The enzyme occurs in many tissues, thus its subunits also have their specific isoforms. The activity of PhK has been studied in such organs as the liver, muscles, kidney, testes, heart and also in erythrocytes, leukocytes and nerve cells [ 32 , 33 ]. The PhK enzyme consists of 4 subunits: α, β, γ, and δ subunits, which are encoded by the following genes:.

PHKB subunit β , PHKG1 and PHKG2 subunit γ expressed in the liver [ 34 , 35 ],. CALM1, CALM2 and CALM3 subunit δ [ 32 ]. The cAMP-dependent protein kinase regulates the phosphorylation of the Ser residues in the α and β subunits.

The γ subunit contains a catalytic site, and the calcium-binding subunit δ has an affinity for calmodulin [ 36 ]. Type IX is the only GSD that is X-chromosome linked recessively inherited: the α1 subunit is X-linked inherited, while the remaining subunit units are AR inherited [ 37 ].

Mutation in the PHKA2 gene is the most common cause of GSD IX [ 38 ]. This type of GSD is characterized by a relatively mild course. Tissues affected by the disorder, depending on the subtype, are liver, erythrocytes, kidneys and muscles [ 39 , 40 ].

The symptoms occur during infancy or early childhood, and include growth delay and liver enlargement [ 41 ]. Episodes of hypoglycemia or ketonuria without a reasonable cause are rare.

If present, they are associated with a prolonged state of starvation or increased physical activity. Lactic acid and urinary acid concentrations are usually normal, and metabolic acidosis with hypocalcemia is rare. Hypertriglyceridemia and hypercholesterolemia, as well as various levels of hypertransaminases, are also observed: from slightly to several times elevated transaminases.

It causes delays in motor development due to the possibility of spreading in the muscle tissue. These disorders normalize during adolescence [ 13 ]. Based on the additional involvement of the skeletal muscles and the heart, there are 2 subtypes of GSD III: hepatic-muscle type subtype a and a hepatic one subtype b.

Like all other GSDs but type IX-α, it is inherited in an autosomal recessive manner; the mutation is in the AGL gene located on chromosome 1p21 [ 46 ]. The first signs of the disease appear in early childhood and include enlarged liver, delayed growth and physical development, whereas hypoglycemia neurohyglycemia is not that common.

As age progresses, the hepatomegaly reverses, and muscle weakness subtype IIIa progresses slowly. Other symptoms common to this type of GSD include muscle hypotension and cardiomyopathy. Frequently, the symptoms regress during adolescence, except in rare cases when cirrhosis of the liver or myopathy occurs [ 47 ].

Type VI is a mild form of GSD. The enzyme block consists of decreased liver enzyme activity — phosphorylase involved in the glycogenolysis process. The disease is inherited in an autosomal recessive manner, with a mutation in the PYGL gene on chromosome 14qq22 [ 48 ].

Symptoms are the same as in type III. In this type of GSD the heart and skeletal muscles are never involved, and liver adenomas are very rare. The disease does not carry the risk of organ failure [ 49 ]. The enzyme defect consists of reduced glycogen brancher enzyme GBE activity, mutation in the GBE1 gene on chromosome 3p12, and autosomal recessive inheritance.

GBE deficiency results in the accumulation of abnormal forms of glycogen that resemble the amylopectin polyglucosan body structure. Hence, its other name is amylopectin or adult polyglucosan body disease APBD [ 50 ]. The symptoms are very heterogeneous and include both the liver and the neuromuscular system.

Children are generally born healthy but, as early as in the first months of life, they develop hepatomegaly and hypotonia and their psycho-motor development is delayed. The disease progresses rapidly.

It leads to liver fibrosis and portal hypertension which manifests as ascites and eventually leads to death. However, several cases of non-available hepatic GSD IV have also been reported in the literature [ 51 ].

Unlike muscles, liver contains the glucosephosphatase membrane enzyme, which removes the phosphate residue to allow the glucose to enter the bloodstream and regulates its concentration [ 52 ].

Glucosephosphatase 1 G6PC enzyme catalyzes the hydrolysis of glucosephosphate to glucose, thus forming the last step of glycogenolysis and gluconeogenesis [ 53 — 56 ]. The G6PC enzyme is encoded by the G6pc gene, which is expressed in the liver, kidneys and pancreas, and its mutation is inherited in an AR pattern [ 52 , 57 ].

The function of the enzyme requires its translocation through the membrane of the endoplasmic reticulum. Another enzyme, G6PC translocase encoded by the SLC37A4 gene, is also involved in this process, which can also be mutated AR inheritance to impair the function of neutrophils, which is inscribed in the GSD type Ib.

After eating a meal, blood glucose rises. Hormone levels regulating these metabolic pathways are in inverse proportions, i. the concentration of glucagon decreases, and the concentration of insulin increases.

There is no breakdown of glycogen then. The phosphorylation pathway of inactivated phosphorylase b to active a is off. On the other hand, the pathway of phosphorylation of active synthase a to inactive b is activated.

We are dealing with the postprandial state of glycogen synthesis stored as a backup material in tissues, primarily in the liver. Before meals, when blood glucose levels fall, insulin levels drop, and another hormone, glucagon adrenalin-like , shows an upward trend.

The glycogen degradation reaction to glucose is started. We obtain an active form of glycogen phosphorylase a and an inactive form of glycogen synthase b. The basic treatment for GSDs is dietary management, which raises many controversies.

Dietary recommendations differ slightly between the United States and Poland, but they are different in Europe, for example, comparing the UK and Poland.

The aim of dietary treatment is to avoid hypoglycemia. Therefore, it is necessary for patients to consume frequent meals during the day every 3—4 h with the addition of raw cornstarch RS and to shorten the night break by an additional portion of RS in the middle of the night [ 58 — 60 ].

Starch, like glycogen, is a polysaccharide — the process of releasing pure glucose into the bloodstream, in this case, is extended in time. This results in constant access of substrates to the biochemical reactions of energy synthesis pathways, limiting its accumulation in tissues and thereby involving glycogen [ 61 , 62 ].

In the UK, overnight glucose infusions through a pump or probe are still used. However, for patients with an unstable glucose level or ketosis, 2 g of unprocessed RS per kilogram of body weight is prepared to prevent morning hypoglycemia [ 63 ]. The situation is different for patients with type I GSD, who present with the most severe hypoglycemia and have most unstable glucose levels — both glycogenolysis and gluconeogenesis are impaired in this type and, additionally, ketogenesis is ineffective and there is a risk of neuroglycopenia.

Therefore, in GSD type I starch is a drug and not just a dietary supplement; it must be given regularly during the day every 3—4 h with a night break not exceeding 7—8 h [ 30 ]. Patients most often need to take an extra dose of starch at night while maintaining a constant supply of carbohydrates in a liquid form, especially during sleep, thus protecting patients with decompensated glycemia from dangerous complications of hypoglycemia.

When intolerance or reluctance to receive RS is observed, either a nasogastric tube or percutaneous endoscopic gastrostomy PEG is required — if the enteral supply is to be maintained for more than 6—8 weeks ESPEGHAN guidelines.

The disadvantage of starch is that it is hard to digest — with an infection associated with gastrointestinal irritation in children with glycogenosis there are often problems with starch supplementation. It is not recommended for patients with type Ib due to their common inflammatory bowel disease and, therefore, additionally impaired absorption.

The formula is used in patients older than 5 years old. Currently, glycosade is to be studied in the United States for its application during the day in adult patients, in whom, due to the slower metabolism than children, the extended-release preparation might be effective not only at night.

According to current US dietary recommendations, the diet should be restricted to simple sugars less than 5—10 g in each meal in all types of GSDs, while it is most restrictive in type I, with RS supplementation in type I every 3—4 h daily plus an extra overnight dose or only 1 night dose in other types [ 64 ].

Because of the increased risk of micronutrient deficiencies vitamin D 3 , calcium-phosphate disturbances, and the risk of osteopenia , multivitamins and vitamin D 3 supplements are also recommended [ 30 , 64 ]. The basic principle of treatment is therefore to limit the simple sugars in a diet rich in complex carbohydrates.

However, the diet is always individually selected for the patient based on its glycemic status, current biochemical findings metabolic equilibrium and anthropometric parameters, and requires close collaboration between the physician, metabolic dietitian, the patient and his family.

Table III summarizes different dietary strategies in ketotic and non-ketotic type I GSDs. Summary of different dietary strategies in ketotic and non-ketotic type I GSDs. As mentioned above, a properly applied specific diet is a treatment in GSDs. It leads not only to stable normoglycemia, but also to decreased hepatomegaly reduction of glycogen storage , improvement of growth and biochemical metabolic control normalization of transaminases, triglycerides, in type I — reduction of lactate and uric acid in blood [ 13 ].

The problem of diet, as an important factor in treatment, may lead to eating disorders in children with GSDs. In the course of metabolic diseases, some eating disorders related strictly to the elimination diet can be observed.

For example, people consuming frequent meals with high carbohydrate content that slows down the release of glucose into the blood may experience a lack of hunger.

Since a lot of attention is paid to eating, it may cause a lack of pleasure from eating a meal, not to mention the lack of taste of non-sweet foods. As far as children are concerned, following the heavy-starch diet is often associated with digestive problems.

Establishing the right diagnosis and setting a proper glycogenic diet will make the patients enjoy eating and discovering new flavors, changing the attitude to a meal as a necessity.

In the treatment of eating disorders, therapies of these disorders adapted to the requirements of GSDs are helpful [ 28 ]. The GSDs, like all genetic diseases, is incurable. Currently, clinical trials on gene therapy for type I glycogenosis clinical phase of GSDI adult safety assessment are ongoing at the Connecticut facility in the US [ 66 ].

Currently, in the USA, the development of adeno-associated virus AAV vector-mediated gene therapy is being carried out for GSD type I based on the success of early-stage clinical trials of gene therapy in hemophilia [ 67 ]. At present, gene therapy for GSD type I is at the stage of a safety clinical trial on adult patients with this type of GSD, and is taking place in the Connecticut Hospital within the GSD program of Prof.

The GSD is a congenital defect of carbohydrate metabolism characterized by hypoglycemia, hepatomegaly, and growth disorders short stature. Basic therapeutic treatment consists in maintaining a proper diet with RS supplementation. Due to the fact that awareness and knowledge about rare diseases are still insufficient, it is important to popularize them among pediatricians, hepatologists and geneticists.

Knowledge of the biochemical basics and glucose metabolism in the human body facilitates proper treatment of GSD. Current issue Archive Manuscripts accepted About the Journal Editorial office Editorial board Abstracting and indexing Subscription Contact Ethical standards and procedures Most read articles Instructions for authors Article Processing Charge APC Regulations of paying article processing charge APC.

Manuscripts accepted. About the Journal Editorial office Editorial board Abstracting and indexing Subscription Contact Ethical standards and procedures Most read articles. Instructions for authors Article Processing Charge APC Regulations of paying article processing charge APC.

Current issue. Hepatic glycogen storage diseases: pathogenesis, clinical symptoms and therapeutic management. Edyta Szymańska 1. Dominika A. Jóźwiak-Dzięcielewska 2. Joanna Gronek 2.

Marta Niewczas 3. Wojciech Czarny 4. Dariusz Rokicki 1. Piotr Gronek 2. Laboratory of Genetics, Department of Gymnastics and Dance, University School of Physical Education, Poznan, Poland.

Department of Sport, Faculty of Physical Education, University of Rzeszow, Rzeszow, Poland. Department of Human Sciences, Faculty of Physical Education, University of Rzeszow, Rzeszow, Poland.

Glycogen storage diseases GSDs are genetically determined metabolic diseases that cause disorders of glycogen metabolism in the body. The first symptoms of the disease usually appear during the first months of life and are thus the domain of pediatricians. Due to the fairly wide access of the authors to unpublished materials and research, as well as direct contact with the GSD patients, the article addresses the problem of actual diagnostic procedures for patients with the suspected diseases.

Knowledge and awareness of the problem among physicians seem insufficient, and research on the diagnosis and treatment of GSD is still ongoing, resulting in a heterogeneous GSD typology and a changing way of its diagnosis and treatment.

Figure 1 Cascade of glycogen breakdown. Glycogen storage diseases glycogenoses Pathophysiology and epidemiology Glycogen storage disease GSD is caused by a genetically determined metabolic block involving enzymes that regulate synthesis glycogenesis or glycogen breakdown glycogenolysis [ 13 ].

Inheritance Glycogen storage diseases, like most metabolic diseases, are inherited in an autosomal recessive AR way. Typology of GSDs It is still an unsettled matter. Table I Various types of GSDs types of GSDs according to tissue-specific enzymatic deficiency. Table II Classification of GSDs into hepatic and muscle types with separate classification of PhK deficiency type IX.

Classic Infantile Juvenile Adult. Clinical symptoms The basic clinical symptoms common for every type of hepatic GSD are hypoglycemia and hepatomegaly [ 24 ]. Glycogen pathway Decomposition of glycogen molecules is directly related to energy production, and its regulation takes place by activation of the relevant substances and enzymes.

Figure 2 Enzymatic activity of phosphorylase and synthase. Release of glucosephosphate-kinase phosphorylase PhK. Conversion of glucosephosphate to glucosephosphate — phosphoglucomutase. Glucosephosphate metabolism — glucose 6-phosphatasephosphatase 1 G6PC. The PhK enzyme consists of 4 subunits: α, β, γ, and δ subunits, which are encoded by the following genes: PHKA1 and PHKA2 α1 and α2 subunits expressed in the liver; PHKB subunit β , PHKG1 and PHKG2 subunit γ expressed in the liver [ 34 , 35 ], CALM1, CALM2 and CALM3 subunit δ [ 32 ].

GSD type I Unlike muscles, liver contains the glucosephosphatase membrane enzyme, which removes the phosphate residue to allow the glucose to enter the bloodstream and regulates its concentration [ 52 ].

Dietary management The basic treatment for GSDs is dietary management, which raises many controversies. Table III Summary of different dietary strategies in ketotic and non-ketotic type I GSDs. CS every 3—4 h during the day plus extra dose at night. Usually only 1 dose of CS at night High-protein diet.

Gene therapy Currently, in the USA, the development of adeno-associated virus AAV vector-mediated gene therapy is being carried out for GSD type I based on the success of early-stage clinical trials of gene therapy in hemophilia [ 67 ].

Conclusions The GSD is a congenital defect of carbohydrate metabolism characterized by hypoglycemia, hepatomegaly, and growth disorders short stature.

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