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. Symptoms vary by the glycogen storage disease (GSD) type and can include muscle cramps and wasting, enlarged liver, and low blood sugar. 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. GSD can be fatal, but the risk hinges on the type of GSD.
Description
Most of the body's cells rely on glucose as an energy source. Glucose levels in the blood are very stringently controlled within a range or 70–100 mg/dL, primarily by hormones such as insulin and glucagon. Immediately after a meal, blood glucose levels rise and exceed the body's immediate energy requirements. In a process analogous to putting money in the bank, the body bundles up the extra glucose and stores it as glycogen in the liver and muscles. Later, as the blood glucose levels begin to dip, the body makes a withdrawal from its glycogen savings.
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, all but one GSD are linked to autosomal genes, which means 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.
The most common forms of GSD are Types I, II, III, and IV, which may account for more than 90% of all cases. The most common form is Type I, or von Gierke's disease, which occurs in one out of every 100,000 births. Other forms, such as Types VI and IX, are so rare that reliable statistics are not available. The overall frequency of all forms of glycogen storage disease is approximately one in 20,000–25,000 live births.
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.
There are at least 10 different types of GSDs which are classified according to the enzyme affected:
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. Growth is impaired, puberty is often delayed, and bones may be weakened by osteoporosis. Blood platelets are also affected and frequent nosebleeds and easy bruising are common. Primary symptoms improve with age, but after age 20–30, liver tumors, liver cancer, chronic renal disease, and gout may appear.
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. Additionally, the immune system is weakened and victims are susceptible to bacterial infections, such as pneumonia, mouth and gum infections, and inflammatory bowel disease. Types Ic and Id are also caused by defects in the translocase system.
Type II, or Pompe's disease or acid maltase deficiency, is caused by lysosomal alpha-D-glucosidase deficiency in skeletal and heart muscles. GSD II is subdivided according to the age of onset. In the infantile form, infants seem normal at birth, but within a few months they develop muscle weakness, trouble breathing, 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 and torso. Unlike the infantile form, treatment can extend life, but there is no cure. Respiratory failure is the primary cause of death.
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. The glycogen molecule is not a simple straight chain of linked glucose molecules, but rather an intricate network of short chains that branch off from one another. In glycogenolysis, a particular enzyme is required to unlink the branch points. When that enzyme fails, symptoms similar to GSD I occur; in childhood, it may be difficult to distinguish the two GSDs by symptoms alone. In addition to the low blood sugar, retarded growth, and enlarged liver causing a swollen abdomen, GSD III also causes muscles prone to wasting, an enlarged heart, and heightened levels of lipids in the blood. The muscle wasting increases with age, but the other symptoms become less severe.
Type IV, or Andersen's disease, is caused by glycogen brancher enzyme deficiency in the liver, brain, heart, skeletal muscles, and skin fibroblasts. 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 birthday 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 deficiency in skeletal muscles. Under normal circumstances, muscles 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, this form of 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 (a breakdown product of muscle) in the urine.
Type VI, or Hers' disease, is caused by liver phosphorylase deficiency, which blocks the first step of glycogenolysis. In contrast to other GSDs, Type VI seems to be linked to the X chromosome. Low blood sugar is one of the key symptoms, but it is not as severe as in some other forms of GSD. An enlarged liver and mildly retarded growth also occur.
Type VII, or Tarui's disease, is caused by muscle phosphofructokinase deficiency. 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.
Types VIII and XI are caused by defects of enzymes in the liver phosphorylase activating-deactivating cascade and have symptoms similar to GSD VI.
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. The symptoms abate after puberty with proper treatment. Most cases of GSD IX are linked to the X chromosome and therefore affect males.
Type X is caused by a defect in the cyclic adenosine monophosphate-dependent (AMP) kinase enzyme and presents symptoms similar to GSDs VI and IX.
Print
