GSD

• Glycogen serves as the primary fuel reserve for the body's energy needs. Glycogen storage diseases, also known as glycogenoses, are genetically linked metabolic disorders that involve the enzymes regulating glycogen metabolism

• Disruption of glycogen metabolism also affects other biochemical pathways as the body seeks alternative fuel sources. Accumulation of abnormal metabolic by-products can damage the kidneys and other organs.

• The system for glycogen metabolism relies on a complex system of enzymes. These enzymes are responsible for creating glycogen from glucose, transporting the glycogen to and from storage areas within cells, and extracting glucose from the glycogen as needed.

• Both creating and tearing down the glycogen macromolecule are multistep processes requiring a different enzyme at each step. If one of these enzymes is defective and fails to complete its step, the process halts. Such enzyme defects are the underlying cause of GSDs.

• The enzyme defect arises from an error in its gene. Since the error is in the genetic code, GSDs can be passed down from generation-to-generation. However, a person inherits one copy of the gene from each parent.

• Following a Mendelian inheritance pattern, the normal gene is dominant and the defective gene is recessive. As long as a child receives at least one normal gene, there is no risk for a GSD. GSDs appear only if a person inherits a defective gene from both parents.

Causes and symptoms

• GSD symptoms depend on the enzyme affected. Since glycogen storage occurs mainly in muscles and the liver, those sites display the most prominent symptoms.

• Type Ia, or von Gierke's disease, is caused by glucose-6-phosphatase deficiency in the liver, kidney, and small intestine. The last step in glycogenolysis, the breaking down of glycogen to glucose, is the transformation of glucose-6-phosphate to glucose. In GSD I, that step does not occur. As a result, the liver is clogged with excess glycogen and becomes enlarged and fatty.

• Other symptoms include low blood sugar and elevated levels of lactate, lipids, and uric acid in the blood. Primary symptoms improve with age, but after age 20-30, liver tumors, liver cancer, chronic renal disease, and gout may appear.

• The key to managing GSD I is to maintain consistent levels of blood glucose through a combination of nocturnal intragastric feeding (usually for infants and children), frequent high-carbohydrate meals during the day.

• Type Ib is caused by glucose-6-phosphatase translocase deficiency. In order to carry out the final step of glycogenolysis, glucose-6-phosphate has to be transported into a cell's endoplasmic reticulum. If translocase, the enzyme responsible for that movement, is missing or defective, the same symptoms occur as in Type Ia.

• The metabolic consequences of the hepatic glucose-6-phosphatase deficiency of von Gierke disease extend well beyond just hypoglycemia that results from the deficiency in liver being able to deliver free glucose to the blood.

• The inability to release the phosphate from glucose-6-phopsphate results in diversion into glycolysis and production of pyruvate as well as increased diversion onto the pentose phosphate pathway. The production of excess pyruvate, at levels above of the capacity of the TCA cycle to completely oxidize it, results in its reduction to lactate resulting in lactic acidemia.

• In addition, some of the pyruvate is transaminated to alanine leading to hyperalaninemia. Some of the pyruvate will be oxidized to acetyl-CoA which can't be fully oxidized in the TCA cycle and so the acetyl-CoA will end up in the cytosol where it will serve as a substrate for triglyceride and cholesterol synthesis resulting in hyperlipidemia.

• The oxidation of glucose-6-phophate via the pentose phosphate pathway leads to increased production of ribose-5-phosphate which then activates the de novo synthesis of the purine nucleotides. In excess of the need, these purine nucleotides will ultimately be catabolized to uric acid resulting in hyperuricemia and consequent symptoms of gout.

• Type II, or Pompe's disease or acid maltase deficiency, is caused by lysosomal alpha-D-glucosidase deficiency in skeletal and heart muscles. The enzyme normally degrades the alpha -1,4 and alpha -1,6 linkages in glycogen, and is required for the degradation of 1-3% of cellular glycogen.

• The deficiency of this enzyme results in the accumulation of structurally normal glycogen in lysosomes and cytoplasm in affected individuals.

• The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and nervous system.

What genes are related to Pompe disease?

• Mutations in the GAA gene cause Pompe disease. The GAA gene provides instructions for producing an enzyme called acid alpha-glucosidase (also known as acid maltase). This enzyme is active in lysosomes, which are structures that serve as recycling centers within cells.

• The official name of GAA gene is “glucosidase, alpha; acid.”

• . A transversion (T → G) mutation is the most common among adults with this disorder. This mutation interrupts a site of RNA splicing.

The GAA gene is located on the long (q) arm of chromosome 17.

• More precisely, the GAA gene is located from base pair 78,075,354 to base pair 78,093,678 on chromosome 17.

• Excessive glycogen storage within lysosomes may interrupt normal functioning of other organelles and lead to cellular injury. In the infantile form, infants seem normal at birth, but within a few months they develop muscle weakness, and an enlarged heart.

• Cardiac failure and death usually occur before age 2, despite medical treatment.

• The juvenile and adult forms of GSD II affect mainly the skeletal muscles in the body's limbs. Unlike the infantile form, treatment can extend life, but there is no cure.

• Biochemical investigations include serum creatine kinase (typically increased 10 fold), aspartate transaminase, alanine transaminase and lactic dehydrogenase.

• Type III, or Cori's disease, is caused by glycogen debrancher enzyme deficiency in the liver, muscles, and some blood cells, such as leukocytes and erythrocytes. About 15% of GSD III cases only involve the liver

• GSDIII is divided into types IIIa, IIIb, IIIc, and IIId, which are distinguished by their pattern of signs and symptoms. GSD types IIIa and IIIc mainly affect the liver and muscles, and GSD types IIIb and IIId typically affect only the liver.

• In addition to the low blood sugar, retarded growth, and enlarged liver causing a swollen abdomen, GSD III also causes muscles prone to wasting, and heightened levels of lipids in the blood.

• What is the official name of the AGL gene?• The official name of this gene is “amylo-alpha-

1, 6-glucosidase, 4-alpha-glucanotransferase.”• Approximately 100 mutations in the AGL gene

have been found to cause glycogen storage disease type III.

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• Most of these mutations lead to a premature stop signal in the instructions for making the glycogen debranching enzyme, resulting in a nonfunctional enzyme. As a result, the side chains of glycogen molecules cannot be removed and abnormal, partially broken down glycogen molecules are stored within cells.

• Type IV, or Andersen's disease, is caused by glycogen brancher enzyme deficiency in the liver, brain, heart, skeletal muscles. The glycogen constructed in GSD IV is abnormal and insoluble. As it accumulates in the cells, cell death leads to organ damage.

• Infants born with GSD IV appear normal at birth, but are diagnosed with enlarged livers and failure to thrive within their first year. Infants who survive beyond their first year develop cirrhosis of the liver by age 3-5 and die as a result of chronic liver failure.

• Type V, or McArdle's disease, is caused by glycogen phosphorylase(myophosphorylase) deficiency in skeletal muscles. Glycogen phosphorylase breaks up glycogen into glucose subunits. Glycogen is left with one fewer glucose molecule, and the free glucose molecule is in the form of glucose-1-phosphate

• Under normal circumstances, muscle cells rely on oxidation of fatty acids during rest or light activity. More demanding activity requires that they draw on their glycogen stockpile.

• In GSD V, glycogenolysis is disabled and glucose is not available. The main symptoms are muscle weakness and cramping brought on by exercise, as well as burgundy-colored urine after exercise due to myoglobin in the urine.

• Type VI, or Hers' disease, is caused by liver phosphorylase deficiency, which blocks the first step of glycogenolysis.Low blood sugar is one of the key symptoms. An enlarged liver and mildly retarded growth also occur.

• Type VII, or Tarui's disease, is caused phosphofructokinase deficiency. impairs the ability of cells such as erythrocytes and myocytes to use carbohydrates (such as glucose) for energy. Although glucose may be available as a fuel in muscles, the cells cannot metabolize it. Therefore, abnormally high levels of glycogen are stockpiled in the muscle cells. The symptoms are similar to GSD V, but also include anemia and increased levels of uric acid.

• PFK is the key regulatory enzyme for glycolysis. PFK catalyzes the irreversible transfer of phosphate from ATP to fructose-6-phosphate, and converts it to fructose-1,6-bisphosphate. Thus, tissues deficient in PFK cannot use free or glycogen-derived glucose as a fuel source.

• Glycogen accumulation is a consequence of impaired degradation or excess synthesis. The hexose monophosphates, which accumulate because of the enzymatic block, activate glycogen synthetase. Although elevated levels of glucose 6-phosphate activate the hexose monophosphate shunt, nucleotide formation is enhanced, leading to increased uric acid production and possible development of gout.

• In classic Tarui disease, the genetic defect involves the M isoform, resulting in the absence of enzymatic activity in the muscle.

• Because the liver and kidneys express only the L isoform, these organs are spared.

• Type IX is caused by liver glycogen phosphorylase kinase deficiency and, symptom-wise, is very similar to GSD VI. The main differences are that the symptoms may not be as severe and may also include exercise-related problems in the muscles, such as pain and cramps.

• Galactosemia is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galactose properly. Galactosemia follows an autosomal recessive mode of inheritance that confers a deficiency in an enzyme responsible for adequate galactose degradation.

• Galactosemia is inherited in an autosomal recessive manner, meaning a child must inherit one defective gene from each parent to show the disease. Heterozygotes are carriers, because they inherit one normal gene and one defective gene. Carriers have been known to show milder symptoms of galactosemia.

The Accumulation of Galactose• Reduction to Galactitol• In galactosemic patients, the accumulation of

galactose becomes the substrate for enzymes that catalyze the Polyol Pathway of carbohydrate metabolism. The first reaction of this pathway is the reduction of aldoses, like galactose, to sorbitols. Galactose is converted to galactitol.

• Aldose reductase is present in all insulin unresponsive cells.

• While most cells require the action of insulin for glucose to gain entry into the cell, the cells of the retina, kidney, and nervous tissues are insulin-independent, so glucose moves freely across the cell membrane, regardless of the action of insulin. The cells will use glucose for energy as normal, and any glucose not used for energy will enter the polyol pathway.

• When blood glucose is normal , this interchange causes no problems, as aldose reductase has a low affinity for glucose at normal concentrations.

• In a hyperglycemic state, the affinity of aldose reductase for glucose rises, causing much sorbitol to accumulate, and using much more NADPH, leaving less NADPH for other processes of cellular metabolism.

• Excessive activation of the polyol pathway increases intracellular and extracellular sorbitol concentrations.

• Sorbitol cannot cross cell membranes, and, when it accumulates, it produces osmotic stresses on cells by drawing water into the insulin-independent tissues.

• Aldose reductase is the enzyme responsible for the primary stage of this pathway. Therefore aldose reductase reduces galactose to its sugar alcohol form, galactitol. Galactitol, however, is not a suitable substrate for the next enzyme in the Polyol Pathway: polyol dehydrogenase. Thus, galactitol accumulates in body tissues and is excreted in the urine of galactosemic patients.

• Accumulation of galactitol has been attributed to many of the negative effects of galactosemia.

• Excess of galactose 1 phospate and depletion of inorganic phosphate causes liver dysfunction.

• Excess of galactose 1 phospate inhibits glycogen phosphorylase and impedes glycogenolysis.

• Glycogen accumulates in the liver.

• Hypoglycaemia bcecause galactosemia provides persistant stimulus for insulin secretion.

• Galactose inhibits glucose 6 phosphate dehydrogenase in RBC and hence HMP shunt leading to haemolysis.