Mitochondrial myopathies are a group of muscle diseases that occur as a result of impaired tissue respiration in mitochondrial pathologies. Diseases are manifested by increasing muscle weakness, muscular atrophy, progressive motor disorders, which can be accompanied by seizures, heart lesions, hearing and vision impairment. Diagnostics involves laboratory (examination of muscle biopsies, genetic testing, biochemical analyses), instrumental methods (EMG, brain MRI). Treatment includes symptomatic medications, physiotherapy, physical therapy.
ICD 10
G71.3 Mitochondrial myopathy, not classified elsewhere
General information
The term “mitochondrial myopathy” combines several pathologies with a similar pathogenesis. Most often, children suffer from MELAS, MERRF syndromes, Kearns-Sayre syndrome with chronic progressive external ophthalmoplegia. The study of the molecular genetic features of these diseases began in the 1980s. The prevalence of pathologies in children is about 11.5 cases per 100 thousand population. Due to the multi-system nature of the lesion, clinical polymorphism, and variability of the course, this type of myopathy presents serious difficulties in diagnosis.
Causes
Myopathies are caused by hereditary or sporadic mutations in mitochondrial DNA or in nuclear genes that control the work of mitochondria. There are more than 300 variants of gene defects — single-nucleotide substitutions, deletions that cause mitochondrial dysfunction. Mitochondrial myopathies have a number of genetic aspects that distinguish them from all hereditary diseases. Fundamental differences:
- Maternal inheritance. The embryo receives all the cytoplasm with the organelles contained in it from the mother, so only she can transfer the mutant mtDNA to the child. At the same time, with nuclear DNA mutations, inheritance occurs according to the autosomal recessive, autosomal dominant or X-linked type.
- Heteroplasmia. In mitochondrial myopathy, mutant and normal genetic material is simultaneously present in muscle tissue cells in different percentages, which explains the variability of clinical manifestations in members of the same family with a hereditary form of the disease.
- Mitotic segregation. When dividing cells containing mutant mitochondrial genes, mtDNA is distributed randomly, unevenly between daughter cells.
Pathogenesis
Mitochondria is a universal organelle present in all cells except red blood cells. It has a respiratory chain that includes 5 enzyme complexes of several dozen subunits each. Enzymes provide oxidative phosphorylation for the synthesis of ATP — adenosine triphosphate, which is the main source of energy in the body.
In mitochondrial diseases, there may be 4 variants of pathogenetic mechanisms of development. As a rule, defects in electronic transport and oxidative phosphorylation are observed in muscle lesions, which is accompanied by disturbances in the formation of energy molecules. Other variants of disorders include pyruvate metabolism disorders, fatty acid metabolism defects, Krebs cycle dysfunction.
With myopathies, polysystemic disorders are noted. Muscle and nerve tissue, which are more dependent on energy production than others, suffer first of all. The lesion is manifested by metabolic disorders in the muscles, degenerative processes, atrophy of myofibrils and their replacement by connective tissue. Over time, the pathological process spreads to the heart muscle, endocrine system, kidneys and liver, which determines the various “masks” of myopathy.
Symptoms
Pathologies manifest in young children, sometimes they are present from birth. A common feature is myopathic syndrome, which includes progressive muscle weakness, decreased skeletal muscle tone, and exercise intolerance. A typical lag in motor development: children start sitting, crawling, walking late, they still have clumsiness of movements, problems with maintaining balance.
Clinical features are determined by the type of disease. In MERRF syndrome, muscle weakness is accompanied by various convulsive attacks (atonic, tonic-clonic, myoclonic), coordination disorders due to cerebellar ataxia. MELAS syndrome is characterized by repeated strokes, mental retardation, sensorineural hearing loss.
In children, Kerns-Sayre syndrome is common, in which clinical signs are supplemented by swallowing disorders, disorders of the conduction system of the heart, hearing loss. Chronic progressive external ophthalmopathy can occur as a component of Kerns-Sayre disease, and develop in isolation, which is more common in older age.
Complications
The distinctive features of myopathic syndrome are irreversibility, steady progression. First, muscle weakness appears in the proximal parts of the extremities, then affects the entire body of the child: the smooth muscles of the respiratory and digestive organs are involved in the process, which is fraught with respiratory failure, aspiration pneumonia, total paralysis. Such patients lose the ability to self-care, require round-the-clock care.
Myopathies are complicated by deformities of the spine, curvature of the lower extremities against the background of weakness of the muscular corset. Due to atrophy of the optic nerves, blindness occurs in patients with MERRF syndrome. A dangerous consequence of many variants of mitochondrial pathology are strokes, epileptic status, cerebral edema, which become the main causes of death.
Diagnostics
The initial examination of children with suspected mitochondrial myopathy is carried out by a neurologist, a consultation with a geneticist is indicated to clarify the diagnosis. The examination takes into account the neurological status of the child, indicators of muscle strength and tone, the level of development of cognitive skills. Diagnosis requires a comprehensive examination, including the following methods:
- Electromyography. The study demonstrates a decrease in the amplitude and duration of the recorded potentials of motor units (PDE), which indicates the heterogeneity of muscle fibers with their mosaic atrophy, hypertrophy of a small part of myofibrils.
- Examination of muscle biopsies. A pathognomonic sign of mitochondrial myopathy is the phenomenon of “ragged red fibers”, which is determined by special staining of biopsies with trichrome Homori.
- MRI of the brain. Neuroimaging is prescribed if the central character of muscle disorders is suspected, to exclude concomitant neurodegenerative lesions of the central nervous system, which are often found in mitochondrial diseases.
- Cytomorphodensitometry. The analysis is necessary to assess the activity of mitochondria in the lymphocytes of a child, shows a decrease in the number of organelles with an increase in their volume, a decrease in the optical density of granules, violations of enzymatic activity.
- Genetic analysis. Given the diversity of mitochondrial myopathies, mitochondrial DNA sequencing is required to confirm the diagnosis. The study checks for the presence of mutations that most often provoke the disease in children.
- Biochemical research. It is possible to suspect muscle lesions associated with impaired oxidative phosphorylation by increasing the indicators of lactate and pyruvate in the blood, cerebrospinal fluid.
Treatment
In clinical neurology there are no effective methods of pathology therapy in children. The essence of medical care is to reduce motor deficiency, timely correction of complications, stimulation of metabolic processes in mitochondria. The following groups of medicines demonstrate the greatest effectiveness:
- Amino acids. L-arginine is recommended by neurologists in the acute phase to improve blood supply to the brain when myopathy is complicated by stroke, in the residual period of the disease to prevent repeated attacks of ischemia of the nervous tissue.
- Energotropic drugs. To improve the energy supply of the child’s tissues, drugs with levocarnitine, succinic acid, coenzyme Q10 are effective, a complex of B vitamins, ascorbic acid, alpha-tocopherol is widely used.
- Anticonvulsants. When myopathy is combined with epileptic paroxysms, anticonvulsants of the group of sulfate-substituted monosaccharides, benzodiazepines are indicated, barbiturates are used only. Valproates for the treatment of children with mitochondrial disorders are not prescribed.
An important component of treatment in children is neurodietology, which involves the exclusion of substances that have a negative effect on metabolic processes (“bypass block” therapy). Recommended ketogenic diet, other types of high-fat diets. According to the indications, therapeutic enteral or parenteral nutrition is carried out, in severe cases, a gastrostomy is established.
To correct motor disorders, an extended complex of physiotherapy is used: ultrasound therapy, electromyostimulation, electrophoresis with acetylcholinesterase inhibitors. A good effect is demonstrated by therapeutic massage, an individually selected exercise therapy complex. To avoid overloading weakened muscles, classes in the pool are widely used. Orthopedic correction is also required, the selection of special shoes for the child.
Prognosis and prevention
Since mitochondrial myopathies are still incurable diseases, the prognosis is unfavorable. It is possible to improve the quality of life of patients with the help of comprehensive rehabilitation, however, with a detailed clinical picture, death often occurs in childhood or at a young age. For prevention, married couples with burdened heredity need medical and genetic counseling when planning pregnancy.
