Glycogen Storage Disease Type VI

Disease Overview

Summary

Glycogen storage disease type VI (GSD6) is a genetic condition in which the liver cannot process sugar properly. The liver is responsible for breaking down a type of sugar called glycogen. Glycogen is a carbohydrate that is stored in the liver and muscle and used for energy. When the liver cannot break down glycogen properly, excess amounts accumulate in the liver and this causes a buildup that is damaging to the body.

Symptoms of the disease vary between individuals with GSD6. Most symptoms begin in infancy or childhood and include low blood sugar (hypoglycemia), an enlarged liver (hepatomegaly) and an increased amount of lactic acid in the blood (lactic acidosis). These symptoms are likely to occur when an individual does not eat for a long time. Symptoms tend to improve as people with this disease get older. Some individuals with GSD6 may not require any treatment. Standard therapy includes eating several meals that are high in carbohydrates. Uncooked cornstarch can be used to quickly improve blood sugar levels.

GSD6 is caused by harmful changes (mutations) in the PYGL gene and this condition is inherited in an autosomal recessive manner.

Introduction

GSD6 is one of a group of several glycogen storage disorders that all impact the liver’s ability to process glycogen.

Glycogen storage disease type VI was originally called Hers disease when Henry-Gery Hers first described it in 1959. Hers reported three children with an enlarged liver, mild hypoglycemia, and increased glycogen content in the liver.

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Synonyms

• Hers disease
• liver phosphorylase deficiency
• phosphorylase deficiency glycogen storage disease
• GDS6

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Signs & Symptoms

Symptoms vary from person to person, and people with GSD6 may not have all the symptoms listed. GSD6 is usually a relatively mild disorder, although rare cases with more severe symptoms have been reported.

Symptoms of GSD6 usually begin in infancy or childhood and may include an enlarged liver (hepatomegaly), low blood sugar (hypoglycemia) or an increase in the amount of lactic acid in the blood (lactic acidosis). Hypoglycemia can also cause symptoms such as faintness, weakness, hunger and nervousness. If present, hypoglycemia is usually mild and occurs more often during an illness. The symptoms of the disease are especially likely to occur when an individual does not eat for a long time.

Some children with GSD6 are shorter than average due to slow growth. They may also have muscle weakness (hypotonia). Intellectual development is usually normal. Although symptoms of GSD6 may not be present during childhood, it has been reported that liver enlargement can be noted, even if no other symptoms are present. 

Many of the symptoms of GSD6 tend to improve as children get older, and most adults do not have symptoms. Liver enlargement often disappears by puberty and final adult height is often average. Muscle strength and tone are usually normal by adulthood as well. In untreated individuals, growth delays and weakening of the bone (osteoporosis) are common. People with GSD6 may be at an increased risk of having liver cancer or an enlarged heart (cardiomyopathy) in late childhood and adulthood.

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Causes

GSD6 is caused by harmful changes (mutations) in the PYGL gene. This gene is responsible for telling the body how to make an enzyme called liver glycogen phosphorylase. This enzyme is responsible for breaking down glycogen. Glycogen is a form of energy that comes from carbohydrates and is stored in the liver. When the body needs more energy, glycogen in the liver is broken down by the PYGL gene product, glycogen phosphorylase. 

When there are mutations in the PYGL gene, there is not enough functioning glycogen phosphorylase to break down glycogen. Therefore, glycogen starts to build up in the liver cells, which causes an enlarged liver. This also means that the body does not get enough energy, which causes symptoms such as hypoglycemia and lactic acidosis.  

GSD6 is inherited in an autosomal recessive manner. 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 chance for two carrier parents to both pass on the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The chance of having 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 chance is the same for males and females. 

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Affected populations

Males and females are affected in equal numbers due to the autosomal recessive inheritance of GSD6. The incidence of all glycogen storage diseases is estimated to be between 1 in 20,000 and 1 in 25,000 persons in the United States. However, GSD6 is estimated to affect only 1 in 1,000,000 individuals in the general population. Because some affected individuals go undiagnosed or are misdiagnosed, it is difficult to determine the exact frequency of GSD6 in the general population. A higher occurrence of GSD6 has been seen in the Mennonite population, about 1 in 1,000 live births. There is a specific PYGL gene mutation that is present in about 3% of the Mennonite population which accounts for this higher incidence. 

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of GSD6. Comparisons may be useful for a differential diagnosis:

Glycogen storage disease type IX (GSD-IX) is a group of at least four disorders characterized by the accumulation of glycogen in the liver and muscles. This is due to a lack of the enzyme phosphorylase kinase. Common symptoms of the form with liver involvement include enlargement of the liver (hepatomegaly), unusually low levels of blood glucose (hypoglycemia), increase in blood ketones, which are byproducts generated when the body burns fats for energy (hyperketosis) during fasting and growth delays. GSD-IX can be inherited in an autosomal recessive or X-linked pattern, depending on the type. (For more information on this disorder, choose “GSD-IX” as your search term in the Rare Disease Database.)

Glycogen storage disease type III (GSD3 or Forbes disease) is characterized by excess amounts of glycogen storage in the liver, muscles, and in some cases, the heart. Symptoms are caused by a lack of the enzyme amylo-1,6 glucosidase. They include growth delays, low blood sugar (hypoglycemia), an elevated level of fatty substances in the blood (hyperlipemia), a protruding abdomen and an enlarged liver. Forbes disease is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “GSD-III” as your search term in the Rare Disease Database.)

Glycogen storage disease type I (GSDI or von Gierke disease) is characterized by the build-up of glycogen and fat in the liver and kidneys that can result in enlargement of the liver and kidneys and growth delay leading to short stature. GSDI is associated with mutations in the G6PC gene or SLC37A4 gene that result in lack of the related enzyme and causes excess amounts of glycogen to be stored in the body tissues and low levels of glucose in the blood. GSD1 is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “GSDI” as your search term in the Rare Disease Database.)

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Diagnosis

GSD6 is diagnosed based on signs and symptoms of the disease, such as an enlarged liver, growth delay and hypoglycemia. The diagnosis can be confirmed by genetic testing of the PYGL gene. A liver biopsy that tests the function of liver glycogen phosphorylase may be necessary if the results of the genetic testing are not clear. 

Clinical Testing and Work-Up
Initial workup in patients presenting with hepatomegaly and hypoglycemia include liver ultrasound and biopsy, liver function tests, blood glucose levels and testing for basic metabolic chemistry. Findings of elevated liver transaminases can be seen, in addition to elevated glycogen content and decreased hepatic phosphorylase enzyme activity. Hepatic glycogen phosphorylase enzyme activity can also be performed on blood and liver cells. However, the blood enzyme assay can be normal in affected individuals and should be interpreted with caution. Even in liver tissue, enzyme assay is challenging. Individuals with GSD6 can have very low levels of hepatic enzyme activity. Carriers, individuals with one copy of a PYGL mutation, cannot be detected by evaluating enzyme activity. Because the enzyme results can be non-specific, genetic testing should be used to diagnose GSD6 and determine carrier status. 

Molecular genetic testing can confirm a diagnosis of GSD6. Molecular genetic testing can detect mutations in PYGL known to cause GSD6. Ideally, testing should be ordered by a medical genetics professional or in a healthcare setting with experience interpreting and counseling families about genetic test results.

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Standard Therapies

Treatment
Because symptoms of GSD6 are generally mild, the disorder usually requires no treatment other than to avoid prolonged periods without eating. Because glycogen is only broken down when stored energy needs to be used, eating frequent meals can prevent the need to break down glycogen. Levels of blood glucose should be monitored to make sure that the diet is working correctly. This will minimize the symptoms of the disease. In some patients, no other treatment is necessary. Frequent, small meals supplemented with uncooked cornstarch are recommended to avoid hypoglycemia. Some individuals may require a bedtime snack and/or cornstarch to prevent nighttime development of hypoglycemia. Even for children and adults with little to no hypoglycemic episodes, a bedtime dose of cornstarch is suggested. Uncooked cornstarch is a complex carbohydrate that is difficult for the body to digest; therefore, it maintains healthy blood sugar levels for a more extended period than most carbohydrates in food. Cornstarch therapy has been noted to improve energy, growth, bone density, well-being and liver size. 

Routine monitoring of blood glucose and ketone levels periodically as well as during periods of increased activity and illness is necessary. Due to the growth delays associated with GSD6, height, and weight should be measured annually to monitor growth. Bone density examinations are recommended after growth is complete.

The outlook for individuals with GSD6 is generally considered very good. However, it has been noted that there is a small increased risk with age for development of liver cancer (hepatic adenocarcinoma). Annual liver ultrasound examinations are recommended beginning at age five years to screen for pre-cancerous tumor formation. Further research is needed to completely understand the risk for liver cancer in adulthood.

Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://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 NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

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:
https://www.centerwatch.com/

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

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References

JOURNAL ARTICLES
Kishnani PS, Goldstein J, Austin SL, et al. Diagnosis and management of glycogen storage diseases type VI and IX: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019; 21, 772–789. doi:10.1038/s41436-018-0364-2 https://www.ncbi.nlm.nih.gov/pubmed/30659246

Jagadisan B, Ranganath P. Glycogen storage disease type VI with a novel mutation in PYGL gene. Indian Pediatr. 2017;54(9):775-776. https://www.ncbi.nlm.nih.gov/pubmed/28984260

Burda P, Hochuli M. Hepatic glycogen storage disorders: what have we learned in recent years?. Curr Opin Clin Nutr Metab Care. 2015;18(4):415-21. https://www.ncbi.nlm.nih.gov/pubmed/26001652

Roscher A, Patel J, Hewson S, et al. The natural history of glycogen storage disease types VI and IX: Long-term outcome from the largest metabolic center in Canada. Mol Genet Metab. 2014 Nov;113(3):171-6. https://www.ncbi.nlm.nih.gov/pubmed/25266922

Chang S, Rosenberg MJ, Morton H, Francomano CA, Biesecker LG, Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI, Human Molecular Genetics 1998;7,5 May 865-870. https://doi.org/10.1093/hmg/7.5.865

INTERNET
Labrador E, Weinstein DA. Glycogen Storage Disease Type VI. 2009 Apr 23 [Updated 2019 Nov 27]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK5941/ Accessed July 29, 2020.

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