McArdle disease

A 51-year-old man had a long-standing history of recurrent exertion-induced cramps and myoglobinuria. While growing up, he had never been able to participate in sports requiring excessive physical activity. In the past, exertion had brought on a sensation of muscle cramps, but more recently this cramping sensation had begun to come on without warning. Recently, after squatting to work on his son's go-cart, he experienced excessive cramps in his legs without warning on standing, and within 30 minutes he had dark-colored urine. He has been unable to work for the past 2 years. His past medical history is significant for multiple hospitalizations for rhabdomyolysis, diabetes, hepatitis C, and psoriasis. A muscle biopsy performed 27 years ago was interpreted as showing changes consistent with muscular dystrophy.

A physical examination revealed protrusion of his right scapula with arm extension and mild axillary/pectoral creases. Mild proximal weakness (4+/5) was present in all limbs. Muscle tone was normal, and there was no hypertrophy. He could stand with his arms crossed but had difficulty doing toe and heel walking. Deep tendon reflexes were normal. Extensor responses were absent.

A biopsy of the left rectus femoris muscle was performed. There was mild variation in muscle fiber size and occasional small, primarily subsarcolemmal vacuoles (Figure 1), which were negative for acid phosphatase. Myophosphorylase staining was weaker for the affected muscle (Figure 2, A) compared with normal muscle (Figure 2, B). Electron microscopic examination revealed scattered muscle fibers with increased glycogen material, corresponding to the vacuoles observed by light microscopy (Figure 3). Mitochondria were normal in configuration and number.

What is your diagnosis?

Pathologic Diagnosis: McArdle Disease (Glycogenosis Type V or Myophosphorylase Deficiency)

McArdle disease, which was initially described in 1951, was the first metabolic myopathy recognized as being due to the deficiency of a single enzyme, myophosphorylase.1,2 Myophosphorylase activity is required to convert glycogen to glucose-1-phosphate and eventually to lactate. McArdle disease is an autosomal recessive disorder, but sporadic, apparently nonfamilial cases have been reported.1,3

Patients with this condition typically present with exercise intolerance that with continued exertion can lead to muscle cramps, rhabdomyolysis, myoglobinuria, and, in severe cases, renal failure.4 Most patients do not manifest the condition until the second or third decade of life, and the disease course is often slowly progressive.3,4 During childhood and the teenage years, manifestations may be mild, consisting largely of easy fatigability and muscle cramps. As the affected individual ages, there is a marked decline in muscle function. Persistent weakness and wasting of individual muscle groups may become apparent.3,4 The degree of disability can be assessed by an ischemic exercise test and lactate acid evaluation, used as a screening test.5 In individuals with normal enzyme levels, there is usually an increase in lactic acid after ischemic exercise of the forearm. This response is lacking in individuals with a total absence of myophosphorylase. However, in patients with a partial deficiency, the response is normal. Therefore, lactic acid test results do not provide enough information for an unequivocal diagnosis of McArdle disease.5 Laboratory tests typically reveal an increase in resting serum creatine kinase. A clinical impression of McArdle disease should be confirmed by skeletal muscle biopsy and assay or staining for myophosphorylase.1

Muscle biopsies from affected individuals are characterized by the subsarcolemmal accumulation of normal-appearing glycogen.1,6,7 The subsarcolemmal accumulation of glycogen forms vacuoles or blebs that can be identified by light microscopy. In many of the vacuoles, glycogen can be detected by the perodic acid-Schiff reaction (diastase digestible). Subsarcolemmal spaces that appear empty can be demonstrated by staining with nicotinamide adenine dinucleotide in its reduced form (NADH tetrazolium reductase).7 Scattered degenerating muscle fibers may be present. Ultrastructurally, increased glycogen accumulation corresponding to the vacuoles observed by light microscopy is evident. Scattered or widespread fibers may not stain for myophosphorylase; however, some staining may be observed in patients with a partial deficiency.5

Vacuolar myopathic changes are associated with various disorders.7 Vacuoles may serve as a depot for fat, glycogen, or other storage materials. In general, the glycogenoses are indistinguishable from one another by routine light microscopic and ultrastructural evaluation, with the notable exception of acid maltase, in which large vacuoles are associated with lysosomes (acid phosphatase positive). Specific enzyme analyses are important in making a precise diagnosis. Other causes of vacuolar myopathy, such as inclusion body myositis, periodic paralysis, and certain drug reactions, can usually be readily distinguished by paying attention to clinical features, consistent pathologic findings, and ultrastructural appearance.

The gene for myophosphorylase has been cloned, sequenced, and assigned to chromosome 11q13.8 The molecular basis of McArdle disease has been linked to several mutations.8,9 Muscle phosphorylase is totally absent in the majority of patients and markedly decreased in a few patients. When assessed at the level of transcription, some affected individuals produce no detectable message or an abnormal message, whereas others produce a messenger RNA of apparently normal size, which either may not be translated or may be translated into an inactive or unstable protein.6,7

References

1. Korenyi-Both A, Smith BH, Baruah JK. McArdle's syndrome. Fine structural changes in muscle. Acta Neuropathol. 1977;40:11-19.

2. Schmid R, Hammaker L. Hereditary absence of muscle phosphorylase (McArdle's disease). N Eng J Med 1961;264:223-225.

3. Felice KJ, Schneebaum AB, Jones HR Jr. McArdle's disease with late-onset symptoms: case report and review of the literature. J Neurol Neurosurg Psychiatry. 1992;55:407-408.

4. Beynon RJ, Bartram C, Hopkins P, et al. McArdle's disease: molecular genetics and metabolic consequences of the phenotype. Muscle Nerve. 1995;3:S18-S22.

5. Fattah SM, Rubulis A, Falloon WW. McArdle's disease: metabolic studies in a patient and review of the syndrome. Am J Med. 1970;48:693-699.

6. Martinuzzi A, Schievano G, Nascimbeni A, Fanin M. McArdle's disease: the unsolved mystery of the reappearing enzyme. Am J Pathol. 1999;154:1893-1897.

7. Banker BQ, Engel AG. Basic reaction of muscle. In: Engel AG, Franzini-Armstrong C, eds. Myology. Vol 1. 2nd ed. New York, NY: McGraw-Hill; 1994:856-877.

8. Tsujino S, Shansk S, Nonaka I, DiMauro S. The molecular genetic basis of myophosphorylase deficiency (McArdle's disease). Muscle Nerve. 1995;3:S23-S27.

9. Vogerd M, Grehl T, Jager M, et al. Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial. Arch Neurol. 2000;57:956-963.

Eskender Getachew, MD; Richard A. Prayson, MD

Accepted for publication March 5, 2003.

From the Department of Neurology, Cleveland Clinic Hospital, Weston, Fla (Dr Getachew), and Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio (Dr Prayson).

Corresponding author: Richard A. Prayson, MD, Department of Anatomic Pathology (L25), Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland OH 44195 (e-mail: praysor@cesmtp.ccf.org).

Reprints not available from the author.

Copyright College of American Pathologists Sep 2003
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