AUTHOR INFORMATION

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Authored by Edward J Cupler, MD, Associate Professor of Neurology, Department of Neurology, Director, Neuromuscular Diseases Center, MDA Clinic Director, Oregon Health and Science University; Co-director, ALS Center of Oregon

Coauthored by Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Head of Division of Metabolism, Department of Pediatrics, Oregon Health & Science University; Director, Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital; Melissa Wasserstein, MD, Assistant Professor, Departments of Human Genetics and Pediatrics, Mount Sinai School of Medicine; Cydney L Fenton, MD, FAAP, Consulting Staff, Department of Pediatric Endocrinology, Children's Hospital Medical Center of Akron

Edward J Cupler, MD, is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and World Muscle Society

Edited by Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Edward J Cupler, MD
Editor's Email:	Edward Kaye, MD

eMedicine Journal, April 6 2006, VOLUME 7, Number 4

INTRODUCTION

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Background: In 1951, McArdle reported 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. In 1959, Schmid and Mahler demonstrated deficient activity of myophosphorylase in a 52-year-old man with exertional fatigue and episodic myoglobinuria. The typical features of McArdle disease include exercise intolerance with myalgia, early fatigue, and stiffness of exercising muscles, which are 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 the patients suffer from acute muscle necrosis and myoglobinuria following vigorous exercise, and some may develop renal failure. Reports exist of a fatal infantile form of McArdle disease with hypotonia, generalized muscle weakness, and progressive respiratory insufficiency. In addition, a late-onset form exists with no symptoms until the sixth decade of
life.

Pathophysiology: 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 the glycogen molecule with release of glucose-1-phosphate. Several tissue-specific isoforms of phosphorylase exist. Myophosphorylase is the only isoform present in skeletal muscle. It also is present in cardiac muscle and the brain. The liver isoform is deficient in 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.

The symptoms experienced by patients with McArdle disease most likely are caused by the pattern of fuel utilization of exercising muscle. Adenosine triphosphate (ATP) requirements are increased dramatically during muscular exercise. Initially, muscle-performing 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. Later on, the exercising muscle derives its energy from blood-borne sources, such as glucose and free fatty acids. The prevailing levels of fatty acids as potential energy sources for muscle may account for the second wind phenomenon experienced by patients with McArdle disease.

Frequency:

• In the US: McArdle disease is inherited in an autosomal recessive manner. It is rare; only a few hundred cases have been reported. It is probably underdiagnosed because of the mild symptoms. The early-onset form is extremely rare; only several cases have been reported. Similarly, the late-onset form is also exceedingly rare.

Mortality/Morbidity:

• Muscular weakness and fatigue: Tiredness, weakness, and cramping can interfere with normal activity. Patients sometimes can adapt their exercise patterns to take advantage of the second wind phenomenon.

• Myoglobinuria: Rhabdomyolysis following vigorous exercise may result in myoglobinuria. Approximately one half of patients with myoglobinuria develop acute renal failure.

• Fatal infantile: Death is caused by respiratory failure resulting from severe rapidly progressive muscular weakness.

Sex: McArdle disease is inherited in an autosomal recessive pattern; therefore, males and females should be affected equally. However, as in Tarui disease (GSD type VII), more males than females have been reported, probably reflecting small numbers and sampling effects.

Age: Classic McArdle disease presents in adolescence with limited exercise tolerance. The fatal infantile form manifests in the newborn period. At the other end of the spectrum, patients have been described to remain asymptomatic until the sixth decade of life.

CLINICAL

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History:

• The usual presenting complaint is exercise intolerance, including stiffness or weakness of the muscle, myalgia, and fatigue. These symptoms typically are relieved with rest. They usually are precipitated by isometric exercise (eg, weight lifting) and sustained aerobic exercise (eg, stair climbing, jogging). Many patients experience a second wind, whereby they can resume activity following a brief period of rest.



• Clinical heterogeneity exists; some patients have extremely mild symptoms manifesting as tiredness without cramps. In some patients, progressive weakness starts in the sixth or seventh decade of life. In contrast, the severe rapidly progressive form 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 half of patients following intense exercise, and about one half of these patients develop acute renal failure.



• Seizures have been described in 4% of patients with McArdle disease.

Physical:

• Classic and late-onset McArdle disease


• • 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
  
  
  

Causes: Nonsense, deletion, missense, and splice-junction mutations exist in the gene encoding the muscular isoform of phosphorylase. The gene is located on band 11q13 and contains 20 exons. Although mutational heterogeneity exists, in most individuals the molecular defect results in the near-complete absence of the protein in skeletal muscle.

DIFFERENTIALS

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Glycogen-Storage Disease Type VII

Other Problems to be Considered:

Mitochondrial myopathy
Phosphoglycerate kinase deficiency
Phosphoglycerate mutase deficiency
Phosphofructokinase deficiency
Lactate dehydrogenase deficiency

WORKUP

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Lab Studies:

• Elevated serum creatine kinase at rest



• No increase in lactic acid following exercise

Imaging Studies:

• Phosphorous 31-nuclear magnetic resonance (31P-NMR) shows a lack of cytoplasmic acidification following exercise.

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, an absence of electrical activity may be observed on EMG.

TREATMENT

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Medical Care:

• Therapies attempting to bypass the metabolic block by providing glucose or fructose yield inconsistent results. Similarly, injection of glucagons yields inconsistent results.



• Because the branched-chain amino acids represent alternative fuels for exercising muscle, a high-protein diet may be beneficial.

Consultations: Acute renal failure may follow episodes of rhabdomyolysis, necessitating consultation with a nephrologist. Monitor renal function in all patients with McArdle disease. This may be done in conjunction with a nephrologist.

Diet: As described above, treatment with a high-protein diet may be beneficial because exercising muscle may be able to use branched-chain amino acids as fuel, thereby reducing the requirement for glucose.

• Recently the use of a ketongenic diet has found to be useful in improving some patient's exercise tolerance.

Activity: Strenuous and isometric exercises are most likely to cause symptoms and, therefore, are most likely to induce rhabdomyolysis. Many patients are able to resume steady exercise comfortably after taking a short rest. This exercise pattern takes advantage of the second wind phenomenon, wherein the exercising muscle no longer relies on stored glycogen for fuel.

MEDICATION

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Drug Category: Vitamins -- Necessary to promote regular growth and good health. Some studies suggest that vitamin B-6 (pyridoxine) may make the muscles of patients with McArdle disease less susceptible to fatigue. Normally, myophosphorylase uses pyridoxal 5'-phosphate (derived from vitamin B-6) as a cofactor; therefore, supplementation may augment the remaining myophosphorylase activity. In addition, the majority of the total body pool of pyridoxine normally is bound to myophosphorylase; therefore, the body's store of pyridoxine may be depleted in patients with McArdle disease.

Drug Name	Pyridoxine (Nestrex) -- Vitamin B-6 is a naturally occurring vitamin normally found in beans, grains, liver, meats, eggs, and vegetables.
Adult Dose	100 mg/d PO
Pediatric Dose	1-3 years: 30 mg/d PO 4-8 years: 40 mg/d PO 9-13 years: 60 mg/d PO 14-18 years: 80 mg/d PO
Contraindications	Documented hypersensitivity
Interactions	Pyridoxine may decrease levodopa, phenytoin, and phenobarbital serum levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adverse effects from overdosage include headache, nausea, vomiting, seizures, tingling, pain, and numbness in the extremities

FOLLOW-UP

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Further Inpatient Care:

• If acute renal failure is present, hemodialysis and appropriate monitoring of fluid and electrolyte status may be necessary.

Deterrence/Prevention:

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

Complications:

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

Prognosis:

• McArdle disease has a relatively benign nature. Limitation or adaptation of exercise to avoid symptoms may be necessary. Acute renal failure, when present, requires appropriate treatment. Progression to chronic renal disease has not been described.

Patient Education:

• Educate patients about modifying their activity in order to avoid the development of renal disease. Patients should avoid isometric exercise (eg, weight lifting, pushing heavy objects), as well as sustained dynamic exercise (eg, stair climbing, walking uphill).

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to monitor renal function after an episode of myoglobinuria



• Failure to inform the family about the autosomal recessive inheritance, which may be important for siblings and future pregnancies

TEST QUESTIONS

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CME Question 1: A 19-year-old male complains of a 1-day history of muscle soreness and dark urine. Upon questioning, he admits that he had pushed his stalled car off the road the previous day. What is the most likely diagnosis?

A: Mitochondrial myopathy
B: Poststreptococcal glomerulonephritis
C: Becker muscular dystrophy
D: McArdle disease (glycogen-storage disease type V)
E: Muscle fatigue

The correct answer is D: The combination of myoglobinuria and muscle soreness following isometric exercise (eg, pushing a car) is consistent with McArdle disease. Patients with mitochondrial myopathy and Becker muscular dystrophy typically are hypotonic, and myoglobinuria is not a feature of either of these disorders. Although patients with poststreptococcal glomerulonephritis may have hematuria, muscular symptoms are not a predominant feature.

CME Question 2: Which of the following laboratory values is abnormal in patients with McArdle disease?

A: Hemoglobin
B: Ischemic lactate response
C: Phosphofructokinase activity
D: Serum glucose
E: Total bilirubin

The correct answer is B: McArdle disease is caused by an inherited deficiency of myophosphorylase, an intermediate enzyme in glycolysis. Pyruvate production is abnormal, and, therefore, lactate fails to rise after exercise. A compensated hemolysis is a feature of Tarui disease (phosphofructokinase deficiency, glycogen-storage disease [GSD] type VII). McArdle disease is a muscular GSD; therefore, glucose levels are not affected.

Pearl Question 1 (T/F): The most typical presenting complaint of a patient with McArdle disease is soreness, cramping, or easy fatigue of exercising muscles.

The correct answer is True: Most patients present with muscle complaints.

Pearl Question 2 (T/F): The most serious complication of McArdle disease is renal failure.

The correct answer is True: Vigorous or isometric exercise can produce rhabdomyolysis with subsequent myoglobinuria, which may cause acute renal failure.

Pearl Question 3 (T/F): A muscle biopsy of a patient with McArdle disease is likely to show ragged red fibers.

The correct answer is False: The muscle biopsy is likely to reveal deposits of glycogen under the sarcolemma. Ragged red fibers are more likely to be observed in patients with mitochondrial myopathies.

Pearl Question 4 (T/F): A patient with McArdle disease is most likely to become symptomatic during infancy.

The correct answer is False: Patients with McArdle disease often first note symptoms during early adolescence.

BIBLIOGRAPHY

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• Beynon RJ, Bartram C, Hopkins P, Toescu V, et al: McArdle's disease: molecular genetics and metabolic consequences of the phenotype. Muscle Nerve 1995; 3: S18-22[Medline].
• Busch V, Gempel K, Hack A: Treatment of glycogenosis type V with ketogenic diet. Ann Neurol 2005 Aug; 58(2): 341[Medline].
• Cornelio F, Bresolin N, DiMauro S, Mora M, et al: Congenital myopathy due to phosphorylase deficiency. Neurology 1983 Oct; 33(10): 1383-5[Medline].
• DiMauro S, Hartlage PL: Fatal infantile form of muscle phosphorylase deficiency. Neurology 1978 Nov; 28(11): 1124-9[Medline].
• DiMauro S, Tsujino S: Nonlysosomal Glycogenoses. Myology: Basic and Clinical. 2nd ed 1994; 1557-1561.
• DiMauro S, Bresolin N: Phosphorylase deficiency. Myology 1585-1601.
• Gamez J, Rubio JC, Martin MA, et al: Two novel mutations in the muscle glycogen phosphorylase gene in McArdle's disease. Muscle Nerve 2003 Sep; 28(3): 380-2[Medline].
• Gautron S, Daegelen D, Mennecier F, Dubocq D, et al: Molecular mechanisms of McArdle's disease (muscle glycogen phosphorylase deficiency). RNA and DNA analysis. J Clin Invest 1987 Jan; 79(1): 275-81[Medline].
• Grunfeld JP, Ganeval D, Chanard J, Fardeau M, et al: Acute renal failure in McArdle's disease. Report of two cases. N Engl J Med 1972 Jun 8; 286(23): 1237-41[Medline].
• McArdle B: Myopathy due to a defect in muscle glycogen breakdown. Clin Sci 1951; 10: 13-33.
• McConchie SM, Coakley J, Edwards RH, Beynon RJ: Molecular heterogeneity in McArdle's disease. Biochim Biophys Acta 1990 Nov 14; 1096(1): 26-32[Medline].
• Milstein JM, Herron TM, Haas JE: Fatal infantile muscle phosphorylase deficiency. J Child Neurol 1989 Jul; 4(3): 186-8[Medline].
• Miranda AF, Nette EG, Hartlage PL, DiMauro S: Phosphorylase isoenzymes in normal and myophosphorylase-deficient human heart. Neurology 1979 Nov; 29(11): 1538-41[Medline].
• Moses SW: Muscle glycogenosis. J Inherit Metab Dis 1990; 13(4): 452-65[Medline].
• Pourmand R, Sanders DB, Corwin HM: Late-onset Mcardle's disease with unusual electromyographic findings. Arch Neurol 1983 Jun; 40(6): 374-7[Medline].
• Schmid R, Mahler R: Chronic progressive myopathy with myoglobinuria: Demonstration of a glycogenolytic defect in the muscle. J Clin Invest 1959; 38: 2044-2058.
• Servidei S, Shanske S, Zeviani M, Lebo R, et al: McArdle's disease: biochemical and molecular genetic studies. Ann Neurol 1988 Dec; 24(6): 774-81[Medline].
• Servidei S, DiMauro S: Disorders of glycogen metabolism of muscle. Neurol Clin 1989 Feb; 7(1): 159-78[Medline].
• Tsujino S, Shanske S, DiMauro S: Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle's disease). N Engl J Med 1993 Jul 22; 329(4): 241-5[Medline].
• Tsujino S, Shanske S, Nonaka I, DiMauro S: The molecular genetic basis of myophosphorylase deficiency (McArdle's disease). Muscle Nerve 1995; 3: S23-7[Medline].

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