eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Glycogen-Storage Disease Type V

Author: 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
Coauthor(s): Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Co-Director: Pediatric and Child Health Research, Oregon Clinical and Translational Research Institute (CTSA).; Melissa P Wasserstein, MD, Associate Professor, Departments of Genetics and Genomic Sciences 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
Contributor Information and Disclosures

Updated: Oct 12, 2009

Introduction

Background

In 1951, McArdle described 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.1 In 1959, myophosphorylase was discovered and was found to be absent in individuals with McArdle disease. The typical features of McArdle disease, or glycogen-storage disease type V, 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.

About one half of patients 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 with no symptoms until the sixth decade of life has been described.

Enzyme histochemistry of 19-year-old male with Mc...

Enzyme histochemistry of 19-year-old male with McArdle disease.

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Enzyme histochemistry of 19-year-old male with Mc...

Enzyme histochemistry of 19-year-old male with McArdle disease.


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 glycogen with the release of glucose-1-phosphate. 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 release glucose from glycogen in muscle. Rarely, patients have residual enzyme activity (<30% of normal).

The symptoms in patients with McArdle disease are most likely caused by the pattern of fuel utilization of exercising muscle. ATP requirements are dramatically increased during muscular exercise. Initially, 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. The exercising muscle then derives energy from blood-borne sources, such as glucose and free fatty acids. The increased levels of fatty acids as additional energy sources for muscle may account for the “second wind” phenomenon.

Frequency

United States

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.

Mortality/Morbidity

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.

Sex

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.2

Age

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.

Clinical

History

  • 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.
  • 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 one third of patients following intense exercise, and a significant proportion of these patients develop acute renal failure.
  • Seizures have been described in 4% of patients.

Physical

  • 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

Causes

  • Genetic abnormalities that include nonsense, deletion, missense, and splice-junction mutations have been found in the gene (PGYM), which encodes the muscular isoform of phosphorylase. PGYM is mapped to 11q13 and contains 20 exons. 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 2 separate investigators, Martinuzzi et al and Rubio et al, have shown that the angiotensin converting enzyme gene (ACE) correlates well with disease severity.2,3
    • The 2 alleles for the ACE gene include I, which confers the presence of a 287 base pair repeat element in exon 16, and D , which confers the absence of the repeat. Both studies found that the number of D alleles correlated strongly with disease severity.
    • 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.2

More on Glycogen-Storage Disease Type V

Overview: Glycogen-Storage Disease Type V
Differential Diagnoses & Workup: Glycogen-Storage Disease Type V
Treatment & Medication: Glycogen-Storage Disease Type V
Follow-up: Glycogen-Storage Disease Type V
Multimedia: Glycogen-Storage Disease Type V
References
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References

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Further Reading

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Keywords

glycogen-storage disease type V, GSD type V, GSD V, McArdle syndrome, McArdle's syndrome, myophosphorylase deficiency, phosphorylase deficiency, McArdle disease, McArdle's disease, McArdle myopathy, McArdle's myopathy, muscle glycogen phosphorylase deficiency, glycogen storage disease type V, acute muscle necrosis, myoglobinuria, glycogen-storage disease type V, glycogen storage disease type VI, glycogen-storage disease type VI, Hers disease, exercise intolerance, early fatigue, treatment, diagnosis

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Contributor Information and Disclosures

Author

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
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
Disclosure: Genzyme Honoraria Speaking and teaching

Coauthor(s)

Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Co-Director: Pediatric and Child Health Research, Oregon Clinical and Translational Research Institute (CTSA).
Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research
Disclosure: Genzyme Honoraria Speaking and teaching; Genzyme Grant/research funds Other; Shire Honoraria Speaking and teaching; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Speaking and teaching; Biomarin Consulting fee Consulting; Amicus  Consulting

Melissa P Wasserstein, MD, Associate Professor, Departments of Genetics and Genomic Sciences and Pediatrics, Mount Sinai School of Medicine
Melissa P Wasserstein, MD is a member of the following medical societies: American Society of Human Genetics
Disclosure: Nothing to disclose.

Cydney L Fenton, MD, FAAP, Consulting Staff, Department of Pediatric Endocrinology, Children's Hospital Medical Center of Akron
Cydney L Fenton, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation
Edward Kaye, MD is a member of the following medical societies: American Academy of Neurology, American Society of Gene Therapy, American Society of Human Genetics, Child Neurology Society, and Society for Inherited Metabolic Disorders
Disclosure: Genzyme Corporation Salary Management position

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Hagop Youssoufian, MD, MSc, Vice President of Clinical Research, ImClone Systems Incorporated
Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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