What is Bethlem myopathy?
Bethlem myopathy is a hereditary muscle disorder, which is named after the Dutch doctor who first described the condition in 1976. People with this condition experience slowly progressing muscle weakness and develop joint stiffness (contractures) in their fingers, wrists, elbows, and ankles that can restrict movement. There is a wide range of severity and symptoms can appear at any age.
Bethlem myopathy falls under the category of congenital muscular dystrophies (CMD). It is caused by a change in one of the collagen VI genes. Another more severe muscle condition called Ullrich CMD is caused by different changes to the same genes and collectively they are known as the collagen VI-related myopathies.

In this factsheet:
• What are the symptoms of Bethlem myopathy?
• What causes Bethlem myopathy?
• How is Bethlem myopathy diagnosed?
• Is Bethlem myopathy inherited?
• Does the condition get worse?
• Is there a treatment or cure?
• What can be done to manage the condition?
• What research is being done?
• Further information

What are the symptoms of Bethlem myopathy?
The first symptoms of Bethlem myopathy can present at any time from birth through to adulthood and are very variable. In childhood these symptoms can be hypotonia (floppiness), joint laxity (double-jointedness), muscle weakness, delayed motor milestones (for example when a baby first sits up unaided or learns to walk), talipes (clubfoot), torticollis (stiff neck) and contractures (tightness) in the ankles, hips, knees and elbows. The contractures are often quite variable and can come and go over time. Some stiffness of the spine can also develop over the years.

Adults with Bethlem myopathy can have tight tendons at the back of their ankles, as well as tightness of various other joints (elbows, knees, joints in the back) and especially some of the muscles in the hands. Other symptoms such as poor stamina/poor exercise tolerance and difficulties walking upstairs or doing tasks which require lifting the arms above the head are related to the subtle muscle weakness that tends to go with Bethlem myopathy.

The muscles used for breathing are only mildly affected, and breathing problems are very rare and limited to the late adult years. The heart, although a muscle, is usually not affected by Bethlem myopathy.

Collagen VI is also found in the skin and consequently the skin of some people with Bethlem myopathy has an unusual appearance. Especially over the outer surfaces of the arms and legs it can feel rough or dry to touch which is called ‘keratosis pilaris’. Others might find that they scar in an unusual way, either by forming keloids (raised, rather angry looking scars) or thin silvery “cigarette paper scars”.

What causes Bethlem myopathy?
Bethlem myopathy is caused by a change in one of the collagen VI genes (which are called COL6A1, COL6A2 and COL6A3). This results in either the production of abnormal collagen VI protein or reduced levels of collagen VI protein in the body. Collagen is the main protein of connective (supporting) tissue in the body and provides support for the muscle cells. The exact mechanisms how these genetic changes lead to the disease are not fully understood but the muscle cells of people with Bethlem myopathy are more sensitive to cell death and there might be a change in the energy supplying parts of the cells called mitochondria.

How is Bethlem myopathy diagnosed?
The diagnosis of Bethlem myopathy is usually suspected from the medical history and examination. The specific diagnosis however is generally made by looking at a piece of muscle or skin (muscle and skin biopsy).

Before doing a muscle biopsy (which involves taking a small piece of muscle, usually from the thigh) a few other tests may be done. One of these tests is a blood test, which measures the level of a muscle protein (creatine kinase or CK). The levels of this protein in the blood are only slightly raised in Bethlem myopathy. Muscle ultrasound may also help to detect changes in the muscle. The technique is very simple, similar to the ultrasound studies carried out in pregnancy and may provide further evidence of the involvement of the muscle. These tests provide a broad indication that there is a muscle condition but cannot pin-point the precise diagnosis.

Muscle biopsy can provide a precise diagnosis in two ways:

1. Signs which might indicate a muscle condition can be observed through the microscope. The muscle fibres of people with muscular dystrophy are not evenly sized and some of the fibres are replaced by fat and fibrous tissue.
2. It is also possible to assess the amount of collagen VI protein present in the muscle under the microscope using specific stains that highlight the presence of this protein.

As collagen VI is normally present both in muscle and skin, taking a small piece of skin (skin biopsy) can also help to confirm the diagnosis. In some cases it is easier to detect a reduction of collagen VI on skin cells than on muscle cells. Taking a piece of skin however cannot provide some of the information that a muscle biopsy can and it is therefore important to have both muscle and skin biopsies to obtain all the information needed.

Genetic tests looking for abnormalities in one of the three genes responsible for Bethlem myopathy are now available and provide the ultimate diagnosis.

Other tests may also be performed because Bethlem myopathy can initially appear like other neuromuscular conditions. These tests may include electromyography (EMG) and nerve conduction velocity (NCV) which determines if it is the nerves or the muscles that are the cause of the weakness.

Is Bethlem myopathy inherited?
Bethlem myopathy is usually inherited in what is known as an “autosomal dominant” way. This means that one copy of the altered gene, inherited from either parent, is sufficient to cause the disorder. There is a 50 percent (one in two) chance of the children of a person affected by Bethlem myopathy inheriting the condition.

Some people are diagnosed as having Bethlem myopathy and neither of their parents seems to be affected. In this case, the parents may be so mildly affected that they don’t realise they have the condition. Alternatively, the fault in the gene may have arisen for the first time in the affected person. These people may still pass the altered gene onto their children.

Occasionally Bethlem myopathy is inherited in an “autosomal recessive” way which means that two copies of the altered gene are inherited – one from each parent.

All families affected by Bethlem myopathy should be referred for genetic counseling. Genetic counseling provides information on the inheritance pattern, risks to other family members, and the ‘prognosis’ (likely outcome of the disorder).

Does the condition get worse?
For most patients with Bethlem myopathy the weakness and contractures are known to get worse over the years, however, this usually only happens very slowly. Whereas some adults remain unaware of any muscle weakness and only have very slight contractures which do not pose them any mobility problems, others need to make use of equipment to remain mobile. About two thirds of adults with Bethlem myopathy over the age of 50 need aids to help movement (i.e. cane, crutches or wheelchair) outside the house and some might also experience breathing problems for which they require treatment.

Is there a treatment or cure?
At the moment, there is no cure, nor any specific drug treatment for Bethlem myopathy. However, there are ways, described below, of helping to alleviate the effects of the condition and to prevent complications from occurring.

What can be done to manage the condition?
The muscle clinic will keep a close eye on mobility and joints and work with the local physiotherapy team. Physiotherapy will involve a programme of exercises to stretch tight joints, help to maintain suppleness and keep the muscles flexible.

Occasionally surgery to release the Achilles tendon can help a person with Bethlem myopathy to stand and walk more easily. Children and adults with Bethlem myopathy are encouraged to remain as active as possible and ensure that they do not become overweight, so that the strain imposed on their muscles is kept to a minimum.

Although breathing is rarely affected in Bethlem myopathy, the muscle clinic may recommend breathing tests to monitor the strength of the breathing muscles. In some cases overnight sleep studies may be required. It is also worth being aware of the early signs of breathing difficulty which might only occur at night. These signs include frequent chest infections, daytime sleepiness and morning headaches. If a breathing problem is detected a non-invasive ventilator device can be used, which is usually only needed at night. People with Bethlem myopathy can be prone to chest infections if their cough is not strong due to weakness of their breathing muscles. It is therefore recommended that the flu and pneumococcal vaccines are given to people with respiratory weakness and that any respiratory infections are promptly treated.

Constipation, possibly due to the fact that a person is not very active, can be a problem. This can be treated by a high fibre diet, drinking plenty of fluids and very occasionally by laxatives.

The MDA can give support and information to schools and other professionals where this is needed to be sure that a person with Bethlem myopathy is getting the help he or she needs.

What research is being done?
In recent years researchers have discovered a lot about what is happening inside the cells of people with Bethlem myopathy (and the related condition Ullrich CMD). One of the findings is that structures in the cells called mitochondria – which are the ‘batteries’ supplying energy – are not functioning correctly. This has led to several drugs that work on the mitochondria being tested in animal models of the conditions. Two drugs have shown promise – omigapil and Debio 025.

A company called Santhera is planning a clinical trial of omigapil to be conducted in the USA. This trial will involve children with CMD, including Ullrich CMD. If the drug proves to be beneficial in this patient group it may be tested for other muscle conditions such as Bethlem myopathy.

Debio 025 has been shown to restore mitochondrial function in muscle cells of patients grown in the laboratory and in a mouse model. Plans for a clinical trial in people with Bethlem myopathy or Ullrich CMD have not been announced.

Another possible avenue being considered for the development of therapies includes drugs that reduce ‘fibrosis’ or scarring in the muscles which is thought to be a major contributor to the muscle weakness in CMD. Losartan, a commonly prescribed medication for high blood pressure, is one possible candidate for testing in clinical trial as it has been shown to reduce fibrosis in mouse models of CMD.

These approaches that target the mitochondria and fibrosis do not address the root cause of the condition so would only be able to treat some of the symptoms of the condition. Ideally a treatment would result in the production of properly functioning collagen in the body. Gene therapy to correct genetic mutations is being researched for other genetic conditions including muscular dystrophy and if these prove to be successful it may be possible to apply this technology to the development of treatments for Bethlem myopathy and Ullrich CMD.

You may be interested in registering with the Congenital Muscle Disease International Registry (CMDIR). This is a patient registry: a database that contains information about patients with a particular condition. Clinical trial organisers and other researchers use this (anonymous) information to learn more about the conditions and plan clinical trials. If a clinical trial were to start the registry would be used to contact suitable potential participants and invite them to take part. Patient registries are also a useful source of information for patients and their families as regular newsletters are sent out. You can find out more about patient registries on our website.

NOTE: Research is moving forward at a fast pace, so this research summary may not be up-to-date at the time of reading.

Further information
Clinical trials – your questions answered
• Read about the research MDA funds which aims to reduce inflammation in the muscles and improve muscle regeneration
• For definitions of any terms that you are not familiar with please take a look at our glossary
• You can get regular updates by becoming a friend of the MDA Facebook page

For further information on any of the areas discussed above, please contact MDA:
Phone: (03) 9320 9555
Email: info@mda.org.au

Revised and uploaded 20 May 2014.

References
Lampe AK, Bushby KM. Collagen VI related muscle disorders. J Med Genet. 2005 Sep;42(9):673-85.
Bushby KM, Collins J, Hicks D. Collagen Type VI Myopathies. Adv Exp Med Biol. 2014;802:185-99.