Mitochondrial diseases due to defects in oxidative phosphorylation

Mitochondrial diseases caused by defects in electron transport and oxidative phosphorylation

The population frequency of this group of diseases is 1:10,000 live births, and diseases caused by a defect in mitochondrial DNA are approximately 1:8000.

Causes. Mitochondrial diseases caused by defects in electron transport and oxidative phosphorylation are characterized by genetic heterogeneity, which is due to the duality of genetic control (nuclear and mitochondrial DNA) of electron transport processes. The vast majority of conditions caused by nuclear mutations in the pedigree are inherited in an autosomal recessive manner, with the exception of Menkes trichopolydystrophy.

Those diseases that are caused by mutations of mitochondrial DNA are inherited through the maternal line (cytoplasmic inheritance). Its deletions, as a rule, are found sporadically in the pedigree. Disturbances of intergenomic interaction - nuclear-encoded multiple mitochondrial mutations and depletions (reduction in the number of DNA copies) - can have an autosomal dominant or autosomal type of hereditary transmission.

In the pathogenesis of this group of diseases, the main role belongs to the genetically determined deficiency of enzyme complexes of the respiratory chain, oxidative phosphorylation, as well as a defect in structural mitochondrial proteins and disorders of transmembrane transport of specific proteins. As a result, the functioning of the entire tissue respiration system is disrupted, oxidation-reduction processes in cells suffer, and underoxidized products accumulate in the mitochondria and cytoplasm, and lactic acidosis develops.

Symptoms. A characteristic feature of diseases associated with a defect in the respiratory chain and oxidative phosphorylation is their progressive course and a wide age range of clinical symptoms manifestation - from the neonatal period to adulthood. In the neonatal period or in the first 3 months of life, congenital lactic acidosis, Pearson syndrome, fatal and benign infantile myopathy, Menkes trichopolydystrophy develop, in the 1-2 year of life - Leigh disease and Alpers disease. After 3 years of age and later - Kearns-Sayre syndrome, MELAS, MERRF, Leber optic neuropathy, progressive external ophthalmoplegia, mitochondrial myopathy, myoneurogastrointestinal encephalopathy, etc.

The following symptoms come to the fore in the advanced stage of the disease: respiratory and neurodistress syndrome, delayed psychomotor development, seizures, ataxia, ophthalmoplegia, decreased tolerance to physical activity, myopathic syndrome. In addition, signs of damage to other organs and systems are often added: cardiovascular (cardiomyopathy, impaired cardiac conduction), endocrine (diabetes mellitus and insipidus, thyroid dysfunction, hypoparathyroidism), organs of vision and hearing (atrophy of the optic nerves, pigment retinitis, cataracts, hearing loss), kidneys (tubular disorders), liver (enlargement). Patients often have impaired physical and sexual development.

Laboratory tests reveal signs that are characteristic of mitochondrial diseases - metabolic acidosis, increased levels of lactic and pyruvic acids in the blood, ketonemia, often detected only after carbohydrate loading, decreased levels of total carnitine, increased excretion of organic acids in the urine (lactic, dicarboxylic acids, 3-methylglutaconic, tricarboxylic acids of the Krebs cycle, etc.). Sometimes an increase in the ammonia content in the blood and hypoglycemia are noted. In leukocytes or fibroblasts, a decrease in the activity of enzyme complexes of the respiratory chain is determined.

In muscle tissue biopsies, light microscopy reveals the characteristic RRF phenomenon and histochemical signs of mitochondrial insufficiency (reduced activity of respiratory chain enzymes). Electron microscopy often reveals abnormal mitochondria and changes in their number.

The absolute criterion for mtDNA damage is the detection of mitochondrial DNA mutations (point mutations, single and multiple deletions, duplications, etc.), which can be detected using modern molecular genetic analysis methods in muscle tissue biopsies. However, the absence of a mitochondrial mutation does not completely exclude the diagnosis of mitochondrial disease, as this may be due to the presence of rare mutations in patients, mosaic cell and tissue damage, and the possibility of damage to nuclear DNA.

Differential diagnostics are carried out with neuromuscular diseases, myasthenia, diseases of impaired β-oxidation of fatty acids, organic acidemias, cardiomyopathies, diabetes mellitus, multiple sclerosis, consequences of perinatal damage to the nervous system, etc.

Treatment of children suffering from mitochondrial diseases caused by defects in electron transport and oxidative phosphorylation should be multicomponent with the prescription of an adequate diet and various medications. Combined use of drugs that differentially affect different stages of energy metabolism has a positive effect compared to monotherapy with individual medications.

The peculiarity of diet therapy is the reduction of carbohydrate content in the diet to 10 g/kg, since high consumption of easily digestible carbohydrates with impaired respiratory chain function deepens the existing defect of cellular energy metabolism.

To correct the processes of impaired electron transport, coenzyme Q-10 (90-200 mg/day for at least 6 months), succinic acid (5 mg/kg per day, in intermittent courses of 3-4 days and a total duration of 3 months) and cytochrome C (4 ml intramuscularly or intravenously daily, 3-4 courses of 10 injections per year) are prescribed.

Electron transport correctors are combined with cofactor therapy that improves the enzymatic reactions of cellular energy metabolism (nicotinamide 60-100 mg/day, vitamins B1, _B2, _B6 10-20 mg/day, biotin 1-5 mg/day), thioctic acid 50-100 mg/day, levocarnitine preparations 25-30 mg/kg per day). To combat acidosis, dimephosphone is used (30 mg/kg or 1 ml of 15% solution per 5 kg of body weight 3 times a day for 1 month). Antioxidants are prescribed: vitamin E (100-200 mg/day), ascorbic acid (500 mg/day).

Thus, by now a great deal of experience has been accumulated in studying mitochondrial pathology and methods of correcting the identified mitochondrial dysfunctions, a new direction has been formed - mitochondrial medicine, and the information presented in this section reflects only a small part of the knowledge of the vast field of human pathology. There remain many unanswered questions that complicate the development of effective methods for diagnosing and treating these diseases, which is especially important for pediatric practice.

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