Type V 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 diagram below illustrates metabolic pathways of carbohydrates.

View Image

Metabolic pathways of carbohydrates.

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)

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 and is a disorder causing glycogen deficiency 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. In general, GSDs are inherited as autosomal recessive conditions. Several different mutations have been reported for each disorder.^[1]

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 patient history and physical examination, creatine kinase testing, muscle biopsy, electromyelography, and ischemic forearm testing. Biochemical assay for enzyme activity is the method of definitive diagnosis.

Myophosphorylase, the deficient enzyme in McArdle disease, is found in muscle tissue. Myophosphorylase deficiency causes muscle cramps, pain, and stiffness. One hallmark of McArdle disease is weakness with exertion. Proximal muscle weakness may progress with time, and no specific treatment exists.

Recent research

To study the role of fat metabolism in GSD type V, Andersen et al manipulated the availability of free fatty acid for oxidation during exercise in 10 patients with the disease.^[2] The patients, who cycled at a constant workload corresponding to 70% of their maximum oxygen consumption, received either nicotinic acid or 20% Intralipid infusion, which, respectively, reduced or increased free fatty acid availability.

Comparing their trial results with those of placebo and glucose infusion studies, the authors concluded that although during exercise lipids are an important fuel source in persons with GSD type V, maximal fat oxidation rates during exercise cannot be raised above physiologically normal rates in these patients. Andersen et al suggested that this limitation results from glycolytic flux impairment, which causes a "metabolic bottleneck" in the tricarboxylic acid cycle.

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Pathophysiology

The phenotype of the individual with GSD results from an enzyme defect. Carbohydrate metabolic pathways are blocked, leading to excess glycogen accumulation in affected tissues and/or disturbances in energy production. Several gene mutations have been described.^[1]

Fatty acids and glucose serve as substrates for energy production. With intense exercise, glucose from glycogen stores in muscle becomes the predominant resource. Fatigue develops when the glycogen supply is exhausted.^{[3, 4]} Each GSD represents a specific enzyme defect, and each enzyme is in specific, or most, body tissues. Myophosphorylase is found in muscle. Hypoglycemia is not an expected finding because liver phosphorylase is not involved.

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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

Immediate morbidity arises from severe exercise intolerance.

Age

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

The majority of patients with McArdle disease present in the second to third decade of life.

Wolfe and colleagues report a unique case of McArdle disease presenting in a person aged 73 years.^[5] Felice and colleagues and Pourmand and colleagues also report late presentations. Physicians should have clinical suspicion regardless of age of presentation.^{[6, 7]}

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History

See the list below:

• Age at onset of symptoms depends on enzyme activity levels. Initial symptoms are cramps, fatigue, and pain after exercise.^[8]
• Because severity depends on enzyme activity, individual presentation is unique.
• Some adults develop a progressive proximal weakness.
• Some adults develop a fixed motor weakness.
• The disorder has a unique "second-wind" phenomenon.^[9] If a patient nearing fatigue slows exercise to a tolerable level, a point exists at which exercise may be increased again without previous symptoms^[10] . According to Braakhekke and colleagues, this phenomenon may be secondary to increased recruitment of motor units, increased cardiac output, and use of free fatty acids for muscle metabolism.^[11]
• Burgundy-colored urine has been reported. It is thought to be a result of rhabdomyolysis after intense exercise.
• Voduc and colleagues report an unusual presentation as unexplained dyspnea.^[12]
• The rate of rise in oxygen consumption per unit time (VO₂) is relative to work rate increases.

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Physical

See the list below:

• Diagnosis is suggested by patient history.
• Clinical findings may be absent upon physical examination.
• Muscle strength and reflexes may be normal.
• In later adult life, persistent weakness and muscle wasting may be present.
• When clinical suspicion is present, diagnostic testing includes the ischemic forearm test, laboratory analysis, and electromyography.
• Pillarisetti and Ahmed report a case of GSD V presenting as acute renal failure.^[13]

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Causes

GSD type V is an autosomal recessive disease, with heterozygotes usually not manifesting clinical features of the disease.

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Laboratory Studies

See the list below:

• Obtain a creatine kinase level in all cases of suspected GSD. Creatine kinase levels are elevated in more than 90% of patients with McArdle disease. Bruno and colleagues report a case of elevated creatine kinase on routine screening as the only sign of McArdle disease in a 13-year-old boy.^[14]
• 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.
• Hepatic failure occurs in some patients with GSDs. Liver function studies are indicated. In general, the liver contains little myophosphorylase.
• Myoglobinuria is found in 50% of patients after exercise.
• Biochemical assay is required for definitive diagnosis. Phosphorylase reaction is absent.

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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 a positive ischemic test result.
• Failure of ammonia to increase with lactate is evidence of myoadenylate deaminase deficiency.
• If a patient has McArdle disease, the ischemic forearm test results are positive.

Electromyography

• In contrast to most GSDs, findings upon electromyography 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, although 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 assay of muscle enzyme activity.

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Histologic Findings

Muscle biopsy findings may reveal fiber size variability, positive subsarcolemmal blebs with periodic acid-Schiff stain, and intermyofibril vacuoles. Felice and colleagues reported selective atrophy of type 1 muscle fibers.^[15]

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Medical Care

In general, no specific treatment exists for 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. A high-protein diet may increase exercise tolerance in some cases, although this practice is controversial.^[16]
• Zingone and colleagues demonstrated the abolition of the murine clinical manifestations of von Gierke disease with a recombinant adenoviral vector.^[17] 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.^[18]
• Interest in glucagon treatment for McArdle disease has developed, but a study by Day and Mastaglia showed no benefit over placebo.^[19]

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Diet

A high-protein diet may increase exercise tolerance in some cases, although this practice is controversial.

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Activity

Avoidance of intense physical activity usually ameliorates symptoms.

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Complications

There are potential anesthetic and perioperative risks.^[20]

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Prognosis

The condition is chronic.

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Patient Education

Genetic counseling is appropriate for all individuals with a genetic disorder.

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