Genetics of Glycogen-Storage Disease Type V (McArdle Disease) Treatment & Management

Updated: Mar 05, 2018
  • Author: Noura Al Dhaheri, MBBS, FAAP; Chief Editor: Maria Descartes, MD  more...
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Treatment

Medical Care

Since there is no cure for McArdle disease, management is focused on treatment of the disease manifestations (detailed below), prevention of secondary complications, and regular surveillance.

A general approach to treatment aims at providing therapies that could bypass the metabolic block. However, providing glucose or fructose or using glucagon injection yielded inconsistent results.

Creatine Monohydrate

It is hypothesized that creatine may improve ATP capacity and exercise tolerability. A placebo-controlled crossover trial showed that 9 individuals with McArdle disease had improved symptoms and increased capacity for ischemic isometric forearm exercise. However, in a subsequent trial by the same group in 19 individuals, high-dose creatine monohydrate worsened exercise intolerance and significantly worsened the clinical symptoms of exercise-induced myalgia. [16] The authors suggested a possible explanation is that insufficient adaptation to improved electromechanical efficacy leads to overuse of the muscle contractility in exercise and thus a worsening of symptoms. However, no significant changes were seen on phosphorous 31 magnetic resonance spectroscopy (MRS) variables. [16]

Angiotensin Converting Enzyme (ACE) Inhibitors: Ramipril

Martinuzzi et al studied a small cohort (10 patients) in a double-blind, randomized, placebo-controlled crossover trial using 2.5 mg ramipril. No significant difference was found between the placebo and ramipril groups in terms of objective exercise parameters, although the WHO-DAS 11 score improved in ramipril-treated participants. The improvement in the perceived disability scores was more pronounced in the D/D genotype and was absent in the I/D genotype. Additional testing in a larger patient population is needed. [17]

Sodium Valproate

A 2015 study by Howell et al hypothesized that sodium valproate, a histone deacetylase inhibitor, might be able to up-regulate the myophosphorylase enzyme. Using sheep as an animal model, they showed that enteral treatment with 20-60 mg/kg was associated with increased expression of myophosphorylase in muscle fibers. This response was found to be dose-dependent. The findings from the study suggest that sodium valproate is a potential therapeutic option for McArdle disease. [18] Randomized trials are needed to study the potential benefits in humans.

Another study in a mouse model showed a dose-dependent decrease in glycogen accumulation, suggesting that sodium valproate can be considered a gene-expression modulator that allows compensatory expression of myophosphorylase and decreased glycogen accumulation in skeletal muscles among patients with McArdle disease. [19] Further studies in humans are needed to determine the efficacy of this approach.

Vitamins/Nutritional Supplementation

Some studies suggest that pyridoxine may reduce the susceptibility of muscles to fatigue in patients with McArdle disease. Normally, myophosphorylase uses pyridoxal 5'-phosphate (derived from vitamin B-6) as a cofactor; therefore, supplementation may augment the remaining myophosphorylase activity. In addition, most of the total body pool of pyridoxine is normally bound to myophosphorylase; therefore, the body's store of pyridoxine may be depleted in patients with McArdle disease.

Evidence for the benefit of supplementation with branched chain amino acids, depot glucagon, vitamin B6, and high-dose oral ribose is low. [20] Studies of oral sucrose administered at different times and in different amounts before exercise showed improvement in exercise tolerance when given before exercise (75 g 30 minutes before exercise). However, the evidence is low and insufficient to determine clinical benefits. [20]

Other

Gene therapy with adenovirus is in the experimental phase. No human gene therapy trials have yet been conducted.

A clinical therapy trial of triheptanoin (medium chain triglyceride) may begin soon.

For more update information, visit ClinicalTrials.gov

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Consultations

Acute renal failure may occur with rhabdomyolysis, necessitating consultation with a nephrologist. Monitoring renal function in all patients with McArdle disease is recommended.

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Diet

A high carbohydrate diet may improve maximal work capacity and exercise tolerance. A randomized controlled trial comparing a carbohydrate rich (20% fat, 15% protein, 65% carbohydrate) and a protein rich diet (15% fat, 55% protein, 30% carbohydrate) surprisingly showed that subjects on the carbohydrate rich diet improved exercise tolerance and maximum oxidative capacity compared with subjects on the protein rich diet. [21] A 2014 Cochrane review systematically examined evidence from available randomized controlled trials of pharmacological and nutritional management for McArdle disease. While a carbohydrate-rich diet resulted in better exercise performance than a protein-rich diet, the evidence quality was low and not strong enough to indicate significant clinical benefit, [20] likely owing to the small number of participants included in each study comprising the systematic review.

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Activity

Regular, moderate aerobic activity has been shown to improve exercise capacity in patients with McArdle disease. Patients should exercise using a heart rate monitor, keeping the heart rate to 60-70% of maximum. [22] Exercise should be preceded by a warm-up period and dose of sucrose prior to exertion if not contraindicated. [23]

Therefore, to improve quality of life, the following activity modifications are recommended in patients with McArdle disease:

  • Participate in regular moderate aerobic exercise, which improves cardiorespiratory capacity and increases delivery of bloodborne fuels, simulating a permanent "second wind" phenomenon.
  • Avoid intense isometric exercise and maximal aerobic exercise, which causes cramps and can potentially trigger rhabdomyolysis and myoglobinuria.
  • Avoid a sedentary lifestyle, which can cause deconditioning.
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Prevention

Because acute renal failure is precipitated by rhabdomyolysis in McArdle disease, avoidance of strenuous and/or isometric exercise may be indicated, including the following: [16]

  • Static muscle contractions (eg, handgrip exercises) or heavy loads on low muscle mass (eg, weightlifting)
  • Dynamic exercises at a high-intensity level (eg, competitive ball games)
  • Exercises with a high involvement of eccentric (lengthening) muscle contractions (eg, jumps)
  • Very intense dynamic aerobic exercise (eg, running, strenuous swimming, or cycling), except in individuals who are very fit and well habituated

General anesthesia

Although rare, the risk of acute muscle damage has been reported with certain general anesthetics (usually muscle relaxants and inhaled anesthetics). Measures to prevent muscle ischemia and rhabdomyolysis should be taken in individuals with McArdle disease. [24]

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Long-Term Monitoring

Patients with McArdle disease should undergo annual routine physical examination and routine review of diet and exercise precautions.

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Further Inpatient Care

If acute renal failure occurs in patients with McArdle disease, hemodialysis and appropriate monitoring of fluid and electrolyte status may be necessary.

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