Genetics of Glycogen-Storage Disease Type V Clinical Presentation

  • Author: Edward J Cupler, MD, FAAN; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Aug 19, 2011
 

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.
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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
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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]

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Contributor Information and Disclosures
Author

Edward J Cupler, MD, FAAN  Head of Neurophysiology Section, Director of Neurology Residency Training Program, Consultant in Neurology, Neuromuscular Disorders, and Sports Neurology, King Faisal Specialist Hospital and Research Center, Saudi Arabia

Edward J Cupler, MD, FAAN 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; Pfizer Honoraria Speaking and teaching

Coauthor(s)

Robert D Steiner, MD  Credit Unions for Kids Professor of Pediatric Research; Faculty, Pediatrics, Molecular and Medical Genetics, and Program in Molecular and Cellular Biosciences; Vice Chair for Research in Pediatrics, Doernbecher Children's Hospital, Oregon Health and Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital

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: Amicus Honoraria Consulting; Actelion Honoraria Consulting; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Consulting; Genzyme Honoraria Consulting; Shire Honoraria 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  Director, Center for Diabetes and Endocrinology, Akron Children's Hospital

Cydney L Fenton, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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.

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 and Genetics, Director RSA, 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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Enzyme histochemistry of 19-year-old male with McArdle disease.
 
 
 
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