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Mitochondrial diseases due to a violation of beta oxidation of fatty acids
Last reviewed: 18.10.2021
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The study of mitochondrial diseases caused by the violation of beta oxidation of fatty acids with different lengths of the carbon chain was started in 1976, when scientists first described patients with deficiency of acyl-CoA dehydrogenase of medium-chain fatty acids and glutaric acidemia of type II. At present, this group of diseases includes at least 12 independent nosological forms, the origin of which is associated with genetically determined disorders of transmembrane transport of fatty acids (systemic deficiency of carnitine, deficiency of carnitine palmitoyltransferases I and II, acyl carnitine-carnitine translocase) and their subsequent mitochondrial beta oxidation (acyl deficiency -CoA and 3-hydroxy-acyl-CoA dehydrogenase fatty acids with different length of the carbon chain, glutaric acidemia type II). The frequency of deficiency of acyl-CoA dehydrogenase of medium-chain fatty acids is 1: 8900 newborns, the frequency of other forms of pathology has not yet been established.
Genetic data and pathogenesis. Diseases have an autosomal recessive type of inheritance.
The pathogenesis of fatty acid metabolism is associated with the depletion of carbohydrate stores in conditions of metabolic stress (intercurrent infectious diseases, physical or emotional overload, starvation, surgical intervention). In such a situation, lipids become an indispensable source of replenishment of the energy needs of the organism. Activation of defective transport and beta-oxidation of fatty acids occurs. Owing to the mobilization of omega-oxidation, dicarboxylic acids, their toxic derivatives, carnitine conjugates accumulate in biological fluids-as a result, secondary carnitine insufficiency develops.
Symptoms. The clinical manifestations of all diseases of fatty acid metabolism are very similar. Diseases, as a rule, are characterized by a paroxysmal course. There are severe (early, generalized) and mild (late, muscular) forms, differing in the degree of enzyme deficiency or its tissue localization.
Heavy form manifests at an early age, including in the period of the newborn. The main symptoms: vomiting, generalized tonic-clonic seizures or infantile spasms, progressive lethargy, drowsiness, general muscle hypotension, impaired consciousness up to coma, cardiac disorder (rhythm disturbance or cardiomyopathy), liver enlargement (Ray's syndrome). The disease is accompanied by lethality (up to 20%) and risk of sudden child death.
The light form is usually first manifested in school age and in adolescents. Muscle pain, weakness, fatigue, motor awkwardness, dark color of urine develop (myoglobinuria).
Characteristic additional clinical signs of deficiency of 3-hydroxy-acyl-Co A-dehydrogenase fatty acids with a long carbon chain are peripheral neuropathy and retinitis pigmentosa. In future mothers, whose children are likely to have this enzyme defect, the course of pregnancy is often complicated - fatty liver infiltrates, thrombocytopenia, transaminase activity increases.
Data from laboratory studies. Biochemical disorders include hypoketotic hypoglycemia, metabolic acidosis, increased lactic acid, ammonia in the blood, an increase in the activity of transaminases and creatine phosphokinase, a low level of total carnitine with an increase in the content of its esterified forms. In urine, a high excretion of dicarboxylic acids with an appropriate length of the carbon chain, their hydroxylated derivatives and acyl carnitines is usually found.
Differential diagnostics is required to be carried out with mitochondrial encephalomyopathies, organic acidemia, cardiomyopathy of other origin, various kinds of epilepsy, acetonemic vomiting.
Treatment. The main way to treat diseases of transport and oxidation of fatty acids is dietotherapy. It is based on 2 principles: elimination of fasting (shortening of intervals between meals) and enriching the diet with carbohydrates with a sharp restriction of lipid intake. In addition, the use of special mixtures of medium-chain triglycerides (contraindicated in the case of acyl-CoA dehydrogenase deficiency of fatty acids with an average and a short carbon chain) is recommended for the treatment of pathology forms associated with a transport defect or the oxidation of fatty acids with a long carbon chain.
For medicamentous correction, levocarnitine is used (50-100 mg / kg of weight per day, depending on the age and severity of the patients), glycine (100-300 mg / day) and riboflavin (20-100 mg / day). During the metabolic crisis, an intravenous injection of a 10% glucose solution was calculated from the calculation of 7-10 mg / kg per minute under the control of its blood level. The purpose of glucose not only replenishes tissue deficit, but also suppresses lipolysis and reduces the production of toxic derivatives of fatty acids.
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