NORD gratefully acknowledges Yuan-Tsong Chen, MD, PhD, Professor, Division of Medical Genetics, Department of Pediatrics, Duke Medicine; Distinguished Research Fellow, Academia Sinica Institute of Biomedical Sciences, Taiwan and Deeksha Bali, PhD, Professor, Division of Medical genetics, Department of Pediatrics, Duke Health; CO-Director, Biochemical Genetics Laboratories, Duke University Health System, for assistance in the preparation of this report.
Glycogen storage diseases are a group of disorders in which stored glycogen cannot be metabolized into glucose to supply energy and to maintain steady blood glucose levels for the body. Type I glycogen storage disease is inherited as an autosomal recessive genetic disorder. Glycogen storage disease type I (GSDI) is characterized by accumulation of glycogen and fat in the liver and kidneys that can result in an enlarged liver and kidneys and growth retardation leading to short stature. GSDI is associated with abnormalities in the G6PC gene (GSDIA) or SLC37A4 gene (GSDIB) that result in enzyme deficiencies that cause excess amounts of glycogen accumulation in the body tissues and low levels of glucose in the blood. This enzyme deficiency also results in derangement of other important metabolites in the body thus causing imbalance or excessive accumulation of these metabolites, especially fats like lipids and triglycerides.
The primary symptom of GSDI in infancy is a low blood sugar level (hypoglycemia). Symptoms of GSDI usually begin at three to four months of age and include enlargement of the liver (hepatomegaly), kidney (nephromegaly), elevated levels of lactate, uric acid and lipids (both total lipids and triglycerides), and seizures caused by repeated episodes of hypoglycemia. Continued low blood sugar can lead to delayed growth and development and muscle weakness. Affected children typically have doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen.
High lipid levels can lead to the formation of fatty skin growths called xanthomas. Other conditions that can be associated with untreated GSD1 include osteoporosis, delayed puberty, gout (arthritis caused by accumulation of uric acid), kidney disease, pulmonary hypertension (high blood pressure in the arteries that supply the lungs), hepatic adenoma (benign liver tumors), polycystic ovaries in females, an inflammation of the pancreas (pancreatitis), diarrhea and changes in brain function.
Impaired platelet function can lead to a bleeding tendency with frequent nose bleeds (epistaxis). In general GSD type Ib patients have similar clinical manifestations as type Ia patients, but in addition GSDIb is associated with impaired neutrophil and monocyte function as well as chronic neutropenia after the first few years of life, all of which result in recurrent bacterial infections and oral and intestinal mucosal ulcers.
Early diagnosis and effective treatment can result in normal growth and puberty and many affected individuals live into adulthood and enjoy normal life activities. Many female patients have had successful pregnancies.
Type I glycogen storage disease is associated with abnormalities in two genes. Mutations in the G6PC gene result in a deficiency in the glucose-6-phosphatase (G6Pase) enzyme and account for approximately 80% of GSDI. This type of GSDI is termed glycogen storage disease type Ia. Mutations in the SLC37A4 gene result in a deficiency in the glucose-6-phosphatase translocase enzyme (transporter deficiency) and account for approximately 20% of GSDI. This type of GSDI is termed glycogen storage disease type Ib. Both these enzyme deficiencies cause excess amounts of glycogen along with fats to be stored in the body tissues.
Type I glycogen storage disease is inherited as an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual happens to inherit two copies of the same abnormal gene for the same trait/disease from each parent. The diagnosis of GSDI is established in a patient by identification of two pathogenic variants in either G6PC or SLC37A4. If an individual receives one normal copy of the gene (allele) and one abnormal/defective copy of gene (allele) for the disease, the person will be a carrier for the disease, but usually will not show symptoms. Thus most parents of the person affected with GSD type I are unaffected carriers if the disease gene. The risk for two carrier parents having a child and passing the same defective gene to the new baby, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for GSDI is 25%. The risk is being affected is the same for males and females.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases their risk to have children with a recessive genetic disorder.
Type I glycogen storage disease occurs in approximately 1 in 100,000 births. The prevalence of GSDI in Ashkenazi Jews is approximately 1 in 20,000. This condition affects males and females in equal numbers in any given population group.
GSD type I is diagnosed by laboratory tests that indicate abnormal levels of glucose, lactate, uric acid, triglycerides and cholesterol. Molecular genetic testing for the G6PC and SLC37A4 genes is available to confirm a diagnosis. Molecular genetic testing can also be used for carrier testing and prenatal diagnosis. Liver biopsy can also be used to prove specific enzyme deficiency for GSD Ia.
GSDI is treated with a special diet in order to maintain normal glucose levels, prevent hypoglycemia and maximize growth and development. Frequent small servings of carbohydrates during the day must be maintained throughout life. Calcium, vitamin D and iron supplements may be recommended. Feeding of uncooked cornstarch is used to improve blood levels of glucose. Allopurinol, a drug capable of reducing the level of uric acid in the blood, may be useful to control the symptoms of gout-like arthritis during the adolescent years. Medications may be prescribed to lower lipid levels and prevent and/or treat kidney disease. Human granulocyte colony stimulating factor (GCSF) may be used to treat recurrent infections in GSD type Ib patients. Liver tumors (adenomas) can be treated with surgery or a procedure in which current is used to heat and eliminate the tumor (radiofrequency ablation). Kidney and/or liver transplantation are sometimes considered if other therapies are unsuccessful or where liver adenomas keep growing.
Individuals with GSDI should be monitored at least annually with kidney and liver ultrasound and routine blood work specifically used for monitoring GSD patients.
Genetic counseling is recommended for affected individuals and their families.
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