Genetics of Glycogen-Storage Disease Type V (McArdle Disease)

Updated: Mar 05, 2018
Author: Noura Al Dhaheri, MBBS, FAAP; Chief Editor: Maria Descartes, MD 



Glycogen storage disease type V, also known as McArdle disease, is an inherited disorder of glycogen metabolism that primarily affects skeletal muscles. It was first identified in 1951, when McArdle described a 30-year-old man who experienced muscle 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 its activity 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, which is a pathognomonic feature of the disease.

About half of patients with McArdle disease 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 without manifestations until the sixth decade of life has been described.


McArdle disease is caused by a deficiency of myophosphorylase (alpha-1,4-glucan orthophosphate glycosyl transferase). In healthy individuals, myophosphorylase initiates glycogen breakdown by removing 1,4-glucosyl groups from glycogen with the release of glucose-1-phosphate (see image below).

Major pathways of synthesis and breakdown of glyco Major pathways of synthesis and breakdown of glycogen in liver. The broken line indicates that several enzymes have been omitted between pyruvate and fructose-1,6-P2. GLUT= glucose transport protein; UDP=uridine diphosphate; UDPG=uridine diphosphate-glucose. Courtesy of McGraw-Hill Education (Fig 71-2 from Valle D, Beaudet AL, Vogelstein B, et al. The Online Metabolic and Molecular Bases of Inherited Disease. 2014. Chapter 71: Glycogen Storage Diseases. Available at:

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 utilize energy (release glucose) from their glycogen stores in muscles. Rarely, patients have residual enzyme activity (< 30% of normal).

During aerobic exercise (eg, walking, gentle swimming, jogging, cycling), the skeletal muscle depends on bloodborne substrates such as free fatty acid as fuel for energy. Free fatty acids are oxidized in the mitochondrial beta-oxidation pathway to produce acetyl-CoA, which is further metabolized through the Krebs cycle and the mitochondrial respiratory chain, resulting in adenosine triphosphate (ATP) production. During anaerobic exercise (eg, weightlifting, sprinting), the myophosphorylase in the skeletal muscles converts glycogen to glucose, which enters the glycolysis pathway to produce ATP anaerobically.

Any exercise has an anaerobic component in the first few minutes. Thereafter, the duration and intensity of exercise determines the type of fuel source used by the skeletal muscles (eg, anaerobic glycolysis, blood glucose, muscle glycogen followed by aerobic glycolysis and fatty acid oxidation). The increased levels of fatty acids as additional energy sources for muscle accounts 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] In a 2017 reanalysis by the same authors, the main clinical features of the disease remained essentially unchanged compared with those found in the prior study, except for a slight decrease in the number of individuals with fixed muscle weakness (decreased from 25% to 21%).[6]


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.


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.

More recent studies suggest heterogeneity of clinical severity, with 8% of patients being asymptomatic during normal daily life and 21% showing limitations during daily activities and fixed muscle weakness.[6] The evidence also supports adopting an active lifestyle, which is key in patients with McArdle disease.[6]

The current evidence also suggests that the disease does not appear to adversely affect pregnancy course or childbirth.[5] However, the optimal method of delivery (vaginal or caesarean) has not been determined.[6]

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.

Genetic counseling should also be provided to educate parents and affected individuals about recurrence risk for future pregnancies.




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.[7]

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 half of patients with McArdle disease following intense exercise, and a significant proportion of these patients develop acute renal failure, which is reversible in most cases.[5]

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 (PYGM), which encodes the muscular isoform of phosphorylase. PYGM is mapped to chromosome 11q13 and contains 20 exons.[8] 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 two separate investigators, Martinuzzi et al and Rubio et al, have shown that an insertion/deletion (I/D) benign variant in the angiotensin converting enzyme gene (ACE) may play a role in modulating the disease phenotype.[4, 9] It has been suggested that ACE I allele has been associated with a higher functional capacity in affected females,[10] while the ACE D allele affected the disease severity score as described by Martinuzzi et al and Rubio et al.[4, 9]

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]


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



Diagnostic Considerations

The differential diagnoses of McArdle disease include conditions that affect the skeletal muscle’s ability to utilize glycogen stores or other sources of energy, such as fatty acid oxidation defects or impaired mitochondrial function resulting in muscle pain and elevated creatine kinase levels, such as in the following disorders:

Other glycogen storage disorders:

  • Glycogen storage disease X (phosphoglycerate mutase deficiency) (OMIM 261670)
  • Glycogen storage disease VII (phosphofructokinase deficiency) (OMIM 232800)
  • Glycogen storage disease XI (lactate dehydrogenase deficiency) (OMIM 612933)
  • Glycogen storage disease IXB (phosphorylase B kinase deficiency) (OMIM 261750)

Fatty acid oxidation defects:

  • Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (OMIM 201475)
  • Mitochondrial trifunctional protein (MTP) deficiency (OMIM 609015)
  • Carnitine palmitoyl transferase II deficiency (255110)

Other: Mitochondrial myopathy

Differential Diagnoses



Laboratory Studies

Elevated serum creatine kinase (CK) levels at rest are noted in McArdle disease (glycogen-storage disease type V), with mean value around 1,000 IU/L (reference range, < 200 IU/L).

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 and nonischemic forearm exercise test

An ischemic forearm exercise test is performed by having the patient squeeze 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 one minute, with one-second contractions followed by one-second rests. The test result is positive if no increase in venous lactic acid levels or pyruvate and ammonia levels is observed following the exercise. Compartment syndrome has been induced with the ischemic forearm test. The test may yield false-positive results in patients who are severely weak or less motivated or who have other glycolytic defects.[11] The ischemic test is no longer routinely used.

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 blood pressure cuff.[12] The nonischemic forearm test has a sensitivity and specificity of 100% and 99.7%, respectively, as has been reported by a 2015 retrospective study.[13]

In controls, plasma lactate and ammonia concentrations increase 5-6 times above basal values, while, in individuals with McArdle disease, the plasma lactate concentration does not increase ("flat lactate curve"), and the postexercise lactate-to-ammonia peak ratios are clearly decreased.

Cycle and walking test

During a cycle or walking test, the patient’s heart rate is monitored to detect the pathognomonic increase in heart rate (average of 30-40 beats/min) that occurs during the second-wind phenomenon in all individuals with McArdle disease, providing sensitive and specific results.[14]

Long exercise test

A 2018 study investigated the use of long exercise test (LET) in McArdle disease in which the compound muscle action potential (CMAP) before and after 5 minutes of isometric contraction is recorded. The test shows an immediate and long-lasting decrease in CMAP amplitude in patients with McArdle disease. LET was found to be highly sensitive and specific. This study suggested that LET can aid in diagnosis. It may also provide correlation and a potential outcome measure for the disease, as normal LET in patients with milder symptoms indicates a relationship of the LET with clinical severity. Furthermore, the study concluded that the observed abnormalities on LET may suggest complex biochemical mechanisms that may result from the absence of myophosphorylase, beyond simple glycolytic blockade (eg, ionic pump dysfunction, sarcolemma excitability).[15]

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

Since there is no cure for McArdle disease, management is focused on treatment of the disease manifestations (detailed below), prevention of secondary complications, and regular surveillance.

A general approach to treatment aims at providing therapies that could bypass the metabolic block. However, providing glucose or fructose or using glucagon injection yielded inconsistent results.

Creatine Monohydrate

It is hypothesized that creatine may improve ATP capacity and exercise tolerability. A placebo-controlled crossover trial showed that 9 individuals with McArdle disease had improved symptoms and increased capacity for ischemic isometric forearm exercise. However, in a subsequent trial by the same group in 19 individuals, high-dose creatine monohydrate worsened exercise intolerance and significantly worsened the clinical symptoms of exercise-induced myalgia.[16] The authors suggested a possible explanation is that insufficient adaptation to improved electromechanical efficacy leads to overuse of the muscle contractility in exercise and thus a worsening of symptoms. However, no significant changes were seen on phosphorous 31 magnetic resonance spectroscopy (MRS) variables.[16]

Angiotensin Converting Enzyme (ACE) Inhibitors: Ramipril

Martinuzzi et al studied a small cohort (10 patients) in a double-blind, randomized, placebo-controlled crossover trial using 2.5 mg ramipril. No significant difference was found between the placebo and ramipril groups in terms of objective exercise parameters, although the WHO-DAS 11 score improved in ramipril-treated participants. The improvement in the perceived disability scores was more pronounced in the D/D genotype and was absent in the I/D genotype. Additional testing in a larger patient population is needed.[17]

Sodium Valproate

A 2015 study by Howell et al hypothesized that sodium valproate, a histone deacetylase inhibitor, might be able to up-regulate the myophosphorylase enzyme. Using sheep as an animal model, they showed that enteral treatment with 20-60 mg/kg was associated with increased expression of myophosphorylase in muscle fibers. This response was found to be dose-dependent. The findings from the study suggest that sodium valproate is a potential therapeutic option for McArdle disease.[18] Randomized trials are needed to study the potential benefits in humans.

Another study in a mouse model showed a dose-dependent decrease in glycogen accumulation, suggesting that sodium valproate can be considered a gene-expression modulator that allows compensatory expression of myophosphorylase and decreased glycogen accumulation in skeletal muscles among patients with McArdle disease.[19] Further studies in humans are needed to determine the efficacy of this approach.

Vitamins/Nutritional Supplementation

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.

Evidence for the benefit of supplementation with branched chain amino acids, depot glucagon, vitamin B6, and high-dose oral ribose is low.[20] Studies of oral sucrose administered at different times and in different amounts before exercise showed improvement in exercise tolerance when given before exercise (75 g 30 minutes before exercise). However, the evidence is low and insufficient to determine clinical benefits.[20]


Gene therapy with adenovirus is in the experimental phase. No human gene therapy trials have yet been conducted.

A clinical therapy trial of triheptanoin (medium chain triglyceride) may begin soon.

For more update information, visit


Acute renal failure may occur with rhabdomyolysis, necessitating consultation with a nephrologist. Monitoring renal function in all patients with McArdle disease is recommended.


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.[21] A 2014 Cochrane review systematically examined evidence from available randomized controlled trials of pharmacological and nutritional management for McArdle disease. While a carbohydrate-rich diet resulted in better exercise performance than a protein-rich diet, the evidence quality was low and not strong enough to indicate significant clinical benefit,[20] likely owing to the small number of participants included in each study comprising the systematic review.


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.[22] Exercise should be preceded by a warm-up period and dose of sucrose prior to exertion if not contraindicated.[23]

Therefore, to improve quality of life, the following activity modifications are recommended in patients with McArdle disease:

  • Participate in regular moderate aerobic exercise, which improves cardiorespiratory capacity and increases delivery of bloodborne fuels, simulating a permanent "second wind" phenomenon.
  • Avoid intense isometric exercise and maximal aerobic exercise, which causes cramps and can potentially trigger rhabdomyolysis and myoglobinuria.
  • Avoid a sedentary lifestyle, which can cause deconditioning.


Because acute renal failure is precipitated by rhabdomyolysis in McArdle disease, avoidance of strenuous and/or isometric exercise may be indicated, including the following:[16]

  • Static muscle contractions (eg, handgrip exercises) or heavy loads on low muscle mass (eg, weightlifting)
  • Dynamic exercises at a high-intensity level (eg, competitive ball games)
  • Exercises with a high involvement of eccentric (lengthening) muscle contractions (eg, jumps)
  • Very intense dynamic aerobic exercise (eg, running, strenuous swimming, or cycling), except in individuals who are very fit and well habituated

General anesthesia

Although rare, the risk of acute muscle damage has been reported with certain general anesthetics (usually muscle relaxants and inhaled anesthetics). Measures to prevent muscle ischemia and rhabdomyolysis should be taken in individuals with McArdle disease.[24]

Long-Term Monitoring

Patients with McArdle disease should undergo annual routine physical examination and routine review of diet and exercise precautions.

Further Inpatient Care

If acute renal failure occurs in patients with McArdle disease, hemodialysis and appropriate monitoring of fluid and electrolyte status may be necessary.



Medication Summary

See Medical Care.