Genetics of Glycogen-Storage Disease Type V

Updated: Nov 10, 2015
  • Author: Edward J Cupler, MD, FAAN; Chief Editor: Maria Descartes, MD  more...
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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 activity. [1] In 1959, myophosphorylase was discovered and was found to be absent in individuals with McArdle disease. The typical features of McArdle disease, or glycogen-storage disease type V, 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 rhabdomyolysis 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 described. See the image below.

Enzyme histochemistry of 19-year-old male with McA Enzyme histochemistry of 19-year-old male with McArdle disease.


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 are noted. 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).

The symptoms in patients with McArdle disease are most likely caused by the pattern of fuel utilization of exercising muscle. ATP requirements are dramatically increased during muscular exercise. Initially, isometric and strenuous exercise relies on glucose derived from glycogen breakdown catalyzed by phosphorylase. The glucose then serves as a substrate for glycolysis, leading to the production of ATP via the Krebs cycle. The exercising muscle then derives energy from blood-borne sources, such as glucose and free fatty acids. The increased levels of fatty acids as additional energy sources for muscle may account for the “second wind” phenomenon. [2, 3]




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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 (PGYM) 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.


Muscular weakness and fatigue are observed. 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. Rhabdomyolysis following vigorous exercise may result in myoglobinuria. As many as one third of patients with myoglobinuria develop acute renal failure. Death is caused by respiratory failure due to severe rapidly progressive muscular weakness.


McArdle disease is inherited in an autosomal recessive pattern. The disease has been reported more often in males than in females, probably reflecting small numbers and sampling effects. Genetic data and disease severity correlations were studied in 99 patients of Spanish descent with McArdle disease; 41% of the female subjects scored in the highest severity category compared with only 20% of the males. [4, 5]


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.