Type VI Glycogen Storage Disease

Updated: Aug 12, 2021
  • Author: Ranjodh Singh Gill, MD, FACP, CCD; Chief Editor: George T Griffing, MD  more...
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Overview

Practice Essentials

glycogen storage disease (GSD) is the result of enzyme defects in the glycogen pathway. These enzymes normally catalyze reactions that ultimately convert glycogen compounds to glucose. Enzyme deficiency results in glycogen accumulation in tissues. [1]  In many cases, the defect has systemic consequences, but in some cases, the defect is limited to specific tissues. Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly. [2, 3]

GSD VI is caused by deficient activity of hepatic glycogen phosphorylase, an enzyme encoded by the PYGL gene, which is located on chromosome 14q21-q22. PYGL is the only gene known to be associated with GSD VI. [4, 5, 6, 7, 8, 9]  

With an enzyme defect, carbohydrate metabolic pathways are blocked and excess glycogen accumulates in affected tissues. Each GSD represents a specific enzyme defect, and each enzyme is either focal or systemic. Hepatic phosphorylase, which is found in the liver and red blood cells, is deficient in GSD VI, which results in glycogen accumulation in the liver and subsequent hypoglycemia. These inherited enzyme defects usually present in childhood, although some, such as McArdle disease and Pompe disease (also known as acid maltase deficiency), have separate adult-onset forms. In general, GSDs are inherited as autosomal recessive conditions. Several different mutations have been reported for each disorder.

Diagnosis depends on findings from patient history and physical examination, muscle biopsy, electromyography, ischemic forearm testing, and creatine kinase testing. Biochemical assay for enzyme activity is the method of definitive diagnosis.

Individuals with GSD VI can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and impaired growth. Symptoms result from mild hypoglycemia. Liver fibrosis and hepatocellular carcinoma have been reported in patients with GSD VI.

A creatine kinase level evaluation is helpful in all cases of suspected glycogen storage disease (GSD). Because hypoglycemia may be found in some types of GSD, fasting glucose testing is indicated. In Hers disease, hypoglycemia is a primary concern. Urine studies are indicated because myoglobinuria may occur in some patients with GSDs. Hepatic failure occurs in some patients with GSDs, although rarely in those with Hers disease. Liver function studies are indicated and may reveal evidence of hepatic injury. Biochemical assay of enzyme activity is necessary for definitive diagnosis. Findings from imaging studies may reveal hepatomegaly.

Liver biopsy may be required to diagnose the cause of hepatomegaly. Identification of 2 pathogenic variants in trans in PYGL confirms a diagnosis of GSD VI. About 30 pathogenic variants have been reported throughout the PYGL gene. [4, 5, 6, 7, 8, 9]

The following list contains a quick reference for 8 of the GSD types:

  • 0 - Glycogen synthase deficiency

  • Ia -Glucose-6-phosphatase deficiency (von Gierke disease) [10]

  • II -Acid maltase deficiency (Pompe disease)

  • III - Debranching enzyme deficiency (Forbes-Cori disease)

  • IV - Transglucosidase deficiency (Andersen disease, amylopectinosis)

  • V - Myophosphorylase deficiency (McArdle disease)

  • VI - Phosphorylase deficiency (Hers disease)

  • VII - Phosphofructokinase deficiency (Tauri disease)

The chart below demonstrates where various forms of GSD affect metabolic carbohydrate pathways.

Metabolic pathways of carbohydrates. Metabolic pathways of carbohydrates.

Although at least 14 unique GSDs are discussed in the literature, the GSDs that cause clinically significant muscle weakness are Pompe disease (GSD type II, acid maltase deficiency) [11] , Cori disease (GSD type III, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), and Tarui disease (GSD type VII, phosphofructokinase deficiency). One form, von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency), causes clinically significant end-organ disease with significant morbidity.  Interestingly, GSD type 0 also is described, which is due to defective glycogen synthase.

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Background

Excess glucose in the body is stored as glycogen in the liver and serves as a reserve for glucose needs, especially during fasting state. Glycogen is formed in periods of dietary carbohydrate loading, and glycogenolysis occurs when glucose demand is high or dietary availability is low (see figure showing metabolic pathways of glycogen metabolism and glycolysis).

Glycogen is most abundant in liver and muscle, which are most affected by disorders of glycogen metabolism. Glycogen serves as a source of glucose for use by organs that lack gluconeogenesis.

glycogen storage disease (GSD) results from mutations in genes for virtually all of the proteins involved in glycogen synthesis, degradation, or regulation.

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Pathophysiology

Hepatic glycogen phosphorylase catalyzes the cleavage of 1,4 glucosidic bonds to release glucose 1-phosphate from glycogen.

The activity of hepatic glycogen phosphorylase is regulated by phosphorylation by phosphorylase kinase, the deficiency of which causes GSD IX.

GSD VI results from deficiency of liver phosphorylase. 

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Epidemiology

GSD VI is probably underdiagnosed because of its indolent course. GSD VI and IX (deficiencies of liver phosphorylase and the enzyme that regulates its activity, respectively) together account for 25-30% of all the GSDs.

The most common GSD IX subtype is IXa, due to mutations in the α-subunit of phosphorylase kinase, encoded by the PHKA2 gene. GSD IXa is likely to be an underdiagnosed cause of ketotic hypoglycemia. [2]

Prevalence estimates for GSD VI range from 1 in 65,000 to 1 in 1 million. The Mennonite population has been identified as a population at risk, with a prevalence of 1 in 1000. [4, 5, 6, 7, 8, 9]

Herling et al studied the incidence and frequency of inherited metabolic conditions in British Columbia. GSDs were found in 2.3 children per 100,000 births per year.

Morbidity results from the consequences of hepatomegaly. In general, GSDs present in childhood. Later onset correlates with a less severe form. Consider Pompe disease if onset is in infancy.

 

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Prognosis

GSD VI typically has a benign course and improves gradually, especially if treated appropriately and early.

Hypoglycemia, hepatomegaly, and fragility fractures are potential issues, and rarely hepatic tumors may occur. Hepatomegaly mitigates slowly.

An annual liver ultrasound scan is recommended for surveillance after age 10.

Complications

The following complications have been associated with GSD VI:

  • Growth retardation
  • Fragility fractures
  • Hypoglycemia
  • Elevated transaminases
  • Hepatomegaly, fibrosis, cirrhosis, and hepatic failure
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Patient Education

Because GSD VI has a genetic predisposition, genetic counseling should be offered to all patients.

A special caution should be observed during pregnancy for hypoglycemia, and it should be managed in a high-risk obstetrics setting.

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Genetics

GSD VI is an autosomal-recessive disorder. GSD IX is an X-linked genetic disorder.

Mutations in the gene for the liver isoform of glycogen phosphorylase (PYGL) are located at 14q21. Missense, nonsense, and splice-site mutations have been described. [4, 12]  Null mutations occur less than in other GSDs. [8]

A founder mutation involving a splice-site alteration was identified in a Pennsylvanian Mennonite population.

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