Glycogen storage disease type 3

In infancy, individuals with glycogen storage disease type 3 (GSDIII) may have low blood sugar (hypoglycemia), increased amounts of fats in the blood (hyperlipidemia), and elevated levels of liver enzymes in the blood.^[3] Hypoglycemia may cause occasional seizures in some individuals.^[4] As they age, children usually develop an enlarged liver (hepatomegaly), which can cause the abdomen to protrude. Liver size may return to normal during adolescence, but some affected individuals develop chronic liver disease and subsequent liver failure years later. Individuals often have delayed growth due to their liver problems, which can lead to short stature. They may also have difficulty fighting infections, and may experience unusually frequent nosebleeds.  A small percentage of individuals develop benign (non-cancerous) tumors in the liver called adenomas.^[3][5]

GSD types IIIa and IIIc typically affect both the liver and muscles, while types IIIb and IIId typically affect only the liver. Individuals with type IIIa may develop myopathy in both the heart and skeletal muscles later in life. The first signs and symptoms of this are typically poor muscle tone (hypotonia) and mild myopathy in early childhood. The myopathy may become severe by early to mid-adulthood.^[3]

Glycogen storage disease type 3 (GSDIII) is caused by changes (mutations) in the AGL gene. This gene provides instructions for making the glycogen debranching enzyme, which is involved in the breakdown of glycogen - an important source of stored energy in the body. Most mutations in the AGL gene lead to production of a non-working form of the glycogen debranching enzyme; these mutations are usually responsible for causing GSD types IIIa and IIIb. The mutations in the AGL gene that cause types IIIc and IIId presumably lead to the production of glycogen debranching enzyme with reduced function. All AGL mutations, however, lead to the increased buildup of abnormal, partially broken down glycogen within cells. This buildup damages tissues and organs in the body, thereby causing the signs and symptoms of GSDIII.^[3]

Glycogen storage disease type 3 (GSDIII) is inherited in an autosomal recessive manner. This means that mutations in both copies of the disease-causing gene (usually one inherited from each parent) are necessary to cause the condition. Individuals with one abnormal copy of the gene are referred to as carriers; carriers are unaffected and typically do not show any signs or symptoms of the condition. When two carriers for an autosomal recessive condition have children together, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of his/her parents, and a 25% chance to not be a carrier and not have the condition.

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.^[2]

Yes. GeneTests lists the names of laboratories that are performing genetic testing for GSDIII. To view the contact information for the clinical laboratories conducting testing, click here.

Please note: Most of the laboratories listed through GeneTests do not accept direct contact from patients and their families; therefore, if you are interested in learning more, you will need to work with a health care provider or a genetics professional.

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.^[6] 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.^[2] Liver transplantation may be indicated for patients with hepatic cancers.^[6]

Individuals seeking personal treatment advice should speak with their health care provider.