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December 20, 2016 00:04

Mitochondrial diseases caused by defects in the oxidative phosphorylation

Mitochondrial diseases caused by defects in electron transport and oxidative phosphorylation

Population frequency of this group of diseases is 1:10 000 live births, and diseases caused by defective mitochondrial DNA, approximately 1: 8000.

reasons.Mitochondrial diseases caused by defects in electron transport and oxidative phosphorylation, different genetic heterogeneity, which is due to the duality of the genetic control (nuclear and mitochondrial DNA) electron transport processes.The vast majority of states due to nuclear mutations in the lineage inherited in an autosomal recessive manner with the exception of three-hopolidistrofii Menkes.

Those diseases are caused by mutations in mitochondrial DNA, inherited through the maternal line (cytoplasmic inheritance).Deletions it is usually in the pedigree occur sporadically.Violations intergenomic interaction - nuclear-encoded mitochondrial mutations and multiple depletion (decrease in the number of DNA copies) - may have an autosomal dominant or aut

osomal type of hereditary transmission.

in the pathogenesis of this group of diseases the main role belongs to the genetically caused by deficiency of the enzyme complexes of the respiratory chain, oxidative phosphorylation, as well as the structural defect of mitochondrial proteins, and disorders of the transmembrane transport of specific proteins.As a result, there is an infringement of functioning of the entire fabric of the respiratory system, suffer redox processes in cells and in the cytoplasm and mitochondria accumulate oxidized products and developing lactic acidosis.

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

to the fore the following symptoms appear in expanded stage of the disease:respiratory and neyrodistress syndrome, psychomotor retardation, seizures, ataxia, ophthalmoplegia, decreased exercise tolerance, myopathic syndrome.In addition, often joined by signs of a lesion of other organs and systems: cardiovascular (cardiomyopathy, cardiac conduction), endocrine (diabetes and diabetes insipidus, thyroid dysfunction, hypoparathyroidism), eye and ear (optic atrophy, retinitis pigmentosa, cataracts,hearing loss), kidney (tubular disorder), liver (increase size).Patients often observed violation of the physical and sexual development.

in laboratory studies show symptoms that are characteristic of mitochondrial disease - metabolic acidosis, increased blood levels of lactic and pyruvic acids, ketonemia, often detectable only after the carbohydrate load, reducing the total carnitine, increased urinary excretion of organic acids (lactic acid, dicarboxylicacid, 3-metilglutakonovoy, tricarboxylic acid cycle, Krebs et al.).Sometimes noted an increase in the content of ammonia in the blood and hypoglycaemia.The leukocytes or fibroblasts determined reduction in the activity of enzyme complexes of the respiratory chain.

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

absolute criterion of mtDNA lesions - Detection of mitochondrial DNA mutations (point mutations, single and multiple deletions, duplications, etc..), Which can be identified with the help of modern methods of molecular genetic analysis in biopsies of muscle tissue.However, the absence of mitochondrial mutations do not completely rule out the diagnosis of mitochondrial disease, as this may be due to the presence of patients with rare mutations, mosaic destruction of cells and tissues, as well as the possibility of damage to nuclear DNA.

The differential diagnosis is carried out with neuromuscular disease, myasthenia gravis, diseases of impaired fatty acid P-oxidation of organic acidemia, cardiomyopathy, diabetes mellitus, multiple sclerosis, the effects of perinatal lesions of the nervous system and others.

Treatment of children with mitochondrial diseases caused by defects in electron transport and oxidative phosphorylation to be multicomponent with the appointment of an adequate diet and various drugs.Concomitant use of drugs that differentially affect the various stages of energy metabolism, exerts a positive effect compared to monotherapy separate medicines.

Feature dietetics - reducing carbohydrate content in the diet to 10 g / kg, as the high consumption of carbohydrates legkousvayaemyh in violation of the respiratory chain function deepens the existing defect of cellular energy exchange.

for correcting violations of transport processes of electrons are appointed Coenzyme Q-10 (90-200 mg / day for at least 6 months), succinic acid (5 mg / kg per day, intermittent courses of 3-4 days and a total duration of 3 months) andcytochrome C (4 ml / m or / day, 3-4 injections of 10 courses per year).

correctors transport electrons combine with cofactor therapy, which improves the flow of energy of the cell enzymatic reactions (nicotinamide 60-100 mg / day, vitamin B ,null, B2, B6 10-20 mg / day, biotin 1-5 mg / day), thioctic acid50-100 mg / day, preparations levocarnitine 25-30 mg / kg per day).To combat acidosis dimephosphone used (30 mg / kg or 1 ml of a 15% solution 5 kg weight 3 times daily for 1 month).Assign antioxidants: vitamin E (100-200 mg / day), ascorbic acid (500 mg / day).

Thus, to date, has accumulated a lot of experience of studying mitochondrial pathology and methods of correction of mitochondrial dysfunction, a new direction - mitochondrial medicine, as presented in this section information reflects only a small part of the knowledge the vast field of pathologyhuman.It remains a lot of outstanding issues impeding the development of effective methods of diagnosis and treatment of these diseases, which is especially important for pediatric practice.