edit | edit source]

• There are no specific laboratory findings associated with [disease name].

• A [positive/negative] [test name] is diagnostic of [disease name].
• An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
• Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

• Creatine kinase (CK) is significantly elevated but not to the degree seen in DMD
• Peak CK levels are usually found around 10 - 15 years of age
• ALT / AST may be elevated
• Can see occasional myoglobinuria following strenuous activity

Imaging Findings[edit | edit source]

• There are no [imaging study] findings associated with [disease name].

• [Imaging study 1] is the imaging modality of choice for [disease name].
• On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
• [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies[edit | edit source]

• [Disease name] may also be diagnosed using [diagnostic study name].
• Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].

The diagnosis of a dystrophinopathy is established in a proband with the characteristic clinical findings and elevated CK concentration and/or by identification of a hemizygous pathogenic variant in DMD on molecular genetic testing in a male and of a heterozygous pathogenic variant in DMD on molecular genetic testing in a female. Females may present with a classic dystrophinopathy or may be asymptomatic carriers.

A dystrophinopathy should be suspected in any male or female patient presenting with progressive limb-girdle weakness, especially if the patient has a positive family history, substantially elevated CK level, or cardiomyopathy. The diagnosis of DMD should be the physician’s first thought when a 3- to 5- year-old boy who is physically slower than his peers presents with toe walking, large calves, neck weakness, a partial Gower’s sign, and a CK level greater than 3000 U/L. CK levels may be elevated 10- to 200-fold. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are also muscle enzymes, are often elevated. This transaminitis reflects muscle involvement rather than liver disease, and this can be verified by checking the liver-specific transaminase +-glutamyltransferase (GGT), which will be normal. In DMD, DNA analysis of the dystrophin gene is the first diagnostic procedure.

In patients with BMD or in manifesting female carriers, weakness may not be as pronounced, the CK level may be lower, and the initial procedure will often be electrodiagnostic testing. The EMG reveals myopathic motor units with or without muscle membrane instability. If the patient has no family history of a dystrophinopathy, then a muscle biopsy may be performed. Immunostaining for the N-terminal, rod, and C-terminal regions of dystrophin will usually reveal diffusely decreased, or patchy, staining of some but not all muscle fiber membranes. Confirmatory testing is through DNA analysis. Mutation analysis consists of analysis for duplications and deletions via multiplex PCR or multiplex ligationdependent probe amplification. If this is negative, then gene sequencing is undertaken. Mutations in DMD causative for DMD and BMD are fairly consistent when assessed across different countries,13Y16 with the composition including 43% to 67% deletions and 9% to 11% duplications of exons, 16% to 26% point mutations, and 5% to 6% splice site mutations. Therapies allowing multiexon skipping from exons 45 through 55 would benefit more than 50% of patients with DMD. Mutations disrupting the reading frame (out-of-frame mutations) in DMD create a truncated RNA transcript that is rapidly degraded. This leads to a virtual absence of dystrophin in muscle and a DMD phenotype. Mutations with maintenance of the reading frame (in-frame mutations) generate shorter or less stable dystrophin. Dystrophin with in-frame mutations retain their amino- and carboxy-terminus domains and thus still maintain the mechanical bridge between actin and "-dystroglycan. Inframe mutations more often lead to a BMD phenotype. In a large series, out-of-frame mutations led to a DMD phenotype in nearly 90% of cases; however, in-frame mutations led to a BMD phenotype in only approximately 60% of cases (Case 2-1).13

Treatment[edit | edit source]

Medical Therapy[edit | edit source]

• There is no treatment for [disease name]; the mainstay of therapy is supportive care.

• The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
• [Medical therapy 1] acts by [mechanism of action 1].
• Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

No curative treatment

Physical therapy to promote mobility and prevent contractures

• Exercise
  • All ambulatory boys with DMD or those in early non-ambulatory phase should participate in regular gentle exercise to avoid contractures and disuse atrophy.
  • Exercise can consist of a combination of swimming pool and recreation-based activities. Swimming can be continued in non-ambulatory patients under close supervision, if medically safe.
  • If patients complain of muscle pain during or after exercise, the activity should be reduced and monitoring for myoglobinuria should be carried out. Myoglobinuria within 24 hours after exercise indicates overexertion leading to rhabdomyolysis.

Surgery[edit | edit source]

• Surgery is the mainstay of therapy for [disease name].
• [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
• [Surgical procedure] can only be performed for patients with [disease stage] [disease name].

Prevention[edit | edit source]

• There are no primary preventive measures available for [disease name].

• Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

• Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].

Appropriate management of individuals with a dystrophinopathy can prolong survival and improve quality of life.

Prevention of secondary complications: Evaluation by a pulmonologist and cardiologist before surgeries; pneumococcal and influenza immunizations annually; nutrition assessment; physical therapy to promote mobility and prevent contractures; sunshine and a balanced diet rich in vitamin D and calcium to improve bone density and reduce the risk of fractures; weight control to avoid obesity.

Cardiomyopathy. Recommendations are based on an American Academy of Pediatrics policy statement and various additional publications [American Academy of Pediatrics Section on Cardiology and Cardiac Surgery 2005, Jefferies et al 2005, Viollet et al 2012] and apply to patients with the DMD or BMD phenotype.

• The authors' institution commonly treats children with DMD or BMD early with an ACE inhibitor and/or beta blocker.
• When used in combination, these appear to lead to initial improvement of left ventricular function; however, ACE inhibitors are also used without beta blockers, with similar results [Viollet et al 2012].
• The optimal time to start treatment in DMD is unknown, but most cardiologists will initiate treatment when the left ventricle ejection fraction drops below 55% and fractional shortening is less than 28% [Jefferies et al 2005, Viollet et al 2012].
• Angiotensin II-receptor blockers (ARBs) such as losartan are similarly effective and can be used in cases of poor tolerability of ACE inhibitors [Allen et al 2013].
• In cases of overt heart failure, other heart failure therapies including diuretics and digoxin are used as needed.
• Cardiac transplantation is offered to persons with severe dilated cardiomyopathy and BMD with limited or no clinical evidence of skeletal muscle disease.

Scoliosis treatment as needed is appropriate. The management of scoliosis involves bracing and surgery. Most patients end up getting a spinal fusion. The use of rods is not contraindicated; therefore, rod and bone grafts are used to fuse the spine. A minority of patients do not develop significant scoliosis and may not require a spinal fusion.

Corticosteroid therapy. Studies have shown that corticosteroids improve the muscle strength and function of individuals with DMD (see Corticosteroid Therapy in DMD). This therapy remains the treatment of choice for affected individuals between ages five and 15 years. Corticosteroid therapy is not recommended in children before age two years [Bushby et al 2010a]. This treatment is also used in BMD, although the efficacy is less clear (see BMD below).

The following published recommendations for corticosteroid therapy are in accordance with the national practice parameters developed by the American Academy of Neurology and the Child Neurology Society [Moxley et al 2005] (full text), as well as the DMD Care Considerations Working Group [Bushby et al 2010a].

• Boys with DMD should be offered treatment with prednisone (0.75 mg/kg/day, maximum daily dose: 30-40 mg) or deflazacort (0.9 mg/kg/day, maximum daily dose: 36-39 mg) as soon as plateauing or decline in motor skills is noted, which usually occurs at age 4-8 years. Prior to the initiation of therapy, the potential benefits and risks of corticosteroid treatment should be carefully discussed with each individual.
• To assess benefits of corticosteroid therapy, the following parameters are useful: timed muscle function tests, pulmonary function tests, and age at loss of independent ambulation.
• To assess risks of corticosteroid therapy, maintain awareness of the potential corticosteroid therapy side effects (e.g., weight gain, cushingoid appearance, short stature, decrease in linear growth, acne, excessive hair growth, gastrointestinal symptoms, behavioral changes). There is also an increased frequency of vertebral and long bone fractures with prolonged corticosteroid use [King et al 2007].
• The optimal maintenance dose of prednisone (0.75 mg/kg/day) or deflazacort (0.9 mg/kg/day) should be continued if side effects are not severe. Significant but less robust improvement can be seen with gradual tapering of prednisone to as low as 0.3 mg/kg/day (or ~0.4 mg/kg/day of deflazacort).
• If excessive weight gain occurs (>20% over estimated normal weight for height over a 12-month period), the prednisone dose should be decreased by 25%-33% and reassessed in a few months. If excessive weight gain continues, the dose should be further decreased by an additional 25% to the minimum effective dose cited above after three to four months.
• If significant weight gain or intolerable behavioral side effects occur in patients treated with prednisone, change to deflazacort on a ten-day-on / ten-day-off schedule or a high-dose weekend schedule. In patients on deflazacort, side effects of asymptomatic cataracts and weight gain should be monitored.

BMD. Information about the efficacy of prednisone in treating individuals with BMD is limited. Many clinicians continue treatment with glucocorticoids after loss of ambulation for the purpose of maintaining upper limb strength, delaying the progressive decline of respiratory and cardiac function, and decreasing the risk of scoliosis. Retrospective data suggest that the progression of scoliosis can be reduced by long-term daily corticosteroid treatment; however, an increased risk for vertebral and lower-limb fractures has been documented [King et al 2007]. Men on steroid therapy were less likely to require spinal surgery [Dooley et al 2010b]. The dose is allowed to drift down to 0.3-0.6 mg/kg/day of prednisone or deflazacort, which is still effective [Bushby et al 2010a].

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