Type VII Glycogen Storage Disease

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:

• 0 - Glycogen synthase deficiency
• Ia - Glucose-6-phosphatase deficiency (von Gierke disease)
• 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 (Tarui disease)

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

View Image

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.

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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]

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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.

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History

See the list below:

• Severity varies based on an individual's enzyme activity level.
• Symptoms include exercise intolerance (premature fatigability), weakness and stiffness with exercise, and painful muscle cramps. Symptoms resolve with rest.
• 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.^[7]
• Exantus and colleagues report one case of acute renal failure secondary to rhabdomyolysis.^[8]
• Finsterer and colleagues report on one patient followed for several years.^{[9, 10]} Neurologic symptoms believed attributable to Tarui disease include complex partial seizures, diplopia, hyporeflexia, central facial palsy, and upper extremity weakness.

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Physical

See the list below:

• Physical examination findings may be normal; therefore, clinical suspicion must be derived from patient history findings.
• Laboratory and procedural studies may be helpful.

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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]

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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:

• Compensated hemolytic anemia in GSD type VII
• Hyperuricemia that is worsened by exercise in Tarui disease

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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.

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Procedures

Muscle biopsy is necessary for definitive diagnosis.

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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).

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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]

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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.

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Activity

Avoidance of intense exercise may ameliorate symptoms.

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Complications

Tarui disease causes exercise intolerance and mild hemolysis.

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Prognosis

No cure exists.

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Patient Education

As with all genetic diseases, genetic counseling is appropriate.

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