Central Core Disease
What is central core disease?
Central core disease (or CCD) is a rare condition and symptoms usually become apparent at during pregnancy, birth or early infancy. The condition is generally either slowly or non- progressive and individuals affected usually have a normal life span.
CCD gets its name from the abnormal cores that are found in the muscle cells and run the length of the muscle fiber. Visible only under a microscope, these cores appear empty, as if there is no metabolic activity (i.e. not producing energy). They also lack mitochondria, which are the ‘engines’ of the cell and are responsible for energy production (See diagram below).
The severity of the condition is difficult to predict as some people who have these ‘empty cores’ do not show symptoms. This suggests that there are also other unknown factors that play a role in CCD that are not currently understood.
What are the common features?
In most cases symptoms become apparent at birth or shortly after, and include hypotonia (floppiness) and weakness of the muscles closest to the trunk of the body. There is often a delay in achieving motor milestones, but the majority of people affected should eventually be able to walk. Muscle cramps are common and mild facial weakness has been seen in some cases, specifically involving the eyes. Weakness round the hips can lead to hip dislocations or tightening of the joints (contractures), particularly the knees and hips. Curvature of the spine (scoliosis) may also occur. Generally the heart and respiratory function are not affected.
The disease is characterized by abnormalities of skeletal (voluntary) muscle (congenital myopathy). Associated symptoms and findings may include abnormally diminished muscle tone (hypotonia), potentially resulting in unusual “floppiness” of muscles, delayed motor development, and muscle weakness. Hip displacement at birth is not uncommon. CCD primarily causes muscle weakness and cramps in the proximal regions of the body (legs and arms), but can also affect limb and facial muscles. The disease can be associated with a variety of orthopedic problems, which include hip dislocation, hip contracture, knee contracture, foot deformity, and scoliosis.
What causes it?
CCD occurs when there is a change in a certain gene that has been passed on from one or both parents to their child.
More specifically, there is a change in the gene that is responsible for the normal development of the ryanodine receptor (RYR1), which is located on chromosome 19. This gene is involved in calcium release in muscle. This is important because calcium is needed for the muscle to contract. However it is unknown at this time how this causes CCD. There are other genes that are associated with the RYR1 gene, which have been linked to the development of CCD, but again, their role in the condition is unknown.
One possible explanation for the development of the ‘empty core’ is a problem with the release of calcium when a muscle contracts. Usually, the nervous system sends a signal, causing a burst of calcium to be released, which makes the muscle contract. The calcium stays in the cell long enough to start a contraction and then drains out.
For patients with CCD, calcium leaks into the main part of the cell even when the muscle isn’t contracting. Because of this, there is less calcium available to provide the burst for the contraction. The constant presence of calcium may also destroy the mitochondria, thus creating the “empty cores” mechanism in the cell. However, at this stage, experts are still unsure if this is in fact the true cause of CCD. In many other families, the genetic cause has not been determined.
Inheritance of Central Core Disease
Central core disease is inherited in an autosomal dominant pattern or by an autosomal recessive pattern. Autosomal dominant involves although many cases occur sporadically, sometimes caused by recessive inheritance with no previous family history. Autosomal dominant inheritance means if a parent has the condition, there is a 50% chance that each child will have the condition also. Both parents can pass on this change in the gene, and both male and female children can be affected.
Are there other problems associated with CCD?
Malignant hyperthermia (MH) is an acute reaction triggered by certain general anaesthetics or muscle relaxants (which are used for general anaesthesia). Symptoms of MH include high fever, muscle rigidity, dark brown colouration of urine and acute kidney failure. MH is potentially fatal if not treated immediately with a drug called dantrolene. MH can be prevented by avoiding the triggering anaesthetic agents with alternative drugs. Local anaesthetics are quite safe. Both MH and central core disease are associated with abnormalities in the RYR1 gene thus it is important to inform the consultant surgeon or anaesthetist if surgery is being considered.
How is it diagnosed?
Diagnosis of CCD is obtained through a muscle biopsy or a genetic test. Symptoms of the disease may be noticed soon after birth.
Lab results that confirm the diagnosis include absent mitochondria in the centre of many type I muscle fibbers and increased urinary creatine. Muscle biopsy shows central cores within muscle fibbers; 20-100% of fibbers within a biopsy may have central cores, and within cores there is an absence of myofibrils (change in myosin ATPase), mitochondria (lack of oxidative capacity), and glycogen (lack of glycolytic capacity – phosphorylase). Serum shows normal CPK, and EMG produces non-specific findings.
- Muscle biopsy – Generally, diagnosis is made through a muscle biopsy. A sample of muscle is taken, and examined under a microscope. This is done in one of two ways: either a small piece of muscle is taken under general anaesthetic (avoiding the drugs which precipitate MH) or a needle biopsy is performed to remove a small sample.Muscle from people affected by central core disease has a distinctive pattern with core structures centrally located within the muscle cells. It is important to note that these structures are also seen in other, unrelated conditions. For this reason, the muscle sample must be considered along with the physical signs and/or molecular tests, in order for a diagnosis of central core disease to be made.
- Molecular testing – In families where the mutation is known to occur in the RYR1 gene, molecular testing is available. This involves taking a blood sample and analysing the DNA for the presence of a mutation. This process can take up to several months to complete.
What other tests are available?
Prenatal diagnosis is available for families where the mutation has been identified as being in the RYR1 gene. The technique is described in the section Molecular testing, but there are two ways to obtain samples for testing:
- Amniocentesis is performed from 15 weeks into the pregnancy. Using ultrasound to visualise, a needle is inserted through the abdominal wall, and a sample of the fluid surrounding the baby (amniotic fluid) is taken.
- Chorionic villus sampling (CVS) is carried out at 10 to 11 weeks. This involves taking a sample of tissue from the placenta. Results are available earlier using this technique than amniocentesis, but the rate of spontaneous miscarriage is slightly higher.
How will it progress?
Central core disease is generally thought to be non- or very slowly progressive. Sometimes progression is seen in adulthood, but some people actually show an improvement over time, with reduced weakness and increased mobility.
Is there a treatment?
There is no treatment for CCD, however, successful management requires a multidisciplinary approach involving paediatrics to promote ambulation; physiotherapy to monitor deformities; surgery to monitor and correct fixed deformities; genetic counselling; and prenatal diagnosis. CCD can be associated with susceptibility to malignant hyperthermia, a potentially life-threatening reaction to certain anaesthetics or skeletal muscle relaxants. Progression: Progression and severity of CCD are variable. Some children have difficulty learning to walk and usually exhibit some muscle weaknesses throughout their lives. Most children with CCD seem to improve as they get older and remain active throughout their lives, living a normal lifespan.
If a healthy diet and lifestyle are maintained, there is no reason why patients with CCD shouldn’t have a normal life expectancy and lead full active lives. As with many other conditions, education about CCD and local support groups can be the greatest tools for managing the disorder and preventing complications.
- Physiotherapy – The primary aim of an individual with a neuromuscular disorder is to increase or at least maintain function and mobility. Physiotherapy can assist in doing this, and it can also maintain breathing capacity, delay the onset of curvature of the spine (scoliosis), and help prevent the development of contractures. It is important that the physiotherapist involved is familiar with the treatment of people with neuromuscular disorders.
- Exercise – There is debate over whether people with neuromuscular disorders should undertake strenuous physical exercise. Some say that putting additional strain on already weakened muscles will cause additional harm, whilst others believe that the exercise may increase muscle strength. Insufficient evidence exists to support either, but it is believed that moderate non-weight bearing exercise such as swimming, walking or peddling may be the best solution. This sort of aerobic exercise helps to maintain a healthy cardiovascular system and a steady weight. It is however, important that this is discussed fully with a clinician.
- Corrective surgery – Scoliosis, or curvature of the spine, is common with central core disease. Spinal surgery aims to correct the posture by realigning the spinal column, and involves the insertion of rods, screws or wires. There are benefits and risks associated with this surgery, and more information is available from the Information and Advice Line. As with other treatments, it is very important that the options are discussed fully with a consultant or specialist, before a decision is made. In young children a spinal brace may be used and in children who do not walk moulded seating is used.
Is there a cure?
Currently there is no cure for central core disease although much research is being conducted into all of the neuromuscular disorders. Although there is no effective treatment, there are a number of different ways in which to manage the symptoms of central core disease and these are outlined above.
What research is currently being done?
Researchers world-wide are exploring many avenues in an attempt to develop more effective treatments and hopefully a cure. Muscular Dystrophy Association regularly monitors research advances in congenital myopathies, and produces releases, which are sent to members when significant scientific advances occur.
Planning for the future
Since central core disease is generally non- or slowly progressive, the needs of a person affected will not vary greatly over time. Depending on the severity of the condition there are things which may have to be considered. Some of these are listed below.
Other things to consider
- Anaesthetics and muscle relaxants – As mentioned, there is an association between central core disease and a condition called malignant hyperthermia, which is triggered by the administration of certain general anaesthetics and muscle relaxants. It is important that this is brought to the attention of the consultant and the anaesthetist if surgery is being considered.
- Medical alert card – It is very important that health professionals are aware of your condition should you require treatment. There are often issues they will have to consider. MDA can provide a Medic Alert Card, which can be carried to advise essential information. In the case of central core disease, the risk of malignant hyperthermia should be clearly displayed.