Myofibrillar myopathy

Myofibrillar myopathy (MFM) primarily affects skeletal muscles, which are muscles that the body uses for movement. In some cases, the heart (cardiac) muscle is also affected. The signs and symptoms of MFM vary among affected individuals, typically depending on the exact genetic cause of the disease. Most people with this disease begin to develop muscle weakness (myopathy) in mid-adulthood. However, features of this disease can appear anytime between infancy and late adulthood.^[1][2]

Muscle weakness most often begins in the hands and feet (distal muscles), but some people first experience weakness in the muscles near the center of the body (proximal muscles). Facial muscle weakness can rarely cause swallowing and speech difficulties. The muscle weakness is progressive, meaning that it tends to worsen over time.^[1]

Other signs and symptoms of MFM can include an enlarged and weakened heart muscle (cardiomyopathy) or an abnormal heart rhythm (arrhythmia), muscle pain (myalgia), and loss of sensation and weakness in the limbs (peripheral neuropathy). For some people, as the disease progresses, the muscles of the lungs may also be affected, which can result in respiratory failure. Individuals with this disease may have skeletal problems including joint stiffness (contractures) and abnormal curvature of the spine (scoliosis). Rarely, people with this disease develop clouding of the front surface of the eyes (cataracts).^[2]

Myofibrillar myopathy (MFM) is caused by a mutation (change) in any of several genes, including DES, CRYAB, MYOT, LDB3, FLNC, BAG3, FHL1, TTN, and DNAJB6.^[1][3] These genes are all responsible for providing instructions to our bodies to make proteins that help keep our muscles strong. Specifically, the muscles are divided into units called sarcomeres. The proteins that are made by these genes are responsible for linking the sarcomeres together so that they are strong enough to help our bodies move.^[2]

When there is a mutation in one of the genes associated with MFM, the muscles are weakened because there is not enough of the linking protein to help make the muscles strong. This causes the symptoms associated with MFM. Because each gene associated with MFM provides instructions for a protein that performs a slightly different function in the muscle, the exact symptoms that are present in each affected individual depends on the exact gene that is changed.^[2] There are rare reports of other genes that may be associated with myofibrillar myopathy.^[3] In about 50% of people who have MFM, the exact genetic cause of the disease is not identified.^[1] This may be because there are other genes that cause MFM that have not yet been discovered.^[3] 

Myofibrillar myopathy (MFM) can be inherited in a number of different ways depending on the exact gene that is changed. Most cases of MFM are caused by changes in genes that are inherited in an autosomal dominant manner.^[1] This means that only one copy of a gene needs to be changed in order for a person to have signs and symptoms of the disease. We inherit one copy of each gene from our mother and the other one from our father. 

In some cases, people with an autosomal dominant form of MFM are the first people in their family who are diagnosed with the disease. This may occur for two reasons. First, it may be that the person diagnosed with the disease is the only person in the family with a genetic change. This means that the genetic change is new (de novo) in the affected individual and it was not inherited from either parent. In other cases, it may be that the parents of the affected individual also have MFM, but they have a form of the disease that is slowly progressing or has not yet been diagnosed. Therefore, if a person is diagnosed with MFM and the exact genetic cause is known, it is important that their parents also receive genetic testing to determine if one of them also has the disease. 

MFM can exhibit reduced penetrance and variable expressivity. Reduced penetrance means that some people who have genetic changes that cause MFM may not have signs or symptoms of the disease. However, these people can still pass on MFM to their children. Variable expressivity means that the exact symptoms of each person with MFM can differ, even within the same family. For example, some affected individuals may have both cardiomyopathy and muscle weakness, while others may just have one or the other.^[1]

If MFM is caused by a change in the FHL1 gene, it is inherited in an X-linked manner.^[1] This means that the FHL1 gene is located on the X chromosome. The X chromosome is one of the sex chromosomes. Each woman has two X chromosomes, and each man has one X chromosome and one Y chromosome. Because men have only one X chromosome, they only have one copy of the FHL1 gene. If this gene has a mutation, they will have MFM. However, women who have changes in one copy of the FHL1 gene are known as carriers of the disease. Most carriers do not have signs or symptoms of MFM because they have another working copy of FHL1. 

If MFM is caused by a change in CRYAB, it is inherited in an autosomal recessive manner.^[1] This means that both copies of the CRYAB gene must be changed in order to have symptoms of the disease. Men and women with a mutation in only one copy of the CRYAB gene are known as carriers, meaning they do not have signs or symptoms of the disease. When two carriers of a CRYAB mutation have children together, for each child there is a:

• 25% chance that the child will have MFM
• 50% chance that the child will be a carrier of MFM like the parents
• 25% chance that the child will have two working copies of CRYAB, so the child will not have MFM and will not be a carrier.

Myofibrillar myopathy (MFM) is diagnosed when an individual has signs and symptoms consistent with the disease such as progressive muscle weakness with or without cardiomyopathy. A healthcare professional may want to perform laboratory tests to rule out other causes of progressive muscle weakness. These tests may include:^[1] 

• Electromyography: a study measuring the response of muscles to an electrical stimulus
• Muscle biopsy: a sample of the muscle is taken to determine how it looks under a microscope
• Creatine kinase test: a test of an enzyme that can provide information about the health of the muscles  

If myofibrillar myopathy is suspected, genetic testing of the genes associated with the disease can be used to confirm the diagnosis and provide more information about long-term outlook.^[4] 

The treatment of myofibrillar myopathy (MFM) depends on the signs and symptoms present in each person. People who have progressive muscles weakness may require physical therapy and assistive devices such as a cane or wheelchair. Individuals who have cardiomyopathy or arrhythmia may require a pacemaker or implantable cardioverter defibrillator (ICD). In severe cases, people with MFM may have progressive heart disease that requires a heart transplant.^[1] Surveillance of the heart, lungs, and muscles are recommended every year or as determined by a doctor.

For some affected individuals, the progressive muscle weakness may affect the ability of the muscles of the lungs to work properly, especially at night. This may require respiratory support such as a ventilator to make sure affected individuals are breathing properly.^[1]

Myofibrillar myopathy (MFM) is a progressive muscle disease. This means that the muscle weakness and other symptoms associated with the disease tend to get worse as people get older. More information may be available about the long-term outlook for each specific genetic change that causes MFM. In general, MFM that first shows symptoms beginning in childhood is more severe than when the onset of symptoms is later in adulthood. 

Because MFM shows variable expressivity, the exact signs and symptoms for each person cannot be predicted, including whether or not an affected individual will have heart problems or breathing problems.^[1] If the heart problems and breathing problems are managed, people with MFM are expected to have a normal life expectancy.^[5]