Myofibrillar myopathies (MFM)

Myofibrillar myopathies (MFM) are a group of genetic conditions that cause progressive muscle weakness. Symptoms can vary depending on the genetic cause, but muscle biopsies normally show a common feature called myofibrillar degeneration, which is the breakdown of muscle fibres that can affect muscle strength and function

Myofibrillar myopathies are now often grouped with a broader category of muscle conditions called distal myopathies, which typically cause weakness that starts in the hands, feet, lower legs, or forearms.

Symptoms usually develop in mid-adulthood (40s to 60s) but can develop anytime between infancy and late adulthood. Symptoms and their severity vary widely between those affected.

The most common symptoms of MFM are listed below, however some people may also experience other symptoms. These could include muscle pain (myalgia), joint stiffness (contractures), a curved spine (scoliosis), loss of sensation in the limbs (peripheral neuropathy), and cataracts. The typical features of specific types of MFM can be found in Table 1 under genetic changes.

Muscle weakness

Progressive muscle weakness is the main symptom of MFM. This usually begins in the muscles furthest away from the body (distal muscles), such as the hands and forearms, ankles, and lower legs. With time, weakness can progress to the muscles closer to the body (proximal muscles), such as the thighs and upper arms. However, for some people, it can be the opposite, where weakness begins in the proximal muscles and involves the distal muscles later.

Weakness in the distal muscles can cause people to trip or fall or have difficulty using their hands – for example, gripping or unscrewing a bottle top. Weakness in the proximal muscles can make it hard to get out a chair, use stairs, lift things above the head, or hold the arms up in the air.

Cardiac

A weakening of the heart muscle (cardiomyopathy) is present in about 3 in 10 people with myofibrillar myopathy. However, the risk depends on which specific gene is causing the condition. This can cause people to experience a rapid or irregular heartbeat and to feel faint or out of breath.

Respiratory

The muscles used for breathing may weaken, leading to breathing difficulties and, in severe cases, respiratory failure. Respiratory muscle weakness can result in significant fatigue, feelings of being unrefreshed upon waking, or morning headaches. This is mainly seen in Desmin/DES MFM and is very rare in other types.

Speech and swallowing

The muscles needed for speech and swallowing can also be affected, leading to difficulties with swallowing and can cause coughing or choking while eating. In these cases, it may be necessary to see a speech and language therapist – a healthcare professional who helps people with speech and swallowing problems. This may be seen in CRYAB MFM but is very rare in other types.

Genetic changes

Changes in several different genes can cause MFM. The most common genes are DES, MYOT, ZASP, BAG3, FLNC, and CRYAB, but there are others. These genes contain instructions to make proteins that build structures called myofibrils. Myofibrils provide strength for muscle fibres during repeated muscle contraction and relaxation. In people with MFM, these proteins don’t work properly. They clump together inside of the muscles, making the myofibrils break down and the muscles become weak. In up to half of patients with MFM, the genetic cause cannot be found, but MFM is still diagnosed based on typical muscle biopsy findings.

Table 1: Typical features of myofibrillar myopathies

Inheritance

MFM is usually inherited in an autosomal dominant pattern. This means that one copy of the gene from an affected parent can cause the condition. In some cases, MFM can be inherited in an autosomal recessive pattern. This means a person would need two copies of the affected gene – one from each parent – to develop the condition. MFM can also occur in someone with no family history if a new genetic change happens in the affected person.

For more information, see our inheritance and genetics page.

A GP can make a referral to a neurologist for testing. A neurologist is a doctor who specialises in conditions that affect the muscles and nervous system. A diagnosis of a genetic muscle condition is typically made using a combination of symptom history, physical examination, family history, electrical tests, and MRI scans of the muscles.

In the past, a muscle biopsy was the next step in testing. This would show the myofibrillar changes in the muscle, and then specific genes linked to MFM would be tested. However, advances in technology now allow for the testing of many genes at once through a method called next-generation sequencing. This involves taking a blood sample for a gene panel test that currently screens 80 genes linked to inherited muscle conditions, including those that cause myofibrillar myopathies.

In some cases, a muscle biopsy may still be performed if the gene test is negative or to clarify the results of the gene tests. If a known genetic change is found in the DES or MYOT genes, it’s possible to be diagnosed with MFM without the need for a muscle biopsy.

For more information, see our diagnosis page.

A multi-disciplinary approach, different health professionals working together, is not only important for the management of the condition and symptoms but for wellbeing too.

Access to a healthcare team

It’s important to have access to a healthcare team who understands your condition and can monitor its progression. Usually, the lead professional will be a neurologist. If you do not have a neurologist or specialist doctor, speak to your GP about getting access to one. The neurologist will work with other members of a multidisciplinary team, for example a physiotherapist, occupational therapist, orthotics expert, speech and language therapist, who may all be involved in looking after you at different times.

Cardiac

Regular cardiac monitoring may be necessary, as some forms of MFM affect the heart. This often includes an electrocardiogram (ECG), 24-hour ECG, and echocardiogram (ECHO). If arrhythmia (abnormal heart rhythm) and/or cardiac conduction defects (problems sending electrical signals through the heart to instruct it to contract properly) are found, a pacemaker and implantable cardioverter-defibrillator (ICD) may be recommended by the clinical team.

Respiratory

For people with types of MFM where respiratory muscles are affected and cause breathing difficulties, non-invasive ventilation (NIV) may be needed to support breathing. Overnight sleep studies can monitor respiratory function during sleep and diagnose night-time breathing problems. This is usually nocturnal hypoventilation, where low oxygen levels and high carbon dioxide levels during sleeping can cause symptoms of morning headaches and daytime fatigue. Nocturnal hypoventilation can be treated using NIV during sleep to help maintain adequate ventilation.

Exercise and physiotherapy

Staying as active as possible is important. A physiotherapist can put together a suitable exercise plan to help maintain strength and mobility. A physiotherapist is a healthcare professional who helps manage symptoms through movement, exercise, and manual therapy. Regular stretching can help to keep joints and muscles flexible and prevent tightness. Strengthening exercises can help prevent muscle weakening, and aerobic exercise such as walking, swimming, and cycling can help keep the heart and lungs as healthy as possible. To find out more about advice for adults, see exercising with a muscle wasting condition.