AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1951, McArdle described a 30-year-old man who experienced pain followed by weakness and stiffness after exercise. The venous lactate level of this patient failed to increase after ischemic activity¹. In 1959, myophosphorylase was discovered and was found to be absent in individuals with McArdle disease. The typical features of McArdle disease include exercise intolerance with myalgia, early fatigue, muscle stiffness, and cramping, which are all relieved by rest. Following a short period of rest, most patients experience a “second wind” phenomenon and can resume exercise without difficulty.

About one half of patients experience acute muscle necrosis and myoglobinuria following vigorous exercise, and some may develop renal failure. Mild proximal muscle weakness occurs in approximately one third of patients and is more common in older patients. A fatal infantile form of McArdle disease, characterized by hypotonia, generalized muscle weakness, and progressive respiratory insufficiency, has been reported. In addition, a late-onset form with no symptoms until the sixth decade of life has been reported.

Pathophysiology

McArdle disease is caused by a deficiency of myophosphorylase (alpha-1,4-glucan orthophosphate glycosyl transferase), which normally initiates glycogen breakdown by removing 1,4-glucosyl groups from glycogen with the release of glucose-1-phosphate. Several tissue-specific isoforms of phosphorylase exist. Although myophosphorylase is present in cardiac muscle and the brain, it is the only isoform present in skeletal muscle. The liver isoform is deficient in individuals with glycogen-storage disease type VI (Hers disease). Most patients with McArdle disease have undetectable myophosphorylase activity and, thus, are unable to release glucose from glycogen in muscle. Rarely, patients have residual enzyme activity (<30% of normal).

Frequency

United States

McArdle disease is inherited in an autosomal recessive manner. The frequency is estimated at 1 per 100,000 population. However, only a few hundred cases have been reported. This disorder is probably underdiagnosed because of the mild symptoms in many patients. The early-onset form is extremely rare; only several cases have been reported. The late-onset form is also exceedingly rare. The gene for myophosphorylase is localized on chromosome 11. More than 65 mutations have been identified. Manifesting heterozygotes occur, and synergistic heterozygosity involving this gene may account for muscle symptoms in some heterozygotes.

Mortality/Morbidity

• Muscular weakness and fatigue: Tiredness, weakness, and cramping can interfere with normal activity. Some patients can adapt their exercise patterns to take advantage of the “second wind” phenomenon. Fixed proximal weakness occurs in as many as one third of patients.


• Myoglobinuria: Rhabdomyolysis following vigorous exercise may result in myoglobinuria. Up to one third of patients with myoglobinuria develop acute renal failure.


• Fatal infantile McArdle syndrome: Death is caused by respiratory failure due to severe rapidly progressive muscular weakness.

Sex

McArdle disease is inherited in an autosomal recessive pattern. The disease has been reported more in males than in females, probably reflecting small numbers and sampling effects.

Age

McArdle disease typically presents in the second to third decade of life with limited exercise tolerance. The fatal infantile form manifests in the newborn period.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The usual presenting symptom is exercise intolerance, including muscle stiffness or weakness, myalgia, fatigue, and cramps. These symptoms are precipitated by isometric exercise (eg, weight lifting) and sustained aerobic exercise (eg, stair climbing, jogging) and are typically relieved with rest. Many patients experience a “second wind” phenomenon, whereby they can resume activity following a brief period of rest.


• Clinical heterogeneity exists; some patients have extremely mild symptoms that manifest as tiredness without cramps. In others, progressive weakness starts in the sixth or seventh decade of life. In contrast, the severe rapidly progressive form (fatal infantile McArdle syndrome) manifests shortly after birth. Fixed weakness occurs in about one third of patients, is more likely to involve proximal muscles, and is more common in older patients.


• Myoglobinuria occurs in about one third of patients following intense exercise, and a significant proportion of these patients develop acute renal failure.


• Seizures have been described in 4% of patients.

Physical

• Classic and late-onset McArdle disease

• Proximal muscle weakness (most pronounced following exercise)

• Fixed limb weakness (more likely to involve the proximal muscle)

• Muscle wasting

• Fatal infantile variant

• Hypotonia

• Diminished deep tendon reflexes

Causes

Nonsense, deletion, missense, and splice-junction mutations have been found in the gene that encodes the muscular isoform of phosphorylase. The gene is mapped to 11q13 and contains 20 exons. Although mutational heterogeneity exists, the molecular defect results in the near-complete absence of the protein in skeletal muscle in most individuals.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Mitochondrial myopathy
Phosphoglycerate kinase deficiency
Phosphoglycerate mutase deficiency
Phosphofructokinase deficiency
Lactate dehydrogenase deficiency

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Elevated serum creatine (Cr) kinase levels at rest


• No increase in venous lactic acid levels following exercise testing

Imaging Studies

• Phosphorous 31-nuclear magnetic resonance (31P-NMR) findings reveal a lack of cytoplasmic acidification during exercise and a greater-than-normal drop in recalculating Cr/inorganic phosphate (Pi) ratio.

Other Tests

• Electromyography (EMG): One half of patients may have nonspecific myopathic changes. Some patients have signs of increased muscle irritability. During exercise-induced cramps, electrical activity may be absent on EMG.


• Ischemic forearm exercise test

Histologic Findings

• Subsarcolemmal deposits of glycogen appear at the periphery of fibers. Accumulation of glycogen between myofibrils may give the fibers a vacuolar appearance. The glycogen is periodic acid–Schiff (PAS) positive. Glycogen may be washed out when the tissue is processed. Therefore, the lack of apparent glycogen accumulation on muscle biopsy findings does not rule out the condition. Electron microscopy findings reveal extensive accumulation of normal-appearing glycogen under the sarcolemma and between the myofilaments.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Therapies used in an attempt to bypass the metabolic block by providing glucose or fructose yield inconsistent results. Similarly, injection of glucagons yields inconsistent results.


• Because the branched-chain amino acids represent alternative fuels for exercising muscle, a high-protein diet may be beneficial.

Consultations

Acute renal failure may occur with rhabdomyolysis, necessitating consultation with a nephrologist. Monitor renal function in all patients with McArdle disease. This may be performed in conjunction with a nephrologist.

Diet

Case reports suggest that ketogenic or high-protein diets may be beneficial, although controlled clinical trials have yet to be published.

Activity

Strenuous and isometric exercises are most likely to cause symptoms and, therefore, are most likely to induce rhabdomyolysis. Many patients are able to comfortably resume steady exercise after briefly resting. This exercise pattern takes advantage of the “second wind” phenomenon, wherein the exercising muscle no longer relies on stored glycogen for fuel.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

In general, no specific treatment exists for McArdle disease. Vitamins such as vitamin B-6 (pyridoxine) may be beneficial to correct depleted body stores and augment myophosphorylase activity. Sucrose may improve exercise tolerance. Creatine may improve ATP capacity and exercise tolerability.

Other treatments, such as d-ribose, glucagon, verapamil, and dantrolene, have not been shown to be effective. Branched-chain amino acids were shown to worsen functional activity and exercise capacity.

Drug Category: Vitamins

These agents are necessary to promote regular growth and good health. Some studies suggest that pyridoxine may reduce the susceptibility of muscles to fatigue in patients with McArdle disease. Normally, myophosphorylase uses pyridoxal 5'-phosphate (derived from vitamin B-6) as a cofactor; therefore, supplementation may augment the remaining myophosphorylase activity. In addition, most of the total body pool of pyridoxine is normally bound to myophosphorylase; therefore, the body's store of pyridoxine may be depleted in patients with McArdle disease.

Drug Category: Nutritional Agent

Sucrose is a disaccharide that is readily split into glucose and fructose. These sugars circumvent the metabolic block in individuals with McArdle disease. Recently, sucrose (75 g 30 min PO before exercise) was shown to improve exercise tolerance to the point that no "second wind" phenomenon is observed².

Drug Category: Nutritional Supplement

Creatine monohydrate supplementation may increase ATP availability and exercise capacity. A single study demonstrated an increase in exercise capacity while low-dose creatine monohydrate (60 mg/kg/d) was administered. Interestingly, a subsequent study by the same group revealed a deleterious effect at a dosage of 150 mg/kg/d³.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• If acute renal failure occurs, hemodialysis and appropriate monitoring of fluid and electrolyte status may be necessary.

Deterrence/Prevention

• Because acute renal failure is precipitated by rhabdomyolysis in McArdle disease, avoidance of strenuous and/or isometric exercise may be indicated.

Complications

• Acute renal failure may complicate muscle necrosis and myoglobinuria following vigorous exercise.

Prognosis

• McArdle disease typically has a relatively benign nature when severe rhabdomyolysis is avoided. Limitation or adaptation of exercise to avoid symptoms may be necessary. Acute renal failure requires appropriate treatment. Progression to chronic renal disease has not been described, but acute renal failure due to myoglobinuria is potentially life threatening.

Patient Education

• Educate patients about modifying their activity in order to prevent rhabdomyolysis. Patients should avoid isometric exercise (eg, weight lifting, pushing heavy objects), as well as sustained dynamic exercise (eg, stair climbing, walking uphill). Educate patients about the “second wind” phenomenon.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to monitor renal function with episodes of myoglobinuria

• Failure to inform the family about the autosomal recessive inheritance, which may be important for siblings and future pregnancies.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: May 17, 2007