Genetics of Glycogen-Storage Disease Type V 

Updated: Nov 10, 2015
Author: Edward J Cupler, MD, FAAN; Chief Editor: Maria Descartes, MD 



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]



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 (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.




The usual presenting symptom of McArdle disease (glycogen-storage disease type V) 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.[6]

Clinical heterogeneity is observed; 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.


See the list below:

  • 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


Genetic abnormalities that include nonsense, deletion, missense, and splice-junction mutations have been found in the gene (PGYM), which encodes the muscular isoform of phosphorylase. PGYM is mapped to 11q13 and contains 20 exons.[7] Although mutational heterogeneity is noted, the molecular defect results in the near-complete absence of the protein in skeletal muscle in most individuals.

A potential modifying gene has been identified. Studies from 2 separate investigators, Martinuzzi et al and Rubio et al, have shown that the angiotensin converting enzyme gene (ACE) correlates well with disease severity.[4, 8]

The 2 alleles for the ACE gene include I, which confers the presence of a 287 base pair repeat element in exon 16, and D , which confers the absence of the repeat. Both studies found that the number of D alleles correlated strongly with disease severity.

Disease severity was scored on a 4-class grading system as follows:

  • 0 - Mild exercise intolerance but no functional limitation in any daily life activity

  • 1 - Exercise intolerance, cramps, myalgia, and limitation of acute strenuous exercise, and occasionally in daily life activities; no record of myoglobinuria, no muscle wasting or weakness

  • 2 - Symptoms included in 1, plus recurrent exertional myoglobinuria, moderate restriction in exercise, and limitation in daily life activities

  • 3 - Fixed muscle weakness, with or without wasting and severely limited exercise and most daily life activities

The correlation of the number of D alleles with disease severity may be due to the D allele's association with elevated ACE activity, which may negatively affect cardiovascular and muscle function.[4]





Laboratory Studies

Elevated serum creatine (Cr) kinase levels at rest are noted in McArdle disease (glycogen-storage disease type V).

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

Patient squeezes a handgrip dynamometer at maximal voluntary contraction (MVC) while a blood pressure cuff is inflated to 250 mm Hg on the upper arm. The exercise lasts for 1 minute, with 1 second contractions followed by 1 second rests. A positive test result occurs if no increase in venous lactic acid levels or pyruvate levels is observed following the exercise.

Compartment syndrome has induced by the ischemic forearm test. The test may also provide false positives in patients who are severely weak or less motivated or in the presence of other glycolytic defects.[9]

Nonischemic forearm testing provides the same level of diagnostic ability with less risk of compartment syndrome. This is performed in the same manner but without the use of the blood pressure cuff.[10]

Histologic Findings

Muscle biopsy

Subsarcolemmal deposits of glycogen appear at the periphery of myofibers. 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.

Enzyme histochemistry for myophosphorylase is easy to perform and when absent is diagnostic for McArdle disease. However, because this is not routinely performed, clinicians must specifically request myophosphorylase testing. Quantitative analysis of myophosphorylase in muscle tissue is also available at specialty laboratories. See the image below.

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

Electron microscopy

Extensive accumulation of normal-appearing glycogen under the sarcolemma and between the myofilaments.



Medical Care

Therapies in patients with McArdle disease (glycogen-storage disease type V) are used in an attempt to bypass the metabolic block by providing glucose or fructose yield inconsistent results. Similarly, injection of glucagons yields inconsistent results.


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.


A high carbohydrate diet may improve maximal work capacity and exercise tolerance. A randomized controlled trial comparing a carbohydrate rich (20% fat, 15% protein, 65% carbohydrate) and a protein rich diet (15% fat, 55% protein, 30% carbohydrate) surprisingly showed that subjects on the carbohydrate rich diet improved exercise tolerance and maximum oxidative capacity compared with subjects on the protein rich diet.[11]


Regular, moderate aerobic activity has been shown to improve exercise capacity in patients with McArdle disease. Patients should exercise using a heart rate monitor, keeping the heart rate to 60-70% of maximum.[12] Exercise should be preceded by a warm-up period and dose of sucrose prior to exertion if not contraindicated.[13]

Strenuous isometric exercises may cause symptoms or rhabdomyolysis.



Medication Summary

In general, no specific treatment is indicated for McArdle disease (glycogen-storage disease type V). 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.


Class Summary

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.

Pyridoxine (Nestrex)

Vitamin B-6 is a naturally occurring vitamin normally found in beans, grains, liver, meats, eggs, and vegetables.

Nutritional Agent

Class Summary

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 observed.


Disaccharide from sugar cane made up of d-glucose and d-fructose.

Nutritional Supplement

Class Summary

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/d.[14]

Creatine monohydrate

Increases intracellular creatine and phosphocreatine levels. Converted to creatinine. Theorized to increase short-term energy supply to muscle tissue by rephosphorylation of ADP. Unknown if increased creatine in muscle improves athletic performance in nondepleted conditions.

Angiotensin-Converting Enzyme (ACE) Inhibitor

Class Summary

Investigators studying a small cohort of 8 adult patients reported that treatment with 2.5 mg of ramipril subjectively improved reported scores of perceived disability but had no effect on objective functional outcomes measures. The improvement in the perceived disability scores was more pronounced in the D/D genotype and was absent in the I/D genotype. Although not significant, the D/D genotype also showed a slight improvement in peak VO2. The improvement in peak VO2 and subjective disability scores suggest a benefit of ramipril treatment in patients with the D/D genotype, but additional testing of a larger patient population is needed.[15]

Ramipril (Altace)

Prevents conversion of Angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.



Further Inpatient Care

If acute renal failure occurs in patients with McArdle disease (glycogen-storage disease type V), hemodialysis and appropriate monitoring of fluid and electrolyte status may be necessary.


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


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


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 extreme isometric exercise.

Educate patients about the “second wind” phenomenon.