Glycogen is an important polysaccharide accumulated in many animals and humans. It plays a key role in energy storage and supply by making glucose rapidly available to cells. Glycogen is synthesized and utilized in the liver and muscles, where it is subsequently stored as granules. When energy is lacking, glycogenolysis occurs, producing glucose that is metabolized by cells to perform various functions. However, the regulation of glycogen and its functions are not limited to energy aspects only. Glycogen also performs an important function in the regulation of blood glucose levels, playing the role of its reserve source. Glycogen levels also determine the level of hormones in the blood. In addition, glycogen is involved in maintaining homeostasis by participating in metabolism and controlling metabolic pathways. Thus, glycogen is an essential component of the body, providing energy reserves and supporting the normal functioning of cells and organs.
To date, it has been proven that there are a number of causes that trigger a disorder of glycogen metabolism in the body. First, it is a genetic mutation that leads to a disruption of glycogen structure or its synthesis.
Mutations can result in the accumulation of defective glycogen or its deficiency, which affects the energy processes of body cells .
Secondly, external factors such as poor nutrition or pathological conditions of organs and systems that also impair glycogen metabolism have an impact. Liver pathologies such as cirrhosis or hepatitis, as well as pathologies of the musculature, which is responsible for glycogen processing and storage, can cause disorders of glycogen metabolism. One of the leading causes is impaired activity of enzymes responsible for glycogen synthesis and breakdown. For example, deficiency of such enzymes as, glucose-6-phosphate, 1-4 glycosidase, alpha-1,6-glucosidase, glycogen phosphorylase, can lead to glycogen accumulation in tissues and organs . Such a typical form of carbohydrate metabolism pathology, which is also combined with hypoglycemia is called glycogenosis or «Glycogen disease» .
Glycogenoses are a rare group of inherited diseases characterized by disorders of glycogen metabolism in the body. In 2020, an extensive genetic-epidemiologic study of hereditary diseases was conducted in Russia, involving 4 million people . This study revealed that more than 70% of hereditary diseases are rare, but their prevalence rate reaches 2% in the population. More than 800 different nosol ogic forms of hereditary diseases were also found.
Among rare diseases, glycogenoses occur with low frequency. For example, in Russia, the incidence rate of glycogen diseases is no more than 10 cases per 100 thousand population, and the total number of children with glycogen diseases is 0.34 per 100 thousand child population.
Glycogenosis type Ia occurs in approximately 80% of patients among all patients with type I glycogenosis. The incidence of this type in the general population is approximately 1:100,000 to 300,000. However, among Ashkenazi Jews, the incidence rises to 1:20,000, which is 5 times higher than in the general Caucasian population .
Type Ib glycogenosis occurs in approximately 20% of patients among all patients with type I glycogenosis. The incidence of this type of glycogenosis is unknown.
The incidence of type II glycogenosis is approximately 1:40,000 newborns.
As of 2019, 36 cases of Pompe disease have been identified in the Russian Federation.
Type III glycogenosis occurs in approximately 24% of all glycogenotic patients. The incidence of this type of glycogenosis is 1:30. In a population of North African Jews in Israel, this type of glycogenosis occurs with an incidence of 1:5,400, and the carrier frequency is 1:35. In Europe and North America, the incidence of type III GD is approximately 1:83,000 .
Type IV glycogenosis accounts for only 0.3% of all glycogenotic patients and its prevalence is unknown.
There are 12 types of glycogenoses, which are categorized according to pathogenesis:
- hepatic — 0, I, III, IV, VI, VIII, IX, X, XI types,
- muscle types V and VII,
- mixed — type II .
The mechanism of muscle-energetic disorders is related to the genetically determined absence or reduced function of enzymes involved in glycogen metabolism.
For example, in the absence of muscle phosphorylase, there is no cleavage of α1,4-glycosidic bonds that are part of the glycogen molecule, hence no formation of glucose-1-phosphate, which is one of the metabolites in the process of glycogenolysis. This leads to the accumulation of glycogen in muscles, which can lead to the development of glycogenosis type V (McArdle’s disease) or glycogenosis type VII (Tarui’s disease).
The GAA gene, located on chromosome 17, encodes acidic alpha-glucosidase, an enzyme that helps break down glycogen in lysosomes. It is similar in functionality to the enzyme that breaks down glycogen, but the two enzymes are on different chromosomes, are processed differently by the cell, and are located in different parts of the cell — lysosomes and cytosol, respectively. Errors in this gene can lead to impaired lysosomal alpha-glucosidase function and glycogen accumulation in cells, which can eventually lead to the development of glycogen accumulation disease type II, also known as Pompe disease. This disease is an example of how genetic factors can be deterministic for the development of a particular body condition. Thus, the GAA gene plays an important role in the normal function of lysosomes and glycogen processing in the body.
The disorder of the «dewetting» enzyme amylo-α1,6-glucosidase associated with its deficiency is characterized by autosomal recessive inheritance. In this pathology, there is no hydrolysis of the α1,6-glycosidic bond, resulting in a lack of formation of free, unphosphorylated glucose. As a result of this defective enzyme function, no branch-free glycogen molecular chain is formed, which is the initial substrate for phosphorylase. This type of glycogenosis belongs to glycogenosis type III, also known as Cory-Forbes disease [1,3,4].
Thus, this group of glycogenoses is characterized by changes in muscle tissue enzymes, leading to impaired muscle energy supply during physical activity, muscle pain, and cramps. Glycogen, which does not undergo decomposition, leads to impaired synthesis of ATP, the main energy molecule necessary for muscle function. This leads to energy deficiency in the muscles and the appearance of characteristic clinical manifestations.
Glycogen diseases have a variety of clinical manifestations, which may be associated with damage to various organs and body systems. However, in most cases, the disease is progressive and severe, often leading to death.
Patients with glycogen diseases have liver, heart and muscle lesions. Liver lesions may manifest as increased abdominal size and various liver dysfunctions, this is due to impaired formation and breakdown of glycogen, leading to its accumulation in the organ. Episodes of cramps are also one of the frequent symptoms of glycogen disease, especially during physical activity, as the muscles are unable to properly process glycogen into energy. Heart damage can manifest as various cardiomyopathies and other cardiac problems, particularly the underlying electrolyte abnormalities associated with the disease can cause arrhythmias.
Patients have difficulty in performing physical tasks. Weakness and increased fatigue combined with impaired physical development in childhood are also characteristic manifestations of glycogenosis.
Glycogen storage disease is characterized by an increased content of glycogen in the muscle, which cannot be completely broken down. This can lead to muscle pain, especially after exercise, as well as myoglobinuria, which manifests as red-colored urine, and severe renal failure.
During physical activity, such as in type V glycogenosis, the «second breath phenomenon» is observed, which is explained by the flow of blood containing glucose into the muscles.
The list of symptoms also includes hypotonia, splenomegaly, liver cirrhosis, and neurologic lesions that may include psychomotor retardation and speech delay. One of the characteristic features is a «doll’s» face, a feature of appearance characterized by wide-set eyes, large nasal openings, and a wide mouth due to local deposition of subcutaneous tissue.
Clinical manifestations of glycogen diseases may vary depending on their type and degree of progression. Some forms, especially those leading to liver damage, may progress rapidly and be severe, so it is important to pay timely attention to these symptoms and perform the necessary examination to make an accurate diagnosis and prescribe appropriate treatment [1,3].
As a laboratory diagnosis for the determination of glycogen disease, patients are recommended to conduct the following types of tests: complete blood count, biochemical blood test with the measurement of such indicators as glucose, ALT, AST, lactate, GGT, alkaline phosphatase, total protein, albumin, cholesterol, triglycerides, uric acid and bilirubin. Blood creatine kinase activity and levels of creatine kinase isoenzymes and LDH are also determined.
The levels of sodium, potassium, chlorine, total and ionized calcium, free and total L-carnitine are also analyzed. Blood lipidogram allows you to determine the level of cholesterol, LDL, HDL and triglycerides. Blood CSF, coagulogram, alpha-fetoprotein content analysis are also performed.
In case of Glycogen Disease with muscular system involvement, the level and activity of creatine kinase isoenzymes (CFK MB) and myoglobin content in urine are additionally tested. Blood phosphate levels are also determined and daily proteinuria, microalbuminuria, calcium and phosphate excretion in daily urine are analyzed.
Additionally, it is recommended to perform molecular genetic studies to verify the type of hereditary pathology.
As an instrumental diagnosis, abdominal ultrasound is performed to determine the size of the liver and the state of its parenchyma. For differential diagnosis of glycogen disease and determining the degree of fibrosis, it is recommended to use the method of puncture liver biopsy, which includes morphological examination of the obtained biopsy specimen. MRI of the muscles of the lower limbs will be useful for assessing the state of the muscular system, detecting degenerative changes, fatty muscle replacement, the presence of edema and inflammatory processes in the skeletal muscles. External respiratory function studies are also recommended to monitor pulmonary function, which may be impaired due to respiratory muscle dysfunction. The study includes measurement of unprovoked respiratory volumes and flows. The use of these types of studies will help to more effectively determine the patient’s condition and prescribe a treatment plan .
With proper nutritional therapy in cases of glycogenosis, metabolic disturbances can be minimized and the risk of complications can be reduced. The diet for patients with different types of glycogenosis differs from that of healthy children because of its higher carbohydrate and protein content and lower animal fat content.
It is recommended to organize frequent meals with an even distribution of digestible carbohydrates throughout the day, especially for patients with type I GD. For this purpose, the number of meals is increased to 6-8 times a day, including early breakfast and late dinner, to maintain normal blood glucose levels. Also in case of low blood glucose concentration, 1-2 night feedings are introduced. Thus, there is no specific treatment for patients with glycogenosis and they require constant monitoring and supportive therapy throughout life. Diet and nutritional regimen are the main therapies to prevent and control various metabolic disorders and functional problems associated with glycogenoses [1,3,4].
In general, understanding of the mechanisms of muscle-energetic disorders in glycogen disease, enzyme defects, and causes of decreased cellular energy potential allows us to review the main aspects of this rare disease. However, further research and the development of new diagnostic and treatment methods are still needed to improve the prognosis and quality of life of patients with glycogen disease
References1. Baranov AA, Namazova-Baranova LS, Surkov AN, Gundobina OS, Vishneva EA, Margieva TV, Vashakmadze ND, Selimzyanova LR Management of children with glycogen storage disease (nosologic forms with liver damage). Modern clinical recommendations. Pediatric Pharmacology. 2020; 17 (4): 303-317.
2. Sagitova G.R., Davydova O.V., Antonova A.A., Ilyenko T.L. Early manifestation of infantile form of Pompe disease (case from practice) // Journal of Siberian Medical Sciences. 2022;6(3):143-153.
3. Emelyanova O.N., Petrukhina I.I., Borovik N.N. Clinical observation of children with glycogenosis // Journal of Scientific Articles "Health and Education in the 21st Century". 2018; 189-192.
4. Litvitsky P.F., Pathophysiology: Textbook / P.F. Litvitsky. - 7th ed., rev. and supplement. - Moscow: GEOTAR-Media, 2023. – 864.: il.
5. Severin, E. S. Biochemistry : textbook / edited by E. S. Severin. - 5th ed. Moscow: GEOTAR-Media, 2016. – 768.