Pathogenesis of glycogenoses

Glycogenosis type 0

Glycogen synthase is a key enzyme in glycogen synthesis. In patients, the concentration of glycogen in the liver is reduced, which leads to fasting hypoglycemia, ketonemia, and moderate hyperlipidemia. Fasting lactate concentration is not increased. After a food load, a reverse metabolic profile with hyperglycemia and elevated lactate levels often occurs.

Glycogenosis type I

Glucose-6-phosphatase catalyzes the final reaction of both gluconeogenesis and glycogen hydrolysis and hydrolyzes glucose-6-phosphate into glucose and inorganic phosphate. Glucose-6-phosphatase is a special enzyme among those involved in liver glycogen metabolism. 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, enzyme or substrate carrier protein deficiency leads to similar clinical and biochemical consequences: hypoglycemia even with the slightest starvation due to blockade of glycogenolysis and gluconeogenesis and to the accumulation of glycogen in the liver, kidneys and intestinal mucosa, leading to dysfunction of these organs. The increase in the blood lactate level is associated with an excess of glucose-6-phosphate, which cannot be metabolized to glucose and therefore enters into glycolysis, the end products of which are pyruvate and lactate. This process is additionally stimulated by hormones, since glucose does not enter the blood. Other substrates, such as galactose, fructose and glycerol, also require glucose-6-phosphatase for metabolism into glucose. In this regard, the intake of sucrose and lactose also leads to an increase in the blood lactate level, only slightly increasing the glucose level. 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 an increase in 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 deficiency leads to the deposition of non-hydrolyzed glycogen in the lysosomes of muscles - cardiac and skeletal, 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 glycogen metabolism at the branching 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, it hydrolyzes the α-1,6-glucosidic bond. A decrease in enzyme activity is accompanied by a violation of the glycogenolysis process, leading to the accumulation of glycogen molecules of abnormal structure in tissues (muscles, liver). Morphological studies of the liver reveal, in addition to glycogen deposits, minor amounts of fat and fibrosis. Violation of the glycogenolysis process is accompanied by hypoglycemia and hyperketonemia, to which children under 1 year of age are most sensitive. The mechanisms of hypoglycemia and hyperlipidemia formation are the same as in glycogenosis type I. Unlike glycogenosis type I, in glycogenosis type III the lactate concentration in many patients is within the normal range.

Glycogenosis type IV

Amylo-1,4:1,6-glucantransferase, or branching enzyme, is involved in glycogen metabolism at the branching points of the glycogen "tree". It connects a segment of at least six α-1,4-linked glucosidic residues of the outer chains of glycogen to the glycogen "tree" by an α-1,6-glycosidic bond. Mutation of the enzyme disrupts the synthesis of glycogen of normal structure - relatively soluble spherical molecules. With enzyme deficiency, relatively insoluble amylopectin is deposited in liver and muscle cells, which leads to cell damage. The specific activity of the enzyme in the liver is higher than in the muscles, therefore, with its deficiency, symptoms of liver cell damage prevail. Hypoglycemia in this form of glycogenosis is extremely rare and has been described only in the terminal stage of the disease in the classic liver form.

Glycogenosis type V

Three isoforms of glycogen phosphorylase are known - expressed in cardiac/nervous tissue, liver and muscle tissue; they are encoded by different genes. Glycogenosis type V is associated with deficiency of the muscle isoform of the enzyme - myophosphorylase. Deficiency of this enzyme leads to decreased ATP synthesis in muscle due to impaired glycogenolysis.

Glycogenosis type VII

PFK is a tetrameric enzyme controlled by three genes. The PFK-M gene is mapped to chromosome 12 and encodes the muscle subunit; the PFK-L gene is mapped to chromosome 21 and encodes the liver subunit; and the PFK-P gene on chromosome 10 encodes the red blood cell subunit. In human muscle, only the M subunit is expressed, and the PFK isoform is a homotetramer (M4), while in erythrocytes, which contain both 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 global decrease in enzyme activity in muscle and a partial decrease in activity in red blood cells.

Glycogenosis type IX

Glycogen breakdown is controlled in muscle tissue and liver by a cascade of biochemical reactions that lead to the activation of phosphorylase. This cascade includes the enzymes adenylate cyclase and phosphorylase kinase (RNA). RNA is a decahexameric protein consisting of subunits a, beta, gamma, sigma; alpha and beta subunits are regulatory, gamma subunits are catalytic, sigma subunits (calmodulin) are responsible for the sensitivity of the enzyme to calcium ions. Glycogenolysis processes in the liver are regulated by glucagon, and in muscles - by 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 into its active conformation. It is this process that is affected in glycogenosis type IX.