Congenital Myopathies: Myotubular (centronuclear) myopathy

Written by Dr.Paola Nicolaides, Consultant Paediatric Neurologist, for the Muscular Dystrophy Campaign

What is myopathy?

The term myopathy is derived from the Greek language and it means muscle disorder.

What is a congenital myopathy?

The congenital myopathies are a group of conditions affecting proximal muscles and causing muscle weakness and wasting. Sometimes symptoms are present at birth but at other times they are not recognised until later on in childhood or adult life.

What is myotubular (centronuclear) myopathy?

The name ‘myotubular myopathy’ was suggested in 1966 and refers to the appearance of the affected muscle fibres which look like myotubes (muscle cells found only during foetal development when the foetus is between 12 and 20 weeks old). The condition is also known as “centronuclear myopathy” because the nuclei of affected muscle cells are found in the centre of each cell instead of the periphery (as occurs in healthy muscle cells).

How does the disease present?

There are different forms of this condition, with the severest form presenting at birth or even ante-natally. The milder forms present later on in childhood.

In the severest form there may be a reduction in foetal movements in the late stages of pregnancy and the baby may appear very floppy at birth and have swallowing and breathing difficulties and facial weakness.

Sometimes, in the very severe early cases the baby may not survive more than a few days of life. The more common form of the disease presents later with muscle weakness, which may also affect the face, arm and leg muscles and the muscles involved in breathing. There may be some ptosis (drooping of the eyelids), and some weakness of the eye muscles causing restriction in the field of vision. In addition there may be weakness of the trunk muscles.

Are the patients at risk of developing any complications?

Children with myotubular myopathy are at increased risk of respiratory infections which occasionally may be severe or even life threatening. Sleep studies and respiratory function tests may be required to fully assess the child’s respiratory status.Constipation may be a feature of the disease and may be caused by lack of exercise and immobility. Hearing, vision and intelligence are usually unaffected.

Is there a risk with General Anaesthesia?

No, unless the patient has significant breathing difficulties.

Is myotubular myopathy inherited?

Yes, although the exact genetic cause is unknown, different patterns of inheritance are recognised; these are known as X-linked recessive, autosomal recessive and autosomal dominant. In the remaining cases there does not appear to be a clear pattern of inheritance and these are described as ‘sporadic’, which means they occur randomly, or as a one-off, with very little risk of other children in the family being affected. However, people who are themselves sporadic cases will be at risk of passing on the condition to their children.

In the X-linked recessive type, which is the most severe form of the disease and presents early in life, the abnormality lies on the X chromosome. In these cases the mother is usually the carrier in which case only boys can be affected. There is a 50% chance (1 in 2) that any of her sons may have inherited the condition. However, new mutations can occur, so not all mothers are carriers. Also some female carriers may have a myopathy.

Written by Dr.Paola Nicolaides, Consultant Paediatric Neurologist, for the Muscular Dystrophy Campaign

What is myopathy?

The term myopathy is derived from the Greek language and it means muscle disorder.

What is a congenital myopathy?

The congenital myopathies are a group of conditions affecting proximal muscles and causing muscle weakness and wasting. Sometimes symptoms are present at birth but at other times they are not recognised until later on in childhood or adult life.

What is myotubular (centronuclear) myopathy?

The name ‘myotubular myopathy’ was suggested in 1966 and refers to the appearance of the affected muscle fibres which look like myotubes (muscle cells found only during foetal development when the foetus is between 12 and 20 weeks old). The condition is also known as “centronuclear myopathy” because the nuclei of affected muscle cells are found in the centre of each cell instead of the periphery (as occurs in healthy muscle cells).

How does the disease present?

There are different forms of this condition, with the severest form presenting at birth or even ante-natally. The milder forms present later on in childhood.

In the severest form there may be a reduction in foetal movements in the late stages of pregnancy and the baby may appear very floppy at birth and have swallowing and breathing difficulties and facial weakness.

Sometimes, in the very severe early cases the baby may not survive more than a few days of life. The more common form of the disease presents later with muscle weakness, which may also affect the face, arm and leg muscles and the muscles involved in breathing. There may be some ptosis (drooping of the eyelids), and some weakness of the eye muscles causing restriction in the field of vision. In addition there may be weakness of the trunk muscles.

Are the patients at risk of developing any complications?

Children with myotubular myopathy are at increased risk of respiratory infections which occasionally may be severe or even life threatening. Sleep studies and respiratory function tests may be required to fully assess the child’s respiratory status.Constipation may be a feature of the disease and may be caused by lack of exercise and immobility. Hearing, vision and intelligence are usually unaffected.

Is there a risk with General Anaesthesia?

No, unless the patient has significant breathing difficulties.

Is myotubular myopathy inherited?

Yes, although the exact genetic cause is unknown, different patterns of inheritance are recognised; these are known as X-linked recessive, autosomal recessive and autosomal dominant. In the remaining cases there does not appear to be a clear pattern of inheritance and these are described as ‘sporadic’, which means they occur randomly, or as a one-off, with very little risk of other children in the family being affected. However, people who are themselves sporadic cases will be at risk of passing on the condition to their children.

In the X-linked recessive type, which is the most severe form of the disease and presents early in life, the abnormality lies on the X chromosome. In these cases the mother is usually the carrier in which case only boys can be affected. There is a 50% chance (1 in 2) that any of her sons may have inherited the condition. However, new mutations can occur, so not all mothers are carriers. Also some female carriers may have a myopathy.

The autosomal dominant type of inheritance is slightly more common than the autosomal recessive one. The age of onset is usually older (late childhood or adult life) but may be earlier. The weakness and wasting is mainly proximal (involving muscles near the trunk such as the shoulders and thighs) and slowly progressive. In this type of dominant inheritance, one (either) of the two parents is affected, may be only very mildly so, but carries the abnormal gene, and each child (of either sex) of that affected parent has a 50% (1 in 2) chance of being affected.

Recent genetic advances in the myotubular myopathies

The X-linked form of myotubular myopathy is the best understood genetically. It usually presents in the newborn period with severe, generalised muscle weakness and hypotonia (floppiness ). The babies make little effort to breathe spontaneously and require breathing assistance by a ventilator.

A gene responsible for the X-linked myotubular myopathy is present on the ling arm of the X chromosome (Xq28). The gene is known as MTMX, after myotubularin in the defective muscle protein. A number of different mutations (genetic defects) have been identified in affected family members causing the X-linked form of myotubular myopathy, otherwise known as (XLMTM).

In families with the X-linked form in which the mutation has been identified, it is possible to use mutation detection to confirm the diagnosis, determine carrier status and offer antenatal diagnosis.

The genes for the autosomal dominant and recessive forms of myotubular myopathies have not yet been identified. Two possible candidate genes MTM2 and MTM3 have been found.

How is myotubular myopathy diagnosed?

The diagnosis of a ‘myopathy’ is usually suspected from the history and examination. However, the specific diagnosis of myotubular myopathy is nearly always made by looking at a piece of muscle (muscle biopsy). Before doing a muscle biopsy (which involves taking out a small piece of muscle usually from the thigh muscle) a few other tests may be done, one of which is a blood test which measures the level of a muscle enzyme (creatine kinase or CK level), which is usually normal but may be raised.

The other is an electrical test of the muscles and the nerves supplying the muscle. This test involves placing a fine needle into the muscle, which then measures the electrical activity coming from that muscle. Although this test may be able to show a “myopathic” pattern of abnormal muscle activity (seen in any myopathy) it is unable to define the exact type.

The muscle biopsy is therefore the important test, which will precisely identify the diagnosis. The muscle in this condition shows evidence of abnormal central nuclei in a proportion of muscle fibres.

Is the condition progressive?

The rate of progression of the condition is variable. In general the earlier the onset, the more severe the disorder is. In most cases the disease is only slowly progressive. Some patients may eventually lose the ability to walk. Occasionally muscle weakness may progress quite rapidly and these patients experience serious breathing problems.

Is there a treatment or a cure?

At the moment, there is no cure, nor any drug treatment for myotubular myopathy. However, other very helpful measures can be taken such as physiotherapy, the use of antibiotics to treat chest infections, or naso-gastric tube feeding when necessary.

What help can be offered?

Physiotherapy is one of the main forms of help. An exercise programme and regular check-ups should follow an initial physiotherapy assessment at the time of the diagnosis. The main aim of physiotherapy is to keep the muscles as active as possible to prevent the formation of ‘contractures’ (muscle tendon tightness causing restriction in the range of joint movement). It is also important to provide good seating and to ensure a proper sitting and standing posture to prevent scoliosis (curvature of the spine). The other role of physiotherapy is to help with provision of appliances, such as splints, calipers, standing frames (mechanical aids helping to keep c hildren on their feet) and wheel chairs where necessary. Children and adults are encouraged to remain as active as possible and ensure that they do not become overweight to limit the strain imposed on their weak muscles. Swimming is a particularly good form of exercise.