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Muscular Dystrophies:

BECKER

What is Becker muscular dystrophy?
There are many types of muscular dystrophy (MD), all are genetic conditions that cause the muscles to weaken and waste away to varying degrees. Becker MD is a milder, more slowly progressing variant of the better known Duchenne type of MD. Like Duchenne MD it only affects males (with very rare exceptions).

What causes Becker muscular dystrophy?
Becker muscular dystrophy is caused by an error in the dystrophin gene. This gene contains the instructions for the construction of dystrophin protein. The dystrophin protein normally protects muscle fibres during muscle contraction.
In the muscles of boys with Duchenne MD there is no dystrophin protein or it does not function at all. However, in Becker MD the dystrophin protein is less abundant than normal or is a different size but is still able to work to some extent. This results in the muscle fibres gradually becoming damaged and the muscles slowly become weaker.

What are the symptoms?
The average age of diagnosis of Becker MD is 11 years but the range is very wide - sometimes the diagnosis may be made in early childhood or well into adult life. Muscle loss usually begins with the hips and pelvic area, the thighs and the shoulders. To compensate for weakening muscles, the person may walk with a waddling gait, walk on his toes or stick out the abdomen.

Symptoms usually begin very mildly in childhood; often cramps when exercising are the only problem at first but a few affected boys are late in learning to walk. Most people with Becker MD are not very athletic in childhood, and many struggle with school sport.

Later, in the teens or twenties, muscle weakness becomes more evident causing difficulty in rapid walking, running and climbing stairs. Later still it may be difficult to lift heavy objects above waist level.

The severity of symptoms can vary widely - some men require wheelchairs by their 30s or later, while some manage for many years with minor aids, such as canes.

Typically men with Becker MD become unable to walk in their 40s or 50s or even later, but sometimes progression is more rapid and this may happen in the 20s or 30s. Over a period of many years some muscles become weak and wasted, especially certain muscles of the shoulders, upper arms and thighs, while others that are less weak are often enlarged - this is usually particularly noticeable in the calf muscles.

Becker MD is usually not painful, except for occasional muscle cramps. The muscles of facial expression, speech and swallowing and the involuntary muscles (for example those of the bowel and bladder) are not affected in Becker MD.

It is important to be aware that people with Becker MD often have problems with their heart and in the long term with the breathing muscles. These often do not cause any symptoms at first, and watching out for these problems, which can often be treated, is an important reason to keep in touch with a specialist clinic.

How is Becker MD diagnosed?
In diagnosing any form of muscular dystrophy, a doctor usually begins by taking a patient and family history, and performing a physical examination. Tests will be done to determine if patient’s weakness results from a problem in the muscles themselves or in the nerves that control them. Doctors often order a special blood test called a CK level. CK stands for creatine kinase, an enzyme that leaks out of damaged muscle. When CK levels are high it is an indication that the muscle weakness might be due to a type of muscular dystrophy.

To obtain a definite diagnosis, DNA testing of the dystrophin gene is done from a blood sample. In many cases, the DNA test alone can tell families and doctors with a fairly high degree of certainty whether the disease course is more likely to be Becker or Duchenne MD.

How common is Becker MD?
Information about the incidence and prevalence of the different types of muscular dystrophy is scarce. Statistics that have been reported range from 1 in every 18,000 to 1 in every 31,000 boys born having Becker MD.

By comparison, Duchenne MD affects about 1 in 3,500 male births.

How is Becker MD inherited and what does this mean for the rest of the family?
For the majority of cases, Becker MD is inherited in a pattern called “X-linked recessive”. This means that it is passed down by unaffected female carriers to their sons. The sons of carriers each have a 50:50 chance of being affected. The daughters of carriers each have a 50:50 chance of being carriers.

The sons of men with Becker MD do not inherit the gene mutation and will not be affected or pass the gene onto their children. However, all the daughters of men with Becker MD are carriers and may transmit the disorder to the following generation.

Some people with Becker MD do not inherited the condition from their parents. This is called a spontaneous mutation and arises because a random error occurs in the DNA of the egg or embryo in very early life.

After a confirmed diagnosis of Becker MD, genetic counseling can be arranged for the family. Genetic counseling provides information on the inheritance pattern, risks to other family members, and the ‘prognosis’ (likely outcome of the disorder). The mothers and sisters of affected males may be carriers and may wish to be tested.

For more information about inheritance please read this booklet on Genetic Counselling.

Is there a cure?
Unfortunately there is no cure at present but there is much that can be done to manage the condition and research is proceeding to try to find an effective treatment (please see below).

What can be done to manage the condition?
Regular exercise can help build muscle, keep the cardiovascular system healthy and contribute to feeling better. Consult with your doctor about how much exercise and what type is best. Swimming and hydrotherapy are often good forms of exercise. Cramps during exercise can bother people with Becker MD at some stage – often especially as a teenager. If they are very troublesome it may be worth experimenting with ‘night splints’ (plastic splints to maintain a gentle stretch of the calf muscles overnight) or with sessions of calf muscle massage.

Physiotherapy is recommended to promote mobility and prevent contractures. Contractures are a shortening of the muscle and tendon which causes discomfort and restricts mobility and flexibility. Exercises will also be prescribed to do at home and braces on the lower legs may also help some people. When contractures have advanced, surgery may be performed to relieve them.

A wheelchair or scooter is likely to be needed eventually at least for getting about independently over long distances. There is other equipment that may be useful and much can be done to help both at home and at work to make certain tasks easier. An occupational therapist can help to get these measures in place.

No special diets or supplements are known to help in Becker MD however the diet should be high in fluid and fibre to help prevent constipation and it is advised to keep an eye on weight gain especially if mobility is restricted.

A few boys with Becker MD have learning problems, usually of a mild degree but it may cause some problems at school. If this does happen it is important to recognise this and get the right educational help.

People with Becker MD may have unexpected adverse reactions to certain types of anesthesia. It is therefore important that the surgical team is informed so that complications can be avoided or quickly treated.

Cardiomyopathy (deterioration of the heart muscle) is common in Becker MD. It is recommended that beginning at the age of 10 cardiac check-ups should be done every year. Medications that lessen the workload on the heart are sometimes prescribed. Carriers of Becker MD are at increased risk of developing cardiomyopathy too.  Carriers should undergo a complete cardiac evaluation in late adolescence or early adulthood, or sooner if symptoms occur, and should be evaluated every five years starting at age 25 to 30.

As some people with Becker MD get older the breathing muscles can weaken to an extent where some help with breathing may be necessary. This involves a non-invasive ventilation mask, usually just at night. Coughing muscles also can become weak, allowing mucus to build up in the respiratory tract, which can lead to obstruction and infection. A device known as a CoughAssist can help with this problem.

Corticosteroid medication has been found to help boys with Duchenne MD to remain walking for several years longer on average. There isn't any information available on whether corticosteroids are helpful for Becker MD, however, some doctors prescribe corticosteroids for more severe cases of Becker MD after carefully considering the risk of side effects.

What research is being done?
Utrophin

It is thought that utrophin, a protein naturally present in our body in small amounts, may be able to compensate for the lack of dystrophin in boys with Duchenne and Becker MD since both proteins are structurally similar and appear to have very similar functions.  Research in mice and dogs lacking dystrophin has shown that increasing the levels of the utrophin protein can prevent muscle damage. Professor Dame Kay Davies' laboratory at the University of Oxford has been researching utrophin for more than 25 years. In recent years, in collaboration with Oxford biotechnology company Summit plc, they found a promising drug - called SMT C1100 - that was able to increase the amount of utrophin in a mouse model of Duchenne MD.  SMT C1100 is now in the early stages of clinical trial – it has been tested in a phase 1 trial in healthy volunteers and a phase 1b trial started in December 2013 to test the drug in 12 boys with Duchenne MD. This trial will further test the safety of the drug and determine the dose to be used in a larger trial. More information is available on the Summit plc website.

Better care for the heart
A lot of Becker MD research centres around optimal treatment of the cardiomyopathy that causes major problems for these patients. Researchers are trying to find best combination of the available drugs and when the optimal time to start treatment is. Scientists are also searching for new drugs to treat the heart.

Increasing blood flow
Experiments have shown that when dystrophin is missing from the muscle, blood vessels supplying muscles do not adequately dilate during exercise, resulting in muscle fatigue and weakness. Clinical trials of blood vessel dilating drugs that are typically prescribed for erectile dysfunction or pulmonary hypertension have already been conducted for Becker MD. A trial of sildenafil (Viagra) was suspended in 2013 due to a negative impact on heart function. A trial of tadalafil (Cialis) showed that the drug was able to restore proper blood flow in eight out of nine trial participants. In the trial they measured forearm muscle oxygenation levels while patients performed handgrip exercises. This is encouraging but more research is needed before recommending tadalafil for patients with Becker MD. Longer term studies are being planned to determine if correcting muscle blood flow leads to improvements in symptoms for people with Becker muscular dystrophy.

Myostatin
Another strategy for the development of a treatment for Becker MD is to boost muscle growth. One way to do this is to interfere with the mechanisms naturally present in the muscle that put the brakes on muscle growth so that muscles remain within the normal size range. This involves a protein called myostatin which inhibits muscle growth when it binds to certain receptors on the muscle. Interfering with this process could result in increased muscle growth and strength.

One trial has already been conducted using this approach. An antibody called MYO-029 was used to attempt to block myostatin in people with Becker, limb-girdle and facioscapulohumeral muscular dystrophy. This small trial showed some small increases in muscle mass in some of the trial participants but no increase in strength was seen. It was commented that more powerful myostatin inhibitors are required and work is ongoing to develop new drugs.

Researchers in the USA are aiming to inhibit the myostatin mechanism using a form of gene therapy. It involves increasing levels of a protein called follistatin which is a natural inhibitor of myostatin. A harmless virus is used to deliver the follistatin gene inside muscle cells and these instructions are used to make the follistatin protein. A phase 1 clinical trial is underway to test this in people with Becker muscular dystrophy and another muscle condition called inclusion body myositis. More information about the follistatin trial.

Steroid drugs
Steroids such as prednisolone are currently the only medications proven to slow down the progression of muscle weakness in Duchenne muscular dystrophy. However, they are not usually prescribed to people with Becker MD because it is thought that the benefit would not outweigh the risk of detrimental side effects which can be very serious, including weight gain, mood changes, stunted growth, fragile bones, cataracts, high blood pressure, diabetes and increased chance of infections.

Researchers in the USA have discovered a drug that is similar to prednisolone which does not seem to cause the worrying side effects when tested in mice. Consequently it be might be useful to treat more mild forms of muscular dystrophy like Becker MD and could replace the steroids currently used to treat Duchenne MD. In studies in mice the drug – called VBP15 – worked better than prednisolone without the harsh side effects. Clinical trials of VBP15 are being planned with an expected start date in 2014.

You can read more about this steroid research on the MDA website.

Reducing inflammation
Research that aims to reduce inflammation in the muscles and improve muscle regeneration, such as the research MDA funds, may also lead to the discovery of a treatment to help reduce the severity of muscle weakness in Becker MD. You can read more about this research on the MDA website.

Ataluren
Ataluren (previously called PTC124) is an oral drug that targets a specific type of mistake in the genetic code, called a nonsense mutation. This is when a stop signal is present part way through the gene. Ataluren encourages the cell to ignore this stop signal and continue to read the full set of instructions contained within the gene. A very small proportion of individuals with Becker MD have this type of mutation. Ataluren has been tested for Duchenne MD in a phase 2b clinical trial which showed that it may be able to slow down the rate of decline in walking ability. A larger phase 3 trial is underway to confirm these results prior to applying for the drug to be approved for sale. Although men and boys with Becker MD caused by a nonsense mutation are unable to take part in the clinical trials, if this drug is approved for sale it may become available for them.

The improvement seen in the ataluren phase 2b trial was quite small, so the search is on to also find drugs with a similar mode of action that are more effective.

Stem cells
Although no proven stem cell therapy is currently available for muscular dystrophy, research is ongoing in the laboratory. Read more about stem cell research here:
• Cell therapy research overview on the TREAT-NMD website
• Scientists, clinicians and MDA urge caution over stem cell “therapies”

NOTE: Research is moving forward at a fast pace, so this research summary may not be up-to-date at the time of reading. Feel free to contact MDA's Scientific Communications Officer for an update on the latest developments - kristina.elvidge@mda.org.au

Further information

  • MDA has a portal called MD-NET for information relating to Duchenne MD which contains a lot of information that is also relevant to Becker MD.
  • OMIM is a continuously updated catalog of human genes and genetic disorders and traits. It is written in technical language 
  • Clinical trials - your questions answered
  • Find out about patient registries
  • You can get regular updates by becoming a friend of the MDA Facebook page.

If you have any questions, please contact us:
Phone: (03) 9320 9555

Click here for PDF version

Revised and uploaded 14 April 2014


 


 

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