Mitochondrial diseases due to impaired pyruvate metabolism

Among the genetically determined diseases of pyruvic acid metabolism, defects of the pyruvate dehydrogenase complex and pyruvate carboxylase are distinguished. Most of these conditions, with the exception of deficiency of the E, alpha component

Pyruvate dehydrogenase complex, have an autosomal recessive or recessive X-linked inheritance pattern. The population frequency of the disease has not been established.

In the pathogenesis of diseases, the main role belongs to the disruption of pyruvate metabolism - the final product of carbohydrate catabolism and the main substrate that enters the Krebs cycle. As a result of enzyme deficiency, severe disorders develop, associated mainly with developing lactate and pyruvate acidosis.

Clinical picture. There are 3 main clinical forms: congenital lactic acidosis, subacute necrotizing encephalomyopathy of Leigh and intermittent ataxia.

Congenital lactic acidosisis characterized by early manifestation in the first weeks or months of a child's life. A severe general condition, convulsions, vomiting, lethargy, respiratory disorders, and developmental disorders develop.

Initial signs of Leigh's subacute necrotizing encephalomyopathyusually appear in the 1st-3rd year of life. The main symptoms are: delayed psychomotor development, muscle hypotonia alternating with dystonia and hypertonia, tonic-clonic and myoclonic seizures, choreoathetosis, limb tremor, coordination disorders, lethargy, drowsiness, respiratory distress syndrome, optic nerve atrophy, sometimes ptosis, ophthalmoplegia. The course is progressive. Characteristic disorders are noted in magnetic resonance imaging of the brain in the form of symmetrical bilateral lesions, including calcification of the basal ganglia (putamen, caudate nucleus, substantia nigra, globus pallidus), as well as atrophy of the cerebral cortex and brain matter. Pathomorphological examination reveals symmetrical areas of necrosis, demyelination and spongy degeneration in the midbrain, pons, basal ganglia, thalamus and optic nerve.

Intermittent ataxiais characterized by a relatively late manifestation and benign course.

Laboratory studies. The main biochemical changes are metabolic acidosis, hyperlactate and hyperpyruvate acidemia.

Differential diagnostics. Phenotypic manifestations of pyruvate metabolism diseases caused by defects of the pyruvate dehydrogenase complex or pyruvate carboxylase are similar. To confirm the diagnosis, a study of the activity of these enzymes in leukocytes or fibroblasts is indicated. When conducting differential diagnostics, it should be taken into account that congenital lactic acidosis and subacute necrotizing encephalomyopathy of Leigh represent genetically heterogeneous clinical phenotypes and can be associated with various hereditary defects, in particular, these conditions can be a consequence of autosomal recessive or mitochondrial inherited deficiency of complexes 1, 4 and 5 of the respiratory chain. Detection of these defects in patients radically changes the treatment tactics and medical and genetic prognosis.

Treatment. Complex treatment of children suffering from pyruvate metabolism diseases includes:

• administration of vitamins and cofactors of enzyme systems involved in the metabolism of pyruvic acid (thiamine 50-100 mg/day, thioctic acid 100-500 mg/day, biotin 5-10 mg/day), dimephosphone 90 mg/kg per day.
• dietary treatment, which is necessary to compensate for the developing acetyl-CoA deficiency. A ketogenic diet is prescribed, providing up to 75% of the energy requirement through fat intake, up to 15% - proteins and only up to 10% - carbohydrates. Information on the effectiveness of complex treatment of patients with pyruvic acid metabolism defects is contradictory.

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