Glycogenoses are hereditary diseases based on a genetic defect in the production of enzymes involved in carbohydrate metabolism. A characteristic common feature is excessive deposition of glycogen in myocytes, hepatocytes and other cells of the body. Glycogenoses are manifested by symptoms of hypoglycemia, hepatomegaly, muscle weakness, hepatic, cardiac, respiratory and renal insufficiency. Diagnostics includes biochemical blood analysis, morphological examination of muscle and liver biopsy material, determination of enzyme activity, molecular genetic tests. Treatment is based on therapeutic nutrition, drug correction of metabolic disorders, in some cases operations are required.
ICD 10
E74.0 Glycogen storage diseases
General information
Glycogenoses have been studied since 1910. In 1928-29, the symptoms of type I glycogenosis – “glycogen accumulation disease” – were described. It was only in 1952 that it was possible to identify an enzyme defect and establish its connection with the development of symptoms. Pathogenetic mechanisms and methods of treatment are still not fully understood. To date, 12 types of glycogenoses have been identified, 9 have been most fully investigated. The prevalence is low, on average 1 case per 40-68 thousand population. Epidemiological indicators are the same among both sexes, but with X-recessive inheritance, men get sick more often. Symptoms appear during the newborn period or in early childhood, the course is more often continuously progressive.
Causes
The only factor provoking the development of glycogen diseases is a genetic defect, as a result of which there is a deficiency of a certain enzyme involved in glucose metabolism. All glycogenoses with the exception of type IX are inherited according to the autosomal recessive principle. This means that the mutational gene is located on a chromosome that is not linked to sex, the manifestation of the disease is possible only if mutations are inherited from each of the parents – if there are two recessive altered genes in the allele. If one gene from a pair is defective, then the other – dominant, normal – provides the body with a sufficient amount of the enzyme. At the same time, a person becomes a carrier of glycogenosis, but does not get sick. In couples where both partners are carriers, the probability of having a sick child is 25%. In type IX glycogenosis, the pathological gene is localized in the sex X chromosome. Hemizygous men have a pair of XY, are always sick with glycogenosis, transmit the defect to all their daughters. The probability of transmission of the mutation from a female carrier to children of both sexes is 50%.
Pathogenesis
The pathogenetic basis of all glycogenoses is the impossibility of the process of synthesis and decomposition of glycogen, its accumulation in tissues. Glycogen is the only reserve polysaccharide of the body, a kind of energy “depot” – after eating, excess glucose is converted into liver and muscle glycogen, then gradually cleaved back to glucose. Thanks to this mechanism, a stable level of sugar in the blood plasma is maintained, the cells and tissues of the body are continuously provided with energy. In agglycogenesis (type 0) – there is no enzyme glycogen synthetase responsible for the production of glycogen. Patients suffer from severe hypoglycemia.
In glycogen diseases of types 1-11, there is a genetically determined deficiency of an enzyme that catalyzes the glucose-glycogen-glucose chain. Type 1 is characterized by a defect of glucose-6-phosphatase and glucose-6-phosphattranslase, type 2 – alpha-1,4-glucosidase, type 3 – amyl-1,6-glucosidase, type 4 – D-1,4-glucano-α-glucosyltransferase, type 5 – glycogen phosphorylase of myocytes, type 6 – starch phosphorylase of hepatocytes, 7 type – phosphoglucomutase, type 8 – phosphofructomutase, type 9 – hepatocyte phosphorylase kinase. Due to the reduced activity or complete absence of the enzyme, glycogen accumulates in the muscles, liver, rarely in other tissues. The structure and functionality of organs are changing, various forms of organ failure are developing.
Classification
Taking into account the enzymatic defect and the peculiarities of clinical manifestations, 12 variants of glycogenoses are distinguished, from 0 to XI. In addition, cases of combined types are described, when a deficiency of two enzymes is determined, as well as cases of unidentifiable types in which it is not possible to isolate an enzyme defect. According to the leading pathogenetic mechanism , glycogen diseases are divided into three large groups:
- Liver. They include glycogenoses of all types except II, V and VII. Glycogen is deposited mainly in hepatocytes. Characterized by hepatomegaly, hypoglycemia 2 hours after the intake of carbohydrates. With type I of the disease, the kidneys are also affected, with types III and IV, myopathies develop.
- Muscular. This group includes diseases of types VII and V. The enzymatic activity in the muscle tissue is changed, the energy supply of the muscles is disrupted. Typical symptoms are myalgia, seizures.
- Mixed. Type II glycogenosis differs in that all glycogen-containing tissues are involved in the pathological process. Glycogen accumulates in the lysosomes and cytoplasm of cells. Many organs suffer, and the risk of death due to heart or respiratory failure increases.
Symptoms
Aglycogenesis develops in the period of neonatal or early childhood. Low glycogen content in the liver is manifested by pronounced fasting hypoglycemia. There is lethargy, deep sleep, loss of consciousness, pallor of the skin, nausea, vomiting, convulsions at night and in the morning. Outwardly, patients are stunted, have a reduced bone density, an increased risk of fractures. In Gierke’s disease (type I), symptoms will debut in the first 4 months of life. Characterized by poor appetite, vomiting attacks, lack of weight, liver enlargement, disproportionality of the body structure – round face, large belly, thin limbs.
Clinical signs of Pompe disease (type II) are determined within a few weeks after birth. Children are sluggish, sedentary, with a weakened sucking reflex, reduced appetite. Hepatomegaly changes the proportions of the body – the abdomen increases, the arms and legs remain thin. The heart, lungs, and nervous system are affected. The risk of heart and lung failure is high. Patients with Forbes disease (type III) have mild to moderate symptoms. Hypoglycemia of the postabsorption period, hepatomegaly, accumulation of subcutaneous fat in the trunk area comes to the fore. The leading symptoms of Andersen’s disease (type IV) are muscle weakness, poor exercise tolerance, seizures.
Thomson’s disease is represented by hepatomegaly, nystagmus, ataxia, progressive neurological disorders with muscle hypertension, and decerebration. Typical manifestations of McArdle’s disease (type V) are pain, spasmodic contractions, excessive fatigue and muscle weakness even after a slight load. Sometimes tonic seizures turn into generalized ones, which is accompanied by general stiffness. Manifestations of Gers disease (type VI) are less pronounced, patients are able to tolerate light and moderate physical activity without experiencing discomfort. Additionally, signs of liver damage are detected – appetite suppression, vomiting, nausea, pain in the right side.
The course of Tarui’s disease (type VII) includes intolerance to physical activity, accompanied by nausea and vomiting, painful muscle spasms. The intake of glucose does not increase the ability to perform physical actions. After eating, the symptoms worsen. The mildest course is characteristic of Haga disease (type IX). In sick children, the liver increases, motor development and growth are delayed, muscle hypotension is formed. With age, the symptoms are reduced independently. Type X glycogenosis is extremely rare, characterized by hepatomegaly, with prolonged course, the tolerance of physical exertion decreases. Type XI glycogenosis is accompanied by a significant increase in the liver, delayed growth and physical development, rickets. In adolescents, there is often a reduction in the volume of the liver, an acceleration of growth.
Complications
With varieties of glycogenoses accompanied by hypoglycemia, there is a risk of hypoglycemic coma. As a rule, a marked decrease in blood glucose occurs when skipping meals, especially after a night’s sleep (skipping breakfast). Patients experience dizziness and convulsions, lose consciousness. Severe forms of muscle glycogenoses with prolonged course and absence of therapy lead to skeletal muscle dystrophy, heart failure. A complication of some hepatic glycogenoses is cirrhosis of the liver.
Diagnostics
If glycogenosis is suspected, the child is recommended to consult a geneticist, pediatrician, gastroenterologist, hepatologist. First of all, the specialist collects anamnesis, conducts a clinical survey and examination. Since the disease is transmitted in an autosomal recessive way, family cases are rarely detected. Complaints of weakness, apathy of the child, pallor and jaundice of the skin, refusal to eat or increased appetite, difficulty waking up in the morning, tremors, convulsions are common. Upon examination, the doctor notes an increase in the size of the liver, abdominal protrusion, growth retardation, muscle hypotrophy, specific deposition of subcutaneous fat, xanthomas. Laboratory and instrumental methods can confirm the diagnosis of glycogenosis, exclude congenital syphilis, toxoplasmosis, cytomegaly, liver pathology, Gaucher disease, myotonia, progressive muscular dystrophy, amyotrophy. Mandatory research methods include:
- Biochemical blood test. According to the results of the analysis, hypoglycemia with an empty stomach glucose level of 0.6-3 mmol / l, lactic acidosis with a lactic acid concentration of 3-10 mmol / l (except for type 4 glycogenosis) is detected. Additionally, an increase in triglycerides, total cholesterol, LDL, VLDL, uric acid, liver enzymes is detected.
- Examination of liver and muscle biopsy. When studying liver tissue, the most common characteristics are an increased amount of glycogen and its lumpy distribution in the cytoplasm of hepatocytes, sometimes in vacuolated nuclei. Pronounced protein and /or large- and small-drop fatty dystrophy of hepatocytes, their necrosis, limited foci of fibrosis at the sites of cell death are determined. There may be signs of cirrhosis. For muscle types of diseases, a muscle biopsy is examined, in which subsarcolemal accumulations of structurally normal glycogen are viewed.
- The study of enzymes. The activity of enzymes is studied in the culture of skin fibroblasts, biopsy of muscle and liver tissue, leukocytes. With glycogenoses with a chronic slowly progressive course, the decrease in the functionality of the enzyme is mild or moderate. In severe cases, the enzyme is absent or its activity is minimal.
- Ultrasound of the abdominal cavity. There is a marked increase in the liver, especially its left lobe. Hyperechogenicity and structural diffuse heterogeneity of parenchyma are characteristic (multiple small hyperechogenic echoes distributed evenly). In the distal parenchyma, the passage of ultrasound is weakened. It is possible to detect structurally diverse hepatic adenomas, an increase in the size of the kidneys, spleen and pancreas.
The complex of diagnostic studies is selected individually depending on the age of the patient and the expected type of glycogen disease. Molecular genetic diagnostics (gene sequencing to detect mutations), electromyography, ECHO-KG, UAC, coagulogram may be required.
Treatment
Specific methods of therapy have not been developed. Pathogenetic treatment is carried out conservatively, aimed at eliminating hypoglycemia, metabolic acidosis, ketosis, hyperlipidemia, correction of dysfunction of the hepatobiliary complex and gastrointestinal tract. With the development of complications (serious damage to internal organs), surgical operations are performed. Medical care for patients includes the following areas:
- Diet therapy. To minimize metabolic disorders, an individual nutrition plan is drawn up. Patients are recommended to reduce the amount of fats, sucrose, fructose and galactose to reduce hyperlipidemia and acidosis. With the first type of glycogenosis, a diet with increased carbohydrate intake is prescribed. In particular, the use of raw corn starch with slow digestibility, which allows to prevent hypoglycemia, is shown. In types 3, 4 and 9, a diet with a predominance of animal protein and fractional nutrition is introduced.
- Drug correction of symptoms. As part of the complex treatment, cocarboxylase is used to increase the production of acetyl enzyme A, corticosteroids and glucagon to stimulate gluconeogenesis. Carnitine deficiency is compensated by levocarnitine. In secondary tubulopathies, hepatic and biliary dysfunctions, choleretic drugs, hepatoprotectors, lipotropic substances are used. With signs of acidosis, alkaline solutions are indicated intravenously. In renal dysfunction, proteinuria – ACE inhibitors. With hyperuricemia – uricodepressors. In neutropenia – granulocyte colony stimulating factor.
- Surgical treatment. Patients with severe fatal liver lesions may require orthotopic organ transplantation. The indication for surgery is cirrhosis with complications, often developing in the third and fourth types of pathology. In some cases, surgical intervention is advisable for liver adenomas with a high risk of transformation into a malignant tumor. Kidney transplantation is sometimes performed in patients with chronic renal failure.
Prognosis and prevention
The effectiveness of therapy, the likelihood of complications and death depend on the type of pathology. Some glycogenoses slightly worsen the quality of life of patients, are compensated as they grow older, while others do not respond to treatment and inevitably end in death. To reduce the risk of having a child with glycogenosis, married couples from the risk group – those with a family history, children with a confirmed diagnosis – need medical and genetic counseling, prenatal diagnostics.
