Type VI Glycogen Storage Disease

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

Overview

Practice Essentials

A 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.

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.

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

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. 

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 ╬▒-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.

 

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

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.

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.

 

Presentation

History

GSD VI starts in early childhood.

The clinical presentation is very heterogeneous and variable.

Hallmark features are growth retardation and hepatomegaly.

Hypoglycemia, dyslipidemia, and ketosis are common features.

There is high risk of bone loss if the condition is untreated.

Physical Examination

The following are characteristic findings on physical examination:

  • Short stature
  • Hepatomegaly
  • Mild cardiomyopathy
  • Fragility fractures and potential deformity if there is associated osteoporosis
 

DDx

 

Workup

Laboratory Studies

Obtain a creatine kinase level 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 GSD VI disease, hypoglycemia is a primary concern.

Urine studies are indicated because myoglobinuria may occur in some patients with GSDs.

Liver function studies are indicated and may reveal evidence of hepatic injury.

Biochemical assay of enzyme activity is necessary for definitive diagnosis. 

Molecular testing of the gene responsible for GSD VI (PYGL) is done first if the patient is female.

Testing of the gene responsible for GSD IX (phosphorylase kinase, liver, alpha-2 subunit [PHKA2]) is done first if the patient is male.

Liver biopsy may be indicated in selective cases.

Manzia et al reported the first documented case of GSD associated with a rapidly growing hepatocellular adenoma as determined by histologic findings.[13]

Imaging Studies

Liver ultrasound scanning for diagnosis and surveillance should be performed.

Bone density testing should be assessed once the patient has stopped growing.[14]

Other Tests

Ischemic forearm test

In the case of GSD VI disease, which is not associated with significant muscle involvement, the forearm ischemic test is most useful to help rule out other GSDs, most specifically Cori disease, McArdle disease, and Tarui disease. Test findings are expected to be negative in patients with Hers disease.

The ischemic forearm test is an important tool for diagnosis of muscle disorders. The basic premise is an analysis of the normal chemical reactions and products of muscle activity. Obtain consent before the test.

Instruct the patient to rest. Position a loosened blood pressure cuff on the arm, and place a venous line for blood samples in the antecubital vein.

Obtain blood samples for the following tests: creatine kinase, ammonia, and lactate. Repeat in 5-10 minutes.

Obtain a urine sample for myoglobin analysis.

Immediately inflate the blood pressure cuff above systolic blood pressure and have the patient repetitively grasp an object, such as a dynamometer. Instruct the patient to grasp the object firmly, once or twice per second. Encourage the patient for 2-3 minutes, at which time the patient may no longer be able to participate. Immediately release and remove the blood pressure cuff.

Obtain blood samples for creatine kinase, ammonia, and lactate immediately and at 5, 10, and 20 minutes.

Collect a final urine sample for myoglobin analysis.

Interpretation of ischemic forearm test results

With exercise, carbohydrate metabolic pathways yield lactate from pyruvate. Lack of lactate production during exercise is evidence of a pathway disturbance, and an enzyme deficiency is suggested. In such cases, muscle biopsy with biochemical assay is indicated.

Healthy patients demonstrate an increase in lactate of at least 5-10 mg/dL and ammonia of at least 100 mcg/dL. Levels will return to baseline.

If neither level increases, the exercise was not strenuous enough and the test is not valid.

Increased lactate at rest (before exercise) is evidence of mitochondrial myopathy.

Failure of lactate to increase with ammonia is evidence of a GSD resulting in a block in carbohydrate metabolic pathways. Not all patients with GSDs have positive ischemic test results.

Failure of ammonia to increase with lactate is evidence of myoadenylate deaminase deficiency.

Positive ischemic forearm test results may occur in patients with Cori disease, McArdle disease, and Tarui disease.

In patients with GSD VI disease, ischemic test results are negative.

 

Treatment

Approach Considerations

The following are recommended:

  • Frequent, small meals
  • Uncooked cornstarch, used at a dose of 1 to 2 g/kg per dose, between meals and at bedtime to avoid hypoglycemia
  • Continuous carbohydrate supply overnight [15]
  • High-protein diet (as a possible source of glucose)

Medical Care

In general, no specific treatment exists for glycogen storage diseases (GSDs).

In some cases, diet therapy is helpful. Meticulous adherence to a dietary regimen may reduce liver size, prevent hypoglycemia, reduce symptoms, and allow for growth and development.

Zingone and colleagues demonstrated the abolition of the murine clinical manifestations of von Gierke disease with a recombinant adenoviral vector.[16] These findings suggest that corrective gene therapy for GSDs may be possible in humans.

An encouraging study by Bijvoet and colleagues provides evidence of successful enzyme replacement for the mouse model of GSD type II, which may lead to therapies for other enzyme deficiencies.[17]

A study by Asami and colleagues suggests that clonidine might be a treatment modality for Hers disease.[18]

Surgical Care

A case study by Ji et al suggested that GSD with hepatomegaly and hepatic adenoma can be successfully treated with reduced-size liver transplantation.[19] The authors retrospectively analyzed clinical data from a young female patient with GSD type I, whose clinical manifestations included hepatic adenoma, hepatomegaly, delayed puberty, growth retardation, sexual immaturity, hypoglycemia, and lactic acidosis. Ji and colleagues reported a satisfactory postsurgical outcome for the patient, including, over a 16-month period, height and weight increases of 12 cm and 5 kg, respectively. The patient was able to start enjoying a "normal life" and, according to Ji and colleagues, was continuing to do so 4 years postsurgery.

Diet

Growing evidence indicates that a high-protein diet may provide increased muscle function in patients with weakness or exercise intolerance.

Evidence also exists that a high-protein diet may slow or arrest progression of the disease.

A high-carbohydrate diet is effective in preventing hypoglycemia.

Most patients require little specific dietary intervention.

Long-Term Monitoring

The following are recommended for long-term monitoring:

  • Periodic fasting glucose measurement
  • Liver function studies
  • Annual liver ultrasound scan
 

Guidelines

Guidelines Summary

Clinical practice guidelines from the American College of Medical Genetics and Genomics (ACMG) address the diagnosis and management of glycogen storage diseases type VI and IX. For more information, please go to the guidelines.[20]

 

Medication

Medication Summary

No specific medication or recombinant enzyme is available.

Management for the most part comprises dietary modifications and treatment of complications.