Glycogenosis is a group of fairly rare hereditary diseases associated with defects in various enzymes necessary for the synthesis and breakdown of glycogen. In this case, normal or “incorrect” glycogen accumulates in human organs and tissues, which causes clinical manifestations of the disease. The predominant accumulation of glycogen can occur in the liver, muscles, and kidneys. A total of 12 forms of glycogenosis have been described, the difference being the nature of the enzyme deficiency. Each type of glycogenosis has its own prognosis: some have a favorable course, and patients live to old age, others end in death in childhood. The diseases are classified as incurable; there is currently no specific therapy. The main role in treatment is given to diet therapy with a high carbohydrate content. In this article we will talk about all the types of glycogenosis known to medicine, their symptoms and treatment options.

What is glycogen and what is it for?

Glycogen is a complex carbohydrate that is synthesized by connecting together glucose molecules that come from food. It represents a strategic reserve of glucose in cells. It is stored mainly in the liver and muscles with the peculiarity that glycogen from the liver, when broken down, provides glucose to the entire human body, and glycogen from the muscles - only the muscles themselves. Glycogen in the liver can account for 8% of its weight, while in muscles it is only 1%. But at the same time, due to the fact that the total muscle mass in the body is much greater than the mass of the liver, the muscle reserve exceeds the liver reserve. A small amount of glycogen is contained in the kidneys.

As soon as a person begins any kind of activity (physical or mental), he needs energy, which he draws from the breakdown of glycogen and glucose. At first, the glucose contained in the blood is broken down, but when its reserves are depleted (and there is no supply from the outside), glycogen is consumed. The spent glycogen reserve is then replenished again (with food intake).

Thus, glycogen allows a person to be active with relatively long breaks in food, and not be “tied to the plate.”

The stages of converting glucose into glycogen and its breakdown in the opposite direction are carried out using various enzymes, and they are different in the liver and muscles. Disturbances in the activity of such enzymes lead to the development of glycogenosis.

Glycogenosis occurs, on average, with a frequency of 1 case per 40-68,000 population. They are always hereditary in nature, that is, they arise when, as a result of gene disorders, the amount or activity of one of the enzymes necessary for the biochemical processes of creating and breaking down glycogen changes. The type of inheritance is mainly autosomal recessive (not related to gender, and for its appearance a coincidence of pathological genes received from the father and mother is necessary). Of all 12 types of glycogenosis known today, 9 are hepatic forms, 2 are muscular, 1 is either muscular or generalized (affecting almost the entire body). Each type of glycogenosis has its own distinctive features.

Types of glycogenosis

Glycogenosis type 0 (aglycogenosis)

With glycogenosis, hypoglycemic conditions often develop, requiring the administration of glucose.

This type of glycogenosis occurs when the enzyme involved in creating glycogen from glucose is defective, resulting in glycogen simply not being produced in sufficient quantities. That is, glycogen deficiency occurs, so this glycogenosis is numbered zero, as if apart from the rest.

With aglycogenosis, as soon as all the sugar in the blood is used up, hypoglycemic syndrome develops with loss of consciousness up to coma. The disease manifests itself almost from the first days of life, especially if the mother does not have enough milk during breastfeeding. Long breaks between feedings and night intervals become the reasons for the development of a coma.

Coma develops as a result of a lack of sufficient energy supply to the brain. The likelihood of death in early childhood is very high. If they manage to survive, then the development of such children, both mental and physical, differs significantly from their peers for the worse. Intravenous administration of glucose brings such patients out of a comatose state, but hyperglycemia persists for quite a long time (since glycogen is not synthesized).

Glycogenosis type I (Gierke's disease)

These children may experience an increase in body temperature for no apparent reason.

The source of this variety is glucose-6-phosphatase deficiency. The consequence is excessive accumulation of glycogen in the liver and kidneys. There is low glucose in the blood (hypoglycemia). A peculiar paradox arises: there is an excess of glycogen, but there is nothing to break it down, so a glucose deficiency occurs. Patients require very frequent meals to ensure that the blood glucose concentration is sufficient to meet energy needs.

The disease manifests itself in the first years of life. These children have no appetite and vomit frequently. There are breathing problems due to metabolic disorders: shortness of breath, cough. Hypoglycemia can lead to the development of coma with seizures. Temperature often rises without infectious causes.

The deposition of glycogen in the liver and kidneys leads to an increase in these organs with disruption of their function. Due to liver damage, hemorrhagic syndrome develops (a tendency to spontaneous bleeding), and impaired filtration function of the kidneys leads to the accumulation of uric acid. If death does not overtake patients at an early age, then later they lag behind in physical development and have a disproportionate body (large head with a “doll” facial expression). Mental development is not affected. Characterized by hypotension and muscle wasting. Puberty occurs much later than among peers. Some patients experience a decrease in the number of neutrophils in the blood. Secondary bacterial infections are often associated. Patients who managed to survive and grow up are overtaken by gouty nephropathy and liver adenomas. Kidney damage causes protein loss in the urine and increased blood pressure. Kidney failure may occur. Liver adenomas can develop into cancer.

Glycogenosis type II (Pompe disease)

This variety can be presented in two forms: generalized (enzyme deficiency observed in the liver, kidneys, muscles) and muscular (enzyme deficiency only in the muscles).

The generalized form makes itself felt in the first six months of life. Associated with α-glucosidase deficiency. Poor appetite, anxiety, lethargy, low muscle tone, developmental delay, and breathing problems become the first symptoms. The heart, liver, kidneys, and spleen gradually increase in size. On the part of the respiratory system, frequent bronchitis and pneumonia develop. Heart failure develops. Damage to the nervous system is manifested by paralysis and impaired swallowing. The prognosis for life in the generalized form is unfavorable.

The muscular form has a more favorable course. It results from a deficiency of acid α-1,4-glucosidase in muscle only. Makes itself known later: at approximately 15-25 years of age. The main manifestation of muscle shape is weakness and decreased muscle tone. In addition to muscle problems, postural disorders (scoliotic deformity of the thoracic spine) and minor heart failure occur. Patients with this form of the disease live to old age.

Glycogenosis type III (Measles disease, Forbes disease, limit dextrinosis)

This is the most common glycogenosis. It is caused by a deficiency of amylo-1,6-glucosidase, resulting in incorrect glycogen synthesis. Incorrect glycogen is stored in the liver, heart and muscles. Initial signs of the disease are detected in infants. Such children have frequent vomiting, delayed physical development, and a “doll” face. Hypoglycemia can lead to loss of consciousness. Muscle tone decreases, along with this, muscle thickening is observed due to the accumulation of glycogen. For the same reason, the heart muscle thickens (myocardial hypertrophy), which disrupts cardiac conduction and heart rhythm.

Sometimes after puberty the disease is less aggressive. In this case, liver disorders fade into the background, and the dominant symptoms become muscle weakness and thinning of the muscles (mainly the calf muscles).

Glycogenosis type IV (Andersen's disease, diffuse glycogenosis with liver cirrhosis, amylopectinosis)

Becomes the result of deficiency of amylo-(1,4-1,6)-transglucosidase. This leads to the formation of incorrect glycogen. This type of glycogenosis can be inherited in a sex-linked manner, and not just autosomal. From the first days of life, the deposition of improper glycogen in the liver begins. This quickly leads to disruption of the activity of liver cells, stagnation of bile, the development of hepatitis, and then cirrhosis of the liver. Jaundice, increased bleeding, enlargement of the abdomen with accumulation of fluid in the abdominal cavity (ascites), skin itching, intoxication of the body - all these are consequences of developed cirrhosis of the liver. Generalized muscle wasting and severe cardiomyopathy develop. Bacterial infections are often associated. Death occurs at 3-5 years of life.

Glycogenosis type V (McArdle disease, myophosphorylase deficiency)

This is exclusively muscle glycogenosis, because it is based on a defect in an enzyme such as muscle phosphorylase. Unsplit glycogen is deposited in muscle tissue, causing the muscles to become denser and thicker, but at the same time they become very weak and quickly tire. Painful muscle spasms occur during physical activity, which may be accompanied by increased sweating and pallor of the skin, and tachycardia. Muscle protein may be excreted in the urine. All these manifestations appear before adolescence and gradually increase. Contractures of large joints may form. Compared to other types of glycogenosis, type V glycogenosis is a benign disease.

Glycogenosis type VI (Hers disease, hepatophosphorylase deficiency)

This glycogenosis is based on problems with liver phosphorylase. As a result, glycogen accumulates in the liver. Already in infants, an increase in the size of the liver is observed, the child’s development is delayed, and children gain little weight. Together with other metabolic disorders, an increased fat content is detected in the blood. There is an increased glycogen content in red blood cells (erythrocytes).

Glycogenosis type VII (Tarui disease, myophosphofructokinase deficiency)

The disease is associated with a deficiency of muscle myophosphofructokinase, which causes glycogen deposition in them. According to its clinical signs, glycogenosis type VII is practically no different from glycogenosis type V and also has a relatively benign course.

Glycogenosis type VIII (Thomson's disease)

With this glycogenosis, the exact genetic cause is not known, and an enzyme deficiency is found in the liver and brain. Disturbances in the nervous system come first. Characteristic is nystagmus (involuntary trembling movements of the eyeballs), which is called “dancing eyes” in this case, incoordination of muscle contractions, which is manifested by inaccuracy of movements. Disorders of muscle tone, paresis, and convulsive twitching gradually develop. Neurological disorders are steadily progressing. The liver increases in size, and manifestations of liver failure increase. Such patients have no prospects of surviving to middle age; the disease ends in death in childhood.

Glycogenosis type IX (Haga's disease)

This type of glycogenosis is transmitted with the sex chromosome. The source is an enzyme deficiency in the liver. Glycogen accumulation leads to liver failure.

Glycogenosis type X

This species has only been described once in the entire world. The inheritance type could not be determined. The disease progressed with liver enlargement and was accompanied by pain and muscle tension when involved in work.

Glycogenosis type XI (Fanconi-Bickel disease)

Glycogenosis with an unknown transmission mechanism. Enzyme defects were found in the liver and kidneys. This type of glycogenosis is characterized by an increase in the size and hardening of the liver, and stunted growth. The difference from other types of glycogenosis is a decrease in the amount of phosphates in the blood and the development of rickets in connection with this. Upon reaching puberty, there is a tendency towards some improvement in the condition: the liver decreases in size, the phosphorus content normalizes, and children begin to grow.

Treatment

Corn starch provides the child with glucose for several hours, this helps to avoid hypoglycemia at night.

Glycogenosis, like almost all genetic diseases, is an incurable pathology. All medical care measures are essentially symptomatic. However, since a number of glycogenoses have a favorable prognosis for life if a number of conditions are met (in particular, the muscular form of type II, type III, V, VI, VII, IX, XI), therapeutic measures help reduce a number of symptoms and improve the patient’s health status .

Treatment for glycogenosis is based on diet therapy to avoid hypoglycemia and secondary disorders of metabolic processes in the body. The essence of the diet is to study the patient’s glycemic profile and select a food intake regimen that will avoid the progression of biochemical disorders (disorders of fat metabolism, lactic acid) and ensure sufficient levels of glucose in the blood. Frequent feedings, including at night, in young children help to avoid hypoglycemia. Usually, food containing a lot of proteins and carbohydrates is prescribed, and fats are limited. The percentages are approximately as follows: carbohydrates - 70%, proteins - 10%, fats - 20%.

In order to avoid having to feed the child several times a night, raw corn starch (prescribed to children over 1 year old), which is diluted with water in a 1:2 ratio, can be used. The administration begins with a dose of 0.25 mg/kg, then it is gradually increased so that the administered dose of starch is enough to provide the body with glucose for 6-8 hours, that is, throughout the night. Thus, taking starch at night allows you to avoid night feedings, which provides children with full sleep without interruptions.

In cases where small children suffer from frequent attacks of hypoglycemia, and it is not possible to influence this only by following a diet, additional administration of pure glucose or a mixture enriched with maltodextrin is prescribed.

For type I glycogenosis, it is necessary to significantly limit foods containing galactose and fructose (milk, most fruits). With type III glycogenosis there are no such restrictions. In type VII, it is necessary to limit the intake of sucrose.

In some cases (especially when other intercurrent diseases occur in such children), enteral nutrition alone becomes insufficient, since the body’s need for energy increases. Then they resort to feeding through a nasogastric tube and intravenous infusions in a hospital setting.

Those types of glycogenosis, in which enzyme defects are localized only in the muscles, require the intake of fructose 50-100 g per day, a complex of vitamins, and adenosine triphosphoric acid.

Medications for type I glycogenosis include calcium supplements, vitamin D and B1, allopurinol (to prevent gout and urate deposition in the kidneys), nicotinic acid (to reduce the risk of calculous cholecystitis and prevent pancreatitis). If the kidneys begin to excrete protein, then angiotensin-converting enzyme inhibitors (Lisinopril, Enalapril and others) are prescribed.

For type II glycogenosis, specific enzyme therapy (replacement therapy) has been developed. The drug Myozim is administered at a dose of 20 mg/kg every two weeks. Myozyme is a genetically engineered human α-glucosidase enzyme. Naturally, the earlier treatment is started, the greater the effect. But so far the drug is approved for use only in some European countries, Japan and the USA. Genetic engineering continues to develop in this direction, trying to synthesize other enzymes necessary for the normal synthesis and breakdown of glycogen in order to help patients with other forms of glycogenosis.

Some patients benefit from the administration of glucocorticoids, anabolic hormones and glucagon. The drugs stimulate certain biochemical processes (for example, gluconeogenesis, that is, the process of synthesis of glucose from non-carbohydrate substances), thereby reducing the manifestations of the disease.

Surgical treatment methods for some forms of glycogenosis include portacaval anastomosis or liver transplantation. Portocaval anastomosis is performed in patients with severe forms of glycogenosis types I and III. It helps reduce metabolic disorders, promotes regression of liver size, and improves the tolerance of hypoglycemia. Liver transplantation from a donor is carried out for types I, III, IV of glycogenosis. For type I glycogenosis, surgery is performed only when diet therapy measures are ineffective; for type III glycogenosis, surgery is performed only when the patient’s liver cannot be saved.

Thus, glycogenoses are a fairly large group of metabolic diseases with genetic origins. Today, medicine does not have 100% effective methods for treating this disease; genetic engineering holds promise in this direction.

MINISTRY OF HEALTH OF THE REPUBLIC OF BELARUS

Educational Institution

"Grodno State Medical University"

Department of Biological Chemistry

Glycogen metabolism disorders: glycogenoses and aglycogenoses

Belko Elena Nikolaevna

Faculty of Medicine, 2nd year, 5th group

Sheybak Vladimir Mikhailovich

Doctor of Medical Sciences, Professor

Grodno, 2014

1. Introduction............................................... ........................................................ ..........3

2. Classification of glycogenoses.................................................... ...........................4

3. Glycogenosis type 0 (aglycogenosis).................................................. ...........................5

4. Glycogenosis type IA.................................................... ..........................................5

5.Glycogenosis type II.................................................... ...............................................6

6.Glycogenosis type III.................................................... ............................................7

7.Glycogenosis type IV.................................................... ...............................................7

8. Glycogenosis type V.................................................... ...............................................8

9. Glycogenosis type VI.................................................... ..............................................8

10. Glycogenosis type VII.................................................... ..........................................9

11.Glycogenosis type VIII.................................................... .........................................9

12.Glycogenosis type IX.................................................... ............................................9

13. Glycogenosis type X.................................................... .............................................9

14. Glycogenosis type XI.................................................... ............................................9

15.Conclusion................................................... ........................................................ ...10

16. List of used literature.................................................... .............eleven

Introduction

Glycogen is one of the most important forms of carbohydrate storage in fungi, animals and humans. Many tissues synthesize glycogen as a reserve form of glucose. The synthesis and breakdown of glycogen ensures a constant concentration of glucose in the blood and creates a depot for its use by tissues as needed.

The main stores of glycogen are in the liver and skeletal muscles. Liver and muscle glycogen is consumed depending on the body's needs (labile glycogen). Glycogen in nerve cells, the conduction system of the heart, aorta, endothelium, epithelial integuments, uterine mucosa, connective tissue, embryonic tissues, cartilage is an essential component of cells and its content does not undergo noticeable fluctuations (stable glycogen). However, the division of glycogen into labile and stable is arbitrary. Regulation of carbohydrate metabolism is carried out by the neuroendocrine pathway. The main role belongs to the hypothalamic region, the pituitary gland (ACTH, thyroid-stimulating, somatotropic hormones), beta cells of the pancreatic islets (insulin), adrenal glands (glucocorticoids, adrenaline) and the thyroid gland.

Hereditary carbohydrate dystrophies, which are based on disorders of glycogen metabolism, are called glycogenoses. Glycogenosis is caused by the absence or deficiency of the enzyme involved in the breakdown of stored glycogen, and therefore belongs to hereditary enzymopathies, or storage diseases.

Glycogenosis (glycogen storage disease, glycogen disease) is a group of hereditary diseases that are caused by a deficiency of enzymes involved in glycogen metabolism; characterized by a violation of the structure of glycogen, its insufficient or excessive accumulation in various organs and tissues. It should be noted that the term “glycogenosis” was first proposed by K.F. Corey and G.T. Corey. The prevalence of glycogenosis in the population is 1:68000 - 1:40000.

Based on the nature of enzymatic deficiency, 12 types of glycogenosis are distinguished.

Classification of glycogenoses

Type of glycogenosis	Enzyme with impaired activity	The main organs, tissues and cells in which the enzyme defect was found
	Glycogen synthetase	Liver
I	Glucose-6-phosphatase	Liver, kidneys, small intestinal mucosa
II	Acid alpha-1,4-glucosidase	Liver, kidneys, spleen, muscles, nervous tissue, leukocytes
III	Amylo-1,6-glucosidase (debranching enzyme)	Liver, muscles, leukocytes, red blood cells
IV	Amylo-1,4,1,6-transglucosidase (branching enzyme)	Liver, muscles, kidneys, leukocytes
V	Muscle phosphorylase (myophosphorylase)	Muscles
VI	Liver phosphorylase	Liver, leukocytes
VII	Phosphofructokinase	Muscles, red blood cells
VIII	Liver phosphorylase	Liver, brain
IX	Phosphorylase kinase	Liver
X	c-AMP-dependent phosphorylase kinase	Liver, muscles
XI	Phosphoglucomutase Phosphohexoisomerase	Liver, kidneys

Depending on the predominance of symptoms of liver or muscle damage, hepatic and muscular forms of glycogenosis are conventionally distinguished.

v Hepatic forms of glycogenosis lead to disruption of the use of glycogen to maintain blood glucose levels. Therefore, a common symptom for these forms is hypoglycemia in the postabsorptive period.

v Muscular forms of glycogenosis are characterized by a disturbance in the energy supply of skeletal muscles. These diseases manifest themselves during physical exertion and are accompanied by pain and muscle cramps, weakness and fatigue.

Hepatic glycogenoses include types 0, I, III, IV, VI, VIII, IX, X and XI, and muscular types V and VII. Type II glycogenosis is manifested by damage to many organs and systems (generalized form) or only muscles. A combination of glycogenosis of several types is possible (for example, types I and III).

Glycogenosis type 0 (aglycogenosis)- a hereditary disease caused by the absence of the enzyme responsible for glycogen synthesis, namely uridine-diphosphate-glucose-glycogen transferase or glycogen synthetase. This disease was described in 1964 by Speneer-Peet in several children of both sexes in the same family, two of whom had mental retardation.

Symptoms of aglycogenosis: With aglycogenosis in children, severe hypoglycemia is observed, the glucose content drops to 7-12 mg%. Hypoglycemic convulsions in patients usually occur in the morning and can only be prevented by frequent feeding of children at night.

Diagnosis of aglycogenosis: If aglycogenosis is suspected (frequent and severe hypoglycemia), a liver biopsy is necessary to test for glycogen and enzymes involved in its synthesis. Differential diagnosis is made with hypoglycemia.

Treatment of glycogenosis type 0 (aglycogenosis): Treatment is symptomatic. The prognosis is unfavorable.

Disorders of carbohydrate metabolism, which are characterized by an enlarged liver (hepatomegaly) and a decrease in blood glucose levels (hypoglycemia), include glycogenosis type I(also known under such names as glucose-6-phosphatase defect, Gierke's disease, hepatonephromegal glycogenosis). Inherited in an autosomal recessive manner.

The cause of the various symptoms that occur with type IA glycogenosis is a deficiency of the multifunctional enzyme glucose-6-phosphatase, which acts at the last stage of glucose formation (gluconeogenesis). This enzyme provides the formation of more than 90% of the glucose released in the liver; therefore, it has a central role in normal glucose homeostasis. During the breakdown of glycogen or as a result of the synthesis of glucose, glucose-6-phosphate is formed, the cleavage of part of the molecule from which converts this compound into glucose that enters the bloodstream.

The persistent symptoms of Gierke's disease are hypoglycemia and low insulin levels.

Highlight pseudoglycogenosis type I, in which the defect concerns not glucose-6-phosphatase, but the glucose-6-phosphate transport system.

The clinical picture of Gierke's disease is characterized by malnutrition (loss of body weight), combined with an enlarged liver (hepatomegaly), hypoglycemia, as well as other biochemical changes in the body. Enlargement of the kidneys is often observed, which may be accompanied by the release of glucose in the urine (glucosuria). Sometimes ketone bodies are excreted in the urine (ketonuria), but the development of a severe condition such as ketoacidosis is uncommon. Quite often complications such as prolonged bleeding, characterized by impaired platelet function, develop. At older ages, xanthomas develop. Sick children have a characteristic face that resembles a Chinese doll.

Diagnosis is based on the presence of a triad of disorders, such as hypoglycemia, hyperlactatemia and hyperuricemia.

Determining the activity of the key enzyme in material taken during a biopsy of liver tissue allows you to confirm the diagnosis and choose the right treatment. The latter involves limiting foods containing lactose and sucrose, from which additional amounts of glucose-6-phosphate are formed.

Generalized form of glycogenosis type II(also called acid maltase deficiency, Pompe disease) is inherited in an autosomal recessive manner. The first symptoms of the disease appear a few days or weeks (up to 6 months) after birth. Cyanosis (general and intermittent), respiratory distress (accelerated, superficial), anxiety or adynamia are noted. The tongue gradually enlarges (macroglossia), and muscle hypotonia increases. Lack of appetite, pylorospasm, and growth retardation are noted. The size of the liver, spleen, kidneys, and heart increases. Due to myocardial hypertrophy, the heart acquires a spherical shape, and ECG changes appear. Bronchitis, pulmonary atelectasis, and hypostatic pneumonia often occur. Myodystrophy, hyporeflexia, bulbar disorders, and spastic paralysis are observed. In the blood serum, the content of uric acid, the activity of transaminases and aldolase are increased.

The muscle form of glycogenosis type II occurs when there is a deficiency of acid alpha-1,4-glucosidase only in the muscles. In these cases, the disease usually manifests itself at a later age and the clinical picture resembles myopathies.

At the core glycogenosis type III(Measles disease, Forbes disease) there is a defect in the enzyme amylo-1,6-glucosidase. In the absence of the above enzyme, complete breakdown of glycogen does not occur.

The clinical picture consists of an enlarged liver, muscle weakness and other disorders, fasting hypoglycemia, and a doll-like face, as with Gierke's disease. The kidneys do not enlarge, but sometimes an enlarged spleen and xanthoma are noted.

The results of laboratory tests are similar to those for glycogenosis type I. A protein-rich diet with frequent meals provides the optimal therapeutic effect. In infancy and during the course of infectious diseases, night feedings become of great importance. The prognosis is relatively favorable, much more favorable than with Gierke's disease.

Glycogenosis type IV(amylopectinosis, Andersen's disease, diffuse glycogenosis with liver cirrhosis) is a rare, severe form of glycogen storage disease that develops as a result of deficiency of the enzyme amylo-1,4,1,6-transglucosidase. With a deficiency of this enzyme, structurally altered glycogen is formed.

Andersen's disease is characterized by cirrhosis of the liver with jaundice and liver failure, which develops in infancy. Glycogen is also deposited in the heart, kidneys, spleen, lymph nodes, and skeletal muscles; as a result of the latter, muscle weakness is quite often noted, which may precede severe liver dysfunction.

Treatment of the disease is only symptomatic.

Glycogenosis type V(myophosphorylase deficiency, McArdle disease) was first described in 1951. This disease was identified in a patient with muscle pain after minor physical activity, while there were no symptoms at rest. Males get sick 5 times more often. In this disease, there is a deficiency of the enzyme (muscle phosphorylase). This enzyme differs from liver phosphorylase, so the liver is not affected in McArdle's disease, and glycogen is deposited in excess in the muscles, which breaks down after physical activity, and therefore the pain previously noted by patients goes away.

The first signs of the disease, as a rule, develop at the end of the second - beginning of the third decade of life. Sometimes it is episodic myoglobinuria, especially after intense physical activity. The diagnosis is based on the determination of increased activity of muscle enzymes in the blood serum after physical exertion (such as lactate dehydrogenase, aldolase, creatine phosphokinase) and the determination of myoglobin in the urine. There is no increase in the concentration of lactic acid in the blood serum, since the energy needs of the muscles are satisfied by fatty acids, and not by glucose.

Treatment involves limiting heavy physical activity. The prognosis is generally relatively favorable; in severe cases, the disease leads to disability.

Glycogenosis type VI(liver phosphorylase complex deficiency, Hers disease) is characterized by a mutation in the structural gene encoding the activity of the liver phosphorylase enzyme and linked to chromosome 14.

Clinical manifestations are less pronounced than with glycogenosis types I and III. Hepatomegaly and a slight slowdown in growth rates are noted, i.e., compared to other glycogen diseases, this is a mild variant of glycogen storage disease. Hypoglycemia is not common. Sometimes the level of transaminase enzymes is elevated.

To confirm the diagnosis, it is necessary to examine the activity of the enzyme system in peripheral blood leukocytes or in biopsied liver tissue.

The basis of treatment is a diet with a high protein content (15-20% of total calories), as well as frequent meals. Fats should account for 30-35% of calories, carbohydrates are recommended in the form of starch and glucose. During adolescence, the size of the liver decreases. Diet therapy prevents possible hypoglycemia. The prognosis for life is good, mental development does not suffer.

Glycogenosis type VII(Tarui disease, myophosphofructokinase deficiency) is similar in clinical manifestations to glycogenosis type V. Characterized by muscle weakness, fatigue and the absence of hyperlactic acidemia after exercise.

Glycogenosis type VIII(Thomson's disease, phosphoglucomutase deficiency) is extremely rare. After birth, the size of the liver gradually increases, then nystagmus (“dancing eyes”) and ataxia appear. Neurological symptoms progress to the development of muscle hypertension and decerebration. Patients usually die. The inheritance type has not been established.

Glycogenosis type IX(phosphorylase b kinase deficiency, Hag's disease) is inherited in a recessive, sex-linked manner. Patients have hepatomegaly. Other symptoms characteristic of hepatic forms of glycogenosis are not pronounced.

Glycogenosis type X described in a single patient. Hepatomegaly was observed, and 6 years after the onset of the disease, muscle pain and muscle spasms appeared after exercise. The inheritance type has not been established.

Glycogenosis type XI characterized by a significant enlargement of the liver and a sharp retardation of growth. Transaminase activity and serum lipid levels may be increased, and phosphate levels may be decreased. Generalized hyperaminoaciduria, galactosuria, glucosuria, and phosphaturia are characteristic. Symptoms of hypophosphatemic rickets are observed. During puberty, a decrease in liver size, accelerated growth, and normalization of phosphorus levels in the blood are possible. The inheritance type has not been established.

Conclusion

To confirm the diagnosis of glycogenosis and establish its type, a biopsy of the liver, muscles (sometimes skin) is performed in the hospital, followed by histochemical examination; at the same time, the glycogen content in tissues and the activity of enzymes involved in its metabolism are determined. In type II glycogenosis, the activity of acid a-1,4-glucosidase in blood cells, as well as in the culture of fibroblast cells of the patient’s skin and muscles, is also determined. Glycogenosis type II can be diagnosed prenatally by biochemical examination of desquamated epithelial cells of the fetal skin found in amniotic fluid obtained by amniocentesis.

List of used literature

1. Biochemistry: Textbook / Ed. E.S. Severina. – 2nd ed., rev. – M.: GEOTAR – MED, 2004. – P. 330 – 333.

2. Berezov T. T., Korovkin B. F. Biological chemistry. – 2nd ed. –

M.: Medicine, 1990. – P. 273-275.

3. Biological chemistry: Textbook. For honey specialist. universities – Higher school, 1989. – P.253-254.

4. Kukhta V.K., Morozkina T.S., Oletsky E.I., Taganovich A.D.

Biological chemistry. – Minsk, M.; Publishing house BINOM, 2008. –

5. Lelevich V.V., Ledneva I.O., Kurbat M.N., Petushok N.E.,

Vorobyov V.V. Fundamentals of biochemistry: a textbook for students

Faculty of Medicine. – Grodno: GrSMU, 2010. – P. 188-189.

The term "glycogenosis" is a general term for a group of hereditary diseases characterized by the deposition in tissues of either abnormally large amounts of glycogen or unusual types of glycogen.

In glycogenosis type 1 (Gierke's disease), the cells of the liver and convoluted renal tubules are filled with glycogen, but these reserves are inaccessible: this is evidenced by hypoglycemia, as well as the lack of increase in blood glucose levels in response to adrenaline and glucagon. Typically, these patients develop ketosis and hyperlipemia, which is generally characteristic of the state of the body with a lack of carbohydrates. In the liver, kidneys and intestinal tissues

Glucose-6-phosphatase activity is either extremely low or absent.

Glycogenosis type II (Pompa disease) leads to fatal consequences and is characterized by the absence of lysosomal β-glucosidase (acid maltase), the function of which is the degradation of glycogen, preventing its accumulation in ribosomes.

Glycogenosis type III (limitedextrinosis; Forbes disease or Measles disease) is characterized by the absence of a debranching enzyme; As a result, a characteristic branched polysaccharide (residual dextrin) accumulates.

Glycogenosis type IV (amylopectinosis; Andersen disease) is characterized by the absence of a branching enzyme, resulting in the accumulation of a polysaccharide containing a small number of branches. Death usually occurs due to heart or liver failure in the first year of life.

The absence of muscle phosphorylase (myophosphorylase) is the cause of glycogenosis type V (myophsophorylase deficiency; McArdle syndrome). Patients have reduced endurance to physical activity. Although their skeletal muscles have an abnormally high glycogen content (2.5-4.1%), little or no lactate is detected in the blood after physical activity.

Glycogenosis associated with phosphorylase deficiency in the liver (type VI glycogenosis), phosphofructokinase deficiency in muscles and red blood cells (type VII glycogenesis; Tarui disease), as well as glycogenosis caused by phosphorylase kinase deficiency, have been described. Cases of adenylate kinase and cAMP-dependent protein kinase deficiency have also been reported.

LITERATURE

Brown D.H., Brown V. I. Some inborn errors of carbohydrate metabolism. Page 391. In: MTP International Review of Science. Vol. 5, Whelan W.J. (ed.), Butterworth, 1975. Cohen P. Control of En/yme Activity, 2nd ed.. Chapman and Hall, 1983.

Cohen P. The role of protein phosphorylation in the hormonal control of enzyme activity. Eur. J. Biochem.. 1985, 151, 439. Exton J. H. Molecular mechanism involved in a-adrenergic responses, Mol. Cell. Endocrinol.. 1981. 23, 233.

Hers H. G. The control of glycogen metabolism in the liver. Annu. Rev. Biochem., 1976, 45. 167.

Randle P.J., Steiner D.F., Whelan W.J. (eds). Carbohydrate Metabolism and Its Disorders, Vol. 3, Academic Press, 1981.

Sperling O., de Vries A. (eds). Inborn Errors of Metabolism in Man. Karger, 1978.

Stanhurv J.B. et al. (eds). The Metabolic Basis of Inherited Disease, 5th ed., McGraw-Hill, 1983.

Biological chemistry Lelevich Vladimir Valeryanovich

Glycogen metabolism disorders

Glycogen metabolism disorders

Glycogen diseases are a group of hereditary disorders based on a decrease or absence of activity of enzymes that catalyze reactions of glycogen synthesis or breakdown. These disorders include glycogenosis and aglycogenosis.

Glycogenosis is a disease caused by a defect in the enzymes involved in the breakdown of glycogen. They are manifested either by an unusual structure of glycogen, or by its excessive accumulation in the liver, muscles and other organs. Currently, it is proposed to divide glycogenoses into 2 groups: liver and muscle.

Hepatic forms of glycogenosis manifest themselves in a violation of the use of glycogen to maintain blood glucose levels. A common symptom of these forms is hypoglycemia in the postabsorptive period. This group includes glycogenosis types I, III, IY, YI, IX and X according to the Measles numbering.

Muscular forms of glycogenosis are characterized by disturbances in the energy supply of skeletal muscles. These diseases manifest themselves during physical exertion and are accompanied by pain and muscle cramps, weakness and fatigue. These include glycogenosis types Y and YII.

Aglycogenosis (glycogenosis O according to classification) is a disease resulting from a defect in glycogen synthase. The liver and other tissues have very low glycogen content. This is manifested by pronounced hypoglycemia in the post-absorptive period. A characteristic symptom is cramps, especially in the morning. The disease is compatible with life, but sick children need frequent feeding.

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Glycogen storage diseases (literature review)

1.1. History, basic concepts.

Glycogen disease is the general name for hereditary diseases of carbohydrate metabolism caused by insufficiency or defects of enzymes involved in the synthesis and breakdown of glycogen. As a result of the disease, excess glycogen accumulates in the liver and hypoglycemia develops. The disease is most common in regions where consanguineous marriages are common. (12)

Clinically, one of the forms of glycogenosis was first described by the French pediatrician C. Lereboullet (1910), but its comprehensive pathological anatomy was presented by E. Gierke (1929), emphasizing the main pathomorphological feature - excessive accumulation of glycogen. (14) Subsequently, a similar disease became known as Gierke's disease, and the author himself called it glycogenosis. (15) In 1932, Pompe reported a sick child in whom a post-mortem examination revealed a large amount of glycogen in the heart muscle. The disease was later named Pompe disease. Important studies on the pathogenesis of glycogen disease were carried out by G. Cori (1952), Forbes (1953), Ilingworth, Andersen (1956), Hers (1959), who showed enzymatic insufficiency of glycogenolysis processes. (34) The discovery of the enzymatic pathogenesis of glycogenosis led to clinical differentiation and more accurate nosological characteristics of these diseases contributed to correct genetic interpretation, as well as an in-depth study of the structure and physiology of glycogen. In subsequent years, glycogen storage disease was reported, caused by the absence of phosphoglucomutase (Thomson 1963), phosphofructokinase (Tarui 1965), phosphorylase a and phosphorylase kinase " V" (Hug 1966), protein kinase kinase phosphorylase " V"(Hug 1970). In 1963, Lewis and co-authors first described cases of the complete absence of glycogen synthetase in the liver of children from the same family. (40) There are descriptions of cases of glycogenosis, when, with obvious clinical manifestations of the disease, it was not possible to detect a deficiency in the activity of enzymes involved in glycogen metabolism. (34) There are known publications when in one form of glycogenosis there is a deficiency of several enzymes involved in glycogen metabolism.

Prevalence

Research in recent years has shown that glycogenosis is a less rare disease than previously thought.(39) According to Huijing data in 1975, the prevalence of the disease is 1: 40,000 population. The fluctuations are different in different countries, for example, in Israel it is 1: 49,000, in Sweden 1: 57,000, in Norway 1: 68,000, in Germany 1: 113,000 (Schaub, Beverl). (1) In 2001, the incidence of hypertension was 1 : 20,000 population.(141) Variations in the prevalence of HD are observed in different areas of the same country. Moe Y. (2000) systematized data on the prevalence of various types of headaches. In the Netherlands, Norway, and Israel, type III glycogenosis is most common. The same type is more often observed in France. In Germany, type III was observed relatively rarely. In Sweden, this type is less common than others; the most common here is type I. In the United States, type IX headache was the most common. In Belgium, out of 316 cases of glycogenosis, 124 patients were diagnosed with type VI glycogenosis, 63 with type III, and 47 with type II. In Thailand (2000) the most common is type II. In Russia, according to Popovich Yu.G. in 1988, among 49 children with hypertension observed at the Research Institute of Pediatrics of the USSR Academy of Medical Sciences, 18.4% had type I of the disease, 38.8% had type III, 40.8% had type VI - IX hypertension, in 2% the type was not identified.

Glycogen is a high-molecular polysaccharide, which is the main source of energy and a reserve of carbohydrates, found in all human and animal cells. (19) Normally, glycogen constitutes up to 4% of the wet weight of the liver, in muscles it accounts for up to 2%. In the body, as a result of the breakdown of polysaccharides and disaccharides, three monosaccharides are formed: glucose, fructose, galactose, which are absorbed in the digestive tract. (15) Glucose can be deposited in the form of glycogen in two main sources: the liver and skeletal muscles. Muscle cells, like liver cells, can also convert glucose into reserve glycogen, but muscle glycogen serves only as a “local” reserve: it is a ready source of fuel for immediate energy supply to the muscles, is consumed during muscle work and cannot be used to regulate glucose levels in the blood.(18) In the liver, glycogen is broken down, providing an uninterrupted supply of glucose to red blood cells, brain, and heart muscle. Glucose enters the body either with consumed food or through gluconeogenesis: it is formed through biochemical reactions from lactate, glycerol and glucoplastic amino acids. The liver can maintain a sufficient supply of glycogen to supply the blood with glucose for 12 to 24 hours; After this time, to maintain glycemia, the liver must use other substances, mainly amino acids (glycine, alanine, serine, threonine, valine, proline, glutamic acid and hydroxyproline). The study of the role of the liver in carbohydrate metabolism and the discovery of glycogen in 1897 belongs to the French physiologist Claude Bernard. (15) He determined the difference in the concentration of blood glucose: the level of glycemia in the blood flowing to the liver was much higher than that outflowing.

^ 1.2.Regulation of glycogen metabolism in the liver

The breakdown and synthesis of glycogen is controlled by hormones and metal ions that affect key enzymes of glycogen metabolism. Coordination of glycogen metabolism must be carried out in such a way that either synthesis or degradation is ensured. Phosphorylation corresponds to the mechanism of glucose turnover in the body, providing both synthesis and breakdown. With an immediate need for glucose, the α-cells of the pancreas secrete glucagon, which binds to the liver cells and stimulates the production of cAMP under the influence of adenylate cyclase, and this, in turn, activates protein kinase. Protein kinase phosphorylates glycogen phosphorylase kinase, converting it into an active form, but at the same time converts glycogen synthetase into an inactive form. (31) As a result of the sequential degradation of glycogen, glucose enters the blood. At the same time, the liver can synthesize glycogen from lactic acid. Thus, the breakdown of glycogen in the liver occurs both hydrolytically and predominantly phosphorolytically.

The synthesis and breakdown of glycogen are reversible reactions, the biological role of which is to create a reserve of glucose or release it in accordance with the needs of the body. The relationship between the synthesis and breakdown of glycogen is regulated by the neurohumoral pathway with the participation of the endocrine glands. Insulin, ACTH, GCS increase the content of glycogen in the liver, adrenaline, glucagon, catecholamines, growth hormone and thyroxine stimulate its breakdown. (11) In addition, there is non-hormonal regulation of gluconeogenesis by one and two valence metal ions: K+, Ca+, Mg+, in significantly activate glycogen synthetase, phosphorylase and phosphorylase kinase " V" (19,20) Glycogenoses are caused by metabolic disorders that lead to abnormal accumulation or changes in the structure of glycogen. (12) They are divided into types according to the identified enzyme defect and based on the characteristics of the clinical picture. Glycogenosis is associated with more than 15 different enzyme defects. Based on the location of the enzyme defect, glycogenosis can be clinically divided into 3 main forms: with liver damage; with muscle damage; to a generalized form - with combined damage to the liver, heart muscle and other parenchymal organs.

The classification based on these criteria is presented in table. No. 1.

General clinical symptoms of the disease are: onset of the disease in infancy or early childhood, lack of growth, significant hepatomegaly, hypoglycemia, manifested by vomiting, convulsions, loss of consciousness, sudden sweating, and weakness. A significant drop in blood sugar can lead to what is known as sudden death or “cradle death.”(17)

Glycogenosis type I (Hepatorenal glycogenosis, Gierke's disease)

Insufficiency of glucose-6-phosphatase leads to blocking of the main pathway of glycogen decomposition and its accumulation in the liver, kidneys, and intestines. The structure of glycogen is normal.

Pathophysiology. Hypoglycemia during fasting is due to the lack of glucose-6-phosphatase activity in the liver. This enzyme plays a major role in regulating glycemic levels. Its activity is especially pronounced in infants. Activation of hepatic phosphorylase by adrenaline and glycogen prevents fluctuations in blood glucose levels in the absence of glucose-6-phosphatase. During fasting and in the absence of the ability to form free glucose, a lot of lactic acid is formed during the breakdown of glycogen. (39) An increase in the concentration of lactic acid, which activates glycogen synthetase, leads to an increase in liver glycogen stores. Lactic acid can be used as a substrate for glycogen synthesis. In patients with type I glycogenosis, the glycogen content in the liver increases to 14-17% of the raw tissue mass. Low blood glucose levels in patients with glycogenosis type I cause increased mobilization of fatty acids in peripheral adipose tissue and increase the synthesis of fat precursors. (18, 20) At the same time, large amounts of fatty acids accumulate in the liver, far exceeding the liver’s ability to oxidize these compounds, which causes accumulation in hepatocytes of lipids, fatty acids, as a result of which hyperlipidemia occurs, pyruvic acid appears in the blood, and cholesterol content increases. Excess fatty acids are not completely oxidized and entail the formation of ketone bodies (acetoacetate, -hydroxybutyric acid, acetone). (15) Persistent hypoglycemia forces the body to take the path of increasing fat metabolism to meet its energy needs. As a result, hyperlactatemia, hyperlipidemia, and fatty degeneration of the liver and kidneys develop. Accumulation of lactic acid inhibits the release of uric acid from the renal tubules and contributes to the development of hyperuricemia. High levels of uric acid are also associated with increased activity of the hexose monophosphate cycle.(40) Hyperuricemia is not accompanied by a corresponding increase in urinary excretion, which is due to the appearance of gout symptoms. Under these conditions, the amount of pyruvic acid increases sharply, which leads to a state of chronic acidosis.

Glycogenosis type III (Forbes Measles disease, limit dextrinosis)

In type III glycogen storage disease, there is a deficiency of the enzymes amylo-1,6-glucosidase and oligo-1,4-glucan transferase, or a combination of them. Since the side chains of glycogen are not completely cleaved off, the main chains are inaccessible to phosphorylase. Glycogen with a short external chain accumulates.

Pathophysiology. Glucose production in type III glycogenosis is not completely impaired, since glucose is formed under the action of phosphorylase from the side chains of glycogen, as well as through gliconeogenesis. The polysaccharide accumulated in the body resembles limitdextrin in structure, which differs from glycogen in significantly shortened outer branches of the molecules. The maximum absorption of its complex with iodine is at 390 nm, in contrast to the maximum absorption of the complex with glycogen iodine (at 460 nm). The accumulation of limitdextrin in cells is the basis for this type of glycogenosis to be called limitdextrinosis.(1)

Localization of mutations in various forms of glycogenosis .

Table No. 1

Type	Localization	Enzyme deficiency	Affected organs
0type aglycogenosis	12р12.2.	glycogen synthetase	Liver.
I Gierke	17q21, 11q23	Glucose-6-phosphatase	Liver, kidneys, intestines
II Pompe	17q23	Lysosomal α-1,4 glucosidase	Generalized lesions
^ IIIForbes Corey,	1p 21	Amylo-1,6-glucosidase	Liver, muscles, leukocytes
IV Andersen	3р14	Amylo-1,4,1,6-transglucosidase	Generalized lesions
VI Khersa	14	Liver phosphorylase	Liver, leukocytes
IX Haga	Xp22	Phosphorylase kinase	Liver, leukocytes, erythrocytes.

An enzyme defect was observed not only in the liver, muscles, heart, but also in leukocytes. There are four known variants of different combinations. Sidbury et al (1961) discovered a high content of abnormal glycogen in the erythrocytes of patients with glycogenosis type III. (57) The absence of amylo-1,6-glucosidase in muscles leads to hypotension and myopathy, the severity of which is proportional to the degree of enzyme deficiency in a particular patient.

Glycogenosis caused by defects in the phosphorylase system:

Phosphorylase sequentially cleaves glucose residues from the ends of glycogen side chains. The amount of glucose formed in this way is 92% of the total amount of glucose formed during glycogenolysis. In the liver, muscles and other tissues and cells there are two forms of phosphorylase - inactive (phosphorylase V) and active (phosphorylase A). Phosphorylase V turns into phosphorylase A under the action of phosphorylase kinase. The activator of phosphorylase kinase is protein kinase A. In turn, its activity is regulated by glucagon and other contrainsular hormones. (39)

Glycogen storage disease type VI (Hers disease)

In glycogen storage disease type VI, there is a defect in liver phosphorylase b. The structure of liver glycogen in patients does not differ from the norm.

Pathophysiology. In this form, a sufficient amount of glycogen with a normal structure is formed in the liver, but it cannot be metabolized due to an enzyme defect. Phosphorylase activity is not detected in the liver, erythrocytes and leukocytes; in skeletal muscles and in the myocardium, enzyme activity is normal. In the liver tissue, lipid globules of different volumes and low phosphorylase activity were histochemically detected.

Glycogenosis type IX a. (Haga disease)

In this form, there is a defect in phosphorylase b kinase in the liver and muscles. Phosphorylase kinase activity is not detected in the liver, erythrocytes and leukocytes; in the muscles is not detected or is reduced.

Glycogenosis type IX b. ( defect in the a-subunit of phosphorylase kinase). Phosphorylase kinase activity is not detected in the liver, and in erythrocytes and leukocytes it may not be detected or may be reduced. Enzyme activity in muscles is normal. The disease is inherited linked to the X chromosome and is transmitted from mother to son. It is generalized in form. Glycogenosis type IX b is one of the most common types of glycogen storage disease.(18)

^ 1.3. Clinical manifestations of various types of glycogen storage disease in children.

Type I Gierke's disease (glucose 6-phosphatase deficiency) is the most severe form, as glyconeogenesis and glycogenolysis are impaired. Currently, 4 subtypes of the disease are known: Ia - lack of enzyme activity, Ib, Ic, Id - normal enzyme ability, defect of transport proteins. The disease is severe. Conditions of acute hypoglycemia occur from an early age. The clinical phenotype is similar to all four forms, but patients with type Ib have significant neutropenia. Hypoglycemic symptoms appear 6-8 hours after feeding, these include: sweating, lethargy, pallor, tremors of the limbs, convulsions. Serious disorders of fat metabolism in children with glycogenosis type I lead to the development of hypercortisolism syndrome. The face of sick children takes on a “doll-like” appearance. By the age of 2, patients develop a characteristic appearance: a “doll” face, a large belly, short stature, and a widened lower aperture of the chest. (42) The body weight of patients corresponds to length. All patients have increased abdominal size due to hepatomegaly and muscle hypotension. By the age of 3, nosebleeds occur. At the age of 3-4 years, the existing characteristic signs are supplemented by symptoms of general intoxication in the form of pale skin, shadows under the eyes, and irritability. A bright capillary network appeared on the skin of the cheeks, a venous network and bright palmar erythema appeared on the chest and abdomen. Some patients have spider veins. Severe hepatomegaly was observed in all patients. The lower edge of the liver protruded from under the edge of the costal arch by 10-16 cm or descended into the small pelvis. The enlargement of the spleen was usually not detected or its edge was palpated at the level of the costal arch. Intermittent diarrhea, vomiting, and abdominal pain may occur. Hemorrhagic syndrome (ecchymosis, nasal, uterine bleeding) is often detected, which is caused by the lack of glucose - 6 - phosphatase in platelets, resulting in the accumulation of glycogen in them and a decrease in their adhesive properties. In most patients, hypochromic anemia is detected, blood clotting time is increased. (40) Pale skin is characteristic, in 10% of cases xanthelasmas are detected on the eyelids, xanthomas on the skin. X-ray examination reveals osteoporosis and late formation of ossification nuclei, and spontaneous fractures are possible. Associated metabolic acidosis may manifest as muscle weakness, hyperventilation, malaise, headache, or recurrent fever. After puberty, complications such as gout, arthritis, glomerular sclerosis, and renal hypertension may develop. (45.53)

Glycogenosis type 1b - translocase deficiency. Most of the clinical symptoms of this type are identical to those of type 1a. Susceptibility to bacterial infections due to neutropenia and impaired neutrophil function reduces the number of patients surviving into old age. These patients have a history of frequent reports of recurrent aphthous stomatitis and bacterial and viral infections. (51)

Glycogenosis type III (Forbes disease, Measles - limit dextrinosis) this disease is characterized by a deficiency of the enzyme amylo-1, 6-glucosidase. Usually the liver and muscles are involved in the process. In 15% of cases, only the liver is involved. In patients from an early age, states of acute hypoglycemia are observed. Children, especially at an early age, are similar to patients with type I glycogen storage disease. Patients can only partially compensate for hypoglycemia, the process of glycogenolysis is impaired. (8) At 3-4 years, symptoms of general intoxication and nosebleeds appear. Unlike patients with type I of the disease, the majority of children in this group have stunted growth combined with excess body weight (grade I obesity). Cardiomyopathy appears in 50% of cases. Type III is characterized by the formation of adenomas in 1 out of 10 cases. With established liver fibrosis, splenomegaly may be present, the kidneys are not enlarged. The severity of symptoms decreases with age and often disappears during puberty. Clinical manifestations are less pronounced due to the absence of lactic acidosis.

Glycogenosis type VI. Hers disease is caused by liver phosphorylase deficiency. The structure of glycogen is not changed, but its concentration in the liver is increased. Characteristic signs of type VI are: significant hepatomegaly, manifested mainly in the first year of life, growth retardation, increased activity of aminotransferases, high levels of cholesterol and neutral fats in the blood serum. The disease progresses more favorably than with other types of glycogen storage disease. Hypoglycemia is minimally expressed and develops 3-3.5 hours after eating. Clinical symptoms of hypoglycemia occur 8-10 hours after feeding. Symptoms of intoxication, hemorrhagic syndrome, and retardation in physical development are, as a rule, less pronounced and rare. It is not possible to detect any disorders in the muscular system, either from clinical manifestations or from biochemical studies.

Glycogenosis type IX (Haga disease.) The disease is caused by the absence or decrease in activity of phosphorylase kinase V in the liver. There are three subtypes of the disease, two of which are characterized by an autosomal recessive type of inheritance affecting only the liver, and the third is sex-linked and transmitted from mother to son with the X chromosome, and is generalized in form. (39) Refers to the hepatic form of the disease, since there is significant hepatomegaly. Other symptoms characteristic of glycogen storage disease - hypoglycemia, hypercholesterolemia, hyperlactic acidosis - are not expressed in this form. In this regard, a milder course of the disease is observed. To clarify the diagnosis, it is necessary to conduct a study of the liver, heart, and muscles. If the heart muscle is involved in the process, progression of cardiomyopathy is possible. Myoglobinuria is detected in the urine. Muscle weakness may progress.

Sick children do not require treatment if this is a common type of combined enzyme deficiency. The final diagnosis is made based on the results of studies of phosphorylase and phosphorylase kinase activity in liver biopsy or in leukocytes.

A characteristic feature of glycogenoses is their extreme heterogeneity, leading to a variety of clinical manifestations. Mixed forms of glycogenosis have been identified, manifested in the deficiency of not one, but several enzymes. The most common combination of glucose-6-phosphatase and amylophosphatase deficiency is detected.

Classification of glycogen storage disease due to enzyme defect

Table No. 2.

Type	Enzyme defect	Affected tissues	Diagnostic material
Ia	Glucose-6-phosphatase	Leukocytes, intestines.	Liver
Ib	Glucose-6-phosphate translocase	Leukocytes, intestines.	Liver
Ic	Phosphate-pyrophosphate translocase	Leukocytes. intestines.	Liver
ID	Glucose-6-phosphate stabilizing protein	Leukocytes. intestines.	Liver
III	Amylo-1,6 glucosidase (phosphorylase kinase deficiency)	Liver, muscles. Heart (in various combinations)	Leukocytes, liver or muscle
VI	Liver phosphorylase deficiency	Liver	Leukocytes, liver
IX	Liver phosphorylase kinase V	Liver	Red blood cells. Leukocytes, liver
X	c-AMP-dependent protein kinase	Liver, muscles.	Liver, muscles.
XI	Glucose transporter (Glut-2)	Liver, kidneys	Liver

1,6-glucosidases. At the same time, there are patients with glycogen disease whose enzyme defect cannot be identified; such variants of the disease are classified as an unidentified type of glycogen disease.(1)

^ 1.4.Long-term forecast

In type I glycogen storage disease, 75% of patients have hepatogenic adenomas by the age of 15 years. (45) In rare cases, these formations have been observed at the age of less than 3 years. Over time, adenomas tend to increase in both size and number. In patients over 15 years of age with type I B, adenomas may form in one of 3 cases. Some adenomas undergo malignant transformation.(139) There is extensive evidence of adenoma transformation into hepatocellular carcinoma. In some patients, after undergoing appropriate treatment, regression and disappearance of hepatocellular adenomas were observed. If, after the diagnosis of Gierke's disease is established, the child is not given replacement therapy, death is possible. Such deaths are due to hypoglycemic episodes, metabolic acidosis, or complications of hepatocellular carcinoma. In 15% of patients with type III glycogen storage disease, reduction of hepatomegaly and a picture of clinical and biochemical remission are possible. The prognosis is favorable.

Forecast of probable clinical manifestations in hepatic types of glycogen storage disease.

Table No. 3 .

The prognosis for glycogenosis type VI is usually favorable. Disturbances in glycogen metabolism caused by a phosphorylase defect can be compensated by gluconeogenesis. Determination of phosphorylase activity in leukocytes makes it possible to identify heterozygous carriers of this disease. Over time, delays in growth and body weight are overcome, and the size of the liver is restored to normal.(153) In adults, the disease does not affect life expectancy. Types IXa and IXb are a benign condition manifested by growth retardation and hepatomegaly. The prognosis is favorable; over time, the growth of patients reaches normal levels, and hepatomegaly becomes less pronounced.

^ 1.5. Differential diagnosis of glycogen storage disease.

Knowledge of clinical symptoms is necessary for diagnosing inborn errors of metabolism in children. In newborns with hepatomegaly, differential diagnosis is carried out between the following conditions:

1. intrauterine infections: toxoplasmosis, cytomegalovirus infection

2. other hereditary diseases occurring with hepatomegaly: Gaucher disease, Niemann-Pick disease, Wolman disease, mucopolysaccharidoses, galactosemia, x-histiocytosis, Caroli disease.

3. congenital leukemia, fibrocholangiocytosis, liver tumors.

Using a limited number of tests, a preliminary assessment is carried out: the level of glucose, lactate, transaminases, lipids, uric acid and amino acids is determined in the blood serum, and the size of the liver is determined using ultrasound.

Load tests

Type I. To clarify the type, it is necessary to conduct stress tests with glucose and glucagon. Normally, in healthy people, there is a sharp increase in blood glucose levels when hormones and carbohydrates are administered.

In type I glycogen disease, glucose phosphate, formed during the breakdown of glycogen, in the absence of glucose-6-phosphatase, is not hydrolyzed to glucose, but is exchanged to lactate, the excess of which is detected in the blood. On an empty stomach, severe hypoglycemia and hyperlactatemia are detected, causing metabolic acidosis. After taking glucose, lactate levels decrease. The load curve has a diabetes-like shape - a high peak of glucose rise and a slow decline.

Normally, adrenaline activates the phosphorylase system, increasing the breakdown of glycogen and causing a rise in glucose levels above the initial level by 50-70% at 40-60 minutes. (27.11)

Loading with adrenaline (0.1 ml% solution per 1 year of life) in type I does not cause a hyperglycemic effect and leads to an increase in lactate levels. Galactose loading in type I is not carried out, since metabolic acidosis increases, as a result of which the lactate content increases. Disorders of carbohydrate metabolism lead to disturbances in lipid metabolism. There is an increase in aminotransferase activity and uric acid levels.

In type III headache, in contrast to type I, a significant increase in aminotransferase activity is detected, the level of transaminases is significantly increased, and ketoacidosis is detected. Diagnostic tests and stress tests: tests with glucagon and adrenaline on an empty stomach do not cause a hyperglycemic effect and an increase in glucose levels. A stress test carried out after eating 3-4 hours later revealed the same as normal rise in glucose levels, which makes it possible to distinguish this form of the disease from type I. A characteristic feature of type III is the polyhumped nature of the glycemic curves. (6)

VI type GB. The content of glucose and lactate in the blood on an empty stomach is within normal limits. Hypoglycemia is not constant and can only be detected during physical exertion, ARVI and forced fasting. Oral administration of sugars (glucose, galactose and fructose) leads to a significant increase in blood lactate. The reaction to the administration of glucagon or adrenaline is sometimes not clearly expressed.

In type IX glycogenosis, glucagon causes a normal increase in blood glucose levels, which distinguishes it from type VI, in which the glucagon tolerance curve remains flat.

The final diagnosis depends on biochemical examination of tissue biopsies. “Biochemical diagnosis” also provides the correct approach to treatment

The tissue for examination must be obtained from the organ or organs in which abnormalities have been identified. More often than other studies, a liver biopsy is performed, which is not associated with a greater risk for the patient. However, needle biopsy only obtains 20 mg of tissue, which may not be sufficient for diagnostic testing. In this regard, open biopsy is preferable, which has the additional advantage of allowing easy obtaining and evaluation of abdominal skeletal muscle specimens.(12)

Enzyme analysis

To determine the activity of enzymes in tissue biopsies, micromethods proposed by Hers in 1964 are now universally accepted and widely used. When using these methods, 1% and 10% homogenates are prepared in distilled water from frozen tissue samples (or from fresh tissue) obtained by biopsy and stored in the cold. To avoid enzyme inactivation, repeated freezing, thawing and long-term storage (within 24 hours) are not carried out. First of all, after preparing tissue homogenates, the activity of the most labile enzymes of glycogen breakdown - phosphorylase and glucose-6-phosphatase - is determined. (2)

When diagnosing glycogenosis, the results obtained from the study of whole blood and its formed elements are taken into account (12). In some types of glycogen disease, similar disturbances in glycogen metabolism occur in blood cells, associated with changes in its content, structure, and enzyme activity, as occurs in the tissues of various organs of patients with glycogen disease. Leukocytes and erythrocytes are isolated from whole blood and these samples are analyzed in the same way as the patient’s tissues. However, the use of leukocytes also has some limitations, since low phosphorylase activity in them is observed in individuals who do not have hepatomegaly. The experimental results suggest that the study of blood cells is a complement to the analysis of tissues of internal organs.

A morphological study of the liver parenchyma makes it possible to identify characteristic structural features of different types, to clarify the severity of cirrhotic changes and infiltration of the portal tracts of the liver, the presence of protein and fatty degeneration and glycogen content in hepatocytes.

^ 1.6. Morphological features of the hepatic form of glycogenosis in children.

According to McAdams (1974), with glycogenosis type I, hepatocytes are significantly increased in size. De Bruijin (1973) found that hepatocyte glycogen in healthy people and patients with type I glycogenosis mainly consists of a-particles. With this type, a uniform distribution of glycogen is found throughout the liver cell. The liver parenchyma has the appearance of “plant” tissue, the cell boundaries are clear, have a stamped appearance, optically empty cytoplasm, a nucleus that is often vacuolated and shifted to the periphery, large fat vacuoles. (17,15) Therefore, the cells of the liver tissue have a pale color and are clearly visible in them. cytoplasmic membranes. No fibrous structures are detected in the parenchymal tissue. A characteristic feature of type I glycogenosis is the presence of a huge amount of glycogen in the nuclei. Glycogen is found in the nuclei of liver cells normally, however, in type I glycogenosis, due to the huge amount of accumulated glycogen, the nuclei are sharply increased in size. A uniform increase in the size of glycogen particles with a noticeable displacement of cellular organelles is also found. In addition, numerous fat droplets containing glycogen particles included in them are found in hepatocytes. In type Ia, pericellular fibrosis of zone “three” and the appearance of Mallory bodies are described. The morphological features of the liver in type III glycogen storage disease are caused by the abnormal structure of glycogen - limitdextrin. Hepatocytes are vacuolated and have a foamy appearance, and fibrosis and round cell infiltration are noted in the portal spaces. Electron microscopically, liver glycogen is detected in the form of a and b particles, cellular organelles are normal and are located outside the glycogen accumulations. Histologically, large swollen fibrils that have undergone vacuolization are detected. According to I.I. Potapova - Vinogradova (1988), with type III glycogen storage disease, a high content of glycogen in hepatocytes was noted; the predominance of protein cell degeneration over fatty cells. In a morphological study of liver biopsy from patients with hypertension type IX, vacuoles filled with glycogen and fat, minor round cell infiltration and fibrosis were found in hepatocytes. Based on the above, we can conclude that liver cirrhosis is more common in types I and III of glycogenosis, in contrast to phosphorylase defect. Morphologically, differences are revealed between types I, III, VI, IX of glycogenosis in the severity of cirrhotic changes and infiltration of the portal tracts of the liver, the presence of protein and fatty degeneration and the glycogen content in hepatocytes.

Glycogenosis is inherited in an autosomal recessive manner, with the exception of type IXb, which is inherited in a sex-linked recessive pattern.

Morphological features of glycogen storage disease.

Table No. 4.

Type	Organelles	Inclusions	Glycogen structure	Coloring With iodine	Structural changes
I	Displaced	Fat (nuclear glycogenosis)	Norm, A particles	Red-brown	Pericellular fibrosis of zone III Taurus Mallory Cirrhosis does not develop, adenomas
III	norm	nuclear glycogenosis	short chain, A, b-particles.	Red-brown	Fibrous septa, round cell infiltration. Cirrhosis. Possible adenomas. Carcinomas.
IV	norm	Amylopectin	Extended chains	Lilac	Micronodular cirrhosis, portal fibrosis, Basophilic inclusions. adenomas.
VI	Shifted to the periphery	Fat	Norm	Red-brown	Connective tissue and infiltration of histiocytes, eosinophilic and polynuclear leukocytes
IX	norm	Fat	Norm	Red-brown	Large cell infiltration and fibrosis In the area of ​​the portal vein.

^ 1.7.Prenatal diagnosis of glycogen storage disease.

Glycogenosis is inherited in an autosomal recessive manner, with the exception of type IXb, which is inherited in a sex-linked recessive pattern. Prenatal diagnosis is confirmed by the study of cultured amniotic fluid cells, which normally contain certain enzymes (13,40,42). This method cannot be used to diagnose glycogen storage disease type I, since G-6-P is not normally detected in these cells . However, with types I, III, VI, IX, prenatal diagnosis is not required, since most sick children lead a normal life. In types IIa and IV, on the other hand, antenatal diagnosis is carried out using cultured amniotic fluid cells. Amniocentesis is not usually performed until 16 weeks of pregnancy. It takes several weeks to culture amniotic fluid cells. For microanalysis, rapidly grown cell microcultures are used. On the other hand, prenatal diagnosis of type IIa is possible within one day using electron microscopy of uncultured cells, which reveals altered lysosomes, while cells of healthy individuals, including heterozygous carriers, do not contain them. Glycogenosis IIa is the only type in which a prenatal diagnosis can be established with sufficient reliability based on the study of cell ultrastructure.

Molecular diagnostics of glycogen storage disease consists of identifying frequent mutations characteristic of certain types, carried out using the following methods: PCR, RT-PCR - to determine possible damage to splicing sites, sequencing PCR products to determine mutations in genes encoding the corresponding proteins.

^ 1.8.Glycogen storage disease therapy .

Therapy for patients with glycogenosis varies depending on the type of disease, the nature of the enzyme disorder, age, glycemia level and is determined by the degree of involvement of organs and systems in the pathological process. There are conservative and surgical methods of therapy. The goal of treatment is to eliminate or minimize clinical features and biochemical abnormalities by maintaining blood sugar levels within normal limits.

Diet therapy

Glucose and/or glucose polymers are used to achieve normal blood sugar levels.(44) The intensity of treatment depends on the severity of the disorder. The general principle of treatment for all types of glycogen storage disease is split meals aimed at maintaining normoglycemia. The amount of food is determined by the age and individual appetite of the child. The total calorie content of food is not limited unless there is excessive weight gain. Food must contain proteins, fats, mineral salts and vitamins in quantities necessary for the normal growth of the child. The main sources of these substances are dairy products and fruits. Since milk and fruits contain galactose and fructose, they are recommended to be given in moderation. Fat calories should be divided equally between monounsaturated, polyunsaturated and saturated fatty acids. The daily diet must be divided into 6-8 meals. (1,3,7.) Fractional meals with an even distribution of easily soluble carbohydrates throughout the day allows you to maintain the concentration of glucose in the blood at least 3.3 mol/l. The first meal at 6-7 hours, consisting of porridge, tea, glucose, the last at 22 hours (cottage cheese, kefir), at 24 hours - corn starch at the rate of 1.5-2.0 g/kg. The ratio of the main nutrients for different types of HD liver disease provides for type I - an increase in the amount of carbohydrates in the daily diet, for types III, VI, IX - an increase in the amount of protein. This reduces the fat percentage.