What is Congenital muscular dystrophy with collagen VI deficiency?

                                  
Congenital muscular dystrophies (CMD) are a group of hereditary disorders, frequently presenting at birth or within the first six months of life. There are many different forms of CMD and each form is caused by a specific defect in a gene. All forms of CMD share some symptoms and signs; such as weakness and degeneration of muscles, contractures and joint deformities. Usually CMD leads to difficulty in movement, skeletal deformation (scoliosis) and respiratory failure. Mental retardation is sometimes present.

Congenital muscular dystrophy with collagen VI deficiency (Ullrich congenital muscular dystrophy and Bethlem Myopathy) is caused by a defect in one of the collagen VI genes. 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 defects lead to the disease are not fully characterized but the muscle cells of the patients are more sensitive to cell death and there might be a defect in the energy supplying parts of the cells called mitochondria. Bethlem myopathy represents a milder variant of Ullrich congenital muscular dystrophy.

Congenital muscular dystrophy with collagen IV deficiency spectrum
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Mild end of spectrum
Bethlem Myopathy

Severe end of spectrum
Ullrich congenital muscular dystrophy


Although both Bethlem and Ullrich are a part of the same spectrum, the information will be broken up into each subtype.

 

Bethlem Myopathy – Mild form (BM)

How does the disease present?

First symptoms of BM can present at any time from birth through to adulthood and are very variable. In childhood these symptoms can be hypotonia (floppiness), 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. Adults with BM 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.

In addition, the skin of some people with BM can be unusual. Over the outer surfaces of the arms and legs especially it can feel rough or dry to touch and has been described as looking like “plucked chicken skin”. Other patients might find that they scar in an unusual way, either by forming keloids (raised, rather angry looking scars) or thin silvery “cigarette paper scars”.

How is Bethlem myopathy diagnosed?

The diagnosis of BM is usually suspected from the 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 out 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) that however is generally only mildly raised.

Muscle ultrasound may also help to detect abnormalities 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 problem but cannot pin-point the precise diagnosis.

Muscle biopsy can provide a precise diagnosis in two ways:

1. When the muscle is studied under the microscope, it is possible to look for signs, which might indicate a muscle problem. In children with a muscular dystrophy the muscle fibres, instead of being evenly sized, show a great variation and some of these fibres are replaced by fat and fibrous tissue.
2. It is also possible to look at the presence of collagen VI in the muscle under the microscope. There are specific ‘tags’ which can interact with collagen VI and detect whether collagen VI is normally present or reduced. A reduction in collagen VI in a patient with evocative clinical features strongly suggests the possibility of BM.

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 one can achieve with a muscle biopsy 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 BM are now available and provide the ultimate diagnosis.

Is Bethlem myopathy inherited?

BM is inherited in what we call an autosomal dominant way. This means that there is a 50% (one in two) chance for the children of a person affected by BM to inherit the faulty gene and be affected by BM themselves. This is independent of how mildly the parent might be affected. Sometimes when people are diagnosed as having BM, neither of their parents seems to be affected. In this case the fault in the gene may have arisen for the first time in the affected person, which is quite a common situation.

Are patients at risk from developing any complications?

The main complications we look out for at the regular check ups in the muscle clinic are contractures (muscle tightness causing restriction in the range of joint movement) and chest problems. People with BM can be prone to chest infections if their cough is not strong due to weakness of their breathing muscles and in some cases overnight sleep studies may be required to assess breathing. From what we know so far the heart, although a muscle, is usually not affected by BM.

Does the condition get worse?

For most patients with BM 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 functional problems others need to make use of practical home aids to work around their muscle weakness and contractures. A proportion of adults over the years might need aids to help movement (i.e. cane, crutches or wheelchair) outside the house and 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 help can be offered?

Physiotherapy is one of the main forms of help. A programme of exercises is usually worked out with a physiotherapist at the time of the diagnosis to stretch tight joints and help to maintain suppleness and keep the muscles flexible. We keep a close eye on mobility and joints and we do this in conjunction with the local physiotherapy team as well as through regular check-ups at the muscle clinic.

Occasionally surgery to release the Achilles tendon can help a person with BM to stand and walk more easily. Children and adults with BM 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. People with BM can have chest problems if their cough is not strong. In our muscle clinic we routinely keep a close eye on things by doing specific breathing tests. Where there may be a problem, we will recommend the flu and pneumovax immunisations. It is also important, that every chest infection is treated promptly with antibiotics.

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. We will be able to give support and information to schools and other professionals where this is needed to be sure a person with BM is getting the help he or she needs. Our specialised family care officers can help to liaise between the various professionals, e.g. physiotherapists, occupational therapists, social workers and teachers and may also be able to put you in touch with like-minded people in similar positions.

Ullrich congenital muscular dystrophy – Severe form (UCMD)

What is Ullrich congenital muscular dystrophy?

Ullrich congenital muscular dystrophy (UCMD) is a form of congenital muscular dystrophy with specific features:

  • Children are often double jointed in their hands and feet but have some tightness in other joints such as elbows or hips.
  • They have rigidity (stiffness) of the spine.
  • Children tend to develop respiratory problems, which result in frequent chest infections and might require ventilatory support at night.

The genes responsible for Ullrich congenital muscular dystrophy have recently been identified and lie on chromosomes 21 and 2. These three genes are responsible for the production of the protein collagen VI.

What are the first signs?

Babies with Ullrich congenital muscular dystrophy often have hypotonia (low muscle tone or floppiness), and may have reduced movements. Other common signs are hip dislocation and a stiff neck (torticollis) and contractures (tightness) in the hips, knees and elbows. Some of these babies may also have feeding problems, which improve after a few weeks or months.

Sometimes the first signs are only noted after a few months when babies are observed to have poor head control or have a delay in learning new skills such as sitting unaided, crawling or walking.
Is Ullrich congenital muscular dystrophy inherited?

Yes. The pattern of inheritance is known as ‘autosomal recessive’. This means that both parents are carriers of the condition (although clinically unaffected) and they have risk of 25%, or a one in four chance in each pregnancy, of passing the condition on to their children.

Occasionally a case may be ‘sporadic’ which means is a one-off with little risk of recurrence in other children. However, the risk of recurrence in the offspring of these sporadic cases can be significant. All families with Ullrich congenital muscular dystrophy should be referred for genetic counselling.
How is Ullrich congenital muscular dystrophy diagnosed?

The diagnosis of Ullrich congenital muscular dystrophy is usually suspected from the 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 out 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) that however is generally only mildly raised.

Muscle ultrasound may also help to detect abnormalities 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 problem but cannot pin-point the precise diagnosis.

Muscle biopsy can provide a precise diagnosis in two ways:

1. When the muscle is studied under the microscope, it is possible to look for signs, which might indicate a muscle problem. In children with a muscular dystrophy the muscle fibres, instead of being evenly sized, show a great variation and some of these fibres are replaced by fat and fibrous tissue.
2. It is also possible to look at the presence of collagen VI in the muscle under the microscope. There are specific ‘tags’ which can interact with collagen VI and detect whether collagen VI is normally present or reduced. A reduction in collagen VI in a patient with evocative clinical features strongly suggests the possibility of Ullrich congenital muscular dystrophy.

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 one can achieve with a muscle biopsy 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 Ullrich congenital muscular dystrophy are now available and provide the ultimate diagnosis.
Prenatal diagnosis

Prenatal diagnosis is a promising development in the diagnosis of inherited conditions. It is based on the ability to detect the abnormality in the developing foetus. In families who have a child with Ullrich congenital muscular dystrophy who decide to have another baby it is possible to detect whether the baby has deficiency of collagen VI and/or the same gene defect early in pregnancy.
Is there a treatment or a cure?

At the moment there is no cure for Ullrich congenital muscular dystrophy, but there are ways, described below, of helping to alleviate the effects of the condition.
Can a child with Ullrich congenital muscular dystrophy learn to walk?

The severity of this condition varies greatly from person to person. Some children will walk but sometimes this can be delayed. Children who have successfully walked may lose the ability later on because as they grow taller and heavier, their muscles are unable to cope with a greater strain. Leg splints (callipers) are often used to assist the child to walk.

Other children never achieve the ability to walk independently but can only stand and walk with leg splints.
What other physical effects might Ullrich congenital muscular dystrophy have on a child?

As the muscles are weak and mobility is limited, the child may be born with or develop ‘contractures’, this means that the muscle tendons tighten up and the child is unable to move the limbs or the joints as freely as a healthy child. Physiotherapy can help prevent this and a programme of exercises which may be carried out daily by parents at home should be worked out with a physiotherapist very soon after diagnosis.

Even a very young baby can be helped to maintain suppleness. Hips are commonly affected and if they are dislocated this may require treatment with a splint or, only very, rarely surgery.

Most of the children with Ullrich congenital muscular dystrophy also develop a curvature of the spine (scoliosis)

As collagen VI is also normally present in the skin, children may have a tendency for scars to heal slowly or become thickened and elevated (keloid formation).

Is Ullrich congenital muscular dystrophy progressive and is it life threatening?

In the first years the condition is fairly stable and the child usually appears to gain strength as he or she gets older. Motor function remains relatively stable but when children reach puberty, might experience increasing difficulties, as muscles find it difficult to cope with the greater strain of increased weight and height.
Children who have achieved independent walking often need some help at this age and long leg callipers are often provided to assist them to walk.

While motor function remains relatively stable or only slowly progressive, children often experience breathing problems at night because the muscles which assist breathing are affected. It is therefore very important to monitor this function on a regular basis by performing ‘sleep studies’. This test is very simple and consists in applying a small wrapping around one finger. The wrapping is connected to a small machine which records the level of oxygen throughout the night. Night-time breathing problems may happen in children of any age and, when present, children feel tired, often have headaches on waking in the morning, may feel sleepy during the day and lose appetite and weight.

Another problem can also be that of frequent chest infections. If these signs are present or if the level of oxygen recorded at night are not satisfactory, children can be helped by referring them to a respiratory physician who will provide a means of supporting breathing at night (ventilator). This usually requires a special facial or nasal mask attached to a small machine which pumps air in and out of the lungs.

Another frequent problem after the first few years is failure to thrive and it is therefore also important to monitor weight and height to be sure that children with Ullrich congenital muscular dystrophy receive enough food and energy. In several cases feeding supplements are needed. Sometimes a small surgical procedure called gastrostomy can be performed to help the child to receive the appropriate level of feeding to maintain his or her weight.
What help is available?

Physiotherapy is one of the main forms of help. An initial physiotherapy assessment at the time of the diagnosis should be followed by an exercise programme and regular check-ups. The main aim of physiotherapy is to keep the muscles as active as possible and to prevent the formation of contractures (muscle tendon tightness causing restriction in the range of joint movement). Children are encouraged to remain as active as possible. Swimming is a particular good form of exercise.

Physiotherapy can also help provide orthoses, such as splints and long leg callipers and a wheel chair when necessary.

It is also important to provide a proper sitting and standing posture to prevent curvature of the spine (scoliosis). If a curvature occurs a spinal brace may help to prevent further deterioration of the curvature. Surgical intervention (scoliosis surgery) might be needed in some cases.

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