What are glycogen storage diseases?

Causes and Symptoms

Glycogen storage diseases are caused by inherited defects in the enzymes involved in the synthesis or breakdown
of glycogen
and are characterized by the accumulation of an abnormal type or amount of glycogen. At least twelve such diseases have been identified; they can be diagnosed by enzymatic analysis of a biopsy tissue sample. Prenatal diagnosis of most of these conditions is possible but, because their overall frequency is estimated at 1 in 20,000 to 25,000 live births, is generally not performed unless warranted. Most of these diseases are inherited as autosomal recessive traits, although phosphorylase kinase deficiency is X-linked. In many cases, the causative deoxyribonucleic acid (DNA) mutations have been identified. These diseases primarily affect the liver and muscles, which normally contain most of the glycogen in the body.

Maintaining normal blood glucose levels is essential for the function of various tissues and particularly the brain, which depends on blood glucose as a source of energy. In the fed state, when dietary carbohydrate is digested, blood glucose levels rise and are used to replenish liver glycogen. In the fasting state, when blood glucose levels otherwise fall, liver glycogen is broken down and used to maintain normal blood glucose levels. This cycling in the storage and breakdown of liver glycogen is essential to permit the body to survive periods without meals, especially overnight.

In liver glycogen storage diseases, this cycling is disrupted. Most cases are attributed to defects in four enzymes: glucose-6-phosphatase, glycogen branching enzyme, glycogen debrancher enzyme, and glycogen phosphorylase (or phosphorylase kinase). Because glucose-6-phosphatase is responsible for converting the breakdown product of glycogen (glucose-6-phosphate) to free glucose for release into the blood, its deficiency does not allow stored liver glycogen to restore depleted blood glucose, as during an overnight fast. If untreated, this condition, also known as von Gierke’s disease, results in seizures, coma, and death. Inadequately treated patients may survive but are more likely to experience growth retardation and to develop kidney problems and liver cancer.

Muscle glycogen is also synthesized in the fed state, but it is broken down to provide energy for muscle contraction. Glycogen storage diseases of muscle usually cause intolerance to exercise and susceptibility to fatigue. Most of these cases are attributed to defects in three enzymes: lysosomal glucosidase, glycogen phosphorylase, and phosphofructokinase. The glucosidase found in lysosomes is responsible for breaking down any glycogen that accumulates in these intracellular organelles. When this enzyme is missing, the lysosomes become engorged with glycogen, disrupting their normal function and other cellular metabolism. In the most severe cases, glycogen accumulation in the heart is pronounced, resulting in an enlarged heart and death from heart failure before age two. Glycogen phosphorylase in muscle breaks down glycogen for its use in contraction. When this enzyme is deficient, muscle tissues lack the fuel to provide for extensive exercise, resulting in cramping. Phosphofructokinase is a crucial enzyme in the metabolism of glucose; in the muscle, its deficiency has a consequence much like that of glycogen phosphorylase, namely the inability to engage in strenuous exercise.

When glycogen is synthesized, the branching enzyme inserts branchpoints to give it a treelike structure. A defect in this enzyme leads to an abnormal, long, unbranched glycogen. Because it folds back on itself in a way that makes it difficult for glycogen-breakdown enzymes to act on it, it is not broken down. While this condition generally does not lead to low fasting blood glucose, as alternative pathways are available, the accumulated abnormal glycogen, apparently considered a foreign object, leads to liver cirrhosis and death by age five; no treatment is available other than liver transplantation. A defect in the debranching enzyme that removes the branchpoints during the breakdown of glycogen severely restricts the yield of glucose to those units beyond a branchpoint. Glycogen phosphorylase is the main enzyme that breaks down glycogen to monomeric units, and its deficiency or that of an enzyme controlling its activity (phosphorylase kinase) results in variable manifestation, depending on the severity of the condition. Most patients with the latter diseases usually require no specific treatment.

Treatment and Therapy

A defect in glucose-6-phosphatase can be treated by providing continuous sources of glucose during the day (snacks between meals) and especially overnight (nightly nasogastric infusions of glucose or eating slowly digested carbohydrate, such as uncooked cornstarch, before sleep). If this condition is detected early and treated properly, then normal growth and development are observed. A liver transplant surgery may be necessary in certain cases. Medications such as alglucosidase alfa may help to replace the enzymes needed for proper muscle function.

Perspective and Prospects

The first observation of a defect in glycogen metabolism was made in 1928. In 1929, Edgar von Gierke first noted glucose-6-phosphatase deficiency, and in 1932, J. C. Pompe first reported the lysosomal glucosidase deficiency; their names remain associated with these conditions. As normal glycogen metabolism came to be understood, the enzymatic basis for at least twelve glycogen storage disorders were identified. Each is a candidate for enzyme replacement therapy or gene replacement therapy.

Bibliography:

Badash, Michelle. "Glycogen Storage Diseases." Health Library, September 12, 2012.

Chen, Y.-T. “Glycogen Storage Diseases.” In The Metabolic and Molecular Bases of Inherited Disease, edited by Charles R. Scriver et al. 8th ed. New York: McGraw-Hill, 2001.

Hirschhorn, R., and A. J. J. Reuser. “Glycogen Storage Disease Type II: Acid-Glucosidase (Acid Maltase) Deficiency.” In The Metabolic and Molecular Bases of Inherited Disease, edited by Charles R. Scriver et al. 8th ed. New York: McGraw-Hill, 2001.

Maheshwari, Anurag, et al. "Outcomes of Liver Transplantation for Glycogen Storage Disease: A Matched-Control Study and Review of Literature." Clinical Transplantation 26, no. 3 (2012): 432–436.

Professional Guide to Diseases. 10th ed. Philadelphia: Lippincott Williams & Wilkins, 2012.