Mitochondrial diseases due to impaired beta fatty acid oxidation

The study of mitochondrial diseases caused by impaired beta oxidation of fatty acids with different carbon chain lengths was started in 1976, when scientists first described patients with a deficiency of acyl-CoA dehydrogenase of medium-chain fatty acids and glutaric acidemia type II. Currently, 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 carnitine deficiency, deficiency of carnitine palmitoyltransferases I and II, acylcarnitine-carnitine translocase) and their subsequent mitochondrial beta oxidation (deficiency of acyl-CoA and 3-hydroxy-acyl-CoA dehydrogenases of fatty acids with different carbon chain lengths, glutaric acidemia type II). The incidence of medium-chain fatty acid acyl-CoA dehydrogenase deficiency is 1:8900 newborns; the incidence of other forms of the pathology has not yet been established.

Genetic data and pathogenesis. The diseases have an autosomal recessive type of inheritance.

The pathogenesis of fatty acid metabolism diseases is associated with the depletion of carbohydrate reserves under metabolic stress (intercurrent infectious diseases, physical or emotional overload, starvation, surgery). In such a situation, lipids become a necessary source of replenishment of the body's energy needs. Defective processes of transport and beta-oxidation of fatty acids are activated. Due to the mobilization of omega-oxidation, dicarboxylic acids, their toxic derivatives, and carnitine conjugates accumulate in biological fluids - as a result, secondary carnitine deficiency develops.

Symptoms. The clinical manifestations of all fatty acid metabolism diseases are very similar. The diseases are usually characterized by an attack-like course. There are severe (early, generalized) and mild (late, muscular) forms, distinguished by different degrees of enzyme deficiency or its tissue localization.

The severe form manifests itself in early childhood, including the neonatal period. The main symptoms are vomiting, generalized tonic-clonic seizures or infantile spasms, progressive lethargy, drowsiness, general muscle hypotonia, impaired consciousness up to coma, cardiac dysfunction (rhythm disorder or cardiomyopathy), liver enlargement (Reye's syndrome). The disease is accompanied by mortality (up to 20%) and the risk of sudden infant death.

The mild form usually first appears in school age and in adolescents. Muscle pain, weakness, fatigue, motor clumsiness, and dark urine (myoglobinuria) develop.

Characteristic additional clinical signs of deficiency of 3-hydroxyacyl-Co A dehydrogenase of fatty acids with a long carbon chain are peripheral neuropathy and retinitis pigmentosa. In expectant mothers whose children are likely to have this enzyme defect, the course of pregnancy is often complicated - fatty infiltration of the liver, thrombocytopenia, and increased transaminase activity develop.

Laboratory findings. Biochemical abnormalities include: hypoketotic hypoglycemia, metabolic acidosis, increased blood lactic acid and ammonia levels, increased transaminase and creatine phosphokinase activity, low total carnitine levels with increased levels of its esterified forms. Urine usually shows high excretion of dicarboxylic acids with the corresponding carbon chain length, their hydroxylated derivatives, and acyl-carnitines.

Differential diagnostics must be carried out with mitochondrial encephalomyopathies, organic acidemias, cardiomyopathies of other origins, various types of epilepsy, and acetonemic vomiting.

Treatment. The main method of treating diseases of transport and oxidation of fatty acids is diet therapy. It is based on two principles: elimination of fasting (shortening the intervals between meals) and enrichment of the diet with carbohydrates while sharply limiting lipid intake. Additionally, for the treatment of forms of pathology associated with a defect in the transport or oxidation of fatty acids with a long carbon chain, it is recommended to use special mixtures of medium-chain triglycerides (contraindicated in case of a defect in acyl-CoA dehydrogenases of fatty acids with a medium and short carbon chain).

For drug correction, levocarnitine (50-100 mg/kg of body weight per day depending on the age and severity of the patient's condition), glycine (100-300 mg/day) and riboflavin (20 to 100 mg/day) are used. During a metabolic crisis, intravenous administration of a 10% glucose solution at a rate of 7-10 mg/kg per minute is indicated, while monitoring its level in the blood. The administration of glucose not only replenishes tissue deficiency, but also suppresses lipolysis and reduces the production of toxic derivatives of fatty acids.

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