NEJM
Perspective
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Anthony A. Amato, M.D.
Carbohydrates are often stored as glycogen in the body. Pathways for the synthesis and breakdown of glycogen (see Figure) permit the maintenance of a steady blood glucose level and provide a source of energy. There are 14 recognized glycogen storage diseases, most of which are "dynamic" in nature, in that the major symptoms are related to exercise intolerance; these symptoms are attributable to an inability to break down glycogen and its metabolites to form ATP. Glycogen storage disease types II, III, and IV are considered to be "static" in nature in that they are associated with fixed weakness, rather than exercise intolerance.
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Glycogen storage disease type V, also known as McArdle's disease, is the most common of these diseases. It is an autosomal recessive disorder caused by mutations in the gene that encodes myophosphorylase, an enzyme that is essential for glycogenolysis. Exercise intolerance usually develops during childhood in patients with McArdle's disease, along with pain, cramps, and fatigue in exercised muscle. These symptoms are more likely to be induced by brief, intense activities (e.g., weight lifting or sprinting) but can also occur after prolonged, low-intensity exercises (e.g., swimming or jogging). Severe muscle damage can lead to myoglobinuria and renal failure. Many patients note a "second-wind" phenomenon, whereby exercise becomes more easily tolerated after approximately 10 minutes of continued activity. This phenomenon is considered to be related to the body's ability to metabolize free glucose that is mobilized into the bloodstream. Most patients have normal findings on physical examination. However, mild, fixed proximal weakness eventually develops in as many as one third of patients as a result of recurrent bouts of rhabdomyolysis.
There is a certain amount of clinical heterogeneity among patients with McArdle's disease. Some patients report that they become fatigued easily but have no clinically significant muscle cramps or pain, whereas others present with progressive atrophy and weakness of proximal muscles in late adulthood. In rare cases, McArdle's disease is manifested as congenital weakness accompanied by progressive respiratory failure.
When a disorder of glycolysis is suspected, the first step in the evaluation of the patient should be a forearm exercise test. A small intravenous catheter is placed in the antecubital fossa, and base-line lactate and ammonia levels are measured. Next, the patient is asked to open and close the ipsilateral hand rapidly for one minute to exercise the forearm muscles. Immediately after exercise and then 1, 2, 4, 6, and 10 minutes after exercise, additional blood samples are obtained for the measurement of lactate and ammonia. Normally, the lactate and ammonia levels increase to three to four times the base-line levels. If neither the lactate level nor the ammonia level increases, the test is inconclusive and suggests that the muscles were not sufficiently exercised. In patients with a deficiency of debrancher, myophosphorylase, phosphofructokinase, phosphoglycerate mutase, phosphoglycerate kinase, phosphorylase b kinase, enolase, or lactate dehydrogenase enzyme, the ammonia level increases appropriately but the lactate level does not. An increase in the lactate level but not the ammonia level is diagnostic of myoadenylate deaminase deficiency.
If the forearm exercise test is abnormal, a muscle biopsy is performed to identify the specific enzyme defect. Specimens from muscle biopsies in persons with glycogen storage diseases are characterized by an accumulation of glycogen in the subsarcolemmal and intermyofibrillar areas. In patients with McArdle's disease, myophosphorylase staining is absent, and biochemical assays reveal that myophosphorylase activity is absent or substantially reduced.
Unfortunately, no treatments have been shown to alleviate the symptoms of exercise intolerance or reduce the risk of myoglobinuria in patients with McArdle's disease. In this issue of the Journal, Vissing and Haller (pages 2503�2509) report the results of a single-blind, placebo-controlled, crossover study of oral sucrose (75 g) in 12 patients with McArdle's disease. Sucrose is the most prevalent dietary sugar and is rapidly metabolized to glucose and fructose after ingestion. The ingestion of sucrose 30 to 40 minutes before patients cycled at maximal intensity led to increases in the plasma glucose level and marked improvement in exercise tolerance, as documented by reductions in both the patients' perceived level of exertion and the maximal heart rate recorded during exercise testing. This improved exercise tolerance was noted during the period when severe muscle injury often develops in patients with McArdle's disease; such injury may lead to severe muscle damage and myoglobinuria.
The important implication for the treatment of patients with McArdle's disease is that the oral ingestion of sucrose before aerobic exercise improves exercise tolerance and reduces the risk of myoglobinuria. The limitations of oral sucrose loading are that the beneficial effect is short-lived and that repeated dosing may lead to weight gain, which can itself reduce exercise tolerance. It may also inhibit the utilization of fatty acids, an important source of fuel during prolonged physical activity. In addition, sucrose loading will not be helpful in situations that are characterized by unexpected exertional activity, prolonged physical activity, or static exercise (such as weight lifting).
Some patients with McArdle's disease appear to benefit from mild aerobic conditioning programs that improve exercise capacity by increasing cardiovascular fitness and the supply of free glucose and fatty acids available to muscle.1 Patients should be instructed to moderate their physical activity. Any planned moderate exercise should be preceded by 5 to 15 minutes of low-level warmup activity to promote the transition to the "second wind."1
Better treatments are clearly needed for McArdle's disease and all the other glycogen storage disorders. Realistically, gene therapy is years away. But until better treatments become available for McArdle's disease, the oral ingestion of sucrose before exertional activity, used in moderation and combined with an aerobic conditioning program, is a reasonable approach to the management of this difficult myopathy.
Source Information
From Brigham and Women's Hospital, Boston.
References
- Haller RG. Treatment of McArdle disease. Arch Neurol
2000;57:923-924.
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