Becker's Muscular Dystrophy

The muscular dystrophies (MD) are a group of inherited disorders characterised by progressive muscle wasting and weakness.¹

Becker muscular dystrophy (BMD) is a type of muscular dystrophy, originally described by Becker in 1955. It is inherited in an X linked recessive pattern. BMD is similar to the more common Duchenne muscular dystrophy, in that the distribution of muscle wasting and weakness is mainly proximal; but BMD runs a slower and milder course compared with Duchenne MD. Generally, walking difficulties begin after age 16.²

BMD usually carries a poor prognosis, with cardiomyopathy and death around age 40-50. However, there is wide variability in the time course and clinical severity of BMD, with individual case reports of subclinical disease, or people remaining well until later in life.²

Female carriers of BMD may be affected, either by some degree of muscle weakness, and/or they may develop cardiomyopathy, but at a later age than men with BMD.²

There is probably not much variation in incidence worldwide. It is about 1 in 30,000 male births (compared with about ten times that rate for Duchenne muscular dystrophy.) There may be some under-reporting of milder cases. About 50% of cases are familial, the other 50% being spontaneous mutations.^2,3

A unifying feature of the muscular dystrophies is the histology of muscle biopsies, which includes variations in fibre size, areas of muscle necrosis, and, ultimately, increased amounts of fat and connective tissue.¹

BMD is caused by abnormalities of the dystrophin gene, which produces a cytoskeletal protein named dystrophin, located in muscle fibres. In BMD, abnormal but partly functional dystrophin is produced (this contrasts with Duchenne MD, where dystrophin is lacking). Muscle biopsies show reduced intensity of dystrophin staining compared to normal in BMD muscle fibres, and absence of staining in Duchenne MD. It is not known exactly how the dystrophin abnormalities cause muscle weakness.¹

There are various gene defects which give rise to BMD, affecting different parts of the dystrophin gene. The clinical severity of BMD varies, and this is probably due to:

• Differences in the genetic defects, and the dystrophins thus produced
• Factors other than the dystrophin gene, which determine the severity of BMD in an individual. In one reported family, two brothers with an identical gene defect had very different clinical manifestations of BMD.²

Genetics of BMD

BMD is an X-linked recessive trait, therefore:

• Sons of carriers have a 50:50 chance of being affected. Daughters of carriers have a 50:50 chance of being carriers.
• The mothers and sisters of affected males may be carriers and may need to be tested. They are not necessarily carriers, because BMD can occur as a new mutation or through mosaicism (in the latter, only some cell lines are affected).
• The sons of affected males do not carry the gene and will not be affected or transmit the gene. However, all the daughters of affected males are carriers of the gene and may transmit the disorder.⁴

Symptoms

• The mean age of onset of symptoms is 11 years with a range of between 2 and 21 years. In contrast to Duchenne MD, most patients remain able to walk at age 16 or beyond.³
• There is often a history of delayed motor milestones for walking, running and jumping. The child may initially be labelled as "clumsy". Later, difficulty with climbing stairs or getting up off the floor may appear. Frequent falls or toe walking may be noticed.³
• Cramp on exertion may occur with myoglobinuria. The latter presents as dark urine after exertion. Exercise intolerance and recurrent myoglobinuria may be the only expression of BMD.²
• Subclinical BMD may present with features of cardiomyopathy in adulthood.²
• In one reported case, the patient had no symptoms, and a raised serum creatinine phosphokinase was the only manifestation of the disease.²
• There may be a family history of the condition - but not necessarily, as some cases arise from new mutations.

Signs³

• Muscle weakness in the proximal muscle groups (shoulders, upper arms, hips and thighs).¹
• There is no sensory loss or muscle fasciculation, which helps differentiate muscular dystrophy from neurological disease.
• As in Duchenne MD, there may be:
  • Pseudo-hypertrophy of the calf muscles - though weak, they are enlarged.
  • The Gower sign - patients 'climb up their legs' when rising from the lying position; this is due to weakness of the gluteal muscles and is not specific for muscular dystrophy.
• Signs of cardiac impairment may be present, or may be the only presenting feature.

Investigations³

• Serum creatinine kinase levels are raised (5-100 times normal levels).
• Muscle biopsy shows reduced dystrophin staining.
• Electromyography may be helpful, and may assist in identifying a suitable biopsy site.
• Cardiac investigations (such as ECG and echo) are required to assess the presence and severity of cardiomyopathy.
• Genetic counselling and DNA analysis (see below).

• Other muscular dystrophies: differentiation is by the clinical features such as age of onset and pattern of muscle weakness, by muscle biopsy features,¹ and by DNA analysis.
• Other myopathies, e.g. thyrotoxicosis, Cushing's syndrome.
• Neurological causes of muscle weakness: spinal cord lesions, spinal muscular atrophy, motor neurone disease, multiple sclerosis: these conditions may have additional features such as sensory loss, upper motor neurone signs or muscle fasciculation.

• Skeletal muscles:
  • Weakness can lead to joint contractures and scoliosis.³
  • Immobility has its own complications, such as constipation³ and osteoporosis.
• Cardiac complications⁵ are:
  • Dilated cardiomyopathy:
    • This can occur before the onset of skeletal muscle weakness.²
    • Female carriers may develop dilated cardiomyopathy without skeletal muscle weakness (see below).²
  • Arrhythmias
• Respiratory problems occur due to scoliosis, muscle weakness, aspiration pneumonia and cardiac failure.
• Dysphagia due to muscle weakness can occur late in the disease, causing problems of malnutrition and aspiration pneumonia.
• Anaesthetic:
  • Rhabdomyolysis, which may be fatal, is a recognised problem when patients with BMD undergo general anaesthesia.²
  • Succinylcholine chloride should be avoided as it may cause a hyperkalaemic response. Prolonged exposure to inhaled anaesthetic agents should also be avoided, because they may provoke a life-threatening hypermetabolic state similar to malignant hyperthermia.⁵
  • All patients should be monitored during surgery by measuring expired carbon dioxide concentration and body temperature.⁵
  • BMD patients may also be at higher risk from GA due to limited cardiac and respiratory function.⁵
• CNS: A higher than expected incidence of learning difficulty (IQ<75) and schizophrenia have been reported in some families. Possibly these are due to additional gene defects.²

There are no specific treatments for BMD, but many supportive treatments.

General health¹

• A well balanced diet with adequate fibre to overcome problems of constipation is important, especially when individuals become immobile and to prevent excessive weight gain.
• Prolonged bed rest should be discouraged because it can accelerate weakening of the muscles.
• Occupational therapists can advise about daily living aids.³

Muscle function¹

• Exercise: daily activity within the individual's limits should be encouraged, but strenuous exercise should be avoided. Supervised swimming is excellent exercise.¹
• Passive exercises help prevent contractures that result from immobility. These can be carried out by carers following physiotherapy advice.
• Lightweight polypropylene splints or orthoses, when used with appropriate surgical correction of contractures, can prolong ambulation. In the less severe forms of dystrophy such measures are particularly important in improving the individual's quality of life.

Cardiac screening and care

There are recommendations for cardiac management of BMD patients:⁵

• It is preferable to identify cardiomyopathy before it becomes symptomatic.
• BMD patients should have 6-monthly cardiology assessments from the age of 10 years, or as soon as the condition causes symptoms and signs.
• Standard tests such as ECG and echo may be difficult to interpret due to scoliosis, and specialized investigations may be needed.
• Clinicians should also be aware that typical symptoms of cardiac failure may go unrecognised, being ascribed to skeletal muscle weakness.
• Cardiac impairment and arrhythmias are treated in the standard way.
• If glucocorticoids given, blood pressure and weight gain should be monitored.
• Patients are at increased risk of thromboembolism; consider anticoagulation.

One study suggests that early treatment of cardiomyopathy, using ACE inhibitors and beta blockers, could be beneficial as it allows cardiac remodelling.⁶

NSAIDs should be used cautiously in BMD patients with cardiac involvement, after one case report of NSAIDs linked to (reversible) cardiac deterioration.⁷

Respiratory function¹

• It is important to preserve respiratory function, which may be compromised by immobility and the chest deformity that results from scoliosis.
• Influenza and pneumococcal immunization is advised.³
• All respiratory infections must be treated thoroughly, as soon as they occur, with postural drainage and antibiotics.
• The surgical correction of scoliosis makes sitting easier and more comfortable and also helps to preserve lung function.
• As the respiratory muscles become increasingly affected, assisted ventilation may be needed. In the late stages of the disease tracheostomy with artificial ventilation is an option. Increasingly, patients with severe neuromuscular disorders are managed this way.

Anaesthesia

Awareness of potential problems is essential (see above under complications); all BMD patients require expert pre-operative assessment.⁵

Dysphagia³

• In the late stages of BMD, dysphagia due to muscle weakness can occur, with the risk of aspiration pneumonia.
• Speech therapist advice, adjusting the food texture, and positioning can help.
• Gastrostomy may be needed.

Psychological and practical support

• Counselling may be helpful for the patient and their family.
• As in any long-term illness, support for the carers is important.

Genetic counselling

This is important for the patient and family:

• To establish the diagnosis (and distinguish it from other muscular dystrophies, some of which have a different pattern of inheritance).
• For the patient, to discuss the risk of transmission to his children.
• For the family, to determine the carrier status of the mother and female siblings. Despite the inheritance pattern of BMD, they will not necessarily be carriers because:
  • Many cases of BMD are new mutations rather than inherited.
  • Some cases of BMD involve mosaicism.

Genetic testing

Because BMD can be due to a variety of gene mutations, molecular genetic diagnosis is not a "one size fits all" DNA test. Instead, it is often necessary to know the specific gene mutation occurring in a family, usually accomplished by having first studied an affected male in the family.^1,8

Identification of carriers:

• Most carriers can be detected by DNA analysis, provided that samples from their affected male relatives and certain other key members of the family are available for comparison. Although the serum creatine kinase is positive in many carriers, only DNA studies can rule out the carrier state in a woman at risk.⁴
• However, a major problem in genetic counselling is that some mothers have transmitted a mutation to their offspring, which they themselves did not have in their somatic cells (in their peripheral blood leucocytes). This has been attributed to germline mosaicism. In this situation, subsequent pregnancies will need prenatal testing to identify affected sons.¹

The severity and course of BMD has a large variation. Some individuals and families have a milder form of BMD: for example, in one family who all had mild symptoms, one patient remained able to walk at age 61.² The usual course is:

• Onset of symptoms is usually at around 12 years.²
• Loss of walking ability usually begins around age 16 onwards.²
• Life expectancy is much reduced, with death usually age 40-50 years, due to cardiac or respiratory failure.⁵

Female carriers of BMD may develop clinical manifestations of the disease, namely, some degree of skeletal muscle weakness, and dilated cardiomyopathy. In one study:⁹

• 18% had an abnormal echocardiogram or ECG; 7% had cardiomyopathy by echocardiographic definition. Mostly, subjects with abnormal cardiac findings were asymptomatic, and often the measurements of left ventricular dimensions were only just outside the normal ranges.
• The prevalence of skeletal muscle weakness was 12%. It was usually mild and did not substantially affect activities of daily living.

The age of onset of clinically significant disease is unclear, but is thought to be in the adult years. The severity of cardiac involvement varies greatly, ranging from asymptomatic to severe heart failure necessitating cardiac transplantation. Recommendations are:⁵

• Carriers of BMD should be aware of cardiomyopathy and its symptoms.
• They should have an initial cardiac assessment in late adolescence; or at the onset of cardiac signs and symptoms, if these appear earlier.
• Carriers should be screened, with a complete cardiac evaluation, at least every 5 years starting at around age 25.
• Treatment of cardiac disease is similar to that outlined for boys with BMD.

Currently there is no specific treatments for BMD, but various strategies have been suggested: cell-based therapy using myoblast or stem cell transfer; pharmacological treatment with utrophin, a homologue of dystrophin; and gene therapy using viral vectors. Some research has been done in these areas.^10,11

Interestingly, there is one reported case of Becker muscular dystrophy coinciding with spina bifida. The muscle biopsy specimens of the patient showed dystrophic changes in upper extremities, but clearly less in lower extremities - in which the patient's mobility was limited due to spina bifida. This suggests that restriction of exercise might have a role in BMD.¹²