By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports no financial relationships relevant to this field of study.
Synopsis: Traditionally, the ischemic forearm exercise test has been used to help in the diagnosis of glycogen storage diseases of muscle, but this test is fraught with dangerous complications. A non-ischemic forearm test has been proven to be highly sensitive and specific, with minimal side effects, and should replace the traditional test.
Source: Hogrel JY, et al. Diagnostic power of the non-ischaemic forearm exercise test in detecting glycogenosis type V. Eur J Neurol 2015;22;933-940.
When McArdle’s disease (glycogen storage disease type V, myophosphorylase deficiency) is suspected, diagnostic evaluation begins with ischemic forearm exercise testing, which, if showing a flat venous lactate curve, is followed by genetic analysis. Serum lactate, pyruvate, creatine kinase, and ammonia are measured at rest, and then, with the blood pressure cuff inflated to just over diastolic pressure, they are repeated after 1 minute of one-per-second hand grips, performed at 75% of maximum effort, with venous blood drawn at 1, 2, 3, 5, and 10 minutes after exercise. If muscle pain or an acute cramp develops, as it often does, the cuff is deflated and the test stopped. Given the risk of focal rhabdomyolysis, myoglobinuria, or acute compartment syndrome, caution is required, and testing should never be performed under completely ischemic conditions. When performed without a blood pressure cuff, under non-ischemic conditions, it is stated that results are less specific and sensitive. Is this statement true?
Over 15 years, spanning 1999-2013, 1226 patients were referred to the Institute of Myology, Pitie-Salpetriere Hospital, Paris, France, for evaluation of muscle complaints, including exercise intolerance, lifelong myalgias, episodic myoglobinuria, painful muscle swelling, and elevated creatine kinase. All underwent non-ischemic forearm exercise testing, followed by muscle biopsy and/or genetic testing to confirm diagnosis, with McArdle’s disease diagnosed in 40 patients. Sixty healthy volunteers served as controls. Non-ischemic forearm testing was performed by sustaining 70% of maximum voluntary contraction for 30 seconds, with three blood samples drawn prior to exercise and six following exercise, at 1, 2, 3, 4, 6, and 10 minutes. Maximum voluntary contraction was determined as the strongest of three brief grip contractions. Lactate, ammonia, and creatine kinase were measured, and statistical analysis comprised the Mann-Whitney and Wilcoxon tests, with P < 0.05 considered statistically significant.
Among the 40 McArdle’s disease patients, 38 confirmed by genetic analysis of the PYGM gene, 21 were male and 19 female, ages 8-72 years, with 90% presenting as childhood-onset exercise intolerance and myalgias. All had prior elevation (above 500 IU/l) of creatine kinase, half experienced at least one episode of myoglobinuria, four reported painful muscle swelling with dark urine, and 93% noted a second wind phenomenon. Non-ischemic forearm exercise testing revealed a sensitivity and specificity of 100% and 99.7%, respectively. Lactate values at rest did not differ significantly from controls, but lactate peak levels were abnormally low in 95% following exercise. Ammonia at rest, ammonia peak after exercise, and the ratio between ammonia and lactate production were significantly higher in patients compared to controls. Creatine kinase values did not significantly rise following testing. Non-ischemic forearm exercise testing is safe, sensitive, and specific, and may preclude the need for muscle biopsy in McArdle’s disease, as follow-up gene analysis allows for the detection of most PYGM mutations.
With prevalence estimated at 1:100,000 in European-descended Americans, or perhaps even 1:50,000 based on next-generation sequencing data, McArdle’s disease is one of the most common glycogen storage disorders. Diagnosis is often confirmed by identification of pathogenic variants in the PYGM gene that encodes the myophosphorylase protein, and, if results are unclear, by muscle biopsy with measurement of myophosphorylase enzyme activity. Recent findings suggest that analysis of myophosphorylase expression in T lymphocytes may also offer a useful and less-invasive test for diagnosis.1
- de Luna N, et al. PYGM expression analysis in white blood cells: A complementary tool for diagnosing McArdle disease? Neuromuscul Disor 2014;24:1079-1086.