Ullrich congenital muscular dystrophy

What is Ullrich congenital muscular dystrophy?

The congenital muscular dystrophies are a group of conditions which share early presentation and a similar appearance of the muscle. Congenital means ‘from birth’ and in congenital muscular dystrophy the initial symptoms are present at birth or in the first few months. Congenital muscular dystrophies are a very heterogeneous group of conditions and in the last few years a lot of effort has gone into identifying the separate entities and in locating the genes responsible for a number of these forms.
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 3 genes are responsible for the production of the protein collagen VI.

Which are the first signs?

Babies with UCMD 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 UCMD 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 1 in 4, 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 UCMD should be referred for genetic counselling.

How is UCMD diagnosed?

The diagnosis of UCMD 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:
• 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 replacedby fat and fibrous tissue.
• 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.
The illustration overleaf shows where collagen VI is produced in the muscle fibres. In the upper part of the illustration, a number of relevant extracellular proteins and their interactions are showed. Collagen VI interacts, among other proteins, with biglycan and eventually with dystrolgycan. Dystroglycan is in turn associated, intracellularly, with the protein dystrophin. Genetic tests looking for abnormalities in one of the 3 genes responsible for Ullrich congenital muscular dystrophy are now available and provide the ultimate diagnosis. These tests however are still only done on a research basis and are very time consuming. The results are often only available after many months.
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 cure?

At the moment there is no cure for congenital muscular dystrophy, but there are ways, described below, of helping to alleviate the effects of the condition.

Can a child with UCMD 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 CMD 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 UCMD 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.

Oculopharyngeal muscular dystrophy (OPMD)

The term muscular dystrophy is used to cover a wide range of conditions which have in common progressive muscle weakness due to an inherited genetic defect (mutation). There is huge variation in severity between the different conditions. Some present in very early childhood and progress to severe disability, whereas others can be extremely mild and not problematic even in old age. Each type relates to a specific genetic abnormality and if more than one family member is affected they each have the same type of muscular dystrophy. It has been recognised for many years that some patients with muscle disease have particular problems with the muscles around the eyes, although other parts of the body can also be involved. Whilst research is continuing, it appears that most of these patients have either oculopharyngeal muscular dystrophy (OPMD), the subject of this factsheet, or mitochondrial chronic progressive external ophthalmoplegia (CPEO). Often, when patients first present, it may not be clear whether the patient has OPMD or CPEO but specific investigations can differentiate between the two. The medical terms relating to these conditions may cause the lay person some confusion. They include: ptosis, external ophthalmoplegia, diplopia and dysphagia. Ptosis - this describes drooping of the eyelids due to weakness of the muscle that normally lifts up the eyelid. External ophthalmoplegia - this means weakness and restriction of muscle movement around the eye (external to the eye). It shows as slowness and incomplete range of movement of the eyes, and includes the eyelid muscle weakness that causes ptosis. These problems typically progress very slowly, hence the term 'chronic progressive external ophthalmoplegia'. Diplopia - this simply means double vision and occurs when the eye muscles on each side arenot affected equally, so that the eyes point in slightly different directions.
Dysphagia - this means difficulty in swallowing. When mild, it may simply be a feeling of food sticking in the throat, but patients with severe dysphagia may not be able to swallow at all and can even choke on their own saliva.

Symptoms and signs

Although the abnormal gene causing OPMD is present from birth, patients do not usually develop symptoms until the fifth or sixth decade of life. The first sign of the disorder is usually ptosis, but occasionally it is dysphagia. Very slowly, over many years, these problems progress. There is progressive restriction of eye movements and in rare cases this can lead to diplopia. The increasing ptosis may lead to the eyelid covering the pupil and impairing vision, and in an effort to compensate for this the forehead muscle becomes overactive, trying to help to lift up the eyelids, giving a frowning appearance, and the patient adopts a rather characteristic posture with the head tilted backwards. Dysphagia, which is initially mainly for solid and dry foods, progresses slowly and eventually
even swallowing fluids, including saliva, may become a problem. If dysphagia is severe there is a danger of aspiration (food, drink or saliva "going down the wrong way" - into the chest rather than stomach) which greatly increases the risk of a chest infection. After many years the patient may become aware of limb weakness, first around the shoulders and later around the hips. This is usually relatively mild but can occasionally be severe and disabling, many years after the first onset of symptoms. Facial weakness may develop, and be commented upon by the specialist, but rarely causes any particular problems. Life expectancy is little, if at all, altered.

Management

There is no specific treatment for OPMD, but much can be done to help the main symptoms of ptosis and dysphagia. Glasses can be fitted with fine metal bars (ptosis props) that lift up the drooping eyelids. If these are unacceptable, and if the ptosis is severe, surgical elevation of the eyelids can be very successful – several procedures are possible and should be tailored to the individual patient.
Mild dysphagia can be helped by suitable attention to the consistency of the diet (with a dietician's advice) and by exercises taught by a speech therapist. In more severe cases, a relatively minor operation called cricopharyngeal myotomy, which cuts one of the throat muscles
internally, can be valuable. Another approach that is sometimes helpful is to inflate a balloon to dilate the gullet. But as for all surgical procedures there are potential hazards and the final choice of treatment depends upon many individual factors. Recently there have been a few reports of the use of botulinum toxin injections; rather than cut or stretch a muscle, the toxin relaxes the muscle and that can aid swallowing. However, further studies are needed to see whether this will prove to be a useful long-term treatment. If the dysphagia is preventing adequate nutrition or there is a risk of aspiration pneumonia, then alternative methods of feeding can be used. The most acceptable, in the long term, is gastrostomy. A minor operation is used to pass a tube through the front of the abdomen directly into the stomach. Patients and their relatives find this easy to manage at home. If the normal diet is compromised, then a dietitian can offer advice with respect to supplements which can help to maintain adequate nutrition.
Physiotherapy may be useful to help patients cope with limb weakness, although this is usually mild, and to reduce the risk of chest problems.

How is OPMD inherited?

In almost all cases the condition is inherited as an autosomal dominant disorder which means that each child of an affected individual has a 50% risk of inheriting the same condition. It is now possible, through a blood test, to determine whether somebody has inherited the abnormal gene (called PABPN1) but that is not always terribly helpful. Even if somebody has inherited the abnormal gene, it is impossible to predict when, if ever, they will develop symptoms. Such testing should only be performed after detailed discussion with a suitably experienced neurologist or genetic counsellor.

Diagnosis

The diagnosis can be confirmed by a blood test that identifies the underlying genetic abnormality. Electrical tests (EMG) and muscle biopsy are now rarely necessary.

Is there any research being conducted into OPMD?

The genetic fault that causes OPMD was identified in 1998. Although this was a very important discovery, which has given us a simple diagnostic test, it is likely to be some considerable time before the research allows us to identify a specific treatment for this condition. In the meantime, there is a great deal of research trying to identify how the genetic fault causes the physical problem. Since 1998 over 100 research papers on OPMD have been published. Whilst none of these have yet led to a major change in management, they should be regarded as the building blocks for progress in the future.

Mitochondrial chronic external ophthalmoplegia (CPEO)

As mentioned above, this condition can be confused with OPMD. It is often sporadic (i.e. occurs in an individual with no family history of a similar condition) but occasionally is inherited so that there is a history of similarly affected relatives.
In CPEO the restriction of eye movements tends to be much more severe than in OPMD, but diplopia is still uncommon. As in OPMD, ptosis can be marked. Dysphagia is less common in CPEO than OPMD. Limb muscle weakness can be similar to that in OPMD, but may be more severe, and associated with exercise-intolerance.
Mitochondrial disorders can also affect other organs giving rise to deafness, diabetes, heart problems, and brain problems including epilepsy and dementia.
Other factsheets that may be useful
• Gastrostomy
• Mitochondrial myopathy (for more information on CPEO)

Nemaline (rod) myopathies

Nemaline, or rod, myopathies are a group of conditions which fall under the umbrella of congenital myopathies. They are characterised by rod-like structures in the muscle cells, and clinical features such as muscle weakness, breathing problems, and feeding problems. There are 6 sub-groups which are defined according to age of onset and severity. Around 1 in 50,000 individuals are estimated to be affected, and these include both males and females. There is currently no effective treatment or cure to halt the progression, but management of the condition is very important and includes physiotherapy, and where necessary the use of ventilation and/or a feeding tube.

What is nemaline myopathy?

Nemaline myopathies, or rod body myopathies, are a group of conditions which fall under the category of congenital myopathies. There are a number of different types of rod myopathies and they affect both males and females. In the majority of cases (90%) the condition becomes apparent at birth or early childhood, although in very rare cases, it does not become apparent until adulthood. Rod myopathies are estimated to affect 1 in 50,000 individuals.

What causes it?

In the majority of cases, a rod myopathy is inherited, although there are sometimes sporadic cases where there are no other family members affected. There have been mutations identified in 5 different genes, which cause a rod myopathies. The protein products of all of these genes are involved in muscle tone and contraction.
ACTA1 - This gene produces a protein called α- actin. Mutations in this gene account for around 15-25% of cases. Errors in this gene are inherited in an autosomal dominant or autosomal recessive pattern.
NEM2 - The product of this gene is a protein called nebulin. It is thought that mutations in this gene are a common cause of nemaline myopathy but definite statistics are unavailable. Mutations in this gene are inherited in an autosomal recessive pattern.
TPM3 - The product of this gene is a protein called α- Tropomyosin 3. Mutations in this gene account for only 2-3% of affected individuals, and are inherited in an autosomal dominant or autosomal recessive pattern.
TPM2 - This gene encodes a protein called β-Tropomyosin. Only very few individuals have been identified with errors in this gene. Inheritance is in a autosomal dominant pattern. TNNT1 - This gene produces a protein called Troponin 1. Errors in this gene have only been identified in a population of Old Order Amish individuals. Inheritance is in an autosomal recessive pattern.

What are the common features?

There are six sub-groups of nemaline myopathy which are defined based on age of onset and severity of condition, although there is a high degree of overlap between the conditions. There does not seem to be a correlation between severity of the condition and the gene which has the mutation.
Although heart problems are not common in people with a rod myopathy, it is important that cardiac function is regularly monitored.
The six sub-groups are described in the table below. Sub-group Onset
Clinical signs Severe congenital form
Birth Severe floppiness and muscle weakness
Little spontaneous movement Difficulties with sucking and swallowing
Severe breathing problems
Death usually occurs early
Amish nemaline
myopathy
Birth Floppiness/hypotonia
Contractures/ tightening of joints
Breathing problems
Death usually within 2 years of life
Intermediate
congenital form
Birth Severity in-between severe and mild forms
Early development of contractures/ tightening of
joints
Delayed motor milestones
Independent breathing at birth
Use of ventilatory support and/or wheelchair by
11 years
Typical (mild)
congenital form
Birth →
1 year
Floppiness/ hypotonia
Weakness in muscles closest to trunk, and
sometimes spreading to more distal muscles.
Feeding difficulties
Some respiratory weakness, but less severe
than other forms
Childhood-onset 8 → 15
years
Early motor development normal
Symmetrical weakness of ankle including foot
drop
Slowly progressive weakness with eventual
involvement of all ankle movement.
Motor development normal
Adult-onset 20 → 50
years
Generalised weakness with rapid progression
Muscle pain
Sometimes severe neck weakness
Usually no previous family history

How is it diagnosed?

• 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 or a needle biopsy is performed to remove a small sample. Muscle from people affected by nemaline myopathy has a distinctive pattern with thin thread- or rod-like structures in 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 nemaline myopathy to be made. A factsheet on Muscle biopsies is available from the Information and Support Line, or from the website at www.musculardystrophy. org
• Molecular testing - In families where the mutation is known to occur in the gene for α- actin, molecular testing is available. This involves taking a blood sample and analysing the DNA for the presence of a mutation. The gene is “read” from end to end, and this sequence is compared to a normal α- actin sequence. This process can take up to several weeks to complete. Once this error has been identified in one family member, it is possible to use this sequence to diagnose other family members.

What other tests are available?

Prenatal diagnosis - Prenatal diagnosis is available for families where the mutation has been identified as being in the gene for α- actin, and the precise nature of the mutation established. The technique is described in the section Molecular testing, but there are two ways to obtain samples for testing:
• Amniocentesis is traditionally performed at 15 to 17 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 abortion is slightly higher.
Carrier testing - As with prenatal diagnosis, carrier testing is currently only available for families where a mutation in the α- actin has been identified and characterised.

How will it progress?

The progression of these conditions is variable, and some may progress more quickly then others. Generally it is accepted that the earlier the onset, the more severe the condition. For children who live beyond the early years, only some will lose the ability to walk. Respiratory function is thought to improve over time, with the most severe problems occurring earlier in life.

Is there a treatment?

There is currently no effective treatment to halt the progression of the nemaline myopathies, but management of the condition is very important for prolonging life.
• Night time ventilation - Breathing problems are common with the nemaline myopathies,
and thus respiratory function should be regularly monitored. A decrease in oxygen intake can lead to, among other things, headaches, breathlessness, poor appetite and disturbed sleep. Night time ventilation involves the use of a face mask attached to a small machine, which assists in breathing. This aids the muscles which control breathing, and allows a greater intake of oxygen. Night time ventilation may be beneficial to people with a rod body myopathy, but this should be discussed fully with a consultant to determine whether it is appropriate.
• Feeding tube (or gastrostomy) - This is a tube that goes into the stomach through the stomach wall and enables a person to be given food and fluids by passing them directly into the stomach via the tube. People with a myopathy may have problems with swallowing which can lead to choking and inhalation of food. This can results in chest infections. A feeding tube prevents this from happening. There are a number of different types of feeding tube which are available, and these are fitted by a short surgical procedure. A factsheet on Gastrostomy is available from the Information and Support Line, or from the website at www.muscular-dystrophy.org
• 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.
• Antibiotics - Chest infections are common with the nemaline myopathies and complications with breathing can lead to a variety of other problems, including lethargy, headaches, and poor appetite. Antibiotics are used to treat chest infections. There are a variety of antibiotics available, and a GP will be able to advise on the most suitable. If there is a tendency to chest infections it is worth considering pneumovax (prevenar in children under two years) and the flu vaccine.

Is there a cure?

Currently there is no cure for the nemaline myopathies although much research is being currently being conducted into the myopathies, including the rod body myopathies. Although there is no effective treatment to halt the progression, there are a couple of different ways in which to manage the symptoms of the nemaline myopathies 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. The research department at the Muscular Dystrophy Campaign, regularly monitors research advances in the congenital myopathies, and produces releases which are sent to members when significant scientific advances occur.

Planning for the future?

Nemaline myopathies are progressive conditions which means that the needs of individuals with the condition will change with time.

There are a number of things which should be considered:
• Education
• Holidays
• Home adaptations
• Ventilation
• Wheelchairs
More information on any of these topics can be obtained by contacting the Information and Support Line.
Other things to consider
• Anaesthetics - It has now been recognised that the use of both local and general anaesthetics in people with neuromuscular disorders, can cause a variety of different problems. Although anaesthetics are generally well tolerated by people with a nemaline myopathy, due to the nature of the anaesthetic drugs used, problems can include dysfunction of the heart, and relaxation of the muscles round the lungs causing problems with breathing. Generally if a patient is properly assessed and monitored, the risks associated with anaesthetic use are low, but it is very important that the medical professionals involved are fully aware of the muscle condition.
• 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. Many companies are able to provide a Medic Alert Card, which can be carried to advise of any medical condition. These come in the form of bracelets, pendants etc and carry essential information.
• Pregnancy - Pregnancy and delivery are generally well tolerated in mothers with nemaline myopathy. It is however, important to monitor breathing and heart function, and consideration should be given to any muscle weakness of contractures which may complicate the delivery.

Myotubular (centronuclear) myopathy

Myotubular, or centronuclear, myopathy falls under the umbrella of congenital myopathies. It is characterised by a specific pattern in the muscle tissue when viewed under a microscope. There are three different types of myotubular myopathy, described according to the pattern of inheritance seen. Each of these is very rare. There is currently no effective treatment or cure for myotubular myopathy, but management of the condition is very important and includes physiotherapy, and where necessary the use of ventilation and/or a feeding tube.

What is myotubular myopathy?

Myotubular, or centronuclear, myopathy belongs to the family of congenital myopathies which are characterised by muscle weakness. Congenital means “from birth” and myotubular myopathy is generally apparent very early in life. Myotubular myopathy is so named because of the presence of structures that look like myotubes, immature muscle cells.

What causes it?

There are three different types of myotubular myopathy each defined by the pattern of inheritance seen. There are also sporadic cases where there is no previous family history, but the prevalence of these has not yet been determined. X-linked myotubular myopathy (or XMTM) -This is the most common form of myotubular myopathy, and is caused by an error in the myotubularin (MTM1) gene which produces a protein called myotubularin. This protein is known to be required in m uscle development, for the formation of adult muscle.
The MTM1 gene is located on the X chromosome. Individuals have 46 chromosomes, two of which are called the sex chromosomes. Females have two copies of the X chromosome whilst males have one copy of X and one copy of the Y chromosome. If a female has an error on one copy of her X chromosomes, usually she will have enough protein from the “good” chromosome to compensate for the error, and will not have the condition. Manifesting carriers are the exception to this rule (see later section).
If males have the error on their X chromosome, they have no “good” gene to compensate and they will have the condition.
Autosomal dominant myotubular myopathy - This pattern of inheritance is very rare and only a few families have been described with this condition. The gene abnormality causing the condition was very recently identified by researchers in Paris; it is called the Dynamin 2 gene (DNM2). Autosomal dominant inheritance means that only one copy of the genetic error is needed to cause the condition, and one good copy cannot compensate. This form of the condition affects both males and females.
Autosomal recessive myotubular myopathy -This pattern of inheritance is also very rare. As with the autosomal dominant form, the gene involved has not been identified, but is expected to have a similar function to the myotubularin gene.
Autosomal recessive means that, in order for a person to be affected, he or she must have two copies of the genetic error. Each parent must carry a copy of the error, but usually they do not show any signs of the condition. This form of the condition also affects males and females.

What are the common features?

X-linked myotubular myopathy (or XMTM) - This is the most severe form of myotubular myopathy. It generally affects only males, and has the earliest onset. Commonly there are signs of the condition before the baby is born, and often an excessive accumulation of amniotic fluid around the baby is seen. Most individuals are born with severe floppiness (hypotonia), muscle weakness, and infants may fail to breathe spontaneously at birth, most will require breathing support. There are usually problems with feeding, in particular swallowing, and breathing problems can persist. Chest infections may occur frequently. The child may have a long face, which could seem expressionless. The eyelids may be puffy, and some of the muscles in the eyes may not function correctly. There may be tightening of the knee and ankle joints (contractures).
The severity of the condition varies considerably. In many cases death occurs in the first few months. Some children who survive infancy may show improvement in the first few years, although many will be severely disabled. Many of these children will require ventilatory support to assist their breathing. Occasionally, some children improve significantly and are left with only mild residual weakness even into adulthood.
Female manifesting carriers of XMTM - Manifesting carriers of myotubular myopathy are very rare. As mentioned earlier, every female has two copies of the X chromosome. In every cell, one copy is “switched off”. Usually this is random, but in some exceptional cases, more copies of the “good” chromosome are inactivated. In such cases a female may show signs of the condition, but this is likely to be only mild weakness. Autosomal recessive myotubular myopathy - This is the intermediate form, with onset occurring in infancy or early childhood. Weakness of the muscles in the face may occur, as may droopiness of the eyelids. Some people may have problems with feeding. There is usually weakness of the proximal muscles (those closest to the trunk of the body).
Autosomal dominant myotubular myopathy - Onset of this form is very variable, ranging from birth to 30 years. It is not as severe as X-linked, and the condition generally follows a mild course. There is weakness of the muscles closest to the trunk of the body, although some people may show weakness of the more distal muscles. A problem with the heart has been seen in one person previously, and so is rare. It is, however, important to regularly monitor heart and lung function.

How is it diagnosed?

The clinical signs are usually the first indication that there is a problem with the muscles. In order to confirm the diagnosis a muscle biopsy is required. Muscle biopsy - This is done in one of two ways: either an open biopsy where small piece of muscle is taken under general anaesthetic or a needle biopsy is performed under local anaesthetic to remove a small sample. The sample will be analysed under a microscope. Muscle from people affected by myotubular myopathy shows a characteristic pattern, similar to that seen in foetal muscle. The nuclei are centrally located (hence the name centronuclear) instead of being at the outer edges of the fibres. A factsheet on muscle biopsies is available from the Information and Support Line (contact details are shown below).
• Molecular testing - This is only available for X-linked myotubular myopathy, testing for the dynamin mutation will become available in the future. It seems likely that the genetic cause for the X linked form will be identified in the future. DNA testing involves taking a blood sample and analysing the DNA for the presence of a mutation. The gene is either “read” from end to end, and this sequence is compared to a normal MTM1 sequence, or only certain sections of the gene are analysed. This process can take up to several weeks to complete. Once this error has been identified in one family member, it is possible to use this sequence to diagnose other family members.

What other tests are available?

Prenatal diagnosis is available for families that are known to have a history of X-linked myotubular myopathy. The technique is described in the section Molecular testing, but there are
two ways to obtain samples for testing:
• Amniocentesis is traditionally performed at 15 to 17 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 abortion is slightly higher. Carrier testing - As with prenatal diagnosis, carrier testing is currently only available for families known to be affected by the X-linked form of myotubular myopathy.

How will it progress?

Myotubular myopathy is a non-progressive or slowly progressive condition. However, infants with X-linked myotubular myopathy may progress into respiratory failure rapidly and the majority of those who survive beyond infancy are dependent on artificial respiration. The autosomal forms are usually less severe.

Is there a treatment?

There is currently no effective treatment for myotubular myopathy, but management of the condition is very important for prolonging life.
• Night time ventilation - Breathing problems can occur with myotubular myopathy, and thus respiratory function should be regularly monitored. A decrease in oxygen intake can lead to, among other things, headaches, breathlessness, poor appetite and disturbed sleep. Night time ventilation involves the use of a face mask attached to a small machine, which assists in breathing. This aids the muscles which control breathing, and allows a greater intake of oxygen. Night time ventilation may be beneficial to people with myotubular myopathy, but this should be discussed fully with a consultant to determine whether it is appropriate.
• Feeding tube (or gastrostomy) - This is a tube that goes into the stomach through the stomach wall and enables a person to be given food and fluids by passing them directly into the stomach via the tube. People with a myopathy may have problems with swallowing which can lead to choking and inhalation of food. This can result in chest infections. A feeding tube prevents this from happening. There are a number of different types of feeding tube which are available, and these are fitted by a short surgical procedure. A factsheet on gastrostomy is available from the Information and Support Line.
• 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.
• Antibiotics - Chest infections are common with myotubular myopathy and complications with breathing can lead to a variety of other problems, including lethargy, headaches, and poor appetite. Antibiotics are used to treat chest infections. There are a variety of antibiotics available, and a GP will be able to advise on the most suitable. If there is a tendency to chest infections it is worth considering pneumovax (prevenar in children under two years) and the flu vaccine.

Is there a cure?

Currently there is no cure for myotubular myopathy although much research is being conducted into the congenital myopathies, including myotubular. Although there is no effective treatment for the condition, there are a couple of different ways in which to manage the symptoms of myotubular myopathy 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. The research department at the Muscular Dystrophy Campaign, regularly monitors research advances in the congenital myopathies, and produces research updates, which are sent to members when significant scientific advances occur.

Planning for the future?

Myotubular myopathy, although thought to be non-progressive, may change with time, especially as the child grows. This means that the needs of individuals with the condition may change over time.
There are a number of things which should be considered:
• Wheelchairs
• Home adaptations
• Education
• Ventilation
• Holidays
More information on any of these topics can be obtained by contacting the Information and Support Line.

Other things to consider

• Anaesthetics - It has now been recognised that the use of general anaesthetics in people with neuromuscular disorders, can cause a variety of different problems. Although anaesthetics are generally well tolerated by people with myotubular myopathy, due to the nature of the anaesthetic drugs used, problems can include dysfunction of the heart, and relaxation of the muscles round the lungs causing problems with breathing. Generally if a patient is properly assessed and monitored, the risks associated with anaesthetic use are low, but it is very important that the medical professionals involved are fully aware of the muscle condition.
• 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. Many companies are able to provide a Medic Alert Card, which can be carried to advise of any medical condition. These come in the form of bracelets, pendants etc and carry essential information.
that provide alert cards.

Myotonic dystrophy

What is myotonic dystrophy?

People with myotonic dystrophy, like those with other dystrophies, experience muscle weakness and wasting which is usually progressive. There are many differences, though, in the type of problem that people with myotonic dystrophy may have. These may include the following: Types of muscles involved are usually in the face, jaw and neck area; the large, weight-bearing muscles of the legs and thighs are much less affected.
Rate of deterioration is commonly slow, with little change over a long period; some people never have significant muscle disability. Muscle stiffness or 'myotonia' is characteristic, especially affecting the hands. Involvement of other body systems is frequent; associated problems may include cataracts, disturbance of heart rhythm, hormonal problems and, in children, learning difficulties. Age at onset is very variable. Symptoms may appear at any time from birth to old age.

How is myotonic dystrophy inherited?

This condition follows a 'dominant' inheritance pattern, which means that on average half of the children of an affected person are themselves affected. Both men and women are equally likely to be affected and to pass on the disorder, but affected women are more likely to have a severely affected child. In general (though not always) the disorder tends to be more severe in successive generations.
Most healthy adult relatives will not be likely to develop or pass on the disorder, but a careful assessment by an expert is important as mild features can easily be missed. Genetic testing on a blood sample for such relatives can now provide greater certainty, but should always be done with full information as part of genetic counselling. Genetic testing of healthy young children is not recommended.
Very few cases of myotonic dystrophy occur 'out of the blue'. Almost always, one parent proves to be affected, often very mildly. Some parents (or grandparents) prove to carry a very slight genetic change that will never give them symptoms. Careful study of the whole family often shows more members to be affected than would appear likely at first.

What is the cause?

The changes in muscle and other body systems in myotonic dystrophy are now known to result from a specific genetic change (mutation) which in most cases involves a gene on chromosome number 19. The same change occurs in patients world-wide, but it is variable in extent, even in a single family, because it is unstable. The length of a particular ‘triple repeat sequence’ (CTG) is expanded in patients and this may vary from a slight expansion in mildly affected individuals to a very large one in severely affected children. Until recently it has not been clear how genetic change causes the condition: the most likely mechanism is now thought to be that the expanded repeat is converted normally into the next stage (RNA), but then is unable to leave the cell nucleus. As a result of this trapping, a range of other types of RNA are affected, as are the protein they produce, which helps explain how a single genetic change can affect different body processes.
‘PROMM’ (proximal myotonic myopathy) and type 2 myotonic dystrophy. An important recent advance is the recognition of a second disorder with features resembling myotonic dystrophy.The muscle weakness tends to differ in distribution (more in proximal limb muscles, less in the face) and myotonia is often mild or absent. Cataract and heart involvement occurs as in myotonic dystrophy. It is now clear, that this condition (PROMM: proximal myotonic myopathy), is the same as some rare families thought, clinically, to have myotonic dystrophy but
not showing the expected mutation and termed ‘type2 myotonic dystrophy’ or ‘DM2’. The gene involved has now been isolated on chromosome 3. Although quite different to that for myotonic dystrophy it contains a very similar, expand repeat (CCTG), which is likely to explain the clinical similarity of the two disorders. We are still learning about the details of this condition, but it is probably uncommon and accounts only for a small proportion of patients thought clinically to have myotonic dystrophy.

Future advances

The research advances of the past 10 years have increased our understanding to the point where we can begin to see future possibilities for preventing or limiting the damage to muscle and other systems that occurs in myotonic dystrophy. In particular the genetic changes can now be re-produced in mouse models, which could allow the study of the effects of drugs and other agents that might be too untried to use safely on humans initially. It is difficult to predict howrapidly this work will progress, but possibilities exist now that were not present until very recently.

Problems and management

Although no 'cure' for myotonic dystrophy exists at present, there is a lot that can be done to help those affected. Indeed, since many doctors are unfamiliar with the condition, it is essential that people who have myotonic dystrophy are themselves aware of the problems and dangers they may face. Some of these are mentioned here; of course they rarely all occur in one person, and many people have few symptoms, but it is important to be aware of them. Operations and anaesthetics can be risky, even for mildly affected people. It is most important that any surgeon or anaesthetist should know a person has myotonic dystrophy before surgery is planned. Problems usually occur when doctors are unaware of the disorder; if care is taken, surgery is usually safe. A person may wish to wear a bracelet or locket stating their condition. A specific warning card is available that can be carried in a wallet. This can be obtained from the Myotonic Dystrophy Support Group (address below). 'Keep out of trouble' is a good motto for those with myotonic dystrophy. A minority of people can develop heart problems, which are commonly treatable but can be serious if ignored. A regular cardiogram (ECG) is wise.
Some people who have myotonic dystrophy may have more trouble with other body systems than they do with their muscles. A symptom that appears quite unrelated may be connected.
Excessive daytime sleepiness, swallowing difficulties and a range of bowel symptoms are examples. It is important that people with myotonic dystrophy should make sure that whoever treats them is aware that they have the condition and knows the wide range of associated problems.
If troublesome, muscle stiffness due to myotonia can be helped with certain drugs. Children with myotonic dystrophy may have learning problems at a time when there are no muscle complaints. Again, be sure that myotonic dystrophy is borne in mind if this disorder is in the family. Affected women need careful management if undertaking a pregnancy. Not only is there a risk of a baby being severely affected, but problems in pregnancy and delivery may affect the mother.
Equipment for mobility and adaptations in the house can be very useful, though few affected people need a wheelchair. Weak neck muscles make a sound head-rest essential when driving.

In summary

In summary, we now know a lot about myotonic dystrophy, but still have a long way to go. Helpful genetic counselling and family testing are now possible, but the best approach to treatment is to know about the condition, its risks and complications, and to be sure that your doctors do too.

The Myotonias

What is myotonia?

Myotonia refers to the condition in which muscles are slow to relax after contracting. It occurs in
a number of diseases such as myotonic dystrophy, myotonia congenita and paramyotonia congenita. However myotonic dystrophy is a very distinct condition in which myotonia is only a part. For this reason, and also because it is relatively common, there is a separate leaflet dealing specifically with this disorder. In the other two disorders myotonia is the main and often only symptom. They are the subjects of this leaflet.

Myotonia congenita

The principal complaint in myotonia congenita is failure of muscle to relax normally after contracting; this can be severe enough to interfere with normal everyday activities. Myotonia most often occurs after long periods of rest, for example on waking in the morning, or on standing up and starting to walk after prolonged sitting. Most often it affects the limb muscles making walking and climbing stairs difficult. The face may also be affected and opening the eyelids can sometimes be difficult. Stiffness may not only occur after prolonged rest, but can often be brought on by cold, fatigue or emotional stress. It is relieved by exercise and is generally not accompanied by pain. One problem, which can be serious, is after a sudden movement, for example turning quickly to avoid traffic while crossing the road; the muscles tend
to remain stiff and the individual may fall down as a result. Apart from myotonia, muscle enlargement, which may be pronounced, often occurs and affects the calves, thighs, shoulders and forearms.

How is myotonia congenita inherited?

There are two types of myotonia congenita, both of which are inherited. The commoner type (the so-called Becker type) is inherited as an autosomal recessive trait (Becker myotonia congenita). In this case there is a 1 in 4 chance that any brother or sister may be affected, but affected individuals themselves are very unlikely to have affected children. In this form of myotonia, symptoms are often first noticed in late childhood and may then progress until adulthood when there may also be some degree of muscle weakness. Muscle enlargement can be marked.
The less common form is inherited as an autosomal dominant trait (Thomsen myotonia congenita) when there is a 1 in 2 chance of an affected parent transmitting the disease to any child he or she may have. In this form of myotonia, symptoms first appear in early childhood, often in infancy, and parents may notice that when their baby cries the eyes remain closed for an unusually long time. However, myotonia is mild and does not become more severe with time.
Treatment is not usually necessary.

What is the cause?

The underlying genetic fault in both the autosomal dominant and recessive forms of myotonia congenita causes a structural change in the channel (or pore) in the muscle cell wall that lets in chloride ions. Chloride ions help muscle to relax after contraction and the damaged chloride ion channels in myotonia congenita let in too few chloride ions for efficient relaxation.

Can it be treated?

Many affected individuals learn to cope with their disability by working off the myotonia through repeated movements and avoiding the cold as much as possible. When severe, myotonia can be relieved by certain drugs (such as mexiletine) which can be prescribed by the doctor.

Paramyotonia Congenita

In this condition myotonia evident from early childhood, is generalised but particularly affects the face and hands, and characteristically is aggravated by, or only occurs on exposure to, cold. It
is not progressive and usually does not require treatment. Often muscle stiffness may actually be made worse by exercise, especially in cold weather. For this reason myotonia in paramyotonia congenita is referred to as "paradoxical" because repetitive activity often makes it worse rather than better. The condition is inherited as an autosomal dominant trait.
Here the defect is in so-called sodium ion channels in the muscle membrane. A few patients may experience periodic paralysisa sudden ‘floppy’ weakness of one or more limbs that can last minutes or hours. Episodes can be brought on by certain foods or drinks rich in potassium (e.g. bananas, orange juice), resting after exercise, missing meals or an infection.

Other forms of Myotonia

Other rarer forms of myotonia have also been described, including one type in which prolonged attacks of weakness may occur. Because the myotonias are an uncommon group of disorders with differing severities and modes of inheritance, it is important to seek advice from a neurologist or medical geneticist with particular knowledge of these conditions.

Myopathy

A fact sheet for parents whose child has had a muscle biopsy that confirms a myopathy. Adults with a myopathy may also find it helpful.

What is a myopathy

We look at the muscle biopsy under the microscope for evidence of damage. Some changes suggest that the problem is not with the muscle itself, but with the nerve that controls that muscle and we call this neurogenic. Other changes suggest that the problem is with the muscle itself, and this appearance is called myopathic. When certain specific features are present we use the term dystrophic rather than myopathic.

Why do biopsies?

We do muscle biopsies to be able to see what is going on in the muscle and to see if we can discover what is causing the problems that your child is experiencing. This will then allow us to be aware of any possible, future problems. In an abnormal muscle biopsy there is more variation in fibre size and more irregularities in the muscle fibre than in normal muscle.
However, contrary to what is found in dystrophic processes, there are no significant signs of damage or scarring. This may be an important distinction because the kinds of conditions that are associated a myopathic process in the process are different to the kinds that are associated with dystrophic changes, which can indicate more severe muscle damage.

What causes a myopathy?

There are many different underlying causes of a myopathic biopsy.
If a muscle looks myopathic, there may be special features present, like ‘cores’ or ‘rods’ in the muscle which then point to an even clearer diagnosis than just a ‘myopathy’, but in many cases there are no specific features or clues that will point to a particular type of myopathy. In these situations it can take us a long time to work out the exact cause of the problem.

Is it possible that in the future they may be a more specific diagnosis?

When we do not come up with an exact diagnosis straight away, we continue to look at the biopsy using more specialised tests, as and when they become available, this process may take several years. We can also learn from follow-up appointments how things develop at the clinical level, and this can give us clues as to what is happening to your child. Sometimes, later on, we need to do a further biopsy as this can occasionally show up features, which were not present on the initial biopsy, but this will need to be discussed at the time.

What problems should I be aware of?

It is frustrating for parents who, when planning their child’s future, do not know the exact cause of their child’s myopathy; however, there are the things we have to look after. It is important to realise that not al of the following problems may come up in an individual child, but because there is a risk of these kinds of issues we must be aware and be careful to watch out for: Muscle weakness. The weakness in the muscles in patients with myopathy is often fairly non-progressive, but can lead to problems with the range of movement of the joints or with the back. This means that we need to keep a close eye on mobility and joints and we do this in conjunction with the local physiotherapy team as well as through the muscle clinic. People with myopathies can have chest problems because their cough is not strong. Where this may be a problem, we will be recommending the flu and pneomax immunisations. We also keep a close eye on your child’s chest and teach some specialised physiotherapy techniques to help him cough. If your child becomes ill with a chest infection, it is important this is treated promptly. Feeding difficulties can also be an issue, and if someone is not eating or feeding very well then that can lead to undernutrition. You will need to be aware of this. Some people with a myopathy can also have problems with constipation, which can be managed in the usual kinds of ways. To ensure that a child is getting the help he or she needs, support and information to schools and other professionals may be necessary. You may have other questions about the long term implications of this condition on your child’s health. It is very difficult to generalise about this, for children with a myopathy may be very different from one another. This is something that is best discussed with your local doctor. As time goes by there may be other issues which come up and these will be all be dealt with, in partnership with the local services, when you come to the muscle clinic.

Myasthenia Gravis

What is Myasthenia Gravis?

Myasthenia Gravis (MG) is a chronic, autoimmune disease that causes muscle weakness and excessive muscle fatigue. It is uncommon, affecting about 15 in every 100,000 individuals in the UK. The disease can vary in severity and distribution of weakness between individuals, and in any one patient the symptoms fluctuate with relapses and remissions. MG can resolve spontaneously, but for most patients MG persists for life. It can be life threatening, but 90% of patients become symptom-free with modern treatments.

Who is at risk of developing MG?

MG affects all races and can develop at any age from childhood to extreme old age. Young patients are more commonly women, whereas older patients, over 50 years, are more often men. People who inherit a tendency to develop autoimmune disease are at increased risk of developing MG, so a patient with MG may have another autoimmune disease, such as diabetes or thyroid disease, or have a relative with autoimmune disease. Occasionally MG develops in patients with rheumatoid arthritis who are given the drug penicillamine. In these cases, the MG symptoms usually disappear when the drug is stopped.

Is MG hereditary?

MG is not an inherited disease and does not usually occur in families. This is in contrast to the congenital myasthenic syndromes that are genetic disorders (see below). However, it is thought that an individual¡¦s genetic make-up is one factor, of perhaps many, that leads them to develop MG, and it may occasionally be found in more than one family member.

What are the symptoms of MG?

The hallmark of MG is weakness of voluntary muscles, which gets worse with repeated or sustained use of the muscle (fatiguable muscle weakness). Symptoms fluctuate and are typically worse at the end of the day, in hot weather, during or immediately after an infection, or during menstruation. In two thirds of patients with MG, the first muscles to be affected are those controlling eye and eyelid movements, and almost all patients have involvement of these muscles at some stage. In some patients, the MG only ever involves the eye muscles (ocular MG) while in the majority there is also involvement of other muscles (generalised MG). MG itself does not cause pain, but the weakness may lead to non-specific aches and pains. For instance, neck pain may occur because of weakness in the neck muscles.

What causes MG?

MG develops in adult life as the result of a defect in the immune system. The immune system job is to produce antibodies against bacteria and viruses. Unfortunately, it sometimes produces antibodies against ¡§self¡¨ proteins causing ¡§auto¡¨immune disease. The majority of patients with
MG produce antibodies against a self-protein called the acetylcholine receptor (AChR). This is found at the junction between the nerve and the muscle (the neuromuscular junction (see figure 1 & 2). It acts as a ¡§receiver¡¨ for the chemical signal, acetylcholine that is released from the nerve when we want to use a muscle. The antibodies bind to the acetylcholine receptors on the muscle membrane and greatly reduce their ability to receive the chemical signal. As a result the patient experiences muscle weakness which becomes worse as they repeatedly try to use the same muscle. Although we now understand how antibodies to the acetylcholine receptor cause muscle weakness, we do not know why patients with MG develop these particular antibodies. In some patients with MG, the thymus gland in the chest appears to be important in triggering the abnormal immune response.

Fig. 1 Below: The normal neuromuscular junction
Fig. 2 Below: The neuromuscular junction in Myasthenia Gravis (MG)
The diagram shows the chemical signal, acetylcholine, and the receivers, acetylcholine
receptors. The inverted Y shaped molecules are antibodies binding to the acetylcholine
receptors and preventing them from working.

Is MG all the same disease?

MG presents in two main forms:
OCULAR MG affects the eye muscles only.
1) Drooping of the eyelids (ptosis) is often intermittent, and can affect one or both eyes
2) Double vision (diplopia) may be intermittent, and sometimes occurs only when looking in a
particular direction.

GENERALISED MG patients usually have symptoms of ocular MG but there is also involvement
of:
1) Face and throat muscles, affecting smiling, speech (dysarthria), chewing and swallowing
(dysphagia).
2) Neck muscles, causing difficulties in holding the head up.
3) Limb muscles, causing difficulties in walking upstairs, and in holding the arms up (e.g. when
brushing hair).
4) Breathing muscles, causing shortness of breath when exercising or when lying flat.

How is MG diagnosed?

The history and examination of the patient can suggest the diagnosis but it is important to confirm the diagnosis by special investigations:
Antibodies to the acetylcholine receptor are found in 85% of patients with generalised MG, and 50% of patients with ocular MG. They are detected by a blood test.
Electromyography (EMG) is performed by a specialist doctor and involves measuring the electrical response in the muscle with a very fine needle. An electrical stimulus is applied to a nerve and the response in the muscle is recorded. It is a very sensitive test, showing an abnormality in most patients with MG, but is not available at all hospitals.
TensilonR test, an injection of Edrophonium is given which results in a rapid but short-lived improvement in symptoms in many patients.
Chest scan should be done to check whether the thymus is abnormal as many patients with MG have an enlarged thymus, and some have a benign tumour.

What else could it be?

The key feature that differentiates MG from many other diseases is the fatiguable character of muscle weakness and fluctuating nature of the symptoms. Diseases affecting the muscles themselves (e.g. mitochondrial cytopathy or muscular dystrophies) can cause several of the symptoms seen in MG, and the eye symptoms can present in-patients with thyroid disease.
There are other even rarer diseases that can be confused with MG and which are described briefly below.

What will the doctor do?

Since MG is uncommon, the General Practitioner usually refers the patient to a specialist neurologist for further assessment and tests, and for initiation of treatment. Once the diagnosis has been made the General Practitioner has a very important role in prescribing and monitoring the medication.

What can the patient do themselves?

Patients should use common sense and avoid things that would put them in danger if their weakness suddenly increased (for instance swimming on their own). Taking medications regularly is the key to maintaining the lowest possible levels of symptoms.

Can women with MG have babies?

Many women with MG develop the disease as teenagers and the disease is well controlled before they want to have children. The MG symptoms sometimes get worse during pregnancy but equally often get better. Sometimes the baby is born with a transient form of MG, due to the transfer of antibodies across the placenta, but these symptoms respond well to treatment and usually disappear within days to weeks causing no permanent disability. On very rare occasions, an untreated mother may give birth to a baby with severe symptoms, (including joint deformities) requiring intensive care. This has never been reported in a mother who has been diagnosed and adequately treated for MG.

What is the treatment?

Anti-cholinesterase medication
The first specific form of treatment is anti-cholinesterase drugs (usually one called Pyridostigmine), which prevent the breakdown of acetylcholine and so improves the efficiency of
the chemical signal at the neuromuscular junction. The benefits of Pyridostigmine occur within 30-60 minutes, but wear off in 3-4 hours, so tablets should be taken at regular intervals throughout the day. Patients may develop colicky abdominal pain and diarrhoea on Pyridostigmine, because the medication also increases nerve and muscle action in the intestine.
If this occurs the dose can be reduced, or alternatively Propantheline can be taken 30 minutes before each Pyridostigmine dose to counteract the effects on the bowel. For some patients MG symptoms disappear with Pyridostigmine alone, but most require additional treatments, which vary for each patient.

Thymectomy

Since the thymus can be abnormal in-patients with MG, surgical removal of the thymus (thymectomy) is recommended for some patients. Following thymectomy, MG symptoms do not
usually improve in-patients with a thymoma, but may improve in young patients with an enlarged thymus. In these patients, approximately 1 in 4 are cured by thymectomy, 2 in 4 have significant improvement, but 1 in 4 do not improve. Improvement following thymectomy is usually apparent in the first year, but may take up to 3 years to occur. If the patient recovers, or improves significantly following thymectomy, then they may not need any additional therapy. But many patients will need further treatments.

Immunosuppression:

„h Steroids. Patients who do not respond to thymectomy, or do not undergo a thymectomy, are treated with steroids. Patients are usually started on a low dose of steroids, which is gradually increased over the next few weeks to reach the full dose. During this period the patients are often kept in hospital as symptoms sometimes deteriorate before they improve. Once the symptoms are controlled, the dose of steroids is gradually reduced to find the minimum dose at which the symptoms remain under control. Patients then remain on that dose. There are several side effects associated with steroids, some of which can be prevented by taking additional medication. Thinning of the bones (osteoporosis) can occur and so patients will have a bone densitometry (DEXA) scan and will have medication to protect the bones if appropriate. Patients should never stop taking steroids suddenly, as this can result in a serious condition because the body has become used to regular steroids. All patients should carry a ¡§steroid card¡¨ so that in an emergency other doctors will know that they require regular steroids. „h Steroid-sparing agents. Although steroids are extremely effective in controlling MG, there are potential side effects. Therefore, additional drugs are often used which allow the doctors to reduce the dose of steroids required and may even allow the patient to stop steroids completely. These drugs also suppress the immune system but they act in a different way to the steroids, take longer to work and have different side effects.
Thus by using a small dose of steroids and one of these other medications, the side-effects are kept to a minimum, while maximising the immunosuppressive effect. Azathioprine is the only steroid- sparing agent that has been tested formally and found to be beneficial in treating MG. However in-patients who cannot take Azathioprine, alternatives such as Methotrexate or Cyclosporin appear to be effective. Patients taking steroids or steroidsparing agents are at increased risk of infection. It is best for patients to consult their doctors before having any vaccinations (live vaccines should be avoided), or engaging in unusual activities that could put them at risk of contracting infections.

Emergency treatments

If a patient is very weak or is having trouble with breathing or swallowing then they are usually admitted to hospital for more aggressive treatments such as plasma exchange or intravenous immunoglobulin (IVIg). These treatments can produce a rapid improvement in symptoms but the benefits only last for about 6 weeks. They are reserved for situations when symptoms need to be controlled quickly, and they are not appropriate long-term treatments.

What is the prognosis?

The prognosis of MG has improved significantly with the introduction of immunosupressive therapy. The majority of patients become symptom free if they are adequately treated. However most patients do have to remain on tablets for life as the symptoms generally return if they stop the medication.

What other diseases can be mistaken for MG?

MG is the most common of the neuromuscular junction conditions, but about 3 in 20 of patients presenting with symptoms of MG will not have antibodies to the acetylcholine receptor. Some of these will have antibodies to another muscle protein, called MuSK. MuSK antibody myasthenia is treated in much the same way as the usual form of MG, although thymectomy may not be needed. Some will have the Lambert Eaton myasthenic syndrome. In this condition, the patients are also weak and fatigue easily, but eye symptoms are less common. About half the patients are smokers and a particular type of lung cancer may be found. Antibodies to another neuromuscular junction protein, the voltage-gated calcium channel, cause the disease. Treatment is similar to that for MG but thymectomy is not performed. There are also rare congenital myasthenic syndromes, which are due to hereditary gene mutations in the acetylcholine receptor. Antibodies do not cause these and thymectomy and immunosuppressive drugs are not used.

Mitochondrial Myopathies

What are mitochondrial myopathies?

Mitochondrial myopathy is a collective term for a group of diseases that particularly affect muscle, but which may also affect every other part of the body including the brain and the eye.
Other names for these diseases include: Kearns-Sayre Syndrome (KSS), Chronic Progressive External Ophthalmoplegia (CPEO), Mitochondrial Encephalopathy, Lactic Acidosis, and Strokelike
Episodes (MELAS), Myoclonus Epilepsy Associated With Ragged-Red Fibres (MERRF), Leigh’s disease, and Mitochondrial Cytopathy.

Why do I have it?

Our bodies are made up of many different tissues, for example muscle, nerve, and liver. Each tissue is composed of small ‘building blocks’, called cells, and within each cell are small objects known as mitochondria. The job of these mitochondria is to produce energy. Just like a power generator, they take in fuel (the food we eat) and burn it up to generate energy. If this process fails, the cell cannot function adequately and this can lead to disease. Muscle and brain require a lot of energy, and are often the most severely affected.
The part of mitochondria concerned with energy production is called the respiratory chain.
Components (called proteins) of this respiratory chain pathway are produced from a genetic blueprint (the DNA) found either within the mitochondria themselves (mtDNA), or on the chromosomes in what is called the nucleus of the cell. Many mitochondrial diseases, even though they involve the mitochondrial DNA, are sporadic. This means that only one individual in a family is affected – the parents and any children of that person are unaffected. Other mitochondrial diseases are only inherited from the mother. Diseases that arise because of defects within the genes found on chromosomes within the nucleus may be inherited from either parent.

How did they diagnose me?

When the doctor examines you, certain things may raise the possibility of a Mitochondrial Myopathy, for example droopy eyelids (ptosis), or difficulty moving the eyes (ophthalmoplegia), there is a separate Muscular Dystrophy Campaign (MDC) fact sheet covering Ocular Myopathies. A blood test may show a raised lactic acid level. The final diagnosis often depends on taking a muscle biopsy – where the doctor removes a small piece of muscle for further laboratory tests. Under the microscope, mitochondria from people with mitochondrial myopathies often look abnormal, and they accumulate around the edges of muscle fibres giving the so-called ‘ragged red’ appearance. It is also possible to make measurements of how well the respiratory chain functions and identify where the defect lies. In some cases it is possible to establish the diagnosis by looking for the defect (we call the mutation) in the genetic blueprint (either mtDNA or nuclear DNA).

What happens to people with mitochondrial myopathies?

Mitochondrial myopathies affect people in different ways. The most common problem is a combination of mild weakness of the arms and legs together with droopy eyelids (ptosis) and difficulty in moving the eyes (ophthalmoplegia). Others only have weakness of the arms and legs, which gets worse after exertion. This may be associated with nausea and headache. If the illness is severe, muscle weakness may be obvious in small babies, and they may have difficulties with swallowing and feeding. Less commonly, some of these conditions affect the brain. This can lead to epilepsy (fits) and progressive loss of memory. Not all individuals with brain involvement (called encephalopathy) get worse, but some will. The light-sensitive membrane at the back of the eye (the retina) is often affected (abnormal pigment accumulates) and hearing difficulties are common. In addition the heart may be affected requiring the insertion of a pacemaker - an electrical device that helps the heart to beat properly.

Is the condition life threatening and is my life span going to be affected?

The most common mitochondrial myopathy, Chronic Progressive External Ophthalmoplegia (CPEO), is usually only a mildly disabling disorder with normal lifespan, whilst others, that begin early in life, are life threatening. Some, such as Leber’s Hereditary Optic Neuropathy (LHON), affect only vision. The presence of epilepsy, heart involvement and breathing difficulties are all associated with greater risk.

Is there a treatment or cure?

There are no miracle cures. Many of the problems associated with mitochondrial myopathies can, nevertheless, be treat effectively. For instance, diabetes can be treated with tablets or insulin; pacemakers are very effective for the disturbances of heart rhythm. Muscle fatigue can be improved by regular gentle exercise. A few patients improve on treatment with specific vitamins such as ubiquinone, but most do not.

Are there any special risks involved?

Energy demand increases when we are ill. Fasting, either voluntarily or because of illness, also increases the demand put on mitochondria. Regular intake of calories during the day is, therefore, important. If this becomes difficult, particularly during illness and/or if the patient is a
young child, you should contact your doctor. Certain drugs may affect mitochondrial function, and we generally recommend avoiding alcohol. If in doubt you should consult your doctor.

Are any other members of my family at risk?

Recent research has provided a lot of information about the genetic aspects of mitochondrial myopathies and the risk to other family members depends on the precise diagnosis. Most people with mitochondrial myopathies do not have similarly affected relatives, but these are reported in about 20%. Mitochondrial myopathies can be inherited (passed from parent to child) and the genetic error (mutation) can affect either the mitochondrial DNA or the genes found in the nucleus. In those individuals with defects in mtDNA, inheritance will be through the mother whilst for those defects affecting genes in the nucleus either parent may be able to transmit the condition.

What if I want another baby? Can I avoid passing a faulty gene on to my child?

This is a complex question and the advice will vary depending on both the individual and the type of disease (for example whether it is transmitted from the mother or the father). In cases where the disease comes from the mother, the use of eggs (oocytes) from an unaffected donor eliminates the risk of transmission, though of course the donor should not be a maternal relative such as a sister. It is possible in certain types of mitochondrial myopathy, to analyse the baby’s placenta (CVS), or even the very early embryo (pre-implantation diagnosis), but this is neither widely available nor applicable to all of these disorders.
Your local genetics clinic should be able to advise further. In the case of Leigh’s disease, where a mutation has been identified in the affected child, prenatal diagnosis will usually be possible with planned help from specialist centres.

What if I am already pregnant?

There is no easy way during pregnancy to assess how severely the baby will be affected for most mitochondrial diseases (see above).

What can I do to help myself (my child)?

A good diet, including adequate vitamin intake and the avoidance of obesity are important. Since fasting increases demand on mitochondria, regular meals with, if possible, a high proportion of carbohydrate is recommended. Excessive exertion should be avoided. What level of physical activity you take will depend on how severely your muscle is affected, but for those able to exercise, this will improve well being and in some cases lead to improved muscle function. Our Regional Care Advisers can provide practical support and information. They also help families liaise between the various professionals e.g. physiotherapists, occupational therapists, social workers and teachers.

Minicore (multicore) myopathy

Minicore myopathy, also called, multicore myopathy and multiminicore myopathy, falls under the umbrella of congenital myopathies. These are a group of conditions characterised by muscle weakness and wasting.
Minicore myopathy is a rare condition, and is so named because of the presence of core structures in the muscle fibres. There are four subgroups of minicore myopathy, each with varying symptoms and severity. There is currently no cure for minicore myopathy, but management of the condition is very important and includes physiotherapy, ventilation and corrective surgery where appropriate.
Minicore myopathy is sometimes called multicore myopathy, or multiminicore myopathy, and may also be abbreviated to MmD.

What causes minicore myopathy?

Minicore myopathy is often inherited in an autosomal recessive pattern. This means that both parents must carry the genetic error for their child to be affected, although neither parent is affected. Both males and females can be affected. Around half of cases of minicore myopathy are caused by a genetic error in one of two genes- Selenoprotein N1 (SEPN1) and Ryanodine receptor 1 (RYR1).
SEPN1. Errors in this gene account for around 30% of all cases of minicore myopathy. The gene is located on chromosome 1 and produces a protein called Selenoprotein N1. This gene is also associated with rigid spine muscular dystrophy, and it is now believed that the severe form of classic minicore myopathy and rigid spine muscular dystrophy are the same condition. RYR1. Some of the non-classic forms of minicore myopathy are associated with errors in the RYR1 gene. This gene is located on chromosome 19 and produces a protein which functions as a calcium channel in muscle. Errors in this gene are also associated with central core disease and a condition called malignant hyperthermia (MH). Core structures are also often seen in the muscle of people with central core disease. An overlap of the pathological appearance of what are two genetically distinct conditions may complicate the diagnosis. People with an error in the RYR1 gene, may also be susceptible to the condition malignant hyperthermia. This is an acute reaction to certain anaesthetics or muscle relaxants used for general anaesthesia. Symptoms of MH include high fever, muscle rigidity, dark brown colouration of urine and acute renal failure. MH is potentially fatal if not treated immediately with dantrolene, but can be prevented by avoiding the triggering agents. This should be brought to the attention of the consultant if surgery is to be considered.
Often cases are sporadic, with no previous family history, and the exact cause of the condition is not known.
More information on genetic inheritance is available in the factsheet ‘Inheritance and the muscular dystrophies’.

What are the common features?

There are four subgroups of minicore myopathy.
Classic form. This form accounts for around 75% of cases of minicore myopathy. Onset is usually at birth or within the first few months, and presents with floppiness (hypotonia) and delay in achieving motor milestones. Sometimes young infants can have problems with feeding and a feeding tube may be required. Most children are able to walk independently by 28 months. There is generalised weakness, although weakness of the muscles around the trunk and neck are more severe, and curvature of the spine (scoliosis) is common. There are often problems with the respiratory muscles, causing difficulties with breathing.
Progressive form with hand involvement. This form affects less than 10% of cases of minicore myopathy. It is less severe than the classic form and scoliosis and respiratory problems are mild or absent. The characteristic feature is that people with this form are doublejointed (hyperlaxity).
Antenatal form with arthrogryposis multiplex congenita (AMC). This form also affects less than 10% of people with minicore myopathy. The general feature is the presence of tightened joints (contractures) at birth, due to poor foetal movement. This form is also associated with a range of physical features including long head, low set ears, and a short neck. The respiratory muscles can be moderately to severely affected, thus problems with breathing are common Ophthalmoplegic form. The main characteristic of this form is external ophthalmoplegia. This is a condition which results in weakness of the muscles around the eye. This can lead to problems with eye movement and sometimes droopiness of the eyelids (ptosis). Along with the weakness around the eyes, there is weakness of the muscles closest to the trunk of the body.

How is it diagnosed?

Muscle biopsy. This is done in one of two ways: either a small piece of muscle is taken under general anaesthetic or a needle biopsy is performed to remove a small sample. The sample will be analysed under a microscope.
Muscle tissue from a person with minicore will have a characteristic pattern. Normal muscle tissue has two different types of fibre; type 1 and type 2. Muscle from people with minicore myopathy has more type 1 fibres than type 2. Also, within these fibres, there are structures which are called ‘cores’; which can be seen under the microscope. These structures are not specific to minicore myopathy, and so the clinical signs must be considered together with the muscle sample to give a diagnosis of minicore myopathy. A fact sheet on Muscle biopsies is available from the Information and Support Line.
Molecular testing is currently not available for minicore myopathy. It may be available for families where the specific genetic error has been identified, but a genetic testing centre would have to advise whether this was possible.

What other tests are available?

Since genetic testing is not available for this condition, prenatal diagnosis is also not available. In families where the error has been identified, both prenatal diagnosis and carrier testing may be possible, but a genetic testing centre would have to advise whether this was the case.

How will it progress?

Progression in minicore myopathy is very variable between individuals. In some people the condition remains static, whilst in others muscle weakness may worsen with time. Sometimes, individuals with the classic form of minicore myopathy may have progressive scoliosis and may show a decline in respiratory function. In most of these cases the course becomes stable in late childhood and many people continue to walk into adulthood, despite scoliosis and the requirement for respiratory support through ventilation.

Is there a treatment?

Currently there is no treatment for minicore myopathy although management of the condition is
very important.
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 nonweight 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. Ventilation. Breathing problems are common with minicore myopathy, and thus respiratory function should be regularly monitored. A decrease in oxygen intake can lead to, among other things, headaches, breathlessness, poor appetite and disturbed sleep. Night time ventilation involves the use of a face mask attached to a small machine, which assists in breathing. This aids the muscles which control breathing, and allows a greater intake of oxygen. Night time ventilation may be beneficial to people with minicore myopathy, but this should be discussed fully with a consultant to determine whether it is appropriate. If there is a tendency to chest infections it is worth considering pneumovax and the flu vaccine.
Corrective surgery. Scoliosis, or curvature of the spine, is common with minicore myopathy. 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 Support 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.
Feeding tube (or gastrostomy). This is a tube that goes into the stomach through the stomach wall and enables a person to be given food and fluids by passing them directly into the stomach via the tube. People with a myopathy may have problems with swallowing which can lead to choking and inhalation of food. This can result in chest infections. A feeding tube prevents this from happening. There are a number of different types of feeding tube which are available, and these are fitted by a short surgical procedure. A fact sheet on Gastrostomy is available from the Information and Support Line.

Is there a cure?

Currently there is no cure for minicore myopathy although much research is currently being conducted into all the congenital myopathies. Although there is no effective treatment to halt the progression, there are a couple of different ways in which to manage the symptoms of minicore myopathy 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. The research department at the Muscular Dystrophy Campaign, regularly monitors research advances in congenital myopathies, and produces releases which are sent to members when significant scientific advances occur. Email: research@muscular-dystrophy.org

Planning for the future?

Since the progression of minicore myopathy is very variable, planning for the future may be
difficult. Depending on the severity of the condition there are things which may have to be
considered, such as:
• Education
• Holidays
• Ventilation
• Transport
• Home adaptations
Further information on these subjects can be obtained from the Information and Support Line.
Other things to consider
Anaesthetics and muscle relaxants. As mentioned, there is an association between minicore myopathy caused by RYR1 mutations and a condition called malignant hyperthermia, which is triggered by the administration of 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. Many companies are able to provide a Medic Alert Card, which can be carried to advice of any medical condition. These come in the form of bracelets, pendants etc and carry essential information.