Glycogen Storage Diseases (GSD) are inherited metabolic disorders that affect the Glycogen metabolism (Marcolongo et al.,1997). They are characterized by the deficiency of one of the enzymes responsible for making or breaking down glycogen in the body. All the proteins that are involved in the synthesis or degradation of glycogen have been discovered to cause some type of glycogen storage disease. GSDs can be classiï¬ed according to the type of enzymatic defect or on the basis of distinctive clinical defects .There are at least12 different types of GSD. The forms of GSD are generally described by the part of the body that has trouble because of the enzyme deficiency. The enzyme deficiency causes either abnormal tissue concentrations of glycogen or incorrectly or abnormally formed glycogen.Â Depending on the type of GSD a person has, their enzyme deficiency may be important in all parts of the body, or only in some parts of the body, like the liver or muscle. The categories are the liver only, the muscles only, or both the liver and the muscles. Other systems that are involved may include the blood cells (red blood cells, white blood cells, and platelets), heart, and kidneys.
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Liver and muscles have abundant quantities of glycogen and are the most commonly affected tissues. Because the carbohydrate metabolism in the liver is responsible for plasma glucose homeostasis, glycogen storage diseases that mainly affect the liver usually have hepatomegaly and hypoglycaemia as the distinguishing features (Marcolongo et al., 1997). The role of glycogen in the muscle is to provide substrates for the generation of ATP for muscle contraction. The features of the disease which affects the muscle are muscle cramps, exercise intolerance, susceptibility to fatigue and progressive weakness.
Glycogen storage disease type 1 (GSD1) is a group of autosomal recessive disorders that disrupts blood glucose homeostasis by affecting gluconeogenesis and glycogenolysis. The heterogeneity of the GSD1 disorder originates from the alteration or absence of a component in the microsomal glucose-6- phosphatase system, which consists of the enzyme (G6PC) and the transport protein G6PT1. GSD Ia is caused by a deficiency of the glucose-6-phosphatase (G6Pase) enzyme in the liver, kidney and other organs of the body, Clinically, patients afflicted with GSD1a are characterized by hypoglycemia, hepatomegaly, kidney enlargement, growth retardation, hyperlipidemia, hyperuricemia, and lactic acidemia. GSD type Ib is caused by a deficiency in glucose-6-phosphate translocase, or transporter (G6PT) enzyme, that helps in transporting G-6-Pase enzyme from one point to another. In addition to the clinical features of GSD1a, GSD1b patients have neutropenia and neutrophil dysfunction. The heterogeneity of the GSD1 disorder originates from the alteration or absence of a component in the microsomal glucose-6- phosphatase system, which at least consists of the enzyme (G6PC) and the transport protein G6PT1 (Lam et al.,2006). These two enzymes work together to help the body break down the storage form of sugar (glycogen) in to free glucose (sugar) for use when required.
The human G6PT is a single copy gene consisting of 9 exons and is located at chromosome 11q23 approximately spanning 5.3 kb of DNA . It is a 10-transmembrane domain protein embedded in the Endoplasmic Reticulum membrane. Expression assays show G6PT promotes the uptake and accumulation of G6P in the lumen of the endoplasmic reticulum. This accumulation is stimulated dramatically when G6PT and G6Pase are co-expressed, demonstrating a tight functional coupling between G6P transport and hydrolysis. In GSD-Ib patients the G6PT gene is mutated. Sixty-nine distinct mutations which greatly reduce or completely abolish microsomal G6P transport function have been identified in patients (Kure et al., 1998).
2.REVIEW OF LITERATURE
Glycogen is a polysaccharide that is the principal storage form of glucose in animal and human cells. Glycogen is found in the form of granules in the cytosol in many cell types. Hepatocytes have the highest concentration of glycogen approximately up to 8% of the fresh weight in well fed state or 100-120 g in an adult. In the muscles, glycogen is found in a much lower concentration (1% of the muscle mass), but the total amount exceeds that in liver. Small amounts of glycogen are found in the kidneys, and even lesser amounts are found in certain glial cells in the brain and white blood cells.
2.1. Function of glycogen
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In different tissues the primary function of glycogen varies. In skeletal muscle, glycogen is the fuel source for the cells in which it is stored and it is used for short term high energy consumption. In the brain it provides an emergency supply of energy for use during brief periods of hypoglycaemia or hypoxia. In the liver it takes up glucose from the blood stream at times of plenty and stores it as glycogen, whenever the blood glucose starts to fall it releases the glucose into the blood for use by tissues that cannot themselves make significant amount of glucose. Glycogen storage diseases are genetic deficiencies which result in abnormal amounts and forms of glycogen. Some deficiencies affect only one tissue others can affect several tissues.
2.2. Structure of glycogen
Glycogen is a branched structure with a chain of glucose subunits held together byÂ aÂ 1-4 glycosidic bond and at the branch points, the subunits are joined byÂ aÂ 1-6 glycosidic bonds. The branches occur at intervals of 8-10 residues.
2.3. Glycogen Metabolism
BothÂ synthesis and breakdown of glycogen are spontaneous. In the liver, glycogen synthesis and degradation are regulated to maintain blood-glucose levels as required to meet the needs of the organism as a whole. In contrast, in muscle, these processes are regulated to meet the energy needs of the muscle itself. ( Stryer, 2005)
2.4. Enzymes involved in Glycogen metabolism
The genetic deficiencies of the proteins involved in both glycogen metabolism and its regulation result in a wide spectrum of clinical disorders. Many varieties of proteins are involved in glycogen metabolism. Proteins like debranching enzymes, phosphorylkinase and glucose 6 phosphotase, glycogen synthase, phosphorylase etc.
2.5. Glycogen degradation
Glycogen degradation consists of three steps, first, glucose 1-phosphateis released from glycogen, then the remodelling of the glycogen substrate takes place to permit further degradation, and the conversion of glucose 1-phosphate into glucose 6-phosphate for further metabolism. The glucose 6-phosphate derived from the breakdown of glycogen has three fates (1) It is the initial substrate for glycolysis, (2) it can be processed by the pentose phosphate pathway to yieldÂ NADPHÂ and ribose derivatives; and (3) it can be converted into free glucose for release into the bloodstream. This conversion takes place mainly in the liver and to a lesser extent in the intestines and kidneys.
Figure 21.3. Fates of Glucose 6-Phosphate.
Glucose 6-phosphate derived from glycogen is used as a fuel for anaerobic or aerobic metabolism,l as in the muscle converted into free glucose in the liver and subsequently released into the blood and processed by the pentose phosphate pathway to generateÂ NADPHÂ or ribose in a variety of tissues.
2.6. Glycogen synthesis
Glycogen synthesis begins when the activated form of glucose, uridine diphosphate glucose (UDP-glucose), formed by the reaction ofÂ UTPÂ and glucose 1-phosphate,Â is added to the nonreducing end of glycogen molecules and the glycogen molecule must be remodelled for continued synthesis. GlucoseÂ is first converted intoÂ glucose-6-phosphateÂ by the action ofÂ glucokinaseÂ orÂ hexokinase. The glucose-6-phosphate formed is converted intoÂ glucose-1-phosphateÂ by the action ofÂ Phosphoglucomutase, passing through an obligatory intermediate step ofÂ glucose-1,6-bisphosphate and in turn glucose-1-phosphate is converted intoÂ UDP-glucoseÂ by the action ofÂ Uridyl TransferaseÂ (this also calledÂ UDP-glucose pyrophosphorylase) andÂ pyrophosphateÂ is formed, which is hydrolyzed by pyrophosphatase into 2 molecules of Pi. Glycogen synthase assembles the glucose molecules in a chain , which act on a pre-existing glycogen primer orÂ glycogeninÂ which small protein that forms the primer. Glycogen synthase binds to UDPG, causing it to break down into an oxonium ion and joins the glucose molecules. This oxonium ion which is broken down can readily add to the 4-hydroxyl group of a glucosyl residue at the end of the glycogen chain. Branches are made byÂ branching enzyme, which transfers the end of the chain onto an earlier part via an Î±-1:6 glucosidic bond, forming branches, this further grows on addition of more Î±-1:4 glucosidic units.
The regulation of these processes is quite complex. Several enzymes taking part in glycogen metabolism allosterically respond to metabolites signalling the energy needs of the cell. The adjustment of enzyme activity is allowed by the allosteric responses to meet the needs of the cell in which the enzymes are expressed.Â Glycogen metabolism is also regulated by hormonally stimulated cascades that lead to the reversible phosphorylation of enzymes, which alters their kinetic properties.Â Regulation by hormones allows glycogen metabolism to adjust to the needs of the entire organism.Â By both these mechanisms, glycogen degradation is integrated with glycogen synthesis.
2.7. Glycogen Storage Disease
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Glycogen storage disorders are inherited diseases which result due to the problem with one of the enzymes involved in the conversion of glucose to glycogen or the breakdown of glycogen back into glucose. They mostly affect the liver and muscles. Most cases of GSDs' are diagnosed in childhood. The growth can be affected and generally the symptoms are weakness, tiredness and low blood sugar levels.
Â There are about 12 types of glycogen storage disorders. Each disorder is different from the other due to a different enzyme lack or malfunction. If the enzyme problem is with one of the enzymes involved in glycogen synthesis less amounts of normal glycogen is produced and sometimes abnormal amounts of glycogen is produced. If the problem is due to one of the enzymes involved in glycogen breakdown back into glucose, it can either lead to low levels of glucose in your body (a condition known as hypoglycaemia) or a build-up of glycogen in your muscles and liver.
The glycogen storage disorders are inherited , they can affect energy production and metabolism within your body, so they are also known as inborn errors of metabolism.
2.8. Types of Glycogen Storage Disorders
GSD type I is also known as Von Gierke's disease it is caused due to the deficiency of glucose-6-phosphatase.
GSD type II known as Pompe's disease is due to the deficiency of acid maltase.
GSD type III knowns as Cori's diseaseÂ or Forbes' disease is caused due to the deficiency of glycogen debranching enzyme.
GSD type IV known as Andersen disease is caused to due to the deficiency of glycogen branching enzyme.
GSD type V known as McArdle disease is caused due to deficiency of muscle glycogen phosphorylase.
GSD type VI known as Hers' disease is caused due to the deficiency liver glycogen phosphorylase.
GSD type VII known as Tarui's disease is due to the deficiency of the muscle phosphofructokinase.
GSD type IX is due to the deficiency of phosphorylase kinase, PHKA2.
GSD type XI known as Fanconi-Bickel syndrome is caused due to the deficiency of glucose transporter,GLUT2.
GSD type XII known as Red cell aldolase deficiency is due to the deficiency of Aldolase A.
GSD type XIII is due to the deficiency of Î²-enolase.
GSD type 0 is due to the deficiency of glycogen synthase.
2.9. Glycogen Storage Disease Type I
2.9.1. History of the disease
In 1929 Von Gierke first described the type I glycogen storage disease as "hepatonephromegalia glycogenica" and it is widely referred to as Von Gierke's disease. Cori in 1952 demonstrated that the absence of glucose 6 phosphatase activity was the enzymatic defect responsible for the disease and the first enzymatic metabolic disorder was identified. In the later years with increasing number of patients it was found that the patients were not deficient in glucose 6 phosphatase activity, then the term "Glycogenosis 1b" was proposed. Bialek et al and Narisawa et al proposed that a defect in the microsomal membrane transport system of glucose 6 phosphate was the cause of type 1b and this was later described by Lange et al in 1980 (MMBID).
Glycogen storage disease type 1 affects gluconeogenesis and glycogenolysis by disrupting the blood glucose homeostasis. GSD1 is due to the deficiency of glucose 6 phosphatase enzyme is located in the endoplasmic reticulum of the liver and the kidney. According to the substrate transport model the enzymatic system comprises of a hydroloase, the catalytic sites of the hydrolase faces the lumen of the organelle and various translocases that are responsible for the transport of glucose6 phosphate, pi and glucose (Gerin et al., 1997). The heterogeneity of the GSD1 disorder is due to the alteration or absence of a component in the microsomal glucose-6- phosphatase system, which consists of the enzyme G6PC and the transport protein G6PT1(Lam et al., 2006). G6PC catalyses the terminal reaction of glycogenolysis and gluconeogenesis and plays a key role in the maintenance of blood glucose homeostasis (Marcolongo et al., 1997). GSD type Ia or von Gierke Disease, is caused by deficiencies in glucose-6- phosphatase (G6Pase) activity in the liver, kidney and intestinal mucosa.
2.10. Glycogen Storage Disease 1b
GSD type Ib is caused by deficiency in glucose-6-phosphate translocase, which leads to defective transport of glucose-6-phosphate from the cytoplasm into the lumen of the endoplasmic reticulum (Hsiao et al., 2009). GSD 1a results due to the alterations in the gene coding for G6PC and several mutations reducing or abolishing the enzyme activity have been described. In patients with GSD1b who are deficient in liver microsomal G6P transport no such mutations in the G6PC gene have been found. GSD subtypes show same clinical profile with the exception of GSD1b that usually shows, neutropenia and impaired neutrophil function in addition to hypoglycemia and hepatomegaly and is therefore, the most severe form (Marcolongo et al., 1997).
Glycogen Storage Disease 1b is caused by the deficiency of glucose-6-phosphate transporter (G6PT). G6PT is a 10 trans membrane domain endoplasmic reticulum protein (Chen et al., 2002). G6PT is mainly present in the liver and kidney, the catalytic subunit is localized in the endoplasmic reticulum. At least three transport systems are necessary to allow G6PT activity according to the substrate transport model. It has been proposed that the enzyme utilizes one transport system (G6PT1) to translocate glucose-6-phosphate (G6P) from the cytosol to the lumen of the ER and two other transport systems to transport to transport the reaction products phosphate(pi) and glucose (G6PT2 and G6PT3 respectively) to the cytosol, GSD1b is due to the deficit in the transport of G6P (Marcolongo et al.,)
2.12. Human Glucose 6 Phosphate Transporter gene (G6PT)
Human G6PT is a single copy gene, it consists of 9 exons spanning 5.3kb of DNA (approximately). It is located at chromosome 11q23.
2.13. G6PT mutations that cause GSD Ib
The full length cDNA sequence of two GSD1b patients was found to be mutated, therefore it is found that it encodes the G6P translocase or a protein involved in the regulation of the translocase (Marcolongo et al., 1997) When the human cDNA encoding a protein homologous to the bacterial glucose 6 phosphate transporters , mutations in two cases as expected also maps 11q23 (Gerin et al,.1998) 69 separate mutations have been identified in G6PT gene of GSD1b patients. These mutations include 28 missense, 2 codon deletion, 15 insertion/deletion, 10 nonsense and 14 splicing mutations. Characterization of missense and codon deletion mutations, that resulted in single amino acid alterations provided valuable information on functionally important residues in G6PT. To date, 28 missense and 2 codon deletion G6PT mutations scattered throughout the primary amino acid sequence have been identified in GSD1b patients(Chen et al., 2002). When all the 30 codon mutations were characterized with a G6PT assay based on an adenoviral vector mediated expression system, it was found that 20 of the naturally occurring mutations completely abolish microsomal G6P uptake activity while the other 15 mutations partially inactivate the transporter(Gerin et al., 1999). Mutation of the amino terminal domain of G6PT showed that the optimal G6P uptake activity is required. Using a functional assay for G6P transport, proved that one of the deletion mutation and the 15 missense mutations abolish microsomal G6P transport activity and one deletion and one missense mutation (F93 del and 1278N mutations respectively) destabilize the G6PT. It was clearly established that the deficiencies in G6P transport cause GSD1b (Chen et al., 1999).
2.14. Clinical features
GSD1b is clinically characterized with growth retardation, hepatomegaly, failure to thrive, hypoglycemia induced seizures, anaemia, lactic acidemia, hyperuricemia, hyperlipidemia (Kannourakis, 2002) and inflammatory bowel disease (Ozen, 2007). Most patients exhibit neutropenia and dysfunction of the neutrophils leading to recurrent bacterial infections (Janecke et al.,2001). Hypoglycemia is often very severe and precipitates in either seizures or coma but rarely results in neurological damage as the brain metabolizes lactic acid (Hou et al., 1999) , patients are susceptible to recurrent bacterial infections, which commonly involves the perirectal area, ears, skin, and urinary tract, although life-threatening infections, such as septicemia, pneumonia, and meningitis occur less frequently (Kannourakis, 2002).
The degree of hepatomegaly, severity of hypoglycemia and lactic acidosis is often parallel. The cause of neutropenia and the neutrophil dysfunction is yet unknown (Kannourakis, 2002) however it is said that the neutrophils are defective in both motility and respiratory burst, this may be due to the impaired glucose transport across the cell membrane of the polymorphonuclear leukocytes (Ozen, 2007). The granulocyte and granulocyte colony stimulating factors are said to have been used successfully to correct neutropenia, to decrease the number and severity of bacterial infections and to improve the chronic inflammatory bowel disease (Scriver, 2001)
The association of GSD1b with neutropenia and neutrophil dysfunction indicates that the putative glucose-6-phosphate translocase has an important function in the leucocytes (Gerin et al., 1999). The microsomal G6P transport has a role in the antioxidant protection of neutrophils and the transporter's genetic defect leads to the impairment of the cellular functions and apoptosis, which may lead to the neutrophil dysfunction (Ozen, 2007). The G6PT mutations with residual transporter activity are found in GSD1b patients without neutropenia. Neutrophil count less than 1000cells/mL is found commonly in all the patients affected by the disease. Other accompanying symptoms include fever, diarrhea and perioral and anal ulcers. The intestinal symptoms do not correlate with the severity of the intestinal symptoms (Janecke et al., 2001). In children frequent otitis, gingivitis and boils are common. Terminal kidney disease may rarely develop which may lead to kidney transplantation. Increased prevalence of hypothyroidism is also possible in the patients (Ozen, 2007).
The current laboratory diagnosis of GSD-Ib is confirmed by measuring the enzymatic activities of G6Pase system in both fresh and detergent treated liver specimens obtained by biopsy or autopsy according to the method of Narisawa et al (Kure et al., 1998).
Refractory hypoglycemia liver transplantation can be done to prevent malignant transformation of hepatic adenomas and hypoglycemia improves after liver transplantation, however neutropenia generally continues to be present (Chen et al., 2002).
In infants, feeding of uncooked starch is beneficial in controlling hypoglycemia and lactic acidosis. It also reduces hepatomegaly and improves the linear growth of children. As the patients grow older the disorder is easily managed with frequent ay time and the metabolic complications become less severe (Hou et al., 1999).The kidney disease often is treated by kidney transplantation (Ozen, 2007). The dietary therapy also involves the nasogastric infusion of glucose or frequent oral administration of uncooked corn starch, granulocyte colony stimulating factor (GCSF) therapy may restore myeloid functions (Chen et al., 2002). Defects in neutrophil chemotaxis and intracellular bacterial killing have been described and appear to be corrected by the use of G-CSF (Ozen, 2007).