Mitochondrial diseases due to defects in oxidative phosphorylation

Mitochondrial diseases due to defects in electronic transport and oxidative phosphorylation

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

Causes. Mitochondrial diseases caused by defects in electronic transport and oxidative phosphorylation are distinguished 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 type, with the exception of Menkes' tri-hopidystrophy.

Those diseases that are caused by mitochondrial DNA mutations are inherited on the maternal line (cytoplasmic inheritance). Its deletions, as a rule, occur sporadically in the pedigree. Violations of intergenomic interaction - nuclear-encoded multiple mitochondrial mutations and depletion (decrease in the number of copies of DNA) - may 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 to the defect of structural mitochondrial proteins and disorders of transmembrane transport of specific proteins. As a result, there is a disruption in the functioning of the whole system of tissue respiration, oxidation-reduction processes in cells suffer, and in the mitochondria and the cytoplasm, under-oxidized products accumulate and lactate acidosis develops.

Symptoms. A characteristic feature of diseases associated with a respiratory chain defect and oxidative phosphorylation is their progressive course and a wide age range of manifestation of clinical symptoms from the period of the newborn to the adult. In the newborn period or in the first 3 months of life, congenital lactate acidosis, Pearson's syndrome, fatal and benign infantile myopathy, Trincholipidystrophy of Menkes, in the 1-2 years of life - Leia's disease and Alper's disease develop. After 3 years of age and later - the syndromes of Cairns-Seyr, MELAS, MERRF, Leber's optical neuropathy, progressive external ophthalmoplegia, mitochondrial myopathy, myoneurogastrointestinal encephalopathy, and others.

At the forefront in the advanced stage of the disease are the following symptoms: respiratory and neurodistress syndrome, delayed psychomotor development, convulsions, ataxia, ophthalmoplegia, decreased exercise tolerance, myopathic syndrome. In addition, signs of defeat of other organs and systems are often added: cardiovascular (cardiomyopathy, cardiac conduction disorder), endocrine (sugar and diabetes insipidus, thyroid dysfunction, hypoparathyroidism), vision and hearing (atrophy of optic nerves, retinitis pigmentosa, cataract, deafness), kidneys (tubular disorders), liver (increase in size). Patients often observe a violation of physical and sexual development.

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

In biopsy specimens of muscle tissue, light microscopy reveals a characteristic phenomenon of RRF and histochemical signs of mitochondrial insufficiency (decreased activity of enzymes in the respiratory chain). Electron microscopy often reveals abnormal mitochondria and a change in their number.

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

Differential diagnosis is carried out with neuromuscular diseases, myasthenia gravis, diseases of broken p-oxidation of fatty acids, organic acidemia, cardiomyopathy, diabetes mellitus, multiple sclerosis, the effects of perinatal damage to the nervous system, etc.

Treatment of children suffering from mitochondrial diseases due to defects in electronic transport and oxidative phosphorylation should be multicomponent with the appointment of an adequate diet and a variety of medications. The combined use of drugs that differentially affect different stages of energy metabolism has a positive effect in comparison with monotherapy with separate medications.

The peculiarity of dietotherapy is the reduction of carbohydrates in the diet to 10 g / kg, since high consumption of easily digestible carbohydrates in violation of the function of the respiratory chain deepens the existing defect of cellular energy exchange.

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

Correctors of electron transport combine with cofactor therapy, improving the course of enzyme reactions of cellular energy metabolism (nicotinamide 60-100 mg / day, vitamins B ,, B ₂, B ₆ 10-20 mg / day, biotin 1-5 mg / day), thioctic acid 50-100 mg / day, preparations of levocarnitine 25-30 mg / kg per day). To combat acidosis, use dimephosfon (30 mg / kg or 1 ml of 15% solution for 5 kg of body 3 times a day for 1 month). Assign antioxidants: vitamin E (100-200 mg / day), ascorbic acid (500 mg / day).

Thus, by the present time, a great deal of experience has been accumulated in the study of mitochondrial pathology and methods of correcting detected 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 a huge area of human pathology. There remain many unclear issues that hamper the development of effective ways of diagnosing and treating these diseases, which is especially important for pediatric practice.

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