Type VI Glycogen Storage Disease 

Updated: Feb 21, 2019
Author: Wayne E Anderson, DO, FAHS, FAAN; Chief Editor: George T Griffing, MD 

Overview

Practice Essentials

A glycogen storage disease (GSD) is the result of an enzyme defect. 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 in specific, or most, body tissues. Liver phosphorylase, which is found in the liver and red blood cells, is deficient, 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 poor growth. Symptoms result from mild hypoglycemia. Liver fibrosis and hepatocellular carcinoma have been reported in patients with GSD VI.

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 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. Diagnosis by DNA analysis is considered preferable to liver biopsy so as to avoid an invasive procedure. 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 4 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. The remaining GSDs are not necessarily benign but are less clinically significant; therefore, the physician should consider the aforementioned GSDs when initially entertaining the diagnosis of a GSD. Interestingly, GSD type 0 also is described, which is due to defective glycogen synthase.

Epidemiology

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

Herling and colleagues 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 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.

 

 

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.

Hepatic failure occurs in some patients with GSDs, although rarely in those with GSD VI disease. Liver function studies are indicated and may reveal evidence of hepatic injury.

Biochemical assay of enzyme activity is necessary for definitive diagnosis.

Manzia et al reported the first documented case of GSD associated with a rapidly growing hepatocellular adenoma as determined by histologic findings.[12]

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

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.[13] 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.[14]

A study by Asami and colleagues suggests that clonidine might be a treatment modality for Hers disease.[15]

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.[16] 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.

High-carbohydrate diet is effective in preventing hypoglycemia.

Most patients require little specific dietary intervention.