Glycogenosis type 1 Gierke's disease. Genetic diseases

Symptoms of the disease are varied and depend on the age of the child.

• Hypoglycemia (low blood glucose) is the main clinical problem in this disease, which is one of the first symptoms of the disease.
  • Hypoglycemia is accompanied by convulsions, vomiting and a drop in blood pressure with deterioration of blood supply to vital organs.
  • Symptoms are observed in the morning and during long breaks between meals.
• Dyspnea.
• Body temperature is 38° C without signs of infection, such as headache, weakness, skin rashes.
• Enlarged abdomen as a result of significant enlargement of the liver. The edge of the liver may reach the level of the navel or below it.
• Kidney enlargement. Most patients experience only minor changes in kidney function, such as traces of protein in the urine. However, in severe cases, changes in the kidneys can lead to chronic renal failure.
• Repeated nosebleeds or bleeding after various surgical interventions associated with impaired platelet function (blood platelets that perform the function of blood clotting).
• Xanthomas are the deposition of fat-like substances (lipids) in the skin as a result of lipid metabolism disorders. Most often found on the elbows, knees, buttocks, and thighs.
• Stunted growth, poor body proportions (eg, large head, short neck and legs), wide, full face, decreased muscle tone.
• Delayed puberty
• Neuropsychic development is satisfactory.

Forms

• glycogenosis type Ia - defect of glucose-6-phosphatase;
• glycogenosis type Ib - defect of glucose-6-phosphate translocase.

These types are manifested by a similar clinical picture and biochemical disorders. However, with glycogenosis Ib, the patient may experience additional complications, such as staphylococcal infections and candidiasis (damage to the skin and mucous membranes caused by yeast-like fungi), so this type is considered somewhat more severe.

The following variants of the course of the disease are distinguished.

• Acute course - occurs more often in the 1st year of a child’s life. Manifests:
  • vomiting;
  • muscle cramps;
  • breathing disorders such as shortness of breath (impaired frequency and depth of breathing, accompanied by a feeling of lack of air).

• Chronic course - impaired renal and liver function, growth retardation, and delayed puberty progress.

Causes

• Gierke's disease is caused by a mutation in the gene encoding glucose-6-phosphatase.
• Glycogenosis type 1 is inherited in an autosomal recessive manner, that is, healthy parents with a mutant gene may have children born sick.

Diagnostics

• Collection of medical history and complaints of the disease:
  • muscle cramps due to a decrease in blood glucose levels, vomiting more often in the morning and during long breaks between meals;
  • dyspnea;
  • body temperature up to 37.5° C;
  • enlarged abdomen due to an enlarged liver;
  • xanthomas - deposition of fat-like substances in the skin on the elbows, knees, buttocks, and thighs;
  • stunted growth, disproportion of body shape (large head, short neck and thin legs), round, moon-shaped face, decreased muscle tone;
  • delayed puberty.

• Laboratory data:
  • decreased blood glucose levels;
  • increased levels of lactic and uric acid;
  • high blood fat levels;
  • increased activity of liver enzymes: AST (aspartate aminotransferase) and ALT (alanine aminotransferase);
  • provocative test with glucagon;
  • special study: liver biopsy, glycogen study (reservoir glucose reservoir);
  • measurement of glucose-6-phosphatase activity;
  • polymerase chain reaction (PCR) is a highly accurate diagnostic method, the essence of which is that a small amount of material for research containing DNA is taken, and during the PCR process the amount of genetic material increases, and thus it can be identified. Special studies and methods of molecular biology are available only to specialized laboratories.
• Additional instrumental methods:
  • Ultrasound of the abdominal cavity;
  • excretory urography of the kidneys is an x-ray method for examining the kidneys and urinary tract using intravenous administration of a contrast agent.

Treatment of Gierke's disease

The goal of treatment is to maintain glucose levels within normal limits. This can be facilitated by frequent meals with sufficient glucose content. Carbohydrates should enter the body during the night.

Over the past 30 years, 2 methods have been used to constantly provide infants with carbohydrates:

• glucose infusion through a nasogastric tube overnight;
• taking raw cornstarch.

Increased uric acid levels are often noted in Gierke's disease.

To prevent the accumulation of salts in the joints and kidneys, drugs that reduce the level of uric acid are used.

If the disease progresses significantly and there are complications, a liver and/or kidney transplant is performed.

Complications and consequences

• Without timely and adequate treatment, patients with Gierke's disease die in early childhood.
• Some patients develop a liver tumor that can develop into a malignant tumor (carcinoma).
• Other complications include:
  • hyperuricemic gout (a disease associated with an increase in the level of uric acid in the blood with subsequent deposition of salts in the tissue, with primary damage to the joints and kidneys);
  • inflammation of the pancreas;
  • chronic renal failure.

Prevention of Gierke's disease

• Preventive methods include medical genetic counseling and prenatal diagnosis (prenatal diagnosis to detect fetal pathology at the stage of intrauterine development).
• The presence of patients in the pedigree is a direct indication for medical genetic counseling. A medical geneticist, together with clinical diagnostic specialists, clarifies the genetic situation in the family, gives an opinion on the risk of re-birth of a sick child and the need for prenatal diagnosis.
• Prenatal diagnosis is carried out at 18-22 weeks of pregnancy using a liver biopsy. In addition, prenatal diagnosis is possible with fetal DNA obtained through chorionic villus sampling (the outer membrane of the embryo), but only if the child is known to be at risk of developing this disease.

Additionally

Very rarely, symptoms of hypoglycemia appear in children who are breastfed. This is due to frequent feedings and the intake of sufficient glucose into the child’s body.
As the intervals between feedings increase, symptoms of hypoglycemia begin to appear, especially pronounced in the morning. The severity and duration of hypoglycemia gradually increase. This leads to metabolic disorders.

Usually the first symptoms of this pathology are changes in the child’s appearance:

• increase in abdominal size;
• the appearance of shortness of breath and low-grade body temperature (not higher than 38˚C).

If treatment is not carried out, the child’s appearance changes. Characteristic:

• delayed growth and physical development;
• a peculiar distribution of subcutaneous fat (like a patient with Cushing's syndrome: the arms and legs remain very thin, while a huge amount of fat accumulates on the face and torso).

Illustration by Georgy Sapego

A lack of this enzyme in the body leads to a deterioration in the liver's ability to produce glucose. In patients, carbohydrate and fat metabolism is disrupted, hypoglycemia occurs, and the content of lactic and uric acids increases. At the same time, excess glycogen accumulates in the liver and kidneys, which leads to enlargement of these organs. The disease was first described in 1929 by Gierke, after whom the pathology is named. However, the type of enzyme defect was identified only in 1952 through the efforts of the scientist Corey.

The most common forms of Gierke's disease are type Ia (80% of cases) and type Ib (20% of cases). Type Ia results from a mutation in the G6PC gene, which encodes glucose-6-phosphatase (G6P). This gene is located on chromosome 17q21. Type Ib is caused by a mutation in the SLC374 gene, the G6P transporter.

Symptoms of the disease vary depending on the age of the patient, the nature of the course (acute phase or chronic) and a number of other factors. The most common symptoms include hypoglycemia, which may be accompanied by convulsions, vomiting and a drop in blood pressure with deterioration of blood supply to vital organs; dyspnea; enlarged liver and kidneys. Also manifested are increased body temperature, nosebleeds, and xanthomas. Often, patients with Gierke's disease are stunted and are prone to obesity. The body proportions are disturbed, there is a “doll face”, and delayed sexual development is also observed.

Diagnosis of the disease is carried out based on the results of an examination and survey, during which the above-described symptoms are detected. Other diagnostic methods include: measuring the level of glucose and fat in the blood, lactic and uric acid, measuring the activity of liver enzymes: AST (aspartate aminotransferase) and ALT (alanine aminotransferase), a provocative test with glucagon, a liver biopsy, a study of glycogen and glucose-6 activity -phosphatases. The PCR (polymerase chain reaction) method is also used.

Treatment of Gierke's disease involves maintaining glucose levels within normal limits. For this purpose, patients are advised to take frequent meals with sufficient glucose content. Carbohydrates must enter the body, including at night. For this, 2 methods are used: infusion of glucose through a nasogastric tube; taking raw cornstarch. Meals should contain approximately 65-70% carbohydrates, 10-15% protein and 20-25% fat.

Treatment is also symptomatic: taking drugs that reduce uric acid levels is indicated. If the disease progresses seriously, a liver and/or kidney transplant is performed.

Gierke's disease occurs on average in one case per 200 thousand newborns. According to some reports, among Ashkenazi Jews the probability of the disease increases to one case in 20 thousand children.

Without adequate treatment, patients with Gierke's disease die as newborns or in early childhood, mainly from hypoglycemia and acidosis.

Prevention of the disease comes down to medical genetic counseling and prenatal or preimplantation diagnosis. The presence of patients in the family is a direct indication for medical genetic counseling.

Synonyms of Gierke's syndrome. S. (M.) Greveld-v. Gierke. . Glycogenic hepatonephromegaly (v. Gierke). Massive hepatic steatosis. Glycogenic hepatomegaly.

Definition of Gierke's syndrome. Classic hepato-renal form of pathological glycogen deposition. According to modern concepts, this disease, also called glycogenosis, is divided into 4 types:
Type I: classic hepatorenal form (S. v. Gierke in the narrow sense of the word).
Type II: generalized, malignant form (S. Rotre).
Type III: benign hepatomuscular form (so-called borderline dextrinosis).
Type IV: reticuloendothelial form with liver cirrhosis. The disease belongs to fermentopathies.

Authors. v. Gierke Edgar Otto Conrad - German pathologist (1877 - 1945), Karlsruhe, van Creveld S. - modern Dutch pediatrician, Amsterdam. The disease was first described by van Creveld in 1928, the pathological anatomy was developed by v. Gierke (1929). Hanhart studied the hereditary aspects of the disease (1946).

Symptomatology of Gierke's syndrome:
1. Small stature (hepatic infantilism).
2. Large belly due to significant enlargement of the liver; the spleen is not palpable (differential diagnostic sign), there is no ascites (differential diagnostic sign), there is no jaundice (differential diagnostic sign).
3. Attacks of severe hunger with hypoglycemia and a collapsing state. Reducing fasting blood sugar to 50-40 mg% or to even lower numbers. Decreased glucose tolerance (diabetes-like sugar curve after exercise) with normal fructose and galactose tolerance. Ketonemia. High sensitivity to insulin, lack of sensitivity to adrenaline. Blood diastase activity is not increased (differential diagnostic sign).
4. Obesity, especially of the face (sometimes called “doll face”).
5. Increased susceptibility to infectious diseases.
6. Osteoporosis. Slow development of ossification nuclei in bones.
7. Intellectual development in most patients corresponds to age (differential diagnostic sign), in rare cases it is reduced.
8. Urine: the content of the contrast agent used for cholecystography is not increased (differential diagnostic sign). Ketonuria.
9. Increased glycogen content in leukocytes.
10. Positive load test with dihydroxyacetone (after ingestion of dihydroxyacetone at a dose of 1.5 g per 1 kg of weight, it is not detected in the blood, while in people with normal metabolism, dihydroxyacetone appears in the blood within an hour after its administration).
11. Hypercholesterolemia.
12. Sometimes epithelial dystrophy of the cornea develops (S. Meesmann).
13. In cases where an enlarged heart comes to the fore in the clinical picture, it is customary to talk about S. Pompe.
14. Sometimes glycogen deposits in the kidneys are so significant that palpation can easily detect enlarged kidneys (glycogenic nephromegaly). Renal functions, however, remain normal.

Etiology and pathogenesis of Gierke's syndrome. Apparently, a recessive hereditary metabolic disorder in the sense of fermentopathy. The disease is based on genetically determined deficiency of glucose-6-phosphatase (type I), alpha-glucosidase (type II), amylo-1,6-glucosidase (Cori ester) (type III), amino-1,4-transglucosidase (type IV), muscle phosphorylase (type V) or hepatic phosphorylase (type VI).

In this regard, the breakdown of glucose-6-phosphate into glucose and phosphate, as well as the complete conversion of glycogen into free glucose, becomes impossible. Thus, despite significant glycogen reserves, almost all tissues have a chronic lack of usable carbohydrates.

Pathological anatomy of Gierke's syndrome. Pronounced glycogen deposits in the liver cells, as well as in the parenchyma of the renal cortex. Enlarged and filled with glycogen, the cells have the appearance of “plant cells.” There are both sporadic and familial cases of the disease. The blood relationship of the parents is often revealed. Other family members are sometimes diagnosed with diabetes.

Differential diagnosis. Liver cirrhosis in children. S. Mauriac (see). S. Debre (see). Fatty liver. Diabetes. Spontaneous hypoglycemia (S. Harris, see). S.v. Pfaundler-Hurler (see). S. Gaucher (see).

Differentiation of glycogenoses

Type of glycogenosis, name, synonyms	Enzyme with impaired activity	Glycogen structure	Major organs, tissues and cells that store glycogen	Some biochemical indicators	Note
Type I Gierke's disease, hepato-nephromegalic glycogenosis	Glucose-6-phosphatase	Normal	Liver, kidneys, small intestinal mucosa	Hyperlipemia, hyperlacticacidemia, ketosis, hypoglycemia; negative reaction (by glycemia) to adrenaline, glucagon, galactose	Combined forms with block or deficiency of several enzymes have been described
II type. Pompe disease, generalized glycogenosis, cardiomegalia glycogenica	Acid a-1,4-glucosidase	Normal	Liver, kidneys, spleen, muscles, nervous tissue, leukocytes	Reactions (by glycemia) to adrenaline, glucagon, galactose are normal	Same
III type. Measles disease, Forbes disease, limit dextrnosis, debrancher enzyme defect	Amylo-1,6-glucosidase and (or) oligo-1,4-1,4-transglucosidase	Short, numerous outer branches (limitdextrin)	Liver, muscles, leukocytes, red blood cells	On an empty stomach, reactions to adrenaline and glucagon are negative, after a carbohydrate load - weakly positive with two or three peaks	4 forms are described (A, B, C, D)
IV type. Andersen disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis, branching enzyme defect	aD-1,4-glucan, 6-a-glucosyltransferase	Long external and internal branches with a small number of branch points (amylopectin)	Liver, muscles, leukocytes	Hyperlipemia, ketosis, hypoglycemia are moderately expressed; the reaction to adrenaline is normal, to glucagon - hyperglycemic	-
V type McArdle disease, myophosphorylase deficiency	Muscle phosphorylase	Normal	Muscles	Hypolactacidemia after exercise. loads	Combined forms with flare or deficiency of several enzymes have been described
VI type. Hers disease, hepatophosphorylase deficiency	Liver phosphorylase	Normal	Liver, leukocytes	Hyperlipemia ketosis is moderately expressed; reactions to glucagon and adrenaline are normal	-
VII type. Thomson's disease, hepatophosphoglucomutase deficiency	Phosphoglucomutase	Normal	Liver and/or muscles	During ischemic load, glycogenolysis did not occur in muscles	-
VIII type. Tarui disease, myophosphofructokinase deficiency	Phosphofructokinase	Normal	Muscles, red blood cells	Absence of hyperlactic acidemia after exercise. loads	-
IX type. Haga disease	Phosphorylase kinase b	Normal	Liver	-	-

MINISTRY OF HEALTH OF THE REPUBLIC OF BELARUS

EE "VITEBSK STATE ORDER OF FRIENDSHIP OF PEOPLES"

MEDICAL UNIVERSITY"

DEPARTMENT OF GENERAL AND CLINICAL BIOCHEMISTRY

Teacher - Fomchenko G.N.

in "Biological Chemistry"

“Glycogenoses and aglycogenoses. Their characteristics"

Executor:

student 37 group 2nd year

Faculty of Medicine

Shustov D.A.

Vitebsk, 2015

Introduction 2

Classification 3

II. Depending on the type of enzymatic defect and clinical picture of the disease: 3

7. Type VI (Hers disease) 7

9. VIII type 8

Comparative characteristics 8

Conclusion: 9

Literature 10

Introduction

Glycogenosis is a disease caused by metabolic disorders that lead to excessive concentration of glycogen or changes in its structure.

Glycogen is a depot of hydrocarbons that are ready sources for immediate energy supply. They are broken down in the liver, ensuring an uninterrupted supply of glucose to the brain and red blood cells.

This group of diseases is characterized by the accumulation of glycogen in organs and tissues. Glycogenosis is a hereditary disease caused by impaired activity of enzymes involved in glycogen metabolism. In addition, they affect the formation of various metabolites. Several hundred cases of this disease have been described. Its prevalence is 1:40000.

Classification

I. According to clinical signs :

1) liver;

2) muscle;

3) generalized

II. Depending on the type of enzymatic defect and clinical picture of the disease:

1. 0 type (Aglycogenosis)

2. Type I (Gierke's disease)

3. Type II (Pompe disease)

4. Type III (Forbes disease)

5. Type IV (Andersen's disease)

6. Type V (McArdle disease)

7. Type VI (Hers disease)

Characteristics of diseases:

1. 0 type (Aglycogenosis) - a disease resulting from a defect in glycogen synthase. A very low glycogen content is observed in the liver and other tissues of patients. This is manifested by pronounced hypoglycemia in the post-absorptive period. A characteristic symptom is cramps, which occur especially in the morning. The disease is compatible with life, but sick children need frequent feeding.

2. Type I (nephromegalic glycogenosis, or Gierke’s disease) It is characterized by a deficiency or absence of the enzyme glucose-6-phosphatase in the liver and kidneys, as a result of which glycogen is not broken down and accumulates in these organs. The body meets its energy needs by increasing fat metabolism, which leads to hyperlipidemia, fatty degeneration of the liver, kidneys, and xanthomatosis. Pathological anatomy The disease manifests itself immediately after birth or in infancy with lack of appetite, vomiting, weight loss, hypoglycemic convulsions, coma. The liver is enlarged and dense to the touch. There is no enlargement of the spleen. Palpation reveals enlarged kidneys. In most cases there is a disproportion

body - long body, short legs, large head, round, “doll-like” face. If patients do not eat for a long time, loss of consciousness and convulsions may occur due to hypoglycemia and acetonemia - the body cannot use accumulated glycogen. In the blood of Gierke's disease, hypoglycemia, increased glycogen, hyperlipemia, hypercholesterolemia, and increased uric acid are detected. To confirm the diagnosis, stress tests with adrenaline, glucagon, and galactose are performed.

Treatment The main goal of treatment is to prevent the development of hypoglycemia and secondary metabolic disorders. This is done by eating frequent meals high in glucose or starch (which is easily broken down into glucose). To compensate for the liver's inability to maintain normal glucose levels, total dietary carbohydrate levels must be adjusted to provide 24-hour glucose control. That is, food should contain approximately 65-70% carbohydrates, 10-15% protein and 20-25% fat. At least a third of carbohydrates should enter the body during the night, that is, a newborn baby can, without harm to health, not receive carbohydrates for only 3-4 hours a day.

3. Type II (Pomne disease, idiopathic) It is characterized by the retention of glycogen in lysosomes; Glyconen is not broken down due to the absence of acid maltase. Symptoms of the disease appear after birth or after a few weeks. Children are apathetic, eat poorly, and vomit frequently. Hematomegaly develops early. inherited in an autosomal recessive manner. Already in the early period, the most noticeable symptom is hepatomegaly. Sick children have a short body, a large belly, and enlarged kidneys. Sick children lag behind in physical development.

The described disease is sometimes referred to as glycogenosis type Ia, since there is a variety of it - type Ib. Glycogenosis Ib is a rare pathology, which is characterized by the defective enzyme glucose-6-phosphate translocase, which ensures the transport of phosphorylated glucose into the ER. Therefore, despite the sufficient activity of glucose-6-phosphatase, the cleavage of inorganic phosphate and the release of glucose into the blood is impaired. The clinical picture of glycogenosis type Ib is the same as for glycogenosis Ia.

Pathological anatomy The leading symptom in the clinic is damage to the heart, lungs and nervous system. The heart is enlarged, shortness of breath and intermittent cyanosis are observed. Repeated bronchitis, atelectasis, and pneumonia are common. Muscle tone is sharply reduced, as a result of which the disease can acquire myopathic features. The ECG shows sinus tachycardia, increased P wave, negative T wave, high voltage. When examining the blood serum, there is an increase in uric acid, glutamine-oxaloacetic transaminase and aldolase, and a deficiency of alpha-1,4-glycosidase in the muscles and liver. Tests with glucagon and adrenaline were not changed. This type of glycogen disease has the most unfavorable prognosis. Death occurs in the 1st year of life from cardiac or respiratory failure, often accompanied by aspiration pneumonia.

Treatment A drug for enzyme replacement therapy has now been created (the drug "Myozym", produced by "Genzyme"). ERT for Pompe disease is aimed directly at the primary metabolic defect by intravenous administration of recombinant human acid α-glycosidase to correct enzyme deficiency. The effectiveness of treatment depends on the stage of the disease. Some patients experience marked clinical improvement, while others have minimal response to therapy. Bone marrow transplantation was ineffective due to poor penetration of the enzyme into muscle tissue; Perhaps mesenchymal stem cell transplantation will be more effective.

4. Type III (limitedextrinosis, Forbes disease) In the population of Sephardic Jews (immigrants from North Africa), the disease occurs with a frequency of 1:5400 newborns. Amylo-1,6-glucosidase is involved in glycogen metabolism at branch points of the glycogen tree. The enzyme is bifunctional: on the one hand, it converts limit-dextrin into glycogen with outer chains of normal length and, on the other hand, it releases glucose by hydrolysis of the a-1,6-glucosidic bond. Enzyme deficiency leads to disruption of glycogenolysis and accumulation of abnormally shaped glycogen molecules with shortened outer chains in tissues. As with glycogenosis types 1 and 2, in this variant of the disease, impaired glycogenolysis is accompanied by hypoglycemia, lactic acidosis, and hyperketonemia. very common. It accounts for 1/4 of all cases of hepatic glycogenosis. The accumulated glycogen is abnormal in structure, since the enzyme amylo-1,6-glucosidase, which hydrolyzes glycosidic bonds at branching sites, is defective (debmnching enzyme). A lack of glucose in the blood manifests itself quickly, since glycogenolysis is possible, but in an insignificant amount. Unlike glycogenosis type I, lactic acidosis and hyperuricemia are not observed. The disease has a milder course

Pathological anatomy Glycogen accumulates in the liver, muscles and heart. A chemical study reveals an anomaly in the structure of glycogen (limitdextrin). Histologically, large swollen fibrils that have undergone vacuolization are detected. Hepatocytes are vacuolated and have a foamy appearance, and fibrosis and round cell infiltration are noted in the portal spaces. There is an increase in subcutaneous fatty tissue on the face and torso, causing the limbs to look thin. An important clinical symptom is significant hepatomegaly, which is noted already in the first or second month of life. The liver quickly enlarges and occupies the abdominal cavity.

Treatment Due to impaired glycogenolysis in glycogenosis type III, glucose production is insufficient, so hypoglycemia occurs in infants and young children after an overnight fast. Increased gluconeogenesis leads to a decrease in plasma amino acid levels (they are used as gluconeogenesis substrates). Thus, the goal of treatment is to prevent fasting hypoglycemia and compensate for amino acid deficiency. It is carried out as follows: 1. taking the required amount of glucose in the form of raw corn starch in combination with a diet containing sufficient amounts of proteins and other nutrients eliminates metabolic disorders and growth retardation; 2. Patients with severe growth retardation and severe myopathy are shown continuous nightly tube feeding with a mixture containing glucose, oligosaccharides and amino acids, and frequent intake of protein-rich foods during the day.

5. Type IV (Andersen's disease, amylopectinosis, diffuse glycogenosis with liver cirrhosis) An autosomal recessive pathology in which glycogen phosphorylase activity is completely absent in skeletal muscles. Since the activity of this enzyme in hepatocytes is normal, hypoglycemia is not observed (the structure of the enzyme in the liver and muscles is encoded by different genes). Heavy physical activity is poorly tolerated and may be accompanied by cramps, however, during physical activity, hyperproduction of lactate is not observed, which emphasizes the importance of extramuscular energy sources for muscle contraction, for example, fatty acids, which replace glucose in this pathology. Although the disease is not gender-linked, a higher incidence of the disease is characteristic of men.

Treatment Treatment is aimed at combating metabolic disorders, incl. with acidosis. In some cases, the use of glucagon, anabolic hormones and glucocorticoids is effective. Frequent meals high in easily digestible carbohydrates are necessary for hypoglycemia. In muscular forms of glycogenosis, improvement is noted by following a diet high in protein, administering fructose (orally 50-100 g per day), multivitamins, and ATP. Attempts are being made to administer missing enzymes to patients. Patients with glycogenosis are subject to dispensary observation by a doctor at the medical genetic center and a pediatrician (therapist) at the clinic.

6. Type V (McArdle disease) McArdle-Schmid-Pearson disease (glycogenosis type V) is a hereditary autosomal recessive disease caused by a decrease in the activity of muscle phosphorylase, as a result of which the breakdown of glycogen slows down and its accumulation in the muscles occurs. Manifestations of the disease in children become obvious after minor physical activity: muscle pain, spasms, fatigue, and weakness occur. Sometimes tonic muscle contractions become generalized and lead to general stiffness. Later, muscular dystrophy and heart failure develop. At rest, children appear healthy. Treatment not developed.

Glycogenosis type I (Gierke's disease)

What is glycogenosis type I (Gierke's disease) -

Glycogenosis type I- a disease described by Gierke in 1929, but the enzyme defect was identified by Cory only in 1952. Glycogenosis type I occurs in 1 in 200,000 newborns. The incidence of boys and girls is the same. Inheritance is autosomal recessive. In glycogenosis type I (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 completely absent.

Pathogenesis (what happens?) during Glycogenosis type I (Gierke's disease):

The disease is caused by defects in the liver enzyme system that converts glucose-6-phosphate into glucose. Both glycogenolysis and gluconeogenesis are impaired, leading to hypoglycemia of fasting with lactic acidosis, hyperuricemia and hypertriglyceridemia. Excess glycogen accumulates in the liver.

The enzyme system that converts glucose-6-phosphate into glucose contains at least 5 subunits: glucose-6-phosphatase (catalyzes the hydrolysis of glucose-6-phosphate in the lumen of the endoplasmic reticulum), regulatory Ca2(+)-binding protein and transport proteins ( translocases), T1, T2 and T3, which ensure the passage of glucose-6-phosphate, phosphate and glucose across the endoplasmic reticulum membrane.

Defective glucose-6-phosphatase (glycogenosis type Ia) and defective glucose-6-phosphate translocase (glycogenosis type Ib) present with similar clinical and biochemical abnormalities. To confirm the diagnosis and accurately establish the enzyme defect, a liver biopsy and glucose-6-phosphatase activity testing are necessary.

Symptoms of glycogenosis type I (Gierke's disease):

The clinical manifestations of glycogenosis type I in newborns, infants and older children are not the same. The reason is differences in diet and nutrition in these age groups.

Sometimes fasting hypoglycemia occurs in the first days and weeks of life, but in most cases the disease is asymptomatic, since the infant feeds frequently and receives sufficient amounts of glucose. Often the disease is diagnosed several months after birth, when the child is found to have an enlarged abdomen and hepatomegaly. There may be shortness of breath and low-grade fever without signs of infection. Shortness of breath is caused by hypoglycemia and lactic acidosis due to insufficient glucose production. As the intervals between feedings increase and the baby begins to sleep at night, symptoms of hypoglycemia appear, especially in the morning. The severity and duration of hypoglycemia gradually increase, leading to systemic metabolic disorders.

If treatment is not carried out, the child's appearance changes. Characterized by muscle and skeletal wasting, delayed growth and physical development, and deposition of fat under the skin. The child becomes like a patient with Cushing's syndrome. The development of cognitive and social skills is not affected unless repeated episodes of hypoglycemia cause brain damage. If the child does not receive enough carbohydrates and the hypoglycemia of fasting persists, then the delay in growth and physical development becomes pronounced. Some children with glycogen storage disease type I die from pulmonary hypertension.

Platelet dysfunction is manifested by repeated nosebleeds or bleeding after dental and other surgical procedures. There are disturbances in platelet adhesion and aggregation; The release of ADP from platelets in response to adrenaline and contact with collagen is also impaired. Thrombocytopathy is caused by systemic metabolic disorders; after treatment it disappears.

Ultrasound and excretory urography reveal enlarged kidneys. In most patients, there are no significant renal dysfunctions; only an increase in GFR (glomerular filtration rate) is noted. In very severe cases, tubulopathy with glycosuria, phosphaturia, hypokalemia and aminoaciduria (as in Fanconi syndrome) may develop. Albuminuria is sometimes observed in adolescents, and young adults often develop severe kidney damage with proteinuria, increased blood pressure (blood pressure) and a decrease in creatinine clearance due to focal segmental glomerulosclerosis and interstitial fibrosis. These disorders lead to end-stage renal failure.

The spleen is not enlarged.

Without treatment, levels of free fatty acids, triglycerides, and apoprotein C-III, which is involved in the transport of triglycerides and triglyceride-rich lipoproteins, increase sharply. Phospholipid and cholesterol levels increase moderately. Very high levels of triglycerides are due to their excessive production in the liver and a decrease in their peripheral metabolism due to decreased lipoprotein lipase activity. With severe hyperlipoproteinemia, eruptive xanthomas may appear on the extensor surfaces of the limbs and buttocks.

Lack of treatment or improper treatment leads to delayed growth and sexual development.

Liver adenomas for unknown reasons occur in many patients, usually between the ages of 10 and 30 years. Adenomas can become malignant, and hemorrhages into the adenoma are possible. On liver scintigrams, adenomas appear as areas of reduced isotope accumulation. Ultrasound is used to detect adenomas. If malignant growth is suspected, MRI (magnetic resonance imaging) and CT (computed tomography) are more informative, allowing one to trace the transformation of a small, clearly demarcated tumor into a larger one with blurred edges. It is recommended to periodically measure serum alpha-fetoprotein levels (a marker for hepatocellular carcinoma).

The severity of fasting hypoglycemia decreases with age. Body weight increases faster than brain weight, so the relationship between the rate of glucose production and utilization becomes more favorable. The rate of glucose production is increased by the activity of amylo-1,6-glucosidase in the liver and muscles. As a result, fasting glucose levels gradually increase.

The clinical manifestations of glycogenosis type Ia and type Ib are the same, but with glycogenosis type Ib, persistent or transient neutropenia is observed. In severe cases, agranulocytosis develops. Neutropenia is accompanied by dysfunction of neutrophils and monocytes, therefore increasing the risk of staphylococcal infections and candidiasis. Some patients develop inflammatory bowel disease, similar to Crohn's disease.

Diagnosis of glycogenosis type I (Gierke's disease):

In the laboratory diagnosis of glycogenosis type I, the following is carried out:

• mandatory studies: measure the levels of glucose, lactate, uric acid and the activity of liver enzymes on an empty stomach; in newborns and infants with glycogenosis type I, the blood glucose level after 3-4 hours of fasting drops to 2.2 mmol/l and below; if the duration of fasting exceeds 4 hours, the glucose level is almost always less than 1.1 mmol/l; hypoglycemia is accompanied by a significant increase in lactate levels and metabolic acidosis; whey is usually cloudy or milk-like due to very high triglycerides and moderately elevated cholesterol; hyperuricemia and increased activity of AST (aspartate aminotransferase) and ALT (alanine aminotransferase) are also noted.
• challenge tests: to distinguish glycogenosis type I from other glycogenoses and to accurately determine the enzyme defect, levels of metabolites (glucose, free fatty acids, ketone bodies, lactate and uric acid) and hormones (insulin, glucagon, adrenaline) are measured in infants and older children , cortisol and STH (somatotropic hormone)) on an empty stomach and after taking glucose; The research scheme is as follows: the child is given oral glucose at a dose of 1.75 g/kg, then blood is taken every 1-2 hours; the glucose concentration in each sample is quickly measured; the last sample is taken no later than 6 hours after taking glucose or at the moment when the glucose concentration has decreased to 2.2 mmol/l;
• provocative test with glucagon: glucagon is administered intramuscularly or intravenously in a bolus at a dose of 30 mcg/kg (but not more than 1 mg) 4-6 hours after eating or taking glucose; blood for determination of glucose and lactate is taken 1 minute before the glucagon injection and 15, 30.45, 60.90 and 120 minutes after the injection. In type I glycogenosis, glucagon does not increase or slightly increases glucose levels, while the initially elevated lactate level continues to increase;
• special study: liver biopsy is performed, glycogen is examined; glycogen content is greatly increased, but its structure is normal;
• special studies to accurately determine the enzyme defect underlying glycogenosis type I: measure the activity of glucose-6-phosphatase in intact and destroyed liver microsomes (by the formation of glucose and phosphate from glucose-6-phosphate); microsomes are destroyed by repeated freezing and thawing of the biopsy; in type Ia glycogenosis, glucose-6-phosphatase activity is not detected either in intact or in destroyed microsomes; in type Ib glycogenosis, the activity of glucose-6-phosphatase in destroyed microsomes is normal, but in whole microsomes it is absent or greatly reduced (since the defective glucose-6-phosphate translocase does not transport glucose-6-phosphate across microsomal membranes);
• methods of molecular biology (detection of a genetic defect by PCR (polymerase chain reaction) and subsequent hybridization with specific oligonucleotides).

Special studies and methods of molecular biology are available only to specialized laboratories; in the USA, for example, in laboratories: Dr. Y. T. Chen, Division of Genetics and Metabolism, Duke University Medical Center, Durham, North Carolina, U.S.A.; Dr. R. Grier, Biocemical Genetics Laboratory, Nemours Children's Clinic, Jacksonville, Florida, U.S.A.

Treatment of glycogenosis type I (Gierke's disease):

Metabolic disorders in type I glycogenosis, caused by insufficient glucose production, occur within a few hours after eating, and with prolonged fasting they intensify significantly. Therefore, treatment of glycogenosis type I comes down to frequent feeding of the child. The goal of treatment is to prevent the blood glucose concentration from falling below 4.2 mmol/l, the threshold level at which the secretion of contrainsular hormones is stimulated.

If the child receives a sufficient amount of glucose in a timely manner, the size of the liver decreases, laboratory values ​​approach normal, bleeding disappears, growth and psychomotor development are normalized.

Which doctors should you contact if you have glycogenosis type I (Gierke's disease):

Is something bothering you? Do you want to know more detailed information about glycogenosis type I (Gierke's disease), its causes, symptoms, methods of treatment and prevention, the course of the disease and diet after it? Or do you need an inspection? You can make an appointment with a doctor– clinic Eurolab always at your service! The best doctors will examine you, study external signs and help you identify the disease by symptoms, advise you and provide the necessary assistance and make a diagnosis. you also can call a doctor at home. Clinic Eurolab open for you around the clock.

How to contact the clinic:
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(+38 044) 206-20-00

If you have previously performed any research, Be sure to take their results to a doctor for consultation. If the studies have not been performed, we will do everything necessary in our clinic or with our colleagues in other clinics.

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Other diseases from the group Diseases of the endocrine system, nutritional disorders and metabolic disorders:

Addisonian crisis (acute adrenal insufficiency)

Breast adenoma

Adiposogenital dystrophy (Perchkranz-Babinski-Fröhlich disease)

Adrenogenital syndrome

Acromegaly

Nutritional insanity (nutritional dystrophy)

Alkalosis

Alkaptonuria

Amyloidosis (amyloid dystrophy)

Amyloidosis of the stomach

Intestinal amyloidosis

Pancreatic islet amyloidosis

Liver amyloidosis

Amyloidosis of the esophagus

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Gaucher disease (glucocerebroside lipidosis, glucocerebrosidosis)

Itsenko-Cushing's disease

Krabbe disease (globoid cell leukodystrophy)

Niemann-Pick disease (sphingomyelinosis)

Fabry disease

Gangliosidosis GM1 type I

Gangliosidosis GM1 type II

Gangliosidosis GM1 type III

Gangliosidosis GM2

Gangliosidosis GM2 type I (amaurotic idiocy of Tay-Sachs, Tay-Sachs disease)

GM2 gangliosidosis type II (Sandhoff's disease, Sandhoff's amaurotic idiocy)

Gangliosidosis GM2 juvenile

Gigantism

Hyperaldosteronism

Hyperaldosteronism secondary

Primary hyperaldosteronism (Conn's syndrome)

Hypervitaminosis D

Hypervitaminosis A

Hypervitaminosis E

Hypervolemia

Hyperglycemic (diabetic) coma

Hyperkalemia

Hypercalcemia

Hyperlipoproteinemia type I

Hyperlipoproteinemia type II

Hyperlipoproteinemia type III

Hyperlipoproteinemia type IV

Hyperlipoproteinemia type V

Hyperosmolar coma

Hyperparathyroidism secondary

Primary hyperparathyroidism

Hyperplasia of the thymus (thymus gland)

Hyperprolactinemia

Testicular hyperfunction

Hypercholesterolemia

Hypovolemia

Hypoglycemic coma

Hypogonadism

Hypogonadism hyperprolactinemic

Hypogonadism isolated (idiopathic)

Primary congenital hypogonadism (anorchism)

Primary acquired hypogonadism

Hypokalemia

Hypoparathyroidism

Hypopituitarism

Hypothyroidism

Glycogenosis type 0 (aglycogenosis)

Glycogenosis type II (Pompe disease)

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

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

Glycogenosis type IX (Haga's disease)

Glycogenosis type V (McArdle disease, myophosphorylase deficiency)

Glycogenosis type VI (Hers disease, hepatophosphorylase deficiency)

Glycogenosis type VII (Tarui disease, myophosphofructokinase deficiency)

Glycogenosis type VIII (Thomson's disease)

Glycogenosis type XI

Glycogenosis type X

Deficiency (insufficiency) of vanadium

Magnesium deficiency (insufficiency)

Manganese deficiency (insufficiency)

Copper deficiency (insufficiency)

Deficiency (insufficiency) of molybdenum

Deficiency (insufficiency) of chromium

Iron deficiency

Calcium deficiency (nutritional calcium deficiency)

Zinc deficiency (dietary zinc deficiency)

Diabetic ketoacidotic coma

Ovarian dysfunction

Diffuse (endemic) goiter

Delayed puberty

Excess estrogen

Involution of the mammary glands

Dwarfism (short stature)

Kwashiorkor

Cystic mastopathy

Xanthinuria

Lactic acidemic coma

Leucinosis (maple syrup disease)

Lipidoses

Farber lipogranulomatosis

Lipodystrophy (fatty degeneration)

Congenital generalized lipodystrophy (Seyp-Lawrence syndrome)

Hypermuscular lipodystrophy

Post-injection lipodystrophy

Progressive segmental lipodystrophy

Lipomatosis