Pathogenesis of glycogeneses

Glycogenosis of type 0

Glycogen synthase is the key enzyme of glycogen synthesis. In patients, the concentration of glycogen in the liver is reduced, which leads to fasting hypoglycaemia, ketonomia and moderate hyperlipidemia. The concentration of lactate on an empty stomach is not increased. After an alimentary load, an inverse metabolic profile with hyperglycemia and an elevated lactate level often occurs.

Glycogenosis type I

Glucose-6-phosphatase catalyzes the final reaction of both gluconeogenesis and glycogen hydrolysis and carries out the hydrolysis of glucose-6-phosphate to glucose and inorganic phosphate. Glucose-6-phosphatase is a special enzyme among the liver involved in the metabolism of glycogen. The active center of glucose-6-phosphatase is located in the lumen of the endoplasmic reticulum, which necessitates the transport of all substrates and reaction products through the membrane. Therefore, the deficiency of the enzyme or substrate carrier protein leads to similar clinical and biochemical consequences: hypoglycemia, even with the slightest fasting due to blockade of glycogenolysis and gluconeogenesis, and the accumulation of glycogen in the liver, kidneys and intestinal mucosa, leading to dysfunction of these organs. An increase in the level of lactate in the blood is associated with an excess of glucose-6-phosphate, which can not be metabolized to glucose and therefore enters glycolysis, the final products of which are pyruvate and lactate. This process is further stimulated by hormones, since there is no intake of glucose into the blood. Other substrates, such as galactose, fructose and glycerin, also require glucose-6-phosphatase for glucose metabolism. In this regard, the intake of sucrose and lactose also leads to an increase in the level of lactate in the blood, only slightly increasing the level of glucose. Stimulation of glycolysis leads to an increase in the synthesis of glycerol and acetyl-CoA - important substrates and cofactors for the synthesis of triglycerides in the liver. Lactate is a competitive inhibitor of renal tubular secretion of urates, so increasing its content leads to hyperuricemia and hypouricosuria. In addition, as a result of depletion of intrahepatic phosphate and accelerated degradation of adenine nucleotides, hyperproduction of uric acid occurs.

Glycogenosis type II

Lysosomal aD-glucosidase is involved in the hydrolysis of glycogen in muscles and liver; its insufficiency leads to the deposition of negodrolized glycogen in the lysosomes of the muscles - cardiac and skeletal muscles, gradually disrupting the metabolism of muscle cells and leading to their death, which is accompanied by a picture of progressive muscular dystrophy.

Glycogenosis type III

Amylo-1,6-glucosidase is involved in the metabolism of glycogen at the branch points of the glycogen "tree", transforming the branched structure into a linear one. The enzyme is bifunctional: on the one hand, it transfers a block of glycosyl residues from one external branch to another (oligo 1,4-1,4-glucantransferase activity), and on the other hand carries out hydrolysis of a-1,6-glucosidic bond. The decrease in the activity of the enzyme is accompanied by a violation of the glycogenolysis process, leading to an accumulation of abnormal structure in the tissues (muscles, liver) of glycogen molecules. Morphological examination of the liver reveals, in addition to glycogen deposits, insignificant amounts of fat and fibrosis. Violation of the process of glycogenolysis is accompanied by hypoglycemia and hyperketonemia, to which children under the age of 1 year are most sensitive. Mechanisms for the formation of hypoglycemia and hyperlipidemia are the same as for type I glycogenesis. In contrast to type I glycogenosis, with type III glycogenosis, the concentration of lactate in many patients is within the normal range.

Glycogenosis type IV

Amylo-1,4: 1,6-glucantransferase, or branching enzyme, is involved in the metabolism of glycogen at the branch points of the glycogen "tree". It connects a segment of at least six a-1,4-linked glucosid residues of glycogen outer chains with a glycogen "tree" a-1,6-glycosidic linkage. The mutation of the enzyme disrupts the synthesis of normal glycogen - relatively soluble spherical molecules. When the enzyme is deficient, relatively insoluble amylopectin is deposited in the liver and muscle cells, which leads to cell damage. The specific activity of the enzyme in the liver is higher than in the muscles, so when it is deficient, the symptoms of damage to liver cells prevail. Hypoglycemia with this form of glycogenosis is extremely rare and is described only in the terminal stage of the disease with classical hepatic form.

Glycogenosis of type V

Three isoforms of glycogen phosphorylase are known - expressed in cardiac / neural tissue, liver and muscle tissue; they are encoded by different genes. G type glycogenosis is associated with insufficiency of the muscle isoform of the enzyme-myophosphorylase. The inadequacy of this enzyme leads to a decrease in the synthesis of ATP in the muscle due to a violation of glycogenolysis.

Glycogenosis type VII

PFK is a tetrameric enzyme controlled by three genes. The PFK-M gene is mapped on chromosome 12 and encodes a muscle subunit; the PFK-L gene is mapped on chromosome 21 and encodes a hepatic subunit; the PFK-P gene on chromosome 10 encodes a subunit of red blood cells. In the human muscle, only the M subunit is expressed, and the PFK isoform is represented by the homotetramer (M4), while in the erythrocytes that contain the M and L subunits, five isoforms are found: two homotetramers (M4 and L4) and three hybrid isoforms M1L3; M2L2; M3L1). In patients with classic PFK deficiency, mutations in PFK-M lead to a total decrease in the activity of the enzyme in the muscles and a partial decrease in activity in the red blood cells.

Glycogenosis IX type

The cleavage of glycogen is controlled in the muscle tissue and liver by a cascade of biochemical reactions that lead to the activation of phosphorylase. This cascade includes enzymes adenylate cyclase and phosphorylase kinase (RNA). RNA is a decahexameric protein consisting of subunits a, beta, gamma, sigma; alpha and beta subunits - regulatory, gamma subunits - catalytic, sigma subunits (calmodulin) are responsible for the sensitivity of the enzyme to calcium ions. The processes of glycogenolysis in the liver regulate glucagon, and in muscles - adrenaline. They activate membrane-bound adenylate cyclase, which converts ATP to cAMP and interacts with the regulatory subunit of cAMP-dependent protein kinase, which leads to phosphorylation of phosphorylase kinase. The activated phosphorylase kinase then converts glycogen phosphorylase to its active conformation. It is this process that is affected in the course of glycogenesis of the IX type.