What is congenital muscular dystrophy?

Congenital means ‘from birth’ and as such individuals with congenital muscular dystrophy (CMD) usually have symptoms present at birth or in the first few months. There are at least 30 different types of CMD and each has a different genetic cause and a different range of symptoms, but they all primarily affect the muscles used for movement. The severity of CMD varies greatly from person to person.

Babies with congenital muscular dystrophy often appear “floppy” (this may also be described by doctors as having low muscle tone or hypotonia). Contractures (tightness) in the joints – the ankles, hips, knees and elbows – are also common. The contractures are sometimes severe and affect several joints. This is known as arthrogryposis.

Some types of CMD also affect the brain causing learning difficulties and sometimes seizures. Some babies may also have respiratory and feeding problems. In some children who do not have contractures, the first problems may only be noticed after a few months when the child does not reach their motor milestones at the same age as other children.

It is difficult to generalize about the progression of CMD as the different subtypes progress differently and also progression varies from person to person. However, the condition is usually considered fairly stable in terms of the muscle strength in the arms and legs, and often the child appears to gain strength in the first decade of life.  Some children will walk, but sometimes this can be delayed until five years of age or older and sometimes leg splints are needed. Some children who have achieved independent walking may lose this ability later on because, as they grow older and heavier, the muscles are unable to cope with a greater strain.

Children with all types of CMD have an increased risk of developing respiratory problems due to weak breathing muscles. The age when breathing problems may emerge and the severity varies from individual to individual. Therefore, careful monitoring and management of breathing is necessary. In some types of CMD heart problems can develop, especially LMNA related CMD and the dystroglycanopathies (see table below), so individuals diagnosed with these conditions need frequent monitoring of heart function and appropriate treatment.

It is estimated that approximately 1 baby in every 20,000 is born with congenital muscular dystrophy.

What are the different types of CMD?

The most common type of CMD is Ullrich CMD, followed by merosin-deficient CMD (MDC1A). Some of the more common types of CMD are listed in the table below.

Name

Gene/protein involved

Other names

Ullrich CMD and Bethlem myopathy

Collagen VI

Collagen 6 related myopathies

Merosin deficient CMD (MDC1A)

Laminin alpha 2

LAMA2-related muscular dystrophy

Congenital muscular dystrophy type 1C (MDC1C)

Fukutin-related protein (FKRP)

Dystroglycanopathy

Congenital muscular dystrophy type 1D (MDC1D)

Acetylglucosaminyltransferase-like
protein (LARGE)

Dystroglycanopathy

Fukuyama congenital muscular
dystrophy

Fukutin (FCMD)

Dystroglycanopathy

Muscle–eye–brain disease

POMGnT1, FKRP, FCMD

Dystroglycanopathy

Walker-Warburg syndrome

POMT1, POMT2, FKRP, FCMD

Dystroglycanopathy

SEPN1-related CMD

Selenoprotein N

Rigid spine muscular dystrophy, minicore myopathy

LMNA-related CMD

Lamin A/C

L-CMD, dropped-head syndrome

What causes CMD and how is it inherited?

CMD is caused by a change to a gene that contains the instructions for the construction of a protein that is essential for muscle health. In some of the conditions the protein that is affected has a structural role, for example, collagen and laminin which provide structural support to muscle cells.

Some types of CMD have been collectively termed ‘dystroglycanopathies’ (see table above) as they are all caused by defects in the process by which sugar molecules are added to a protein called ‘alpha-dystroglycan’. This protein forms an important link between the muscle cell and its surroundings. The addition of sugar molecules is required for alpha-dystroglycan to function effectively.

Most forms of CMD are inherited in an autosomal recessive pattern, which means that in order for a child to be affected, both parents must be carriers of the abnormal gene and both must pass this gene on to their child. Carrier parents have a 1 in 4 chance of having an affected child.

LMNA-related CMD, Bethlem myopathy and sometimes Ullrich CMD are inherited in an autosomal dominant pattern. 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 a child of an affected person inheriting the condition.

Soon after the diagnosis of CMD it is essential that genetic counselling is arranged. Genetic counselling provides information on the inheritance pattern, risks to other family members, and the ‘prognosis’ (likely outcome of the disorder). Genetic counsellors aim to help individuals, couples and families understand and adapt to the medical and psychological implications of the diagnosis of a genetic condition in their family. A genetic counsellor can also explain family planning options to reduce the risk of passing the condition on to future children. For more information on genetic counselling please see our genetics information page.

How is CMD diagnosed?

When doctors first notice that a baby or infant is floppy, a series of tests may be performed to try to make a precise diagnosis. Firstly, a blood test may be taken to measure levels of a muscle enzyme called creatine phosphokinase (CK). CK leaks out of damaged muscle and can be an indicator of several different types of muscular dystrophy.  In approximately 40 percent of babies with CMD, the CK level is between five and 20 times higher than normal.

An electromyography (EMG) test may also be performed, where a small needle is inserted into muscle and the electric activity recorded. This test may provide evidence of an abnormal pattern of electric activity in the muscle. This test is usually not necessary in children who have increased levels of CK in the blood. Scans of the brain and muscle may also be done to gather more information.

A muscle biopsy is almost always needed to narrow down the type of CMD. This is a surgical procedure in which a small sample of muscle is removed and examined. It is considered to be minor surgery, and is usually conducted as day surgery, under local or general anaesthetic. Diagnosis of CMD is made based on the appearance of the muscle cells under a microscope. Specific muscle proteins can also be studied under the microscope to try to identify the specific cause.

After a muscle biopsy, it may be possible for genetic testing to identify the causative gene and give a definitive diagnosis. This involves a blood test. Genetic testing is a process of elimination and it may take some time for the causative gene to be identified. It is also important to be aware that sometimes a genetic diagnosis cannot be reached.  Researchers are continually learning more about these conditions and the genetic causes though, so as time goes by more and more people will be able to gain a genetic diagnosis. Is there a treatment?

There is currently no specific treatment for CMD but there are many things that can be done to manage the symptoms. Children and adults with CMD should ideally be seen regularly in a specialist neuromuscular clinic, with access to physiotherapy, orthotic, respiratory, orthopaedic, spinal and genetic specialists as needed.

A guide for families called “The Management of Congenital Muscular Dystrophy (CMD)” is available for download which outlines the medical management recommended by a group of 82 international experts. In this guide you will find information on physiotherapy, respiratory and cardiac care, nutrition and feeding, orthopedics and neurologic management (including learning difficulties and seizures).

What research is being done?

Much of the research into congenital muscular dystrophy centres on understanding what genetic changes cause these conditions and the molecular processes that occur inside the body resulting in the symptoms. Advances in these areas have already led to the discovery of some potential therapies that are now in the early phases of testing.

Swiss pharmaceutical company Santhera announced in 2014 that it had started a clinical trial of a drug called omigapil in children with congenital muscular dystrophy (CMD). Omigapil is thought to work by preventing cells dying and testing in a mouse model of MDC1A has shown that it may be able to reduce the severity of symptoms. The study (called CALLISTO) involving children with Ullrich CMD and merosin-deficient CMD (MDC1A) is taking place in the USA. Further information about the trial is available on the clinicaltrials.gov website.

Another possible avenue being considered for the development of therapies includes drugs that reduce inflammation and ‘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. Corticosteroid drugs like prednisone, which have anti-inflammatory properties, have on occasion been given to patients with some types of CMD, and a clinical trial to test prednisone is being considered.

These approaches do not address the root cause of the condition so would only be able to slow down the progression of some of the symptoms. Ideally a treatment would result in correcting the genetic change. 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 CMD. Gene therapy studies using some of the CMD genes, such as the fukutin-related protein gene and the LARGE gene, are under way in laboratory mice.

Patient registry

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.

Further information

• Individual factsheets are available for the following types of CMD:

Clinical trials – your questions answered
• For definitions of any terms that you are not familiar with please take a look at our glossary
• US based organisation CureCMD is a useful source of information relating to all types of CMD
• 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 March 2015

References

The Management of Congenital Muscular Dystrophy (CMD): A guide for families, published in 2011.
Muscular Dystrophy UK Congenital Muscular Dystrophy factsheet:  reviewed, October 2013.
Susan Sparks et al. Gene Review: Congenital Muscular Dystrophy Overview.  Last Revision: August 23, 2012