Glycogen storage disease type 3

Other Names: Forbes disease; Cori disease; Limit dextrinosis; Amylo-1,6-glucosidase deficiency; Glycogen debrancher deficiency

Glycogen storage disease type 3 (GSDIII) is an inherited disorder caused by the buildup of glycogen in the body's cells. This buildup impairs the function of certain organs and tissues, especially the liver and muscles.

Types

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.

Epidemiology

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.

Cause

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.

Inheritance

Autosomal recessive inheritance, a 25% chance

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.

Signs and symptoms

Beginning in infancy, individuals with any type of GSDIII may have low blood sugar (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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Full cheeks(Apple cheeks)
• Hypertriglyceridemia(Increased plasma triglycerides)
• Hypoglycemia(Low blood sugar)
• Immunodeficiency(Decreased immune function)
• Intellectual disability, mild(Mental retardation, borderline-mild)
• Short stature(Decreased body height)

30%-79% of people have these symptoms

• Myopathy(Muscle tissue disease)

Diagnosis

Glycogen storage disease type 3 (GSDIII) should be suspected when three main features are present: hepatomegaly (enlarged liver), ketotic hypoglycemia (low blood sugar accompanied by ketosis), and elevated serum concentration of transaminases (a type of enzyme) and CK. Debranching enzyme activity (which is deficient in individuals with the condition) can be measured in a liver biopsy, but this is now not typically necessary for diagnosis.

Genetic testing of the AGL gene, the only gene known to be associated with GSDIII, confirms the diagnosis.

Treatment

There is not currently a cure for for glycogen storage disease type 3 (GSDIII). In some cases, diet therapy is helpful. Strict adherence to a dietary regimen may reduce liver size, prevent hypoglycemia (low blood sugar), help to reduce symptoms, and allow for growth and development.

Management typically includes a high-protein diet with cornstarch supplementation to maintain a normal level of glucose in the blood. In infancy, feeding every three to four hours is typically recommended. Toward the end of the first year of life, cornstarch is usually tolerated and can be used to avoid hypoglycemia. A high-protein diet prevents breakdown of muscle protein in times of glucose need and preserves skeletal and cardiac muscles. Skeletal and cardiac myopathies may be improved with high-protein diet and avoiding excessive carbohydrate intake.

Liver transplantation may be indicated for patients with hepatic cancers.

NIH genetic and rare disease info

• NIH info on Glycogen storage disease type 3

Glycogen storage disease type 3 is a rare disease.

Glycogen storage disease type 3 Resources
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