Clinical manifestations

Presentation and course

The most common presentations of Becker muscular dystrophy include (1) proximal muscle weakness/myalgias; (2) cardiomyopathy; (3) elevated serum levels of creatine kinase (CK); or, more rarely, (4) malignant hyperthermia after exposure to halothane anesthesia.

(1) Proximal muscle weakness or myalgias. The most typical presentation of patients with Becker muscular dystrophy is juvenile onset of proximal muscle weakness and calf hypertrophy, with gradual progression. Early myalgia and cramps can also occur in patients with later onset of muscle weakness (30; 13; 58). In a large study of patients with Becker muscular dystrophy, the mean age of onset of muscle symptoms was 11.2 years (range 10 months to 38 years) (13). There appears to be a gradual decline in lower extremity muscle function with age, which typically leads to loss of ambulation, similar to Duchenne muscular dystrophy. However, the age at which loss of ambulation occurs is highly variable, usually after 16 years of age, with a mean age in the third decade (13; 17). Severity appears to be associated with muscle dystrophin levels; patients with higher dystrophin expression are more likely to be asymptomatic. However, the correlation of specific clinical presentations with genotype has been challenging (14; 04). About 10% of patients have severe Becker muscular dystrophy and show delayed motor milestones similar to Duchenne muscular dystrophy; they are wheelchair-bound before 20 years of age, though typically later than patients with Duchenne muscular dystrophy (33). These patients are often called "severe Becker dystrophy," "mild Duchenne dystrophy," or "outliers." There are also rare presentations of Becker muscular dystrophy with calf hypertrophy and elevated CK but without muscle weakness or muscle weakness much later in life (81; 31; 67).

(2) Dilated cardiomyopathy. Patients with Becker muscular dystrophy may have dilated cardiomyopathy with or without skeletal muscle involvement (20; 44; 76; 85). Sixty to seventy-five percent of patients with Becker muscular dystrophy have at least subclinical cardiac pathophysiology, and approximately one third of them will suffer from hypertrophic or dilated cardiomyopathy leading to heart failure (24; 73). Sudden cardiac arrest has been reported in patients with Becker muscular dystrophy with undiagnosed disease who undergo anesthesia and surgical procedures (71). Overall, cardiomyopathy represents the most common cause of death in patients with Becker muscular dystrophy (19; 73). It is unclear whether cardiomyopathy correlates with a distinct phenotype or mutation (39; 41; 45; 17). Cardiomyopathy in Becker muscular dystrophy is thought to be the result of diffuse degeneration and fibrosis in the ventricles, with a preference for the inferolateral region and the conduction tissue (73). Early cardiac screening is necessary for patients with Becker muscular dystrophy. Depending on the age of the patient this includes echocardiography or cardiac magnetic resonance imaging, which is more sensitive (90; 93).

(3) Elevated serum CK. Presymptomatic elevation of serum creatine kinase is a frequent presentation of Becker muscular dystrophy. Striking elevation of serum creatine kinase is present from birth (typically 100 to 200 times normal; normal is less than 200 IU/L) and peaks in the teenage years (mean of 5202 IU/L) (92; 13). It is unusual for serum creatine kinase levels to be below 1000 IU/L in patients with Becker muscular dystrophy. In young patients (less than 3 years old) there is evidence that serum CK levels are inversely proportional to Becker muscular dystrophy disease severity, possibly due to increased energy metabolism within muscle that is proportional to creatine degradation (86). Along with elevated creatine kinase, transaminases (ALT and AST) are also elevated, which may mislead physicians to look for liver diseases.

(4) Malignant hyperthermia. This is a rare presentation of Becker muscular dystrophy. Patients undergoing surgery with halothane anesthesia can experience a malignant hyperthermic episode, with an increase in serum creatine kinase levels due to acute muscle necrosis. In a small number of young boys experiencing a malignant hyperthermic episode, serum creatine kinase levels remain dramatically elevated months after the episode. These patients should be investigated for muscular dystrophy.

Clinical course. Progression of extremity weakness is variable, and it is unclear whether it is related to genetic mutation; however, all patients with Becker muscular dystrophy show a downward trend on quantitative assessment (63; 08; 17). Earlier loss of ambulation does appear to be associated with earlier first signs and symptoms (16). Half of affected boys will have muscle weakness by age 10, with loss of ambulation by the third or fourth decade (13). There are cases of Becker muscular dystrophy with onset of muscle weakness later in life or asymptomatic elevated CK (54; 89). Onset of cardiomyopathy in association with genetic causes remains unclear (39; 41; 45; 17). Mental deficiency or other nonmuscle symptoms are seen less frequently than in Duchenne muscular dystrophy, and it is unclear if they correlate with mutation site, but patients with Becker muscular dystrophy do demonstrate a higher incidence of anxiety, learning difficulties, autism, and behavioral problems compared to the general population (91; 60; 50). One studied identified the following prevalences: 6.0% of autistic spectrum disorders, 28.0% of attention deficit hyperactivity disorder, 7.0% of depression, 25.0% of anxiety disorders, and 7.0% of obsessive-compulsive disorder (69). Developmental delay and behavioral difficulties have specifically been identified in patients with deletions in exons 45 to 59 (13). Additionally, patients who are diagnosed with Becker muscular dystrophy in childhood, independent of clinical progression, more frequently present with a developmental delay and reduced IQ (14).

Prognosis and complications

Becker muscular dystrophy is clinically extremely variable. Even with molecular tests it is difficult to determine clinical progression. Patients with more severe Becker muscular dystrophy are typically wheelchair bound between age 14 and 20 years (66; 07; 14; 18). Overall, patients with Becker muscular dystrophy have a wide range of death, 23 to 89 years, with a mean of 47.3 years, due mainly to respiratory and cardiac disease (13).

Progressive deterioration of muscle can result in contractures and respiratory infections due to reduced vital capacity, particularly in more severely affected patients. Any period of immobility may lead to earlier loss of ambulation (13). Cardiomyopathy and death due to cardiac dysfunction are particular concerns in all patients and may be presenting symptoms in less affected patients, who are able to perform strenuous muscle exercise leading to mechanical stress on dystrophin-deficient myocardial cells (53; 78; 64). Heart function should be carefully monitored in all patients with Becker dystrophy with initiation of early cardiac therapy. Additionally, all female Duchenne and Becker muscular dystrophy carriers over the age of 16 years should have yearly cardiac monitoring (70; 65; 52).

Clinical vignette

The patient was a 9-year-old male who complained of increasing difficulty in climbing stairs, which, he indicated, had started about 6 months prior to the evaluation. He was reported to have had “growing pains” since early childhood, but more recently he had had ankle and calf muscle pain after walking longer distances or running. At 2 years of age, he had undergone a liver biopsy after a routine blood test discovered elevated transaminases. The liver biopsy showed a mild “nonspecific hepatitis” for which no treatment was initiated. His developmental milestones were normal, and he was enrolled in regular school classes. His neurologic examination revealed mild weakness in deltoid muscles, pectoral muscles, and hip flexors, and some of his muscles appeared hypertrophic. He had a partial Gowers sign and tight heel cords bilaterally. His creatine kinase level was 13,500. An echocardiogram did not show any abnormality. A genetic analysis of Duchenne muscular dystrophy gene showed an in-frame deletion of exons 46 and 47.

Biological basis

Etiology and pathogenesis

Genetics. Becker muscular dystrophy is caused by in-frame mutations in the Duchenne muscular dystrophy gene (DMD gene), located on the X-chromosome (Xp21) (49). The DMD gene occupies 2.5 million base pairs of DNA and is about 10 times larger than the next largest gene identified to date. The gene contains 79 exons of coding sequence, which together form the 14,000 base pair mRNA molecule (49; 74). Several mRNA and protein isoforms vary in size and tissue distribution (02).

Pathophysiology. Dystrophin is localized to the plasma membrane of all myogenic cells (including cardiac muscle) and some classes of neurons and in small amounts in other cell types (37; 40). Isoforms expressed in liver or other nonexcitable tissues do not seem to cause pathology when lacking in patients (02).

In Becker muscular dystrophy, dystrophin is present but altered in quantity, quality, or both (35; 36). This is mainly due to mutations that keep the “reading frame” intact. In the more severe Duchenne muscular dystrophy, dystrophin is absent due to “out of frame” mutations. Dystrophin deficiency at the plasma membrane of muscle fibers disrupts the membrane cytoskeleton and leads to secondary loss of other components of the cytoskeleton, leading to membrane instability and transient abnormal membrane flux (22). The membrane leakage occurs from birth and causes the classic active myopathy seen histopathologically, yet muscle function is preserved in early childhood. The chronic myopathy leads to aggressive fibrotic replacement of the muscle and eventual failure of regeneration. The clinical severity in Becker muscular dystrophy appears to be linked to structure of truncated dystrophin protein (01; 63).

Advancement in genetic technologies and the expansion of mutation analysis to the introns have increased the list of disease-causing mutations, including, for example, the “founder” mutation in exon 1 (p.Trp3X) that appears to cause a milder Becker phenotype (26; 27). Deletions affecting the N-terminus of the DMD gene seem to be associated with early-onset dilated cardiomyopathy (45); however, other mutations have been associated with a similar phenotype (82).

Epidemiology

Genetic counseling and prenatal diagnosis have begun to lower the incidence in countries where molecular diagnostic techniques are available, however, a high incidence of Becker and Duchenne muscular dystrophy is maintained through the dystrophin gene's high spontaneous mutation rate. About one third of cases with no family history are due to new mutations in single eggs. Thus, even if genetic counseling were effectively implemented for all relatives of patients with dystrophinopathy and if prenatal diagnosis were fully utilized, the disease incidence would change very little (61). This is in marked contrast to other genetic diseases such as Tay-Sachs, in which carrier detection and counseling have virtually eliminated it from specific high-risk populations.

Ten percent of isolated cases of “idiopathic hyper-CKemic myopathy” in females are isolated cases of dystrophinopathy (57; 34). These patients are heterozygous carriers of dystrophinopathy who have skewed lyonization of their X chromosomes and express dystrophin deficiency to a variable extent with variable clinical manifestations (68).

Prevention

Once a boy with Becker muscular dystrophy is identified, it is imperative to obtain molecular diagnosis for consideration of future mutation-specific therapies. Genetic counseling should be offered to his immediate family members; mother's future sons may be at risk for Becker muscular dystrophy, and sisters of the proband may be carriers of the gene (12). Patients with Becker muscular dystrophy often have children who show inheritance consistent with X-linked recessive conditions: all daughters of fathers with Becker muscular dystrophy will be carriers, and all sons will be normal.

Neonatal screening for Duchenne and Becker muscular dystrophy based on elevated CK is under pilot in the United States and Eastern China (47; 48). Newborn screening for Duchenne muscular dystrophy is based on elevated CK. Thus, patients with Becker muscular dystrophy may also be identified (29). Early screening allows for earlier intervention of learning disabilities and initiation of new genetic treatments before the appearance of muscle fibrosis. Genetic counseling can also be provided to unsuspecting parents (56; 77).

Differential diagnosis

Confusing conditions

Duchenne muscular dystrophy. The most common presenting symptom of Becker muscular dystrophy, proximal muscle weakness accompanied by striking elevations of serum creatine kinase, is also seen in children diagnosed with Duchenne muscular dystrophy. The age of presentation in Becker muscular dystrophy is typically later than in Duchenne muscular dystrophy and with slower progression, although there can be substantial overlap in more severely affected patients, pointing to the importance of mutational analysis for accurate diagnosis.

Limb girdle muscular dystrophy. It is nearly impossible to differentiate Becker muscular dystrophy from "limb-girdle muscular dystrophy" (autosomal recessive or dominant conditions with multiple etiologies) on clinical grounds (38; 05; 18). Patients with limb-girdle muscular dystrophy generally show lower serum creatine kinase levels and less frequent cardiac involvement compared to patients with Becker muscular dystrophy (38), but there is substantial overlap. Family history can be helpful: an X-linked family history (the affected proband will have maternal uncles or cousins affected) is consistent with Becker muscular dystrophy, whereas affected female siblings strongly suggest autosomal recessive inheritance (limb-girdle muscular dystrophy). Most limb-girdle patients and about 50% of Becker dystrophy patients are isolated cases, and family history is not informative.

Spinal muscular atrophy. A number of patients carrying the diagnosis of late-onset spinal muscular atrophy (Kugelberg-Welander; spinal muscular atrophy types II and III) have been later found to have Becker dystrophy based on molecular tests. Electromyography (EMG) and serum creatine kinase level are usually sufficient in differentiating these patients. Serum CK is only mildly elevated or normal in spinal muscular atrophy. Patients with spinal muscular atrophy show a neurogenic EMG, whereas patients with Becker muscular dystrophy show a myopathic EMG. However, there may be overlap in the EMG patterns and histopathology in advanced cases (ie, end-stage muscular dystrophy with secondary alteration of motor units), and molecular diagnosis is often necessary.

Collagen defects. Collagen defects (Ullrich and Bethlem syndrome) may cause progressive myopathies with proximal weakness, but the presence of hyperlaxed joints represents a distinctive feature (46).

Polymyositis. Patients with polymyositis often show creatine kinase elevations and distribution of weakness that closely resemble Becker muscular dystrophy. However, polymyositis is often more acute in presentation/progression, and all cases are sporadic with no previous family history. Evidence of inflammatory reaction in muscle biopsy is often diagnostic of polymyositis; however, Becker patients can also occasionally show inflammatory infiltrates in muscle. Molecular diagnosis is the most reliable way to differentiate these disorders.

Transient hyperCKemia. HyperCKemia is a frequent presentation of Becker muscular dystrophy. In normal individuals, serum creatine kinase can show elevations following unusual muscle activity (exercise), viral infection, and muscle damage of any kind. However, the degree of elevation in Becker muscular dystrophy is typically greater than 1000 IU/L (normal less than 200 IU/L) and is persistent. In contrast, hyperCKemia due to most other causes in normal individuals is transient, with values usually returning to normal within days or weeks. Serum aldolase and transaminases (alanine transaminase, serine glutamyltransferase) often show less dramatic elevations.

Diagnostic workup

Although the diagnosis may be clear from family history, DNA testing should be done on all patients for diagnostic confirmation, potential future genetic treatments, and family counseling; early identification of female carriers with consideration of prenatal diagnosis should be offered to the family (12).

Many patients have no previous family history. The percentage of patients presenting as isolated cases of Becker dystrophy is increasing with the increased use of genetic counseling and molecular diagnosis. Prognosis is more difficult in these cases and must rely on molecular tests. The majority of patients with Becker muscular dystrophy have deletion mutations of the DMD gene; about 80% of patients with Becker muscular dystrophy have deletions, even higher (92.6%) in more typical Becker muscular dystrophy phenotypes (14). Given the high incidence of deletions, it is typically more cost-effective to order DMD gene deletion testing first. There is significant clinical heterogeneity based on the deletion identified. Deletions of exons 45 to 57 seem to be associated solely with milder phenotypes and these patients tend to ambulate into their forties (14). Multiple exon (45-55) deletions have been described in a family with asymptomatic males between the ages of 5 and 69 years (23). A tendency toward earlier wheelchair dependence has been observed with distal exon deletions (83). Various deletions may also be associated with cardiomyopathy or lack of cardiomyopathy (32).

It is important to stress that not all patients with Becker muscular dystrophy have deletion mutations; many have smaller types of mutations including duplications and point mutations that cannot be detected by gene deletion testing. Molecular diagnostic tests including “next-generation sequencing” and other methods can directly detect nearly all mutations in the dystrophin gene and should be considered if initial deletion testing is negative. Depending on costs, these tests could also be considered for initial testing (88; 25; 51; 83).

In patients with high suspicion for Becker muscular dystrophy who test negative for a DMD gene mutation, it is important to test the status of the dystrophin protein in a muscle biopsy (43). This is rarely done in patients with a confirmed genetic diagnosis. Dystrophin levels less than 3% of normal or absent are generally considered diagnostic of Duchenne muscular dystrophy (36). Levels of 12% to 18% usually indicate a milder phenotype such as Becker muscular dystrophy (36).

Management

Glucocorticoid treatment. Mildly affected patients require little intervention, and the slowly progressive weakness may not alter their lifestyle. Corticosteroids in these mild patients are controversial due to side effects. Patients with Becker muscular dystrophy who show a clinical picture more similar to Duchenne muscular dystrophy, but with later onset and slower progression, may benefit from corticosteroids (03).

Bone health. More severely affected patients may also benefit from management of contractures or bracing, however, there is no clear evidence that modalities directed at maintaining ankle mobility have any long-term benefit (75).

Pulmonary management. Adult patients with Becker muscular dystrophy experience a significant but mild respiratory decline, which is more rapid and clinically relevant following the loss of ambulation (21). Proactive respiratory care has an important role in the management of patients in the advanced disease stage. Nocturnal respiratory assistance (Bi-PAP) and the use of cough-assisting devices improve survival and the quality of life (80).

Cardiac management. Cardiac monitoring should be done in all patients with Becker muscular dystrophy to include a screening electrocardiogram and echocardiogram at diagnosis and then at least every 2 years and a complete cardiac evaluation starting at 10 years with consideration of cardiac magnetic resonance imaging to evaluate for occult cardiomyopathy (09; 42). Cardiac magnetic resonance imaging is more sensitive in detecting early tissue fibrosis and should be used in place of an echocardiogram if available (32). Additionally, beta-blockers or angiotensin-converting enzyme inhibitors have been shown to prevent progression of myocardial fibrosis with normal ejection fraction (79).

Emerging treatments. Some experimental therapies (eg, gene therapy or stem cell transplantation) being developed for Duchenne muscular dystrophy may also be applied to Becker muscular dystrophy (10; 55).

Exon-skipping, which aims to transform the Duchenne muscular dystrophy phenotype into the milder Becker phenotype by restoring the DMD gene reading frame, has less of a role in mild Becker muscular dystrophy (28).

Special considerations

Pregnancy

Becker muscular dystrophy predominantly affects males. Most affected men are able to reproduce, and fertility is not affected. All daughters fathered by a Becker muscular dystrophy patient will be carriers. A Becker muscular dystrophy father does not transmit his dystrophin gene to his sons; thus, all sons will be unaffected.

In female carriers, either manifesting Becker muscular dystrophy or not, there is no reported increased risk during pregnancy, either to the mother or to the child.

Anesthesia

Patients are at increased risk of developing malignant hyperthermia on exposure to halothane anesthetics; thus, these should be avoided (11). In severe cardiomyopathy, a left ventricular device may be used for assisting non-cardiac surgery (87). Anesthesia by isoflurane has been reported to cause rhabdomyolysis and cardiac arrest (71).

COVID-19

Consensus guidelines for the care of patients with Duchenne muscular dystrophy during the COVID-19 pandemic have been published. Recommendations include continuing current corticosteroid regiments with potential dose adjustments should they become ill to prevent adrenal insufficiency and consideration of stress dose steroids in the setting of acute illness or hospitalization. Exon-skipping agents are encouraged to be continued. The risks and benefits of receiving these infusions during a pandemic should be discussed with the patient’s neurologist. It is recommended that angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prophylaxis or treatment of cardiomyopathy should be continued. Those with chronic respiratory insufficiency should be treated in collaboration with pulmonary or anesthesiology specialists and should not receive supplemental oxygen without ventilatory support. Finally, hydroxychloroquine has uncertain benefit and may cause skeletal or cardiac muscle damage (84). Thus, it should not be prescribed for this patient population.

In a small study of children with neuromuscular conditions and documented SARS-CoV-2 infection (n=29, five Duchenne muscular dystrophy/Becker muscular dystrophy subjects), 89% of patients were asymptomatic or had mild symptoms, including mild upper respiratory symptoms and fever (62). Ten percent of patients had moderate symptoms, including mild respiratory distress without respiratory decline. In a separate review of seven adults with Duchenne muscular dystrophy and SARS-CoV-2, no patients developed moderate to severe symptoms, and all patients with mild symptoms recovered without complication or hospitalization (72). These results indicate that young age may have a protective role, which outweighs neuromuscular risk factors, including reduced respiratory capacity. These findings may also indicate that the known SARS-CoV-2 variants may not be more life-threatening than other respiratory viruses in this population.