When needed, the glycogen polymer can be broken down into glucose monomers and utilized for energy production. Many of the enzymes and transporters for these processes are key to the etiology of GSDs.

An increasing number of GSDs are being identified, but most are very rare. Traditionally the GSDs were named after the clinician who first identified the disorder; however, they each have an identified enzyme and gene focus that will be used to refer to these disorders in this article, although the various diseases have their own classifications.

The etiology of GSDs is best understood by following the metabolic events leading to the synthesis glycogenesis and degradation of glycogen glycogenolysis.

As indicated in Table 1, there are two distinct forms of glycogen synthase, one in the liver encoded by the GYS2 gene and one in skeletal muscle encoded by the GYS1 gene. Both forms of GS work by linking alpha-1,4 links a glucose monomer to the growing glycogen polymer.

As indicated in Figure 1, glycogen has two different types of linkages, alpha-1,4 links and alpha-1,6 links. This is the cause of GSD type 0a. Similarly, the absence or malfunction of muscle glycogen synthase due to mutations in the GYS1 gene will prevent glycogen from being synthesized in muscles, and this is the cause of GSD type 0b.

While glycogen synthase can catalyze the alpha-1,4 glucose linkages in glycogen, a different enzyme, glycogen branching enzyme GBE1 , is needed to produce the branching alpha-1,6 linkages. Mutations in the glycogen branching enzyme can result in the production of glycogen with an abnormal structure.

This is the cause of GSD type IV. In GSD type IV, polyglucosan bodies accumulate in liver and muscle cells. Polyglucosan bodies do not effectively undergo glycogenolysis, and in muscle tissue, this can cause weakness and myopathy. In the liver, the accumulation of polyglucosan bodies causes hepatomegaly.

While GSD 0a and GSD 0b are due to insufficient glycogen storage, most GSDs are unable to remove glucose from glycogen glycogenolysis , resulting in excess glycogen tissue storage.

The first step in glycogenolysis is the release of glucosephosphate GP from glycogen by the action of glycogen phosphorylase. GSD type V is caused by mutations in the glycogen phosphorylase gene-specific for muscle PYGM.

Mutations in the glycogen phosphorylase gene specific for the liver PYGL cause GSD type VI. Glucosephosphate in the liver is, in turn, converted to glucose by glucosephosphatase encoded by the G6PC gene. It should be noted that skeletal muscles lack glucosephosphatase and therefore do not release glucose into the blood.

GSDs type I results from genetic disorders in the metabolism of glucosephosphatase. Glucosephosphate is synthesized in the cytoplasm of hepatocytes and must be transported into the lumen of the endoplasmic reticulum ER , where it is acted upon by glucosephosphatase yielding glucose, which is transported back to the cytoplasm and then through the hepatic GLUT2 transporter into the blood.

Glucosephosphate translocase1 G6PT1 is the transporter protein that provides a GP channel between the cytoplasm and the ER. The G6PT protein is made of three subunits termed G6PT1, G6PT2, and G6PT3 Figure 2. Mutations in the SLC37A4 gene, which encodes the G6PT1 protein, are responsible for GSD type Ib Figure 1.

Fanconi-Bickel disease is a rare GSD caused by a GLUT2 deficiency due to a mutation in the SLC2A2 gene. This leads to increased glycogen storage and hepatomegaly. As mentioned above, glycogen is a branched polymer. While glycogen phosphorylase works well at removing glucose from alpha- 1,4 -linkages, it does not work at branch points.

Branch points are alpha-1,6 linkages. GSD type II is unique among GSDs because it is also classified as a lysosomal storage disease LSD. Lysosomal storage diseases are caused by a missing or nonfunctional lysosomal enzyme.

In the case of GSD II, this enzyme is lysosomal acid alpha-glucosidase encoded by the gene GAA , which breaks down glycogen into glucose for use as a cellular energy source.

Mutation in the GAA gene results in the toxic accumulation of glycogen in lysosomes. The true incidence of metabolic diseases is difficult to determine given the lack of uniform, universal screening at birth.

Individual incidence of specific GSD types is further complicated due to overlap in symptoms and the lack of standardized specific testing in most areas of the world. A study evaluating the incidence of inborn errors of metabolism in British Columbia in the s reported that the incidence of these diseases was approximately 30 cases per live births.

Approximately 2. As stated above, glycogen is the stored form of glucose and is composed of long polymers of 1,4 linked glucose with branch points via 1,6 linked glucose molecules. When these physiologic functions are defective, hypoglycemia, hepatomegaly, muscle cramps, exercise intolerance, and weakness develops.

Some disorders also affect the myocardial tissue and can lead to cardiomyopathy and cardiac conduction defects. In GSD type 1, for example, failure of glycogenolysis in the liver results in increased lactic acid production lactic acidosis due to the intracellular accumulation of glucosephosphate, which stimulates the glycolytic pathway.

GSDs are a diverse set of rare inborn errors of carbohydrate metabolism that can have variable phenotypic presentation even within the same GSD type. Obtaining a family pedigree is useful in establishing the mode of inheritance.

Most GSDs show an autosomal recessive inheritance, but a few GSD type IX show an x-linked inheritance. Patients with a defect in hepatic glycogen metabolism usually present with fasting hypoglycemia and ketosis.

Their symptoms improve with glucose administration. Patients with a defect in skeletal muscle glycogen metabolism present with fatigue and exercise intolerance after short periods of moderate-intense exercise.

In rare cases, progressive weakness may be reported. This, however, is usually limited to GSD type 0, II, and IV. In rare instances, GSD type III, V, and VII can present with weakness rather than muscle cramps and, over time, develop fixed weakness.

Anthropometric measurements should be obtained and graphed in all patients with GSDs to assess the overall growth pattern. Short stature or poor linear growth, especially in a child with hypoglycemia, should warrant workup for glycogen storage disorders. In the liver, this results in hepatomegaly with the potential for cirrhosis.

Hypoglycemia is defined as a plasma concentration of glucose that results in symptoms attributable to hypoglycemia and is reversed with the administration of glucose. There is no set plasma glucose level above which GSDs can be ruled out, particularly for children.

It is important to note that neonates go through a period of transitional hypoglycemia in the first 48 hours of life, during which GSDs cannot be diagnosed. Duration of fasting that leads to symptoms of hypoglycemia is an important element of history that must be obtained.

A short duration of fasting that results in typical symptoms suggests glycogen storage disorder type I or III. Hypoglycemia should be documented by measuring serum glucose levels. In patients where hypoglycemia is suspected, a diagnostic fasting glucose test can be performed but should only be considered in a monitored inpatient setting.

Patients with glycogen storage disease type III also have elevated creatine kinase levels. Patients with type I disorder will also present with elevated liver enzyme and uric acid levels. Triglyceredemia is also common. Urinary myoglobin levels can be detected in patients with GSDs as well, particularly in those affected by GSDs that primarily affect the skeletal muscles.

Although specific genetic testing is now available for diagnosing most GSDs, histologic examination of liver or muscle biopsy is still used in specific scenarios. In GSD type 0, a liver biopsy will show decreased hepatic glycogen and can make a definitive diagnosis for this disease. Muscle biopsies will reveal diastase-sensitive vacuoles and positive for periodic acid-Schiff PAS and acid phosphatase in GSD type IV.

In addition, the biopsy will reveal subsarcolemmal deposits of glycogen detected with periodic acid-Schiff PAS stain. Molecular genetic testing is noninvasive and, for the most part, available for diagnosing these rare genetic disorders. In some cases, they have eliminated the need for invasive muscle and liver biopsies.

The genetic foci of mutations for these disorders are outlined in the following chart. Key goals are to treat or avoid hypoglycemia, hyperlactatemia, hyperuricemia, and hyperlipidemia.

Hypoglycemia is avoided by consuming starch, and an optimal, physically modified form is now commercially available. Hyperuricemia is treated with allopurinol and hyperlipidemia with statins. Some GSDs like GSD type II can now be treated with enzyme replacement therapy ERT , using recombinant alglucosidase alfa, which degrades lysosomal glycogen.

There is ongoing research to use ERT with other forms of GSDs. Liver transplantation should be considered for patients with certain GSDs with progressive hepatic forms that have progressed to hepatic malignancy or failure. Though liver failure and hypoglycemia may be corrected with liver transplantation, cardiomyopathy associated with the GSD will not be corrected and may continue to progress.

Glucagon is only effective in insulin-mediated hypoglycemia and will not be helpful in patients who present with hypoglycemia secondary to a GSD.

With early diagnosis and proper management, the prognosis of most GSDs is good. Rarely, end-stage renal disease requiring kidney transplantation may occur in patients with GSD type Ib. Hypoglycemia-associated seizures and cardiac arrest can occur in early childhood.

whereas in GSD type Ib, recurrent bacterial infections secondary to neutropenia will be seen. Cardiomyopathy and limb-girdle dystrophy can be seen in patients with GSD type II. Hypertrophic cardiomyopathy is a classic complication of GSD type III. Growth retardation and short status are also seen in GSD type IX a, b, c, d and GSD type XII, but a cognitive-developmental delay is also a feature in the latter.

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It is caused by mutations in an enzyme called lysosomal acid maltase and results in heart dysfunction, muscle weakness and difficulty exercising. Liver GSDs are most commonly diagnosed when a child is growing poorly or not gaining weight and has an enlarged liver. In addition, they can be diagnosed if a child has an episode of hypoglycemia and elevated ketone levels.

Muscle GSDs are usually diagnosed when a child is discovered to have heart problems, muscle weakness or difficulty exercising. Using a blood sample, the genes that make the enzymes responsible for GSDs can be tested for mutations.

For those children with liver GSDs with hypoglycemia, the most important goal of treatment is to prevent hypoglycemia and elevated ketone levels. Infants and younger children require frequent feedings, and some may require continuous feeds or glucose-containing fluids through a feeding tube.

Uncooked cornstarch is a long-acting source of carbohydrates which can be given several times a day and overnight when children get older and go longer between feeds. Other medicines may be used to treat liver problems.

When children with liver GSDs get sick, they are at increased risk of hypoglycemia, elevated ketones and lactic acidosis if they have GSD Type I , and may have to be admitted to the hospital for intravenous IV glucose-containing fluids.

While there is no specific treatment for many muscle GSDs, avoiding intense exercise to prevent muscle fatigue may be necessary. There are multiple excellent patient and parent advocacy groups for patients with glycogen storage disease, including The Association for Glycogen Storage Disease www.

Learn More. Join PES Contact Find a Pediatric Endocrinologist. Glycogen Storage Disease: A Guide for Families. Clinical Topic. Publication Date October 4, File Downloads Download PDF English. What are glycogen storage diseases? What causes glycogen storage diseases? What are the symptoms of glycogen storage diseases?

What are the different types of glycogen storage diseases? The treatment for GSD III is a little different than for GSD 1 as these children need to eat a lot of protein in addition to carbohydrates — Type VI : is also called Hers disease. Some children with type VI will not have large livers and may be incorrectly diagnosed with ketotic hypoglycemia — Type IX : is caused by mutations in an enzyme called glycogen phosphorylase kinase, which helps breakdown glycogen in the liver.

This condition is more common in boys as it is passed from mothers to their sons because the gene is on the X chromosome There are several types of muscle GSDs, each of which is very rare. How are glycogen storage diseases diagnosed?

How are glycogen storage diseases treated?