Type VII Glycogen Storage Disease

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Background

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. 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.

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

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



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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), Cori disease (GSD type III, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), and Tarui disease (GSD type VII, phosphofructokinase deficiency), which is often misspelled as Tauri disease. 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 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.

These inherited enzyme defects usually present in childhood, although some, such as McArdle disease and Pompe disease, have separate adult-onset forms.[1] In general, GSDs are inherited as autosomal recessive conditions.[2] Several different mutations have been reported for each disorder.

Unfortunately, no specific treatment or cure exists, although diet therapy may be highly effective at reducing clinical manifestations. In some cases, liver transplantation may abolish biochemical abnormalities. Active research continues.

Diagnosis depends on findings from muscle biopsy, electromyography, ischemic forearm testing, creatine kinase testing, patient history, and physical examination.[3] Biochemical assay for enzyme activity is the method of definitive diagnosis.

Phosphofructokinase catalyzes the rate-limiting step in glycolysis. Phosphofructokinase deficiency leads to muscle pain and exercise-induced fatigue and weakness. Tarui disease resolves with rest, and, although no specific treatment exists, the condition may not progress to severe disability.

Pathophysiology

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. Phosphofructokinase catalyzes the rate-limiting step in glycolysis. Enzyme deficiency decreases the rate of conversion of fructose-6-phosphate to fructose-1,6-diphosphate. Phosphofructokinase is found in muscle tissue and red blood cells.

Tarui disease is an autosomal recessive condition.

Garcia et al investigated the effects of phosphofructokinase deficiency in tissue other than skeletal muscle on the pathogenesis of GSD type VII.[4] In a study of phosphofructokinase-deficient mice, the authors found that because the animals' erythrocytes retained only 50% of their phosphofructokinase activity, severe hemolysis, significant decreases in 2,3-bisphosphoglycerate levels (impairing the extraction of oxygen from hemoglobin), and compensatory reticulocytosis and splenomegaly occurred. Reduced levels of cardiac phosphofructokinase activity were found as well, which, combined with the other hematologic changes, led to the development of cardiac hypertrophy.

Madhoun et al reported a unique case of a man with phosphofructokinase deficiency who also presented with portal and mesenteric vein thrombosis.[5]

Epidemiology

Frequency

International

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

Mortality/Morbidity

As in McArdle disease, immediate morbidity arises from exercise intolerance.

Unlike in McArdle disease, Haller and Vissing found no consistent second wind phenomenon in GSD VII.[6]

Race

The disease appears to be prevalent among people of Ashkenazi Jewish descent.

Age

In general, GSDs present in childhood. Later onset correlates with a less severe form. Consider Pompe disease if onset is in infancy.

History

See the list below:

Physical

See the list below:

Causes

Phosphofructokinase is made of 4 peptides. A genetic defect has been discovered in the muscle subunit locus.

In a study of 5 patients with muscle phosphofructokinase deficiency from different regions of Italy, Musumeci et al found 4 novel genetic mutations.[11]

Laboratory Studies

Obtain a creatine kinase level in all cases of suspected glycogen storage disease (GSD). In patients with Tarui disease, creatine kinase levels are elevated.

Because hypoglycemia may be found in some types of GSD, fasting glucose testing is indicated. Hypoglycemia is of concern and may lead to hypoglycemic seizures.

Urine studies are indicated because myoglobinuria may occur in some patients with GSDs. In patients with Tarui disease, myoglobinuria may be present after exercise.

Hepatic failure occurs in some patients with GSDs. Liver function studies are indicated.

Biochemical assay reveals normal phosphorylase activity. Phosphofructokinase is absent on histochemistry assay.

Some specific features that may help differentiate Tarui disease from McArdle disease include the following:

Other Tests

Ischemic forearm test

Interpretation of ischemic forearm test results

Electromyography

Procedures

Muscle biopsy is necessary for definitive diagnosis.

Histologic Findings

Findings from muscle biopsy may reveal subsarcolemmal vacuoles. Red blood cell examination indicates moderate hemolytic anemia. Phosphorus-31 magnetic resonance spectroscopy may help establish diagnosis. Abnormal polysaccharide, which is resistant to diastase digestion, is present in muscle fibers but is not seen in patients with McArdle disease (GSD, type V).

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, allow for reduction in symptoms, and allow for growth and development in patients with GSDs.

Zingone and colleagues demonstrated the abolition of the murine clinical manifestations of von Gierke disease with a recombinant adenoviral vector.[12] 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 Pompe disease, which may lead to therapies for other enzyme deficiencies.[13]

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.

Activity

Avoidance of intense exercise may ameliorate symptoms.

Complications

Tarui disease causes exercise intolerance and mild hemolysis.

Prognosis

No cure exists.

Patient Education

As with all genetic diseases, genetic counseling is appropriate.

Author

Wayne E Anderson, DO, FAHS, FAAN, Assistant Professor of Internal Medicine/Neurology, College of Osteopathic Medicine of the Pacific Western University of Health Sciences; Clinical Faculty in Family Medicine, Touro University College of Osteopathic Medicine; Clinical Instructor, Departments of Neurology and Pain Management, California Pacific Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Kent Wehmeier, MD, Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

David M Klachko, MD, MEd, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Missouri-Columbia School of Medicine

Disclosure: Nothing to disclose.

References

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  3. Tarnopolsky MA. Metabolic Myopathies. Continuum (Minneap Minn). 2016 Dec. 22 (6, Muscle and Neuromuscular Junction Disorders):1829-1851. [View Abstract]
  4. Garcia M, Pujol A, Ruzo A, et al. Phosphofructo-1-kinase deficiency leads to a severe cardiac and hematological disorder in addition to skeletal muscle glycogenosis. PLoS Genet. 2009 Aug. 5(8):e1000615. [View Abstract]
  5. Madhoun MF, Maple JT, Comp PC. Phosphofructokinase deficiency and portal and mesenteric vein thrombosis. Am J Med Sci. 2011 May. 341(5):417-9. [View Abstract]
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Metabolic pathways of carbohydrates.

Metabolic pathways of carbohydrates.