Nemaline myopathy is a group of genetically heterogeneous hereditary myopathies, the common pathohistological manifestation of which is the formation of filamentous structures in the muscle tissue, which is reflected in the name of the pathology (from the Greek Nema – thread). Symptoms of various forms of the condition can vary significantly in their severity – muscle hypotension, muscle weakness (including respiratory and facial muscles), skeletal abnormalities (scoliosis, elongated skull shape, cleft palate) are possible. Diagnosis is based on the assessment of the patient’s status, the study of a biopsy of muscle tissue, molecular genetic studies. There is no specific treatment, supportive and symptomatic therapy is used.
General information
Nemaline myopathy (NEM) are a set of genetic pathologies with similar clinical manifestations, which are characterized by a pronounced violation of the structure of muscle tissue with the formation of abnormal thread–like or rod-shaped structures in it. The disease was first described in 1963 by two independent groups of researchers led by D. Shaya and P. Konen, in subsequent years, many genetic varieties of this condition were identified. Depending on the gene and mutation in it, nonmaline myopathy can have both autosomal dominant and autosomal recessive inheritance. The incidence of pathology has not been determined to date, but, according to many geneticists, it is one of the most common congenital myopathies – sometimes the numbers 1:50,000 are indicated. At the same time, it is possible to reliably determine the etiology of non-myopathy (the gene responsible for its development and the nature of its defect) only in half of cases, which indicates the incompleteness of the study of this disease.
Causes and classification
The cause of the development of non–myopathy is genetic defects that lead to the formation of abnormal forms of structural proteins of muscle tissue – mainly sarcomeric proteins. As a result, muscle contraction processes are disrupted, as well as, in some cases, their formation, which leads to the appearance of congenital forms of this condition. To date, it has been possible to identify seven genes whose mutations are responsible for the development of non-myopathy, however, as mentioned above, they cause only half of all cases of the disease. In addition, there is a form of pathology with a delayed onset, affecting mainly adults – but, as more detailed studies have shown, it is due to acquired autoimmune disorders, and not genetic factors.
In addition to the classification created on the basis of modern genetics, non-myopathy is also divided according to its phenotypic manifestations into congenital (typical, intermediate and severe varieties) and juvenile forms. The relationship between these two classification systems is rather conditional – different mutations of the same gene can lead to the development of severe and typical congenital forms or juvenile varieties of the disease.
NEM-1, a form of nemaline myopathy caused by a mutation of the TPM3 gene located on the 1st chromosome, is registered in about 2-3% of cases of pathology. The gene encodes one of the chains of slow alpha-tropomyosin, a structural protein of muscle tissue. Various mutations of this gene with different types of inheritance can lead to non-myopathy. Autosomal dominant defects cause the development of the juvenile form of the disease, and autosomal recessive defects are characterized by a congenital severe course of pathology.
NEM-2 is the most common variant of nemaline myopathy, accounting for about half of all genetically identified cases of this disease. It is caused by a defect in the NEB gene, which is localized on the 2nd chromosome and encodes the giant protein nebulin. The latter is functionally connected with thin (actin) strands of muscle fiber. Mutations of the NEB gene lead to non-myopathy of an exclusively congenital nature with a typical or severe course.
NEM-3 is the second most common form of nemaline myopathy, recorded in 20-25% of cases with a certain etiology. The cause of this form is mutations of the ACTA1 gene located on the 1st chromosome. The product of its expression is skeletal muscle alpha-actin, one of the most important structural components of muscle tissue. More than 180 types of mutations of this gene have been identified, leading to the most diverse forms of non–myopathy with different inheritance patterns, mainly with congenital disorders. Some of the genetic defects of ACTA1 are spontaneous mutations that occur de novo, for this reason, germ mosaic is sometimes possible.
NEM-4 is a type of nemaline myopathy that accounts for approximately 3-4% of all cases of this disease. It is caused by a defect in the TPM2 gene localized on the 9th chromosome and encoding the beta-tropomyosin protein, which is part of the sarcomeric protein group. Mutations of this gene are most often transmitted by an autosomal dominant mechanism, there are indications of the possibility of spontaneous damage to the gene. This genetic defect is manifested by a congenital typical type of nemaline myopathy.
NEM-5 is a form of nemaline myopathy, diagnosed exclusively in closed Amish religious communities, where the incidence of this disease reaches 1:500. It is caused by a mutation of the TNNT1 gene, which is located on the 19th chromosome and is responsible for a protein called slow troponin T. Such genetic disorders lead to a severe congenital form of nemaline myopathy with an autosomal recessive inheritance mechanism.
NEM-6 is a rare and poorly studied type of nemaline myopathy, which is presumably caused by a mutation of the KBTBD13 gene localized on chromosome 15. It is not known exactly which protein encodes this gene, so its role in the etiology of this disease is questioned by some researchers. It is assumed that its defects are the cause of autosomal dominant nemaline myopathy with a mild course and development in childhood (juvenile variety).
NEM-7 is also a rare form of nemaline myopathy, which was described in only one family in 2007. Due to a defect in the CFL2 gene located on the 14th chromosome, the product of its expression is the protein cofilin-2 (muscle cofilin), which takes an active part in maintaining a stable state of actin filaments. Mutations of CFL2 lead to a congenital typical form of the disease with an autosomal recessive nature of inheritance.
Symptoms
According to their clinical manifestations, all cases of non–myopathy are divided into two groups – congenital (which, in turn, is divided into typical, intermediate and severe) and juvenile, which is characterized by the appearance of the first symptoms in childhood (8-13 years). The congenital variety is much more common, it can have both an autosomal dominant and a recessive inheritance mechanism, whereas the juvenile one is almost always only autosomal dominant. Patients with congenital nemaline myopathy have a characteristic appearance – an elongated face with poor facial expressions, an open mouth, an elongated skull.
The typical (moderate) variety is the most common, accompanied by myotonia, difficulty feeding, antigravity movements. Respiratory disorders in this form of non-myopathy are expressed slightly, usually reduced to reduced ventilation at night. The weakness of skeletal muscles is mainly proximal in nature, progresses extremely slowly, in some cases patients are able to move on crutches or walk with the help of others.
An intermediate type of congenital nemaline myopathy is a more severe form of the disease. It is characterized by the presence of all of the above disorders, which at the same time tend to progress, possible periarticular retractions, curvature of the spine. Usually, by the age of 6-7, patients with this form of non–myopathy completely lose the ability to move without a wheelchair, and by the age of 10-12, they can breathe independently, which leads to a fatal outcome. A severe form of nemaline myopathy is manifested by pronounced myopathy in the neonatal period, difficulty swallowing and sucking, in some cases the respiratory muscles suffer greatly. Death occurs in the first months of life due to respiratory failure or respiratory infection.
The juvenile form of nemaline myopathy does not manifest itself in the first years of a child’s life, the symptoms of the disease occur at 8-13 years of age. As a rule, muscle weakness affecting both distal and proximal muscle groups is detected, it gradually progresses, reaching its maximum severity by the age of 20. In some cases, patients with the juvenile form of nemaline myopathy completely lose the ability to walk, but unlike congenital varieties of pathology, they have no damage to the respiratory, mimic and masticatory muscles.
Diagnosis and treatment
The main methods of diagnosis of non-myopathy are the study of the patient’s hereditary history, histological examination of muscle tissue, electromyography and molecular genetic studies. In the patient’s history, cases of the disease in relatives can be determined, the absence of such examples indicates the sporadic nature of the mutation. Pathohistological changes in muscle tissue are reduced to the presence of filamentous inclusions in the sarcoplasm – at the same time, they may sometimes not be detected in the muscles of infants even with congenital forms of the disease and appear at an older age. Sometimes, with non-myopathy, heterogeneity of the thickness of muscle fibers and their partial destruction may also be detected. Electromyography in this disease has signs of a characteristic “myopathic triad” – a decrease in the amplitude and duration of action potentials in combination with their polyphase. With the help of the achievements of modern genetics, it is possible to determine some forms of non–myopathy caused by mutations of the genes NEB, ACTA1 and TPM2.
There is no specific treatment for non-myopathy, supportive therapy, physical therapy, gymnastics are used to maintain at least minimal muscle activity and prevent joint contractures. In case of respiratory disorders, forced ventilation of the lungs is used, feeding infants in case of swallowing or sucking disorders is carried out through a nasogastric probe. If spinal curvature or other skeletal disorders can aggravate the patient’s condition, orthopedic surgeons are resorted to.
Prognosis and prevention
In most cases of congenital varieties of nemaline myopathy, the prognosis of the disease is unfavorable – patients have a high risk of developing respiratory failure or respiratory infection, which can lead to death. Persons with a typical form of pathology can, with adequate care, live to adulthood, mental and mental development does not suffer from this genetic disease. The prognosis is much more favorable for juvenile non–myopathy – vital muscle groups are not affected by this type of pathology. Nevertheless, the vast majority of patients sooner or later find themselves confined to a wheelchair. It is very important for people with any form of non-myopathy to monitor their respiratory system and treat any infectious processes in the lungs in a timely manner.