Centronuclear and myotubular myopathies

Centronuclear myopathies (CNMs), which includes myotubular myopathy (X-linked myotubular myopathy – XLMTM), are types of congenital myopathy. This is a group of conditions characterised by low muscle tone and muscle weakness, present at birth or early childhood.

There are different types of CNMs, depending on the specific genetic change and how they’re inherited.

Myotubular myopathy (XLMTM) is inherited in an X-linked recessive pattern. This means the changed gene is located on the X chromosome and usually affects males.

Centronuclear myopathy (CNM) is the name used for other forms of the condition which can be inherited in autosomal dominant or recessive patterns. In autosomal dominant inheritance, a person needs only one changed gene from either parent to develop the condition. In autosomal recessive inheritance, both copies of the gene (one from each parent) must be changed for the condition to occur.

Symptoms vary greatly and the needs of those affected may change over time. Autosomal dominant and recessive CNMs are usually slowly progressive. XLMTM is the most severe form – it can progress rapidly from birth and cause life-threatening complications. Generally, the earlier the onset, the more severe the symptoms will be.

Myotubular myopathy (XLMTM)

Most people with XLMTM will be severely affected, although some may have milder symptoms. XLMTM has an early onset and there can be signs before birth, such as reduced movement in the womb and excessive amniotic fluid around the baby. Babies born with XLMTM usually have severely low muscle tone and weakness.

Weakness in the breathing and swallowing muscles can cause breathing and feeding difficulties. Those affected may need long periods of, or constant, ventilation to support their breathing and are more likely to get chest infections because they cannot cough effectively. This makes XLMTM life-threatening, due to the risk of respiratory failure and infections like pneumonia. Early identification and management are crucial. Some babies may not survive the first few months of life, but those who do could show improvement in the first few years. However, they will still require extensive medical support and management.

People with XLMTM often have a long face and weak facial muscles, which can affect their facial expressions and eye movements. They might also have droopy eyelids (ptosis), curvature of the spine (scoliosis), and joint stiffness (contractures).

Autosomal dominant centronuclear myopathy (CNM)

Autosomal dominant CNM typically starts during adolescence or early adulthood, though it can vary. This form tends to be mild, and the main symptom is progressive weakness in the muscles of the legs. This may cause difficulty with moving around, and some people may need a wheelchair as the condition progresses. Other muscles can also be affected, but this is less common.

Autosomal recessive centronuclear myopathy (CNM)

Autosomal recessive CNM typically starts in infancy (from birth to two years) or early childhood, and severity can vary. Some people may have symptoms as severe as XLMTM, while others will have mild symptoms. This depends on the specific genetic change involved.

Those affected will experience progressive muscle weakness and delays in reaching motor milestones, such as sitting unaided and walking. The muscles in the legs, particularly those closest to the torso, are usually the weakest. In more severe cases, people may have problems with swallowing and/or breathing that require medical support. Facial weakness, droopy eyelids (ptosis), and limited eye movements are common. Other symptoms can include curvature of the spine (scoliosis) and an elongated face.

Myotubular myopathy (XLMTM)

XLMTM is caused by changes in the MTM1 gene, which provides instructions to make a protein called myotubularin. This protein is important for the development and maintenance of muscle cells. In people with XLMTM, the production of myotubularin is disrupted and not enough of it is made. This leads to muscle weakness and other symptoms.

XLMTM follows an X-linked inheritance pattern because the MTM1 gene is located on the X chromosome. Since males only have one copy of the gene, they are more likely to be affected. Females usually have a second, working copy of the gene, which protects them from developing the condition. Females will be carriers but don’t usually experience symptoms. In rare cases, a female carrier may experience symptoms of XLMTM, known as a manifesting carrier.

Centronuclear myopathies (CNM)

CNM is caused by changes in certain genes. CNM can be inherited in two patterns:

• Autosomal dominant inheritance – a change in one copy of a gene can cause the condition. Most cases of autosomal dominant CNM are due to changes in the DNM2
• Autosomal recessive inheritance – a person must inherit two changed copies of a gene (one from each parent) to develop the condition. Autosomal recessive CNM can be caused by changes in several genes, including BIN1, RYR1, TTN, SPEG10, CACNA1S, and ZAK. Some of these genes are also linked to other congenital myopathies.

For more information, see our inheritance and genetics page.

CNM and XLMTM can be diagnosed using a combination of physical examination, family history, genetic testing, muscle scans, and sometimes a muscle biopsy.

In some cases, a muscle biopsy may be used for diagnosis. During this procedure, a small sample of muscle tissue is examined under a microscope. In CNM, the control centre of muscle fibres (nuclei) are abnormally located in the centre, rather than at the outer edges. Genetic testing, using a blood sample, confirms the diagnosis by identifying specific genetic changes associated with CNM.

For more information, see our diagnosis page.

A multi-disciplinary approach, which involves different healthcare professionals working together, is important in not only managing the condition and symptoms but in improving wellbeing too. The severity of XLMTM and some cases of CNMs mean that condition management is required as soon as symptoms begin.

Access to a healthcare team

People should have access to a multidisciplinary healthcare team. Usually, the lead professional will be a neurologist – a doctor specialising in conditions that affect the muscles and nervous system. If you do not have contact with a neurologist or specialist doctor, speak to your GP about getting access to one.

Respiratory

Breathing problems are common. A baby or child with XLMTM is likely to need long-term breathing support for at least some hours of the day and/or night. Respiratory weakness can cause morning headaches, breathlessness, poor appetite, and disturbed sleep.

Regular monitoring of respiratory function is important, even for those who seem to be mildly affected. Some people who need a lot of breathing support during the day and night may require invasive ventilation, which involves placing a tracheostomy tube into the windpipe through a small incision. For those who do not need continuous breathing support, non-invasive ventilation (NIV) may be a better option.

Pneumococcal and annual flu vaccinations should be taken to help prevent chest infections, which would require prompt antibiotic treatment.

Swallowing and nutrition

Swallowing difficulties can be severe and impact feeding. Referral to a speech and language therapy team is necessary for assessment and to begin swallowing therapy. Unmanaged difficulties can lead to inhalation of saliva, food, or drink into the lungs (aspiration) and cause serious infection (aspiration pneumonia).

If feeding difficulties lead to poor weight gain and malnutrition, referral to a dietetics service is necessary. Nutritional supplements and vitamins will be considered. A feeding tube (gastrostomy) may be necessary to ensure adequate nutrition and hydration, especially in people with severe swallowing difficulties – the tube allows food to be put directly into the stomach.

Exercise and physiotherapy

Physiotherapy is recommended as it can help to maintain breathing capacity, manage scoliosis (curvature of the spine), and prevent further worsening of joint stiffness. It can also help maintain physical function and mobility. A specialist physiotherapist, a healthcare professional who helps manage symptoms through movement, exercise, and manual therapy, can put together a suitable exercise plan. This may focus on gentle stretching and range of motion (ROM) exercises. Children will need support from caregivers to guide them through exercises and provide encouragement. Daily respiratory physiotherapy, including airway clearance, is recommended, especially for those on ventilators and those with poor respiratory muscle strength. For advice for adults, see exercising with a muscle wasting condition.

Cardiac

Cardiac symptoms, such as cardiomyopathy, which makes it harder for the heart to pump blood properly, are rare but can occur in those with changes in the TTN or SPEG10 genes. Cardiac monitoring is recommended in these cases.

Anaesthesia stops a person feeling pain during a procedure or surgery. Before any medical procedure, it’s important to make the anaesthetist and other healthcare professionals aware of a diagnosed muscle wasting condition and any heart or breathing complications. This will help them plan for specific needs and ensure safety. Those with a change in the RYR1 gene are at particularly high risk of a severe reaction known as malignant hyperthermia.

Malignant hyperthermia

Malignant hyperthermia (MH) is a potentially life-threatening reaction, triggered by the use of certain general anaesthetics and muscle relaxants. Conditions with changes in the RYR1 gene, such as some forms of autosomal recessive CNM, increase a person’s risk of developing MH.

Symptoms of MH include a rapid rise in body temperature, rigidity of muscles or spasms, rapid heart rate (tachycardia), muscle breakdown (rhabdomyolysis), and dark brown urine due to broken down muscle entering the bloodstream and urine (myoglobinuria). MH must be treated immediately with a drug called Dantrolene, whilst also attempting to cool the person’s body temperature.

MH can be prevented by avoiding triggering anaesthetic agents and using alternative drugs. Suxamethonium (succinylcholine) must be avoided. It’s crucial that the clinical team is made aware of the condition if surgery under general anaesthetics is needed, so that alternative options can be considered.