Glycogen storage disease type III (also known as GSDIII or Cori disease) is an inherited disorder caused by the buildup of a complex sugar called glycogen in the body's cells. The accumulated glycogen is structurally abnormal and impairs the function of certain organs and tissues, especially the liver and muscles.

GSDIII is divided into types IIIa, IIIb, IIIc, and IIId, which are distinguished by their pattern of signs and symptoms. GSD types IIIa and IIIc mainly affect the liver and muscles, and GSD types IIIb and IIId typically affect only the liver. It is very difficult to distinguish between the types of GSDIII that affect the same tissues. GSD types IIIa and IIIb are the most common forms of this condition.

Beginning in infancy, individuals with any type of GSDIII may have low blood glucose (hypoglycemia), excess amounts of fats in the blood (hyperlipidemia), and elevated blood levels of liver enzymes. As they get older, children with this condition typically develop an enlarged liver (hepatomegaly). Liver size usually returns to normal during adolescence, but some affected individuals develop chronic liver disease (cirrhosis) and liver failure later in life. People with GSDIII often have slow growth because of their liver problems, which can lead to short stature. In a small percentage of people with GSDIII, noncancerous (benign) tumors called adenomas may form in the liver.

Individuals with GSDIIIa may develop muscle weakness (myopathy) later in life. These muscle problems can affect both heart (cardiac) muscle and the muscles that are used for movement (skeletal muscles). Muscle involvement varies greatly among affected individuals. The first signs and symptoms are typically poor muscle tone (hypotonia) and mild myopathy in early childhood. The myopathy may become severe by early to mid-adulthood. Some people with GSDIIIa have a weakened heart muscle (cardiomyopathy), but affected individuals usually do not experience heart failure. Other people affected with GSDIIIa have no cardiac muscle problems.

Mutations in the AGL gene cause GSDIII. The AGL gene provides instructions for making the glycogen debranching enzyme. This enzyme is involved in the breakdown of glycogen, which is a major source of stored energy in the body. Between meals the body breaks down stores of energy, such as glycogen, to use for fuel.

Most AGL gene mutations lead to the production of a nonfunctional glycogen debranching enzyme. These mutations typically cause GSD types IIIa and IIIb. The mutations that cause GSD types IIIc and IIId are thought to lead to the production of an enzyme with reduced function. All AGL gene mutations lead to storage of abnormal, partially broken down glycogen molecules within cells. A buildup of abnormal glycogen damages organs and tissues throughout the body, particularly the liver and muscles, leading to the signs and symptoms of GSDIII.

Normal Function

The AGL gene provides instructions for making the glycogen debranching enzyme. This enzyme is involved in the breakdown of a complex sugar called glycogen, which is a major source of stored energy in the body. Glycogen is made up of several molecules of a simple sugar called glucose. Some glucose molecules are linked together in a straight line, while others branch off and form side chains. The glycogen debranching enzyme is involved in the breakdown of these side chains. The branched structure of glycogen makes it more compact for storage and allows it to break down more easily when it is needed for fuel.

The AGL gene provides instructions for making several different versions (isoforms) of the glycogen debranching enzyme. These isoforms vary by size and are active (expressed) in different tissues.

Health Conditions Related to Genetic Changes

Glycogen storage disease type III

Approximately 100 mutations in the AGL gene have been found to cause glycogen storage disease type III (also called GSDIII or Cori disease). Most of these mutations lead to a premature stop signal in the instructions for making the glycogen debranching enzyme, resulting in a nonfunctional enzyme. As a result, the side chains of glycogen molecules cannot be removed and abnormal, partially broken down glycogen molecules are stored within cells. A buildup of abnormal glycogen damages organs and tissues throughout the body, particularly the liver and muscles, leading to the signs and symptoms of GSDIII.

Mutations in the AGL gene can affect different isoforms of the enzyme, depending on where the mutations are located in the gene. For example, mutations that occur in a part of the AGL gene called exon 3 affect the isoform that is primarily expressed in the liver. These mutations almost always lead to GSD type IIIb, which is characterized by liver problems.

Other Names for This Gene

• amylo-1, 6-glucosidase, 4-alpha-glucanotransferase
• GDE
• GDE_HUMAN
• glycogen debrancher
• glycogen debranching enzyme

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

The incidence of GSDIII in the United States is 1 in 100,000 individuals. This condition is seen more frequently in people of North African Jewish ancestry; in this population, 1 in 5,400 individuals are estimated to be affected.

GSDIIIa is the most common form of GSDIII, accounting for about 85 percent of all cases. GSDIIIb accounts for about 15 percent of cases. GSD types IIIc and IIId are very rare, and their signs and symptoms are poorly defined. Only a small number of affected individuals have been suspected to have GSD types IIIc and IIId.