Glycogen storage disease type 1 in children

Introduction to type I glycogen storage disease in children Glycogen storage disease is a disease caused by excessive metabolism of glycogen in tissues due to metabolic disorders of hereditary glycogen. Glycogen storage disease type I is also known as VonGeirk disease, glucose-6-phosphatase deficiency. The disease is autosomal recessive, both sexes can be rickets. Mainly manifested as hypoglycemia, hepatomegaly, acidosis, hyperlipidemia, hyperuricemia, hyperlactosis, coagulopathy, developmental delay and other clinical symptoms. The nervous system of glycogen storage disease type I is mainly characterized by dyskinesia caused by muscle weakness and mental retardation. basic knowledge The proportion of illness: 0.0006%-0.0008% Susceptible people: children Mode of infection: non-infectious Complications: hypoglycemia, convulsions in children

Pediatric glycogen storage disease type I etiology

Causes:

Glycogen is a high molecular polysaccharide composed of glucose, which is mainly stored in the liver and muscle as spare energy, and contains about 4% and 2% glycogen in normal liver and muscle tissues, respectively. The glucose ingested in the body forms uridine diphosphate glucose (UD-PG) catalyzed by glucokinase, glucose phosphate mutase and uridine diphosphate glucose pyrophosphorylase. The glucose molecules provided by UDPG are then linked by a glycogen synthase into -1,4-glycosidic linkages into a long chain; the glucose is converted to 1 by the branching enzyme every 3 to 5 glucose residues. , 6 bits, forming branches, if expanded, eventually forming a macro-structure of the tree structure. The molecular weight of glycogen is up to several million, and the outermost layer of glucose has a long linear chain, and most of them are 10 to 15 glucose units. The decomposition of glycogen is mainly catalyzed by phosphorylase, and glucose 1-phosphate is released from the glycogen molecule. However, the role of phosphorylase is limited to 1,4 glycosidic bonds, and when there are only 4 glucose residues before the branching point, it must be debranching enzyme (starch-1,6-glucosidase, amylo-1,6-glucosidase). Transfer 3 of these residues to other linear chains to ensure that the action of phosphorylase continues. At the same time, the debranching enzyme can release a glucose molecule linked by the -1,6-glycosidic bond, thus repeating the operation to ensure the body's demand for glucose. The -1,4-glucosidase (acid maltase) present in the lysosome can also hydrolyze the linear chains of different lengths into oligosaccharide molecules such as maltose. Defects of any of the above enzymes during glycogen synthesis and decomposition are various types of glycogen storage diseases that result in different clinical manifestations. GSD-I is caused by the deficiency of glucose-6-phosphatase system activity in tissues such as liver and kidney, causing excessive glycogen storage in it, which not only causes its volume to increase, but also impairs its function.

Pathogenesis:

Glucose-6-phosphatase is the only enzyme in all the enzymes involved in the glucose metabolism pathway that exists in the lumen of the endoplasmic reticulum. The coding gene (G6PT) is temporarily located on chromosome 17; the glucose-6-phosphatase system is composed of the following: Composition: 1 polypeptide with a molecular weight of 36.5 kDa, which is the active unit of the enzyme; 2 "stabilized protein" with a protective enzyme activity of 21 kDa, SP; 3 transporter for glucose 6-phosphate into the lumen of the endoplasmic reticulum, T1 ; 4 to transport phosphate through the endoplasmic reticulum transporter T2; 5 to release glucose into the endoplasmic reticulum transporter, GLUT7. Defects in any of the above-mentioned components caused by inheritance can impair the viability of the enzyme system and cause glycogen storage disease type I, which are named Ia, IaSP, Ib, Ic and Id. The glycogen storage disease type I is caused by defects in the activity of the glucose-6-phosphatase system in liver and kidney tissues, and is the most common glycogen storage disease, accounting for about 25% of the total. Among them, the common type Ia is the main one. In normal humans, glucose 6-phosphate produced by glycogenolysis or gluconeogenesis must be hydrolyzed via the glucose-6-phosphatase system to obtain the desired glucose, which provides decomposed by glycogen The resulting 90% glucose plays a leading role in maintaining blood sugar stability. When the enzyme is deficient, the glucose metabolism is disordered: the body can only obtain a small amount of glucose molecules (about 8%) produced by the debranching enzyme to break down the glycoside 1,6 glycosidic bond, so it will inevitably cause severe fasting hypoglycemia. In normal people, when the blood sugar is too low, the glucagon secretion is increased to promote hepatic glycogen decomposition and gluconeogenesis, and glucose is formed to stabilize blood sugar. In children with GSDI, glucose 6-phosphate cannot be further hydrolyzed to glucose due to a defect in the glucose-6-phosphatase system. Therefore, the glucagon secreted by hypoglycemia can not only increase the blood glucose concentration, but causes a part of the glucose 6-phosphate produced by the decomposition of a large amount of glycogen to enter the glycolysis pathway. At the same time, due to the accumulation of glucose 6-phosphate, most of the glucose 1-phosphate is re-synthesized into glycogen. Hypoglycemia continuously decomposes tissue proteins and delivers xenobiotic raw materials to the liver. These abnormal metabolisms accelerate the synthesis of hepatic glycogen. Abnormal glucose metabolism also causes disorders of fat metabolism: hyperglycemia and glycolysis process not only increase the content of pyruvate and lactic acid in the blood, but also produce a large amount of acetyl-CoA, which is a synthesis of fatty acids and cholesterol. Providing raw materials, and also producing reduced coenzyme I (nicotinamide adenine dinucleotide, NADH) and reduced coenzyme II (nicotinamide adenine dinucleotide phosphate, NADPH) necessary for synthesizing fatty acids and cholesterol; In addition, hypoglycemia also reduces insulin levels, promotes the breakdown of peripheral adipose tissue, and increases the level of free fatty acids; these metabolic changes ultimately lead to strong lipid synthesis such as triglycerides and cholesterol, clinical manifestations of hyperlipidemia and liver fat transsexual.

GSD-I type GSD is often accompanied by hyperuricemia, which is caused by hyperactivity of sputum in children: the accumulation of glucose 6-phosphate promotes pentose bypass metabolism, produces excessive 5-phosphate ribose, and then synthesizes Phosphoribosylpyrophosphate (PRPP) is converted to 1-phosphoriboside-1-amine by the action of glutamine PRPP amidotransferase. Thereby promoting sputum metabolism and increasing the terminal metabolite uric acid.

The pathological changes of this disease are that the hepatocytes are lightly stained, the serosa is obvious, the cytoplasm is filled with glycogen and swollen and contains medium or large fat droplets, and the nucleus is also enlarged due to the richness of glycogen. Glycogen accumulation in the nucleus and hepatic steatosis are obvious but no fibrotic changes are prominent pathological changes of this type, which are different from other types of glycogen accumulation diseases.

Pediatric glycogen storage disease type I prevention

The treatment of genetic diseases is difficult, the efficacy is not satisfactory, and prevention is more important. Preventive measures include avoiding the marriage of close relatives, conducting genetic counseling, genetic testing of carriers, prenatal diagnosis and selective abortion to prevent the birth of children. Glucose-6-phosphatase activity can be determined by fetal liver activity, usually at 18 to 22 weeks of gestation. To make a prenatal diagnosis and terminate the pregnancy if necessary.

Pediatric glycogen storage disease type I complications Complications, hypoglycemia, convulsions in children

Severe cases may have severe hypoglycemia, acidosis, difficulty breathing, may be associated with convulsions, often bleeding tendency such as nose bleeding; growth retardation, bone age, osteoporosis.

Pediatric glycogen storage disease type I symptoms common symptoms lactic acid accumulation excessive dyslipidemia slow growth fasting hypoglycemia hepatomegaly coagulopathy ketoacidosis symmetrical muscle weakness

The clinical manifestations of this type of child are different: severe cases of severe hypoglycemia, acidosis, dyspnea and enlarged liver in the neonatal period; mild cases are often due to growth retardation, abdominal distension, etc. And see a doctor. Due to chronic lactic acidosis and long-term insulin/glucagon ratio, the child's body is obviously short, bone age is backward, and osteoporosis. The abdomen is significantly bulged due to the continuous increase of the liver; muscles are slack, and yellow tumors are often seen under the skin of the extremities; however, the proportions and intelligence of the body are normal. There are hypoglycemia episodes and diarrhea in children. A small number of infants and young children can be associated with convulsions in severe hypoglycemia, but there are also blood glucose drops below 0.56mmol / L (10mg / dl) without obvious symptoms, with the increase in age, the number of hypoglycemic episodes can be reduced. Because of platelet dysfunction, children often have bleeding tendency such as nose bleeding.

Pediatric glycogen storage disease type I examination

1. Fast-blood biochemical detection of biochemical abnormalities including hypoglycemia, ketoacidosis, lactateemia and hyperlipidemia. Severe hypoglycemia is often accompanied by hypophosphatemia. Triacylglycerol, cholesterol fatty acid and uric acid were all significantly increased.

2. The glucose tolerance test presents a typical diabetes profile. The patient had a low fasting blood glucose and a specific increase in the fructose tolerance test and the galactose tolerance test. Blood glucose levels did not increase in the galactose or fructose tolerance test because the child was unable to convert galactose or fructose to glucose.

3. Adrenaline test subcutaneous injection of 1:1000 adrenaline 0.02ml / kg, before injection and 10, 20, 30, 40, 50, 60min after injection, blood glucose, normal blood sugar increased by 40% ~ 60%; glycogen There was no significant increase in blood glucose in patients with cumulative disease.

4. Glucagon test: Glucagon or adrenaline test can not make the child's blood sugar rise significantly. Glucagon intramuscular injection of glucagon 30 g / kg (maximum amount of 1 mg), blood glucose was taken at 0, 15, 30, 45, 60, 90, 120 min after injection. In normal time, the blood glucose increased by 1.5 to 2.8 mmol/L within 15 to 45 minutes. When the original storage disease was deficient in glucose-6-phosphatase, there was no increase in blood glucose after fasting or after meal.

5. Mucopolysaccharide examination Blood-viscosity polysaccharide examination: Mucopolysaccharide peripheral blood leukocytes, lymphocytes and bone marrow blood cells can be seen in differently stained granules of different sizes and shapes, sometimes vacuolated, and the particles are called Reilly's granules. It has been confirmed that mucopolysaccharide urinary mucopolysaccharide test: a large amount of acid mucopolysaccharide is excreted in the urine of the patient, which can exceed 100 mg/24 hours (normally 3 to 25 mg/24 h), and urinary sulphate and heparan-like hormone are excreted in the urine. Patient white blood cells.

6. Biopsy Liver biopsy showed increased hepatocyte enlargement of glycogen; glucose-6-phosphate active enzyme decreased or disappeared. Muscle biopsy slightly increases glycogen content Glucose structure The normal glucose platelet glucose-6-phosphate active enzyme can also be reduced or disappeared.

7. Enzyme test: The activity of various enzymes in urine can be measured, and the respective enzyme activities of various types of mucopolysaccharidosis are reduced. Patients lack leukocytes, fibroblasts or hepatocytes and urine lack alpha-iduronidase.

8. Genetic testing can be performed by genetic analysis of peripheral blood leukocyte DNA analysis.

9. The release of ADP from other platelet membranes is reduced, so its adhesion rate and aggregation function are low. Most children have normal liver function.

Diagnosis of type I glycogen storage disease in children

Medical history, physical signs, and blood biochemical tests are available for initial clinical diagnosis. Glucose metabolism function test may be helpful for diagnosis, such as: in the glucose tolerance test, due to insufficient insulin secretion in children, it shows typical diabetes characteristics; glucagon or adrenaline test can not make children's blood sugar rise significantly, injection of glucagon After that, blood lactic acid was significantly increased; blood glucose levels did not increase in the galactose or fructose tolerance test because the child could not convert galactose or fructose into glucose. Although this kind of functional test has the advantage of avoiding liver biopsy, because the individual variation of the response of this patient to this type of test is large, the glycogen quantification and glucose-6-phosphatase activity of liver tissue should still be determined. As a basis for diagnosis.

Differential diagnosis

Infants more common fasting blood glucose with hyperlipidemia hyperuricemia and clinical examination of hepatic and renal enlargement can be diagnosed and diagnosed as adrenaline test. The method is as follows: intramuscular injection of 1:1000 epinephrine 0.03ml /kg. 30 min before injection and 30,090,012,120,150 min after blood glucose measurement, normal humans were injected with adrenaline for 1 h, and the fasting blood glucose increased from 1.65 to 2.48 mmol/L2h to the original level. It can also be diagnosed as a highly specific fructose or galactose tolerance test. The method is fructose (0.5g / kg body weight) or galactose (1g / kg) formulated into a 25% solution for 1h before and after intravenous injection, blood is taken every 10 minutes to determine the content of glucose lactate galactose, fructose Glucose is normal and elevated lactate is diagnosable. Note that it is differentiated from other types of glycogen storage diseases such as diabetes, gout, liver disease, and metabolic syndrome (X syndrome).

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