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Thursday, May 17, 2007

Glycogen Storage Diseases

Type 0: Hypoglycemia due to lack of glycogen synthase [OMIM 240600, OMIM 138571]
Glycogen synthase is the enzyme required for glycogen synthesis [Glycogen Synthesis]. There are two forms of the enzyme; liver and muscle. The muscle form is found in many different tissues but the liver version of the enzyme is only found in liver cells. Mutations in the gene for the liver enzyme (GTS2) cause glycogen storage disease type 0.

The disease is usually recognized in infants who have very low blood sugar (hypoglycemia) after a short fast. The low sugar is due to the fact that there's no store of glycogen in the liver. In normal cases, the liver stores glucose as glycogen right after a meal then breaks it down as blood glucose is depleted. In the absence of liver glycogen synthase the maintenance of blood sugar levels is impaired.
Here's what OMIM has to say about typical cases.
Gitzelmann et al. (1996) described 3 children with liver glycogen synthase deficiency from 2 German families and compared the observations with the previously published 3 families comprising 8 patients. The 2 index cases presented with morning fatigue, had ketotic hypoglycemia when fasting which rapidly disappeared after eating, and hepatic glycogen deficiency with absent or very low hepatic glycogen synthase activity. Metabolic profiles comprising glucose, lactate, alanine, and ketones in blood were typical for hepatic glycogen synthase deficiency. Symptoms were rapidly relieved and chemical signs corrected by introducing frequent protein-rich meals and nighttime feedings of suspensions of uncooked corn starch. The discovery of oligosymptomatic and asymptomatic sibs suggested that there are persons with undiagnosed hepatic glycogen synthase deficiency. Gitzelmann et al. (1996) stated that the disorder should be sought in children who, before the first meal of the day, present with drowsiness, lack of attention, pallor, uncoordinated eye movements, disorientation, or convulsions, and who have hypoglycemia and acetone in the urine.

Type I: Von Gierke's Disease: Deficiency in glucose 6-phosphatase [Ia OMIM 232200, Ib OMIM 602671, Ib OMIM 232220, Ic OMIM #232240]

The synthesis of glucose (gluconeogenesis) in the liver ends with glucose 6-phosphate. It can be stored as glycogen in the liver for use later on or it can be converted to glucose. Glucose is then secreted into the blood stream where it can be taken up by muscle cells. The cycling of glucose between muscle and liver is called the Cori Cycle.

One of the key enzymes is glucose 6-phosphatase. This is the enzyme that removes the phosphate group from glucose 6-phosphate to make free glucose. In mammals, this enzyme is located in the membranes of the endoplasmic reticulum. The enzyme is part of a complex that includes a glucose 6-phosphate transporter (G6PT) and a phosphate transporter. G6PT moves glucose 6-phosphate from the cytosol to the interior of the ER where it is hydrolyzed to glucose and inorganic phosphate. Phosphate is returned to the cytosol and glucose is transported to the cell surface (and the bloodstream) via the secretory pathway.

The other enzymes required for gluconeogenesis are found, at least in small amounts, in many mammalian tissues. By contrast, glucose 6-phosphatase is found only in cells from the liver, kidneys, and small intestine, so only these tissues can synthesize free glucose. Cells of tissues that lack glucose 6-phosphatase retain glucose 6-phosphate for internal carbohydrate metabolism.

Defects in glucose 6-phosphatase affect mostly liver and kidneys where stored glycogen can accumulate to high levels due to the fact that it can't be broken down to free glucose for secretion into the blood stream. Glycogen storage disease Ia results from mutations in the catalytic subunit of glucose 6-phosphatase (G6PC gene) while Ib and Ic are caused by mutations in the transporter subunits.

The major problem is hypoglycemia (low glucose) and lactic acidemia due to inefficient conversion of lactic acid to free glucose. These can be fatal but nowadays the symptoms are treated by feeding carbohydrates at regular intervals throughout the day and though a gut tube at night. This is an autosomal recessive disease.

Type II (Pompe Disease): Deficiency of α-glucosidase [OMIM #232300, OMIM 606800]
Glycogen granules are taken up by lysosomes where they are broken down by a pathway that's different from the normal glycogen degradation pathway. One of the key lysosomal enzymes is α1,4-glucosidase. Mutations in the gene for this enzyme cause glycogen storage disease type II.

This is a very severe form of the disease. Although glycogen breakdown in lysosomes is relatively minor in terms of overall glycogen metabolism, the inability to process glycogen granules leads to their accumulation in lysosomes and consequent disruption of many important lysosomal functions. This disruption takes place in all cells and all tissues.

In the classic cases, infants are inactive and hypertonic with enlarged hearts. Death usually occurs before the first year, usually from heart failure. An adult onset version is known. It usually begins with respiratory difficulties and often ends in death from ruptures of the arteries or respiratory failure.

Type III: (Cori Disease): Defects in glycogen debranching enzyme [OMIM 232400, OMIM 610860]

The glycogen debranching enzyme is required for the complete mobilization of glucose from glycogen. The standard glycogen phosphorylase enzyme will lop off glucose residues until it come to within for residues of a branch point in the glycogen chain. This produces a truncated glycogen molecule known as limit dextrin.

Further degradation of glycogen requires the activity of the debranching enzyme which actually has two separate activities: a glucanotransferase activity that transfers glucose residues from the end of one branch to the end of another, and a glucosidase activity that chops off the last glucose residue on a branch. The gene is the AGL gene (amylo-1,6-glucosidase, 4-α -glucanotransferase) in humans and the GDE gene (glycogen debranching enzyme) in many other species.

There are several subtypes of type III glycogen storage disease. They all result from mutations in the AGL gene. The most common type is IIIa where debranching activity is missing in both liver and muscle cells [see The Cori Cycle]. Patients have muscle weakness and liver problems similar to those in von Gierke's Disease (type I) but the symptoms are milder and not usually life threatening.

In type IIIb the deficiency in debranching enzyme is only detectable in liver. This is probably due to lower production of functional enzyme that only affects liver cells where more debranching enzyme is needed than in muscle cells.

Types IIIc and IIId are quite rare. They only affect the glucanotransferase activity (IIIc) or the glucosidase activity (IIId).

Type IV (Anderson Disease): Deficiency in glycogen branching enzyme [OMIM #232500, OMIM 607839]
Glycogen storage disease IV is caused by a deficiency of glycogen branching enzyme (amylo-(1,4 → 1,6)-transglycosylase). This is the enzyme that adds new branches for glycogen during synthesis. A deficiency in this enzyme results in reduced ability to store glucose residues in glycogen.(This is the enzyme responsible for the wrinkled pea phenotype that Gregor Mendel studied. [ Biochemist Gregor Mendel Studied Starch Synthesis.)

The disease is severe according to OMIM.
Glycogen storage disease type IV is a clinically heterogeneous disorder. The typical 'classic' hepatic presentation is liver disease of childhood, progressing to lethal cirrhosis. The neuromuscular presentation of GSD IV is distinguished by age at onset into 4 groups: perinatal, presenting as fetal akinesia deformation sequence (FADS) and perinatal death; congenital, with hypotonia, neuronal involvement, and death in early infancy; childhood, with myopathy or cardiomyopathy; and adult, with isolated myopathy or adult polyglucosan body disease (Bruno et al., 2004). The enzyme deficiency results in tissue accumulation of abnormal glycogen with fewer branching points and longer outer branches, resembling an amylopectin-like structure, also known as polyglucosan (Tay et al., 2004).

Type V (McArdle Disease): Deficiency of muscle glycogen phosphorylase [OMIM 23600, OMIM 608455]
Glycogen phosphorylase is the enzyme that degrades glycogen [Glycogen Degadation]. Deficiencies in the muscle form of the enzyme lead to severe muscle cramps. Patients are not able to perfom strenuous exercise. The lack of muscle glycogen phosphorylase prevents breakdown of glycogen in muscle and consequent lack of glucose to fuel ATP production via glycolysis. One of the characteristic symptoms is an absence of blood lactate since muscle cells are unable to convert glycogen to glucose and then to lactate.

Muscle tissue breaks down due to lack of ATP leading to general weakness, especially in adults. The disease is not fatal; in fact, it is relatively harmless as long as patients avoid exercise.

Type VI (Hers Disease): Deficiency in liver phosphorylase [OMIM 23700]
Deficiencies of the liver form of glycogen phosphorylase are not as harmful as deficiencies of the muscle version (type V). The disease is inherited as an autosomal recessive and it's due to mutations in the gene for the liver form of glycogen phosphorylase.

The symptoms are mild compared to other forms of glycogen storage disease, giving rise to enlarged liver with mild hypoglycemia, mild ketosis, and retarded growth.

Type VII (Tarui Disease): Muscle phosphofructokinase deficiency [OMIM #232800, OMIM 610681]
According to OMIM,
Glycogen storage disease VII is an autosomal recessive metabolic disorder characterized clinically by exercise intolerance, muscle cramping, exertional myopathy, and compensated hemolysis. Myoglobinuria may also occur. The deficiency of the muscle isoform of PFK results in a total and partial loss of muscle and red cell PFK activity, respectively. Raben and Sherman (1995) noted that not all patients with GSD VII seek medical care because in some cases it is a relatively mild disorder.
Muscle phosphofructokinase (PFKM) is an enzyme required for glycolysis. When glycolysis is blocked in muscle cells glycogen cannot be broken down and there is no abundant supply of ATP available for muscle activity.

Type IXa (X-linked liver glycogenosis): Deficiency of liver phosphorylase kinase [OMIM 306000
Phosphorylase kinase is the enzyme that phosphorylates glycogen phosphorylase in order to regulate its activity [Regulating Glycogen Metabolism]. Defects in the phosphorylase kinase gene (PHK) cause glycogenstorage disease type IXa&mdash a very mild form of the disease according to OMIM.
Deficiency of liver phosphorylase kinase (PHK; ATP:phosphotransferase; EC produces one of the mildest of the glycogenoses of man. The clinical symptoms include hepatomegaly, growth retardation, elevation of glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase, hypercholesterolemia, hypertriglyceridemia, and fasting hyperketosis (Schimke et al., 1973; Willems et al., 1990). With age, these clinical and biochemical abnormalities gradually disappear and most adult patients are asymptomatic.
Phosphorylase kinase consists of α, β, γ, and δ sunbuits each of which is encoded by specific genes. Defects in the α subunit gene (PHKA) are what causes glycogen storage disease type IXa. There are two different genes for α subunits on the X chromosome: one for the liver specific version of the enzyme (PHA2) and one for the muscle specific version of the enzyme (PHA1). Mutations in either one cause the disease, which is why it is called an X-linked glycogen storage disease.

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