Type VII Glycogen Storage Disease

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Practice Essentials

Glycogen storage disease (GSD) VII (Tarui disease) is an autosomal recessive disorder caused by a deficiency of phosphofructokinase (PFK), the enzyme that catalyzes the rate-limiting step in glycolysis.[1] The diagnosis is made on the basis of findings from the history and physical examination, muscle biopsy, electromyography, ischemic forearm testing, and creatine kinase testing.[2] No specific treatment is available; however, diet therapy may reduce clinical manifestations.

Signs and symptoms

Symptoms usually first occur during childhood and include the following:

See Presentation for more detail.

Diagnosis

Laboratory studies

The following laboratory studies are recommended:

Other studies

The following tests and procedures are also recommended:

See Workup for more detail.

Management

Although no specific treatment exists for GSD VII, diet therapy is helpful in some cases. A high-protein diet may help increase muscle function in patients with weakness or exercise intolerance.

See Treatment for more detail.

Background

Glycogen is a complex multibranched polysaccharide that acts as energy storage in the human body and is formed mainly in the liver and skeletal muscles. It plays an important role as a glucose-manipulating system that maintains appropriate glucose levels in the human body. It is degraded to glucose molecules when the body needs energy or is in a "fasting state." On the other hand, it is formed and accumulated in the liver and skeletal muscle when blood glucose is elevated after food intake or during the "fed state."

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, especially liver and skeletal muscle cells. 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, based on which enzyme is affected in the carbohydrate metabolic pathway. Each GSD represents a specific enzyme defect, and each enzyme is also specific for certain body cells. 

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

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



View Image

Metabolic pathways of carbohydrate metabolism

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). 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.[3]  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.[2]  Biochemical assay for enzyme activity is the method of definitive diagnosis.

GSD type VII, or Tarui disease, is named after Dr Seiichiro Tarui, the Japanese physician who first described this disorder in 1965.[4]  He found that 3 Japanese siblings whose parents were first cousins had muscle weakness after prolonged exertion. All of them had absent activity of phosphofructokinase (PFK) in the skeletal muscle.

This article will focus mainly on GSD type VII, or PFK deficiency. We will review the pathophysiology, genetics, disease manifestations, diagnosis, and treatment. 

Pathophysiology

GSD VII, or Tarui disease, is an autosomal recessive condition caused by deficiency of PFK, the enzyme that catalyzes the rate-limiting step in glycolysis. It turns fructose-6-phosphate (F-6-P) to fructose-1,6-bisphosphate. Enzyme deficiency results in glycolysis blockage and accumulation of F-6-P, which can turn to glucose-6-phosphate (G-6-P), leading to increased glycogen formation. This causes myopathy, including 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.

Garcia et al investigated the effects of PFK deficiency in tissue other than skeletal muscle on the pathogenesis of GSD type VII.[5] In a study of PFK-deficient mice, the authors found that because the animals' erythrocytes retained only 50% of their PFK 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 PFK activity were found as well, which combined with the other hematologic changes, led to the development of cardiac hypertrophy.

Currently, it is known that PFK consists of 3 subunit isozymes including M (muscle), L (liver), and P (platelet). Active PFK has tetrameric structure, and each tissue in the human body has a specific different subunit composition. For example, skeletal myocytes express only M subunit, erythrocytes express both M and L subunit equally, and hepatocytes and nephrons express L subunit in the majority.[6, 7]  For GSD type VII, M isozyme is affected. Therefore, muscle cells and red bood cells are affected in patients who have this disease.

Early onset of hyperuricemia and gouty arthritis is found in some patients. It is believed that this condition results from increased shunting of F-6-P to the pentose phosphate pathway, which results in increased production of nucleotide, leading to an increase in uric acid formation and gout crystal formation eventually. Vora et al reported 3 patients with PFK deficiency and hyperuricemia, who had elevated levels of hexose monophosphate.[8]

Some aspects of GSD type VII still have no explanation. For example, brain neurons mainly express M subunit, but there are few data about neurologic involvement in this disease. Madhoun et al reported a unique case of a man with PFK deficiency who also presented with portal and mesenteric vein thrombosis, which did not have clear pathogenesis.[9]

Causes and genetics

GSD type VII is a genetic disorder with autosomal recessive inheritance, caused by homozygous or compound heterozygous mutations in the gene encoding for the M subunit of the PFK enzyme on chromosome 12q13, which contains a total of 24 exons.

Various mutations have been discovered, including missense and frameshift types. Patients of Ashkenazi Jewish descent have been found to have specific splice site mutations in exon 5 and exon 22.[10]

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

Epidemiology

GSDs are very rare conditions. In Europe, Canada, and the United States, the total incidence is between 1 in 20,000 and 1 in 40,000. GSD type VII is extremely rare, and most data are obtained from case reports or case series. The true incidence of the disease may be higher, as clinical features of the disease are mild and affected patients may not be recognized and diagnosed.

Race- and age-related demographics

Raben et al reported that the disease appears to be prevalent among people of Ashkenazi Jewish descent with mutations of the PFKM gene that cause exon slicing site defect.[12, 10]

In general, GSDs present in childhood. Later onset correlates with a less severe form. Most of the infantile forms have a severe course of disease and multisystem involvement, leading to high mortality.[13, 14, 15]

Prognosis

No cure exists for GSD type VII.

Morbidity/mortality

As in McArdle disease, immediate morbidity arises from exercise intolerance. In 1984, Haller et al found that some patients with PFK deficiency have muscle fatigue more rapidly after a high-carbohydrate meal.[16]  Unlike in McArdle disease, Haller el al later found that there is no consistent "second wind phenomenon" in GSD type VII.[17]  Second wind phenomenon is described as a decrease in heart rate and an improvement in exercise tolerance after 6-8 minutes of aerobic excercise.

Complications

Tarui disease causes exercise intolerance and mild hemolysis.

Patient Education

As with all genetic diseases, genetic counseling is appropriate.

The following patient education resources are available from WebMD:

History

Severity varies based on an individual's enzyme activity level. Symptoms typically present in childhood, including exercise intolerance (premature fatigability), weakness and stiffness with exercise, and painful muscle cramps. Most symptoms resolve with resting. Sometimes, symptoms can be of late onset.[18, 19]

Exercise intolerance is noted in childhood much earlier and is more severe in Tarui disease than in McArdle disease. The second wind phenomenon is not seen in Tarui disease as it is in McArdle disease. Haller and Vissing concluded that the inability to properly metabolize blood glucose prevents the spontaneous second wind.[20]

Patients can present with myoglobinuria and rhabdomyolysis. Exantus et al report one case of acute renal failure secondary to rhabdomyolysis.[21]

Finsterer et al reported on one patient who was followed up for several years.[22, 23] Neurologic symptoms believed attributable to Tarui disease included complex partial seizures, diplopia, hyporeflexia, central facial palsy, and upper extremity weakness.

 

Physical Examination

Physical examination findings may be normal; therefore, clinical suspicion must be derived from patient history findings.

Muscle weakness after exercise, muscle contracture, and signs of hemolysis, including anemia and jaundice, may be detected. Hypotonia, seizure, blindness, catatacts, and cardiomyopathy can be found in the infantile form.[13, 14, 15]

Laboratory and procedural studies may be helpful to confirm the diagnosis. (See Workup for more detail.)

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.

Evidence of mild hemolytic anemia can be found, including increased bilirubin and reticulocyte count.

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

Biochemical assay reveals normal phosphorylase activity. Muscle PFK is absent on histochemistry assay, whereas erythrocyte PFK activity is reduced to about 50% of normal PFK.

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

Other Tests

Ischemic forearm test

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. In patients with Tarui disease, ischemic forearm test results are positive.

Electromyography

Findings on electromyography testing in patients with phosphofructokinase deficiency may be normal. Findings from electromyography of resting muscle are normal. Electrical activity is absent during contracture.

Repetitive nerve stimulation at low frequency (2 Hz) does not demonstrate an abnormal response, while repetitive stimulation at high frequency (15 Hz) may produce a decrement with contracture formation.

Single-fiber electromyography may reveal increased jitter.

Histologic Findings

Muscle biopsy is necessary for definitive diagnosis.

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 et al demonstrated the abolition of the murine clinical manifestations of von Gierke disease with a recombinant adenoviral vector.[24] These findings suggest that corrective gene therapy for GSDs may be possible in humans.

An encouraging study by Bijvoet et al provides evidence of successful enzyme replacement for the mouse model of Pompe disease, which may lead to therapies for other enzyme deficiencies.[25]

Diet and Activity

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. Patients who followed a low-carbohydrate ketogenic diet showed improvement in exercise intolerance, as this diet may bypass glycolysis blockage and provide an immediate fuel source that improves normal muscle function.[26, 27]

Activity

Avoidance of intense exercise may ameliorate symptoms.

Author

Natapat Chaisidhivej, MD, Resident Physician, Department of Internal Medicine, Einstein Medical Center Philadelphia

Disclosure: Nothing to disclose.

Coauthor(s)

Catherine Anastasopoulou, MD, PhD, FACE, Associate Professor of Medicine, The Steven, Daniel and Douglas Altman Chair of Endocrinology, Sidney Kimmel Medical College of Thomas Jefferson University; Einstein Endocrine Associates, Einstein 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.

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.

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.

References

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Metabolic pathways of carbohydrate metabolism

Metabolic pathways of carbohydrate metabolism