Myofibrillary myopathy is a group of genetically heterogeneous diseases with different types of inheritance, united by similar pathohistological changes in muscle tissue. Symptoms of this condition are progressive muscle weakness combined with cardiac arrhythmias and respiratory failure. Depending on the form of the disease, the severity of one or another manifestation may vary greatly. Diagnosis of myofibrillary myopathy is carried out on the basis of the data of the patient’s current status, histological examination of muscle tissue samples and molecular genetic studies. There is no specific treatment, supportive and symptomatic therapy is used.
General information
Myofibrillary myopathy (MFM) is a set of hereditary conditions, the cause of which lies in a violation of the structure of the Z–disk proteins of muscle fibers, which is why their main manifestations are muscle weakness and other disorders. At the moment, six genetic types of this condition are known, characterized by a different mechanism of inheritance. X-linked forms of the disease are quite rare – genes of this variety have not been identified to date. Due to such a wide variety of types of myofibrillary myopathy, their sexual distribution is different – mainly autosomal dominant and autosomal recessive forms prevail with the same risk of men and women. Any form of such a condition is quite rare, so the occurrence (both general and each type separately) has not yet been determined. Myofibrillary myopathies are characterized by high phenotypic variability even within a single mutation, which further complicates the diagnosis of the disease.
Causes and classification
The main cause of any form of myofibrillary myopathy is a violation of the structure of the protein components of sarcomeres caused by genetic mutations. At the same time, the different nature of genetic defects, as well as a number of other factors, lead to significant clinical variability of this condition. There are several main varieties of myofibrillary myopathy, which have different etiology and pathogenesis, but at the same time manifest similar symptoms and a very similar pathohistological picture.
- Myofibrillary desmin-dependent myopathy (MFM-1) is the most common form, its share, according to some data, is more than 60% of all cases of this condition. The pathology is caused by a mutation of the DES gene, which is located on the 2nd chromosome and encodes a protein called desmin. This protein is one of the structural components of myofibrils, the largest amount of it is found in the border zone of the Z-disk. With a defective structure of desmin caused by a genetic mutation, it cannot perform its functions and gradually accumulates in the fibers of skeletal and cardiac muscles. However, as geneticists managed to find out, mutations of the DES gene cause only about a third of all cases of type 1 myofibrillar myopathy, the remaining genes have not yet been detected.
- Myofibrillar myopathy of the 2nd type (myofibrillar alpha-B-crystallin dependent myopathy, MFM-2) – in fact, also represents a whole group of genetic lesions of muscle tissues of different types. They are caused by mutations in the CryAB gene localized on the 11th chromosome. The product of its expression is the protein alpha-crystallin, which prevents the aggregation and denaturation of cellular proteins when exposed to elevated temperatures. Thus, alpha-crystallin belongs to the group of heat shock proteins, but various defects in its structure can cause myofibrillary myopathy. The reasons for the development of this condition with mutations of the CryAB gene are reduced to the formation of protein complexes with alpha-crystallin and other proteins in the cells of skeletal muscles and myocardium. They are insoluble and cause myocyte dystrophy, during the formation of such complexes, the functions of their constituent proteins are blocked. Almost all CryAB mutations lead to the development of myofibrillary myopathy with an autosomal dominant inheritance mechanism.
- Type 3 Myofibrillar myopathy (myofibrillar myotylin-dependent myopathy, MFM-3) is caused by mutations in the MYOT gene located on the 3rd chromosome. The gene encodes the protein myotylin, which acts as a structural component of striated muscle tissue (myocardium and skeletal muscles). The functions of myotylin are reduced to stabilizing the structure of myofibrils and the process of muscle contraction, and the ability of this protein to attach F-actin has also been revealed. The genetic defect leading to the development of type 3 myofibrillary myopathy is most often inherited autosomally dominant.
- Type 4 Myofibrillary myopathy (MFM-4) is a rather rare form of this pathology, caused by mutations of the LDB3 gene localized on the 10th chromosome. The LDB3 product is a protein called ZASP (from the English Z-band alternatively spliced PDZ-motif), whose functions are also reduced to stabilizing the structure and functions of the sarcomere. Therefore, disorders in the structure of the LDB3 gene lead to the development of a special form of myofibrillary myopathy.
- Type 5 Myofibrillary myopathy (MFM-5) is caused by defects in the FLNC gene located on the 7th chromosome. It encodes a sequence of actin-binding protein known as filamin-2 or filamin-C, which is able to stitch together actin filaments, both in muscle tissue and in the cytoskeleton of cells. The defective structure of the filamin-C protein leads to the development of mild forms of myofibrillary myopathy.
- Type 6 Myofibrillary myopathy (MFM-6) is caused by a mutation of the BAG3 gene localized on the 10th chromosome. The expression product of this gene is a protein of the same name, which belongs to the group of chaperones, it has the ability to regulate the work of ATPase in many tissues, including muscle. Also, among its functions, the ability to activate the production of myofibrill components under mechanical loads was revealed. In the presence of defects in the structure of BAG3, a large number of different pathologies can develop: some forms of Alzheimer’s disease, cardiomyopathy, myofibrillary myopathy.
Symptoms
The main manifestation of any form of myofibrillary myopathy is progressive muscle weakness, which can affect both a separate group and most of the muscles of the body. The presence of other manifestations – cardiac arrhythmias, cardiomyopathy, respiratory failure, polyneuropathy – depends on the type and severity of the disease. At the same time, each of the forms of myofibrillary myopathy has its own clinical course features that allow it to be roughly classified even without molecular genetic analysis. Thus, MFM-1 is characterized by the onset of the disease in 20-30 years and a fairly variable lesion of the muscles (weakness occurs in the shoulder, lumbar-limb, distal or proximal groups), cardiomyopathy with heart failure often develops. The clinical picture of type 1 myofibrillary myopathy can vary significantly even with the same variant of genetic mutation in relatives.
MFM-2 manifests itself in 25-40 years, several cases of its development at an earlier age have been described. This form of myofibrillary myopathy often affects the proximal muscle groups of the extremities and the myocardium, in some cases it can cause sudden cardiac death. Myofibrillar myotiline-dependent myopathy (MFM-3) is characterized by a later onset (at the age of more than 45 years) and a slow progression of symptoms, mainly limb muscles are affected. Another manifestation of this type of disease is dysarthria, due to the weakness of the musculature of the articulatory apparatus. Approximately half of the patients have cardiomyopathy. Myofibrillary myopathy of the 4th type also most often occurs at an older age, affects the proximal and distal muscle groups of the extremities. Myocardium suffers only in a quarter of patients, a distinctive feature of MFM-4 is the development of polyneuropathy and hyporeflexia in about half of cases.
Myofibrillary myopathy of the 5th type manifests itself at the age of 35-50 years, mainly the proximal muscle groups of the lower extremities are affected, the musculature of the arms is less often affected. Respiratory disorders caused by weakness of the respiratory muscles and back pain caused by compression of the spinal roots due to hypotension of the muscular framework of the spinal column are also not uncommon. Myocardial damage in MFM-5 occurs extremely rarely, almost half of the patients have various kinds of neuropathies. Type 6 myofibrillary myopathy is so far the only variant of this disease that develops in childhood. It is characterized by the defeat of an extensive number of muscles of the extremities, their belts and trunk. By adolescence, with MFM-6, cardiomyopathy occurs, usually having a dilated character, frequent manifestations of this condition are also curvature of the spine, sometimes joint contractures.
Diagnosis and treatment
Myofibrillary myopathy can be detected by examining the patient, by clarifying his hereditary history, histological examination of a biopsy of muscle tissue and molecular genetic studies. Secondary methods of diagnosing this condition are electrocardiography, echocardiography and neurological examination. When examining a patient with myofibrillary myopathy, weakness of certain muscle groups (depending on the form of the disease), tremor is detected, with a prolonged course of pathology, pronounced hypotrophy of muscle tissue. Histological examination of muscles reveals disorganization of Z-disks, sometimes chaotic arrangement of myofibrils and accumulation of protein masses inside myocytes. Modern immunochemical studies allow us to determine the composition of these inclusions – it can be defective desmin (with MFM-1), crystalline complexes (MFM-2), myotylin (MFM-3) and other proteins, depending on the form of myofibrillary myopathy.
Modern genetics is able to detect mutations in some genes that cause myofibrillary myopathy (DES, CryAB, MYOT), which is the final confirmation of the diagnosis. Detection of such defects, as a rule, is carried out by direct sequencing of the sequence of the above genes. Cardiographic studies can confirm arrhythmia, signs of cardiomyopathy and heart failure, which often accompany this hereditary condition. Neurological studies in some forms of myofibrillary myopathy reveal hyporeflexia and polyneuropathy. There is no treatment, supportive therapy is used, antiarrhythmic agents, cardiac glycosides, vitamin preparations and other medications are prescribed for myocardial damage according to indications.
Prognosis and prevention
The prognosis of myofibrillary myopathy is often uncertain, as it is strongly dependent on the type of this disease. Some types of the disease occur at such a late age and develop so slowly that they do not significantly affect the quality of a person’s life until his death for other reasons. Other forms of myofibrillary myopathy can be diagnosed in young people and rapidly lead to cardiac or respiratory failure and death. The most unfavorable prognosis is that of developing MFM-6 in children – in most cases, death occurs before the age of 25 due to myocardial damage. Prevention of myofibrillary myopathy is reduced to medical and genetic consultation of couples with an increased risk of such a disease to identify the carrier of a defective gene.
