Glycogen Storage Disease Type I

Disease Overview

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 excessive 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 (mutations) in the G6PC gene (GSDIA) or SLC37A4 gene (GSDIB). These mutations result in enzyme deficiencies that block glycogen breakdown in affected organs causing excess amounts of glycogen and fat accumulation in the body tissues and low levels of circulating glucose in the blood. The enzyme deficiency also results in an imbalance or excessive accumulation of other metabolites, especially lactates, uric acid and fats like lipids and triglycerides.

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Synonyms

• glucose-6-phosphatase deficiency
• glucose-6-phosphate transport defect
• glycogenosis type I
• GSDI
• Von Gierke disease

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Subdivisions

• glycogen storage disease type IA
• glycogen storage disease type IB

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Signs & Symptoms

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 possible seizures caused due to 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 due to repeated episodes of hypoglycemia.

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 to the above mentioned manifestations, GSDIb is also 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 and childbirth.

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Causes

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 inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, 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 working genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

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.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of glycogen storage disease type I. Detailed evaluations may be useful for a differential diagnosis:

Forbes or Cori disease (GSD-III) is one of several glycogen storage disorders that are inherited as autosomal recessive traits. Symptoms are caused by a lack of the enzyme amylo-1,6 glucosidase (debrancher enzyme). This enzyme deficiency causes excessive amounts of an abnormally digested glycogen (the stored form of energy that comes from carbohydrates) to be deposited in the liver, muscles and, in some cases, the heart. Symptoms become evident during the first years of life with hepatomegaly and/or myopathy, and elevated liver enzymes. In the first few months some symptoms may overlap with GSDI (elevated lipids, hepatomegaly, low glucose).

Andersen disease (GSD-IV) also known as glycogen storage disease type IV; This GSD is also inherited as an autosomal recessive trait. It is caused by deficient activity of the glycogen-branching enzyme (GBE), resulting in accumulation of abnormally formed glycogen in the liver, muscle, and/or other tissues. In most affected individuals, symptoms and findings become evident in the first few years of life. Such features typically include failure to grow and gaining weight at the expected rate (failure to thrive) and abnormal enlargement of the liver and spleen (hepatosplenomegaly).

Hers disease (GSD-VI) is also called glycogen storage disease type VI. It usually has milder symptoms than most other types of glycogen storage diseases. It is caused by a deficiency of the enzyme liver phosphorylase. Hers disease is characterized by enlargement of the liver (hepatomegaly), moderately low blood sugar (hypoglycemia), elevated levels of acetone and other ketone bodies in the blood (ketosis), and moderate growth retardation. Symptoms are not always evident during childhood, and children are usually able to lead normal lives. However, in some instances, symptoms may be severe.

Glycogen storage disease IX is caused due to deficiency of phosphorylase kinase enzyme (PK enzyme deficiency). It can be inherited as an X-linked genetic disorder caused by a deficiency of the enzyme liver phosphorylase kinase (mainly PHKA2 gene) or it can be inherited as an autosomal recessive form (caused due to PHKG2 and PHKB genes) causing liver and/or muscle disease. The disorder is characterized by slightly low blood sugar (hypoglycemia). Excess amounts of glycogen (the stored form of energy that comes from carbohydrates) are deposited in the liver, causing enlargement of the liver (hepatomegaly).

For more information on the above disorders, choose “Forbes,” “Anderson,” “Hers,” and “glycogen storage disease IX” as your search terms in the Rare Disease Database.
Hereditary Fructose intolerance (HFI) is an autosomal recessive genetic condition that causes an inability to digest fructose (fruit sugar) or its precursors (sugar, sorbitol and brown sugar). This is due to a deficiency of activity of the enzyme fructose-1-phosphate aldolase (Aldolase B), resulting in an accumulation of fructose-1-phosphate in the liver, kidney, and small intestine. Fructose and sucrose are naturally occurring sugars that are used as sweeteners in many foods, including many baby foods. This disorder can be life threatening in infants and ranges from mild to severe in older children and adults. (For more information about this condition, choose “fructose” as your search term in the Rare Disease Database.)

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Diagnosis

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.

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Standard Therapies

Treatment
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 must be maintained during the day and night throughout the life. Calcium, vitamin D and iron supplements maybe recommended to avoid deficits. Frequent feedings of uncooked cornstarch are used to maintain and 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 maybe 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 minor surgery or a procedure in which adenomas are ablated using heat and current (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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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Chen YT, Bali DS. Prenatal Diagnosis of Disorders of Carbohydrate Metabolism. In: Milunsky A, Milunsky J, eds. Genetic disorders and the fetus – diagnosis, prevention, and treatment. 6th ed. West Sussex, UK: Wiley-Blackwell; 2009.

Chen Y. Glycogen storage disease and other inherited disorders of carbohydrate metabolism. In: Kasper DL, Braunwald E, Fauci A, et al. eds. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2004.

Weinstein DA, Koeberl DD, Wolfsdorf JI. Type I Glycogen Storage Disease. In: NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott, Williams and Wilkins; 2003:450-451.

JOURNAL ARTICLES
Chou JY, Jun HS, Mansfield BC. Type I glycogen storage diseases: disorders of the glucose-6-phosphatase/glucose-6-phosphate transporter complexes. J Inherit Metab Dis. 2015 May;38(3):511-9. doi: 10.1007/s10545-014-9772-x. Epub 2014 Oct 7. Review. PubMed PMID: 25288127.

Kishnani PS, Austin SL, Abdenur JE, Arn P, Bali DS, Boney A, Chung WK, Dagli AI, Dale D, Koeberl D, Somers MJ, Wechsler SB, Weinstein DA, Wolfsdorf JI, Watson MS; American College of Medical Genetics and Genomics. (2014) Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014 Nov;16(11):e1.

Austin SL, El-Gharbawy AH, Kasturi VG, James A, Kishnani PS. Menorrhagia in patients with type I glycogen storage disease. Obstet Gynecol 2013;122:1246–1254.

Dagli AI, Lee PJ, Correia CE, et al. Pregnancy in glycogen storage disease type Ib: gestational care and report of first successful deliveries. J Inherit Metab Dis. 2010;Dec 33 Suppl 3:S151-7.

Chou JY, Mansfield BC. Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease. Hum Mutat. 2008;29:921-30.

Franco LM, Krishnamurthy V, Bali D, et al. Hepatocellular carcinoma in glycogen storage disease type Ia: a case series. J Inherit Metab Dis. 2005;28:153-62.

Lewis R, Scrutton M, Lee P, Standen GR, Murphy DJ. Antenatal and Intrapartum care of a pregnant woman with glycogen storage disease type 1a. Eur J Obstet Gynecol Reprod Biol. 2005;118:111-2.

Ekstein J, Rubin BY, Anderson, et al. Mutation frequencies for glycogen storage disease in the Ashkenazi Jewish Population. Am J Med Genet A. 2004;129:162-4.

Melis D, Parenti G, Della Casa R, et al. Brain Damage in glycogen storage disease type I. J Pediatr. 2004;144:637-42.

Rake JP, Visser G, Labrune, et al. Guidelines for management of glycogen storage disease type I-European study on glycogen storage disease type I (ESGSD I). Eur J Pediatr. 2002b;161:112-9.

Rake JP Visser G, Labrune P, et al. Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European study on glycogen storage disease type I (EGGSD I). Eur J Pediat. 2002a;161:20-34.

Chou JY, Matern D, Mansfield, et al. Type I glycogen Storage diseases: disorders of the glucose-6-Phosphatase complex. Curr Mol Med. 2002;2:121-43.

Schwahn B, Rauch F, Wendel U, Schonau E. Low bone mass in glycogen storage disease type 1 is associated with reduced muscle force and poor metabolic control. J Pediatr. 2002;141:350-6.

Visser G, Rake JP, Labrune P, et al. Consensus guidelines for management of glycogen storage disease type 1b. Results of the European study on glycogen storage disease type I. Eur J Pediatr. 2002;161:120-3.

Weinstein DA and Wolfsdorf JI. Effect of continuous gucose therapy with uncooked cornstarch on the long-term clinical course of type 1a glycogen storage disease. Eur J Pediatr 2002;161:35-9.

Janecke AR, Mayatepek E, and Utermann G. Molecular genetics of type I glycogen storage disease. Mol Genet Metab. 2001;73:117-25.

Viser G, Rake JP, Fernandes, et al. Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type 1b: results of the European study on glycogen storage disease type I. J Pediatr. 2000;137:187-91.

Chen YT, Bazarre CH, Lee MM, et al. Type I glycogen storage disease: nine years of management with corn starch. Eur J Pediatr. 1993;152:56-9.

INTERNET
Bali DS, Chen YT, Austin S, et al. Glycogen Storage Disease Type I. 2006 Apr 19 [Updated 2016 Aug 25]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1312/ Accessed October 21, 2019.

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