Mitochondrial diseases caused by impaired metabolism of pyruvate

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

Pyruvate dehydrogenase complex, have an autosomal recessive or recessive type of inheritance linked to the X-chromosome. Population frequency of diseases is not established.

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

Clinical picture. There are 3 main clinical forms: congenital lactate acidosis, subacute necrotizing Lech encephalomyopathy and intermittent ataxia.

Congenital lactate acidosis is characterized by an early manifestation in the first weeks or months of a child's life. Develop a severe general condition, convulsions, vomiting, lethargy, respiratory disorders, developmental disorders.

The initial signs of subacute necrotizing encephalomyopathy Leia usually appear in the 1-3-year life. The main symptoms: delayed psychomotor development, muscle hypotension, followed by dystonia and hypertonus, tonic-clonic and myoclonic seizures, choreoathetosis, limb tremor, coordination disorders, lethargy, drowsiness, respiratory distress syndrome, optic atrophy, sometimes ptosis, ophthalmoplegia. The course is progressive. Characteristic disorders are noted in a magnetic resonance study of the brain in the form of symmetrical bilateral lesions, including calcification of the basal ganglia (shell, caudate nucleus, black substance, pale ball), as well as atrophy of the cerebral cortex and brain matter. In the pathomorphological investigation, symmetric areas of necrosis, demyelination and spongy degeneration are revealed in the midbrain, bridge, subcortical nodes, thalamus, optic nerve.

Intermittent ataxia is characterized by a relatively late manifestation and benign course.

Laboratory research. The main biochemical changes are metabolic acidosis, hyperlactate and hyperpyruvatacidemia.

Differential diagnostics. Phenotypical manifestations of pyruvate exchange diseases caused by defects of the pyruvate dehydrogenase complex or pyruvate carboxylase are similar. To confirm the diagnosis, a study was made of the activity of these enzymes in leukocytes or fibroblasts. When conducting differential diagnosis, it should be borne in mind that congenital lactic acidosis and subacute necrotizing encephalomyopathy Leia are genetically heterogeneous clinical phenotypes and can be associated with a variety of hereditary defects, in particular, these conditions may be a consequence of autosomal recessive or mitochondrial inherited deficiency of complexes 1, 4 and 5 of the respiratory chain. Detection in patients of these defects radically changes the tactics of treatment and the medical-genetic prognosis.

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

• the appointment of vitamins and cofactors of enzyme systems involved in the metabolism of pyruvic acid (thiamine 50-100 mg / day, tioctic acid 100-500 mg / day, biotin 5-10 mg / day), dimephosphon 90 mg / kg per day.
• dietary treatment, which is necessary to fill the developing deficit of acetyl-CoA. Assign a ketogenic diet that provides up to 75% of energy needs due to fat intake, up to 15% - proteins and only up to 10% - carbohydrates. Information on the effectiveness of complex treatment of patients with metabolic defects of pyruvic acid is contradictory.

[1], [2], [3], [4], [5], [6], [7]