NORD gratefully acknowledges Kathleen Murphy, MBiochem, MS, NORD Editorial Intern from the Stanford University MS Program in Human Genetics and Genetic Counseling and Jennifer Kohler, ScM, CGC, Clinical Instructor (Affiliated), Dept of Pediatrics, Division of Medical Genetics, Stanford University, for assistance in the preparation of this report.
Myofibrillar myopathies are a group of rare genetic neuromuscular disorders that may be diagnosed in childhood but most often appear after 40 years of age. These conditions are highly variable but are characterized by a slowly progressive muscle weakness that can involve skeletal muscle (muscles that function to move bones) and smooth muscle (muscle often associated with organs, such as the digestive tract). Skeletal muscle weakness can be present in the limb muscles close to the center of the body (proximal) as well as the muscle farther from the center of the body (distal). A weakening of the heart muscle (cardiomyopathy) is common and may result in an irregular heartbeat (arrhythmia or conduction defects) or congestive heart failure.
Specific signs and symptoms of myofibrillar myopathies vary by subtype, which are defined by the causative gene (see below). However, all involve progressive muscle weakness and characteristic abnormalities in muscle cells (myofibrillar disorganization and protein accumulation). Some people with myofibrillar myopathy have muscle stiffness, aching, cramps or decreased muscle mass (atrophy). Cardiomyopathy is sometimes the first symptom and may present as arrhythmia, conduction defects or congestive heart failure.
Most individuals with myofibrillar myopathy due to desmin mutations (desminopathies) present with slowly progressive muscle weakness. Distal muscle weakness is more common than proximal muscle weakness but symptoms may vary between people in the same family. Difficulty breathing may occur and children with desminopathies may present with cardiomyopathy.
For those with alpha-b crystallinopathy, which is myofibrillar myopathy caused due to mutations in the CRYAB gene, symptoms usually occur in adulthood, and include limb muscle weakness that is more severe in the distal muscles than the proximal muscles as well as cardiomyopathy, difficulty breathing and cataracts. If alpha-b crystallinopathy begins in infancy, it can be associated with muscle stiffness and weakness and respiratory failure.
For people with the myotilinopathy subtype, which is caused by mutations in the MYOT gene, symptoms mostly begin in middle or late adulthood. The main symptoms are limb weakness, cardiopathy and difficulty breathing. A small portion of patients have a form that begins in early or middle adulthood. This form involves limb weakness and can result in arrhythmia.
The ZASPopathy subtype, caused by mutations in the ZASP gene, usually presents in middle or late adulthood with the features of limb weakness (proximal more affected than distal) and difficulty breathing. Cardiopathy and neuropathy can occur in a small portion of this group.
Most individuals with the filaminopathy subtype, caused by mutations in the FLNC gene, usually experience symptoms in middle adulthood, with features of muscle weakness that is more severe in the proximal limbs than the distal limbs and difficulty breathing. Cardiopathy may occur in a subset of people, and pain, loss of sensation and inability to control muscles may also occur.
Children with BAG3-related myofibrillar myopathies may present before the age of 20 with proximal weakness, respiratory failure and restrictive cardiomyopathy. This condition is frequently rapidly progressive and fatal.
Myofibrillar myopathies may be caused by disease-causing mutations in a single gene or by many changes in multiple genes in combination with environmental factors. Genes function as the instructions for the creation of proteins, and the disease-causing mutations result in excess amounts of a particular protein in muscle. The genes responsible for myofibrillar myopathies are identified in approximately 20% of affected individuals. These disorders have been categorized by the gene involved.
Desminopathy—(onset age 20-30) DES gene/desmin protein
Alpha-B crystallinopathy—(onset age 20-40 years) CRYAB gene/a-B crystallin protein
Myotilinopathy—(onset age 27-77) titin immunoglobulin domain protein MYOT gene/myotilin protein
Filaminopathy—(onset age 37-57) FLNC gene/filamin C protein
BAG3-related myofibrillar myopathy—(onset childhood) BAG3 gene/BCL2-associated athanogene 3 protein
ZASPopathy—(onset age 44-73 years) ZASP gene/LIM domain-binding protein 3
HSPB8 myopathy—(onset early/middle adulthood) HSPB8 gene/ HSPB8 protein
In some patients, genes that cause other types of neuromuscular conditions have disease-causing mutations that cause features of myofibrillar myopathy. These conditions include reducing body myopathy (FHL1 gene), hereditary myopathy with early respiratory failure (HMERF gene), epidermolysis bullosa simplex with muscular dystrophy (PLEC gene), MFM-actinopathy (ACTA1 gene) and limb girdle muscular dystrophy type 1D (DNAJB6 gene).
Myofibrillar myopathies are usually inherited in an autosomal dominant pattern. Everyone has two copies of the genes that cause myofibrillar myopathy. Autosomal dominant genetic disorders occur when one copy of the gene has a disease-causing change in it. A disease-causing change in a gene is sometimes called a mutation. The gene copy with the mutation can be inherited from either parent or it can be the result of a new mutation in the affected individual. Approximately 25% of affected individuals inherited the disease-causing mutation from an affected parent. In autosomal dominant myofibrillar myopathies, the risk of it passing from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
It is possible for children to have autosomal recessive desminopathy, meaning that disease-causing mutation(s) must be present in both copies of the Desmin (DES) gene in order for a person to develop disease. In this case, onset can be in early childhood.
It is not always possible to know if a person is affected with autosomal dominant or autosomal recessive myofibrillar myopathy. While clues can be found in the family history, some people within the same family with the same disease-causing mutations may remain undiagnosed or be diagnosed later in life.
The frequency of myofibrillar myopathies is not well understood. It is likely that these conditions are unrecognized and underdiagnosed.
A diagnosis of myofibrillar myopathy is made based on clinical evaluation of the patient’s symptoms as well as tests such as electromyography (EMG), nerve conduction studies (NCV) and muscle biopsy. Molecular genetic testing for mutations in the DES, CRYAB, MYOT, ZASP, FLNC, BAG3, FHL1, TTN, PLEC, ACTA1, HSPB8, and DNAJB6 genes may confirm the diagnosis.
There are currently no curative treatments for myofibrillar myopathies. Treatment is directed toward each symptom that a person develops, and should be directed by a specialist.
Individuals affected with cardiomyopathy may consider implantation of a mechanical device to regulate heartbeat (pacemaker) and cardioverter defibrillator (ICD). Heart transplantation may be considered if the cardiomyopathy is progressive or life threatening. Respiratory therapy and physical therapy may be helpful for those with advanced muscle weakness. Orthotics may be helpful if foot drop develops.
Cardiac screening including electrocardiography, echocardiography, and 24-hour Holter monitoring is recommended once per year in individuals with myofibrillar myopathy, and a cardiac MRI when available. Respiratory function should also be monitored.
There is preliminary evidence that metformin may be a candidate for slowing disease progression in those with BAG3-related myofibrillar myopathy.
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