What is Glycogen Storage Disease Type IA?

A metabolic disorder leading to organ and tissue damage

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Glycogen storage disease type IA (GSDIa) is a metabolic disease caused by the build up of fat and glycogen leading to organ and tissue damage.

What are the Symptoms of Glycogen Storage Disease Type IA?

The first sign of GSDIa (low blood sugar) may be detected in newborns. However, generally affected infants do not show any symptoms until 3-4 months of age, when they do not want to feed as often as normal and other symptoms appear. Symptoms include low blood sugar (hypoglycemia) that can cause seizures, an accumulation of lactic acid in the body (lactic acidosis), high uric acid levels (hyperuricemia) and excess fat in the blood (hyperlipidemia). Untreated children have doll-like faces with fat cheeks, relatively thin arms and legs, short stature and an enlarged liver causing a protruding abdomen. The spleen is unaffected but kidneys may also be enlarged and affected individuals may have diarrhea and deposits of cholesterol in the skin (xanthomas). Impaired platelet function can lead to bleeding making nosebleeds a frequent problem.

Individuals with GSDIa may experience delayed puberty and may be affected by thinning of the bones (osteoporosis), the accumulation of uric acid crystals in the joints (gout), kidney disease, and high blood pressure in blood vessels that supply blood to the lungs (pulmonary hypertension). Females with GSDIa may have abnormal development of the ovaries. Some teens and adults develop tumors called adenomas in the liver. These are often noncancerous but can occasionally become cancerous.

Long-term complications of untreated GSDIa include high blood pressure, inflammation of the pancreas, neurocognitive effects, anemia, vitamin D deficiency and irregular menstrual cycles.

What Causes Glycogen Storage Disease Type IA?

Glycogen storage disease type IA (GSDIa) is a disease caused by the buildup of a complex sugar called glycogen in cells. This build up stops certain organ like the liver, kidneys and the small intestine from functioning normally. GSDIa is linked to genetic changes in the G6PC gene that encodes an enzyme called glucose-6-phosphatase. Glucose-6-phosphatase is responsible for breaking down glucose-6-phosphate to glucose. Genetic mutations in G6PC impair the function of the enzyme, so glucose-6-phosphate is not broken down properly, and instead gets converted to fat and glycogen. High levels of fat and glycogen are toxic to the cells leading to organ and tissue damage. The Jewish disease test panel looks at two mutations in G6PC – R83C (c.247C>T) and Q347X (c.1039C>T) – both of which completely abolish enzyme activity. While these two mutations are not unique to individuals of Ashkenazi Jewish descent, they account for all known cases of Ashkenazi Jewish patients with GSDIa, with the R83C mutation seen in 98% of the cases and the Q347X mutation occurring in the remaining 2%.

How is Glycogen Storage Disease Type IA Diagnosed?

Diagnosis of glycogen storage disease type IA (GSDIa) is based on the clinical presentation of abnormal blood/plasma levels of glucose, lactate, uric acid, triglycerides and lipids. Molecular genetic testing is also used, as well as abnormal enzyme level testing from a liver biopsy.

GSDI is suspected when individuals show abnormal laboratory findings that include the following. Hypoglycemia or reduced glucose in blood, where fasting blood glucose concentrations are lower than 60mg/dL (compared to the healthy range of 70-120mg/dL). Lactic acidosis when the levels of lactate in the blood are higher than 2.5mmol/L, compared to 0.5-2.2mmol/L found in normal individuals. Hyperuricemia where uric acid levels are higher than 5.0mg/dL in the blood compared to reference values of 2.0-5.0mg/dL. Hyperlipidemia with triglyceride levels higher than 250mg/dL (reference range 150-200mg/dL) and cholesterol levels higher than 200mg/dL (reference range 100-200mg/dL).

The diagnosis can be further confirmed using a glucagon or epinephrine challenge test. Administering these hormones will increase the levels of blood glucose in normal individuals but will cause little or no increase in blood glucose levels in GSDIa patient samples. However, they will increase the serum lactate concentrations significantly. In rare occasions, enzyme activity can be measured using liver biopsies. This test assays for glucose-6-phosphatase catalytic activity, which is less that 10% of normal in affected people. However, liver biopsies are invasive and are only conducted when diagnosis cannot be made using blood-based assays.

Molecular genetic analysis of the G6PC gene is used for confirmation of GSDIa and also to identify carriers, who are unaffected, but still have one defective copy of the G6PC gene (and one normal copy). Two mutations, R83C and Q347X, are analyzed in the Jewish disease panel available here. These mutations have been detected in all known cases of Gaucher disease in people of Ashkenazi Jewish heritage.

How is Glycogen Storage Disease Type IA Treated?

Glycogen storage disease type IA (GSDIa) is a severe metabolic disease that can be fatal in early childhood if not treated. Dietary management is the only effective treatment for GSDIa and will allow survival into adulthood, however only some of the symptoms of the disease may be prevented using these methods.

A team of specialists is recommended for effective management of GSDIa. This team should include a metabolic specialist (familiar with the different symptoms of GSDIa), a metabolic nutritionist (to monitor nutrition intake, weight management etc.) and a health care provider (nurse, genetic counselor, or physician assistant) familiar with the symptoms and inheritance of GSDIa. Often a medical social worker and psychologist are also involved.

Nutritional therapy goals will involve maintaining normal glucose levels to prevent hypoglycemia, while still providing optimal nutrition for growth and development. Hypoglycemia can be prevented by frequent daytime feedings, nighttime continuous glucose infusion through a nasogastric or gastrostomy tube, and cornstarch therapy, where uncooked cornstarch is given to reduce hypoglycemia. To provide optimal nutrition the diet should be well balanced to include complex carbohydrates (60%-70% of total energy intake), protein (10%-15% of total energy intake), fat as part of a low-fat diet (10%-15% of total energy intake), calcium and vitamin D supplements and iron supplements.

Certain medications may also be used to treat symptoms of GSDIa, when dietary changes are ineffective. Medications include allopurinol (to lower uric acid levels and prevent gout), lipid-lowering medications such as Lipitor, citrate supplements to prevent calcium deposits in the kidneys, and angiotensin-converting enzyme inhibitors (e.g. captopril) to treat renal dysfunction. Human granulocyte colony-stimulating factor can be used to treat recurrent infections. Some patients may also require liver and kidney transplantations and hepatic adenomas are usually treated with surgery or percutaneous ethanol injections and radiofrequency ablation.

Careful monitoring of disease symptoms is essential throughout an affected patient’s life. Annual ultrasound examinations of the kidneys are recommended and should be initiated after the age of 10. Liver surveillance should include annual monitoring of liver enzymes, liver ultrasounds every 12-24 months in children, and liver CT or MRI scans every 6-12 months in affected adults. If hepatic adenomas are detected they should be monitored every 3-6 months. Individuals receiving granulocyte colony-stimulating factor for infections need serial blood counts every three months to assess the response to treatment. Cardiovascular complications are monitored by routine blood pressure measurements (from infancy onward) and echocardiography every three years beginning at the age of 10.

Recommended Links:
Bali DS, Chen YT, Goldstein JL. (2006) [Updated 2013 Sep 19]. Glycogen Storage Disease Type I. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.

Chou JY, Mansfield BC. (2008) Mutations in the Glucose-6-Phosphatase-α (G6PC) Gene that Cause Type Ia Glycogen Storage Disease. Hum Mutat. 29(7): 921-930.

Ferreira JC, Schreiber-Agus N, Carter SM, Klugman S, Gregg AR, Gross SJ. (2014) Carrier testing for Ashkenazi Jewish disorders in the prenatal setting: navigating the genetic maze. Am J Obstet Gynecol. 211(3): 197-204.