Pompe's disease

Definition

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 & 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.

Diagnosis

Diagnosis usually occurs in infancy or childhood, although some milder types of GSD go unnoticed well into adulthood and old age. It is even conceivable that some of the milder GSDs are never diagnosed.

The four major symptoms that typically lead a doctor to suspect GSDs are low blood sugar, enlarged liver, retarded growth, and an abnormal blood biochemistry profile. A definitive diagnosis is obtained by biopsy of the affected organ or organs. The biopsy sample is tested for its glycogen content and assayed for enzyme activity. There are DNA-based techniques for diagnosing some GSDs from more easily available samples, such as blood or skin. These DNA techniques can also be used for prenatal testing.

Treatment

Some GSD types cannot be treated, while others are relatively easy to control through symptom management. In more severe cases, receiving an organ transplant is the only option. In the most severe cases, there are no available treatments and the victim dies within the first few years of life.

Of the treatable types of GSD, many are treated by manipulating the diet. 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, and regular oral doses of cornstarch (people over age 2). Juvenile and adult forms of GSD II can be managed somewhat by a high protein diet, which also helps in cases of GSD III, GSD VI, and GSD IX. GSD V and GSD VII can also be managed with a high protein diet and by avoiding strenuous exercise.

For GSD cases in which dietary therapy is ineffective, organ transplantation may be the only viable alternative. Liver transplants have been effective in reversing the symptoms of GSD IV.

Advances in genetic therapy offer hope for effective treatment in the future. This therapy involves using viruses to deliver a correct form of the gene to affected cells. Another potential therapy utilizes transgenic animals to produce correct copies of the defective enzyme in their milk. In late 1997, a Dutch pharmaceutical company, Pharming Health Care Products, began clinical trials to treat GSD II with human alpha-glucosidase derived from the milk of transgenic rabbits. Researchers at Duke University in North Carolina are also focusing on a treatment for Pompe's disease and, aided by Synpac Pharmaceuticals Limited of the United Kingdom, plan to begin clinical trials of a recombinant form of the enzyme in 1998.

Prognosis

People with well-managed, treatable types of GSD can lead long, relatively normal lives. This goal is accomplished with the milder types of GSD, such as Types VI, IX, and X. As the GSD type becomes more severe, a greater level of vigilance against infections and other complications is required. Given current treatment options, complications such as liver disease, heart failure, and respiratory failure may not be warded-off indefinitely. Quality of life and life expectancy are substantially decreased.

Prevention

Because GSD is an inherited condition, it is not preventable. If both parents carry the defective gene, there is a one-in-four chance that their offspring will inherit the disorder. Other children may be carriers or they may miss inheriting the gene altogether.

Through chorionic villi sampling and amniocentesis, the disorder can be detected prior to birth. Some types of GSD can be detected even before conception occurs, if both parents are tested for the presence of the defective gene. Before undergoing such testing, the prospective parents should meet with a genetic counselor and other professionals in order to make an informed decision.

Key Terms

Amniocentesis

A medical test done during pregnancy in which a small sample of the amniotic fluid is taken from around the fetus. The fluid contains fetal cells that can be examined for genetic abnormalities.

Autosomal gene

A gene found on one of the 22 autosomal chromosome pairs; i.e., not on a sex (X or Y) chromosome.

Chorionic villus sampling

A medical test done during pregnancy in which a sample of the membrane surrounding the fetus is removed for examination. This examination can reveal genetic fetal abnormalities.

Glucose

A form of sugar that serves as the body's main energy source.

Glycogen

A macromolecule composed mainly of glucose that serves as the storage form of glucose that is not immediately needed by the body.

Glycogenolysis

The process of tearing-down a glycogen molecule to free up glucose.

Glycogenosis

An alternate term for glycogen storage disease. The plural form is glycogenoses.

Gout

A painful condition in which uric acid precipitates from the blood and accumulates in joints and connective tissues.

Mendelian inheritance

An inheritance pattern for autosomal gene pairs. The genetic trait displayed results from one parent's gene dominating over the gene inherited from the other parent.

Osteoporosis

A disease in which the bones become weak and brittle.

Renal disease

Kidney disease.

Transgenic animal

Animals that have had genes from other species inserted into their genetic code.

Further Reading

For Your Information

Books

• Chen, Yuan-Tsong, and Ann Burchell. "Glycogen Storage Diseases." In The Metabolic and Molecular Bases of Inherited Disease, 7th Edition, edited by Charles R. Scriver, et al. New York: McGraw-Hill, Health Professions Division, 1995.

  Periodicals

• Goldberg, Teresia, and Alfred Slonim. "Nutrition Therapy for Hepatic Glycogen Storage Diseases." Journal of the American Dietetic Association 93 (12)(December 1993): 1423.
• Talente, Gregg M., Rosalind A. Coleman, Craig Alter, et al. "Glycogen Storage Disease in Adults." Annals of Internal Medicine 120 (1994): 218.
• Triomphe, Teeny J. "Glycogen Storage Disease: A Basic Understanding and Guide to Nursing Care." Journal of Pediatric Nursing 12 (4)(August 1997): 238.

  Organizations

• Acid Maltase Deficiency Association. P.O. Box 700248, San Antonio, TX 78270-0248. (210) 494-6144 or (210) 490-7161. http://members.aol.com/amdapage/index.htm.
• American Liver Foundation. 1425 Pompton Avenue, Cedar Grove, NJ 07009. (800) GO LIVER (465-4837). http://www.liverfoundation.org/.
• Association for Glycogen Storage Disease. P.O. Box 896, Durant, Iowa 52747-9769. (319) 785-6038.

Gale Encyclopedia of Medicine. Gale Research, 1999.