Genetics of Glycogen-Storage Disease Type V Clinical Presentation

Updated: Nov 10, 2015
  • Author: Edward J Cupler, MD, FAAN; Chief Editor: Maria Descartes, MD  more...
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Presentation

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. [6]

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

See the list below:

  • 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. [7] 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. [4, 8]

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. [4]

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