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

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