Glycogen Storage Diseases (Glycogenosis)
Glucose derived from glycogen breakdown is an important source of energy for the body. It provides energy for muscle contraction, and serves as the primary source of energy for the brain. Healthy people maintain a relatively constant 5 mM blood glucose concentration to support tissues and organs.
Several metabolic enzymes are responsible for maintaining this balance. Under normal circumstances they are tightly controlled by the organism. Allosteric control and covalent modification help mediate enzyme activity.
Glycogen Storage Diseases (GSD's) result from genetic defects that cause these enzymes to become inactive. Such defects are inherited, and require that both parents carry at least one defective gene. A zygote whose parents are both heterozygous for a GSD has a 25% chance of inheriting the disease. While each of these diseases prevents the correct production of a different enzyme, most GSD's inhibit a cell's ability to synthesize or metabolize glycogen, create an energy crisis for the body, and have a direct affect on liver and muscle tissues, which contain most of the body's glycogen deposits.
Diagnosis of glycogen storage diseases can usually be made in infancy or early childhood. The more severe types are immediately obvious, while milder types may go unnoticed for many years. Most types have a few distinguishing symptoms in common, including low blood sugar, enlarged liver, retarded growth, and abnormal blood biochemistry. A more definite diagnosis can be made by testing a biopsy sample for glycogen concentration, and by assaying the sample for enzyme activity. DNA-based diagnostic techniques are also available.
GSD's are currently incurable. Some can be treated with appropriate management of symptoms, organ transplants, or simply by changing the patient's diet. Some of the more serious types can only be treated with pain management. Still, the future holds promise for GSD patients. Gene therapy may one day be perfected, whereby viruses would deliver healthy genes to sick cells. The use of animals to produce healthy enzymes for transfer into human patients is also a possibility.
The following entries describe three of the most common glycogen storage diseases.
Type Ia Glycogenosis: von Gierke's Disease
Von Gierke's disease is caused by a deficiency in glucose 6-phosphatase, an enzyme present in liver and kidney cells, but not in muscle or brain cells. G-6-Pase converts glucose-6-phosphate to glucose as it passes from the cytosol into the endoplasmic reticulum. The endoplasmic reticulum membrane can form vesicles to transport the glucose to the plasma membrane. There the vesicles fuse with the plasma membrane, and release their contents into the bloodstream.
Since G-6-P is a charged molecule, it cannot traverse the membrane without first being hydrolyzed into an uncharged molecule of glucose. Patients with von Gierke's Disease are unable to convert G-6-P into glucose, so they cannot transport these chemicals to muscle cells where they are needed for fuel. The result is a severe hypoglycemia and general weakness, especially during exercise.
Since glycogen is not catabolized in the liver of von Gierke's patients, it tends to accumulate and interfere with proper liver function. High concentrations of glycogen and G-6-P in the cell interior create an osmotic pressure gradient across the cell membrane, causing the cell to become bloated with water. This results in an enlarged liver, and may pose a serious threat as liver cells begin to rupture.
Diagnosis may be made at birth. A newborn with von Gierke's Disease may have an enlarged liver and kidneys. The abdomen is protuberant, and older children have a gait that is broad and swinging. Growth is retarded, musculature poorly developed, puberty delayed. Also, look for the trademark signs of low blood sugar: irritability, insomnia, eating difficulty, and seizures. Adiposity in the face causes a cherubic appearance in children, and may even cause adults with the disease to look younger than they really are.
Von Gierke's Disease also correlates with increased incidence of osteoporosis, liver cancer, renal disease, and gout in adults. Nosebleeds and easy bruising are common.
Diet is best managed with frequent, small carbohydrate-rich meals. If blood sugar is not maintained, von Gierke's forces the body to find an alternate source of energy. Fatty acids and ketone bodies must be broken down for energy production. This results in elevated serum levels of triglycerides, free fatty acids, and ketone bodies, and may be accompanied by metabolic acidosis.
Ethnic heritage is an important factor in the severity of disease. Patients from Syria and Lebanon experience especially strong symptoms.
For clinical information about Von Gierke's Disease, see http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?232200#TEXT
Type II Glycogenosis: Pompe's Disease
Pompe's disease is a deficiency in lysosomal-1,4-glucosidase, also known as acid maltase, which causes a buildup of undigested glycogen in lysosomes. Lysosomes are normally responsible for breaking down cellular components, such as proteins and nucleic acids, but they also take up and digest glycogen, maltose, and other oligosaccarides. The interior of a lysosome is typically more acidic than the cytosol. Lysosomal enzymes are more active at acid pH than at neutral pH; hence the name acid maltase.
Glycogen buildup prevents lysosomes, and the rest of the cell, from functioning properly. Since lysosomes are distributed throughout all types of tissue, all major organs - and especially the heart - are affected.
There are two forms of Type 2 Glycogenosis, and they are distinguished by the age of onset. The infantile form of the disease is severe. Affected children generally do not survive past 24 months, with heart failure being the usual cause of death. Therapy for these patients can only be palliative. The adult form is not always fatal, with respiratory failure being the biggest cause of death.
Diagnosis of the infantile form can be made at birth. The heart is unusually large; cyanosis and episodes of dyspnea occur early.
For more general information on Pompe's Disease, including clinical and genetic features, see http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?232300
For answers to clinical questions about Pompe's Disease, see http://www.mdausa.org/experts/ask_amd.html
Type V Glycogenosis: McArdle's Disease
McArdle's disease is due to a deficiency in glycogen phosphorylase. This disease is termed a myopathic glycogen storage disease because it affects primarily muscle tissue, but glycogen phosphorylase is also present in the liver.
Glycogen phosphorylase attacks glycogen at its nonreducing end to release glucose-1-phosphate. The reaction involves attack by a phosphate group, so it is called a phosphorolysis reaction. In muscle cells, glucose-1-phosphate is subsequently converted to glucose-6-phosphate, which proceeds to the glycolytic pathway. In liver cells, it can be hydrolyzed to glucose and released into the bloodstream.
Glycogen phosphorylase a is the phosphorylated, tetrameric form of the enzyme. It is responsible for breaking down glycogen into phosphorylated monomer units (glucose-1-P, which then is converted to glucose-6-P for further metabolism). The b form of the enzyme is de-phosphorylated and inactive. Phosphorylase kinase catalyzes the activation by transferring a phosphoryl group from ATP to a specific serine residue of the phosphorylase monomer. Phosphoprotein phosphatase 1 catalyzes the de-phosphorylation reaction. This enzymic manipulation illustrates the concept of covalent control.
Both forms of the enzyme are also under noncovalent control. Each can be activated and deactivated by allosteric effectors. AMP activates glycogen phosphorylase, while glucose, G-6-P, and caffeine convert it to the inactive form.
McArdle's patients often excrete burgundy-colored urine after exercise. The color is caused by the presence of myoglobin, and is helpful in diagnosis.
McArdle's Disease is managed with a high-protein diet and avoidance of exercise. Patients usually enjoy good health. Patients who make sudden demands for energy may experience painful cramps and weakness due to the expenditure of all available glucose in muscle cells. Persistent muscular weakness may become common later in life.
For clinical information on McArdle's Disease, see http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?232600#TEXT
Other References
An excellent source of information on glycogenosis types I-III, and a resource for the creation of this website is:
Nyhan, William L., Pinar, T. Ozand, Atlas of Metabolic Diseases, Chapman & Hall Medical, 1998.
A comprehensive explanation of glycogen chemistry is given by:
Garrett, Reginald H., Grisham, Charles M., Biochemistry, Saunders College Publishing, 1995.