Correspondence *Department of Physiology, Universidad Europea de Madrid, E-28670 Villaviciosa de Odón, Madrid, Spain

Email alejandro.lucia@uem.es

Introduction

Glycogenosis type V, also known as glycogen storage disease type V (GSD-V) or myophosphorylase deficiency (Online Mendelian Inheritance in Man^® [OMIM^®; Johns Hopkins University, Baltimore, MD, USA] number 232600), is the most common disorder of skeletal muscle carbohydrate metabolism and one of most frequent genetic myopathies (estimated prevalence 1:100,000 in the Dallas Forth Worth area, TX, USA).¹ This disorder is usually known as 'McArdle disease', in homage to the British physician Brian McArdle who first described it in 1951.²

Patients with McArdle disease have mutations in both alleles of the PYGM gene, which encodes myophosphorylase, the skeletal muscle isoform of glycogen phosphorylase. These mutations result in a lack of functional mature protein.³ As the liver and heart isoforms of glycogen phosphorylase are unaffected, McArdle disease presents as a pure myopathy.⁴ McArdle disease is approximately equally represented in both sexes and is inherited in an autosomal recessive manner.³ Heterozygous individuals (1:158)⁵ are usually asymptomatic, but typical symptoms of McArdle disease have been described in some of these individuals because of an unusually low level of myophosphorylase activity (20–40% of the normal level).³ An apparent dominant (or pseudo-dominant) transmission of the disease has been reported in some families when a 'symptomatic' heterozygous individual has children with a homozygous individual.^{5, 6}

The aim of this Review is to summarize the current body of knowledge regarding the pathophysiology of McArdle disease, as well as the available diagnostic tools and possible therapeutic options. This is intended to provide a practical guide to help neurologists recognize and manage this condition in their patients.

Pathophysiology

Muscle glycogenolysis, but not muscle glucose utilization, is blocked

Myophosphorylase initiates the breakdown of muscle glycogen by removing (1,4)--glucosyl units from the outer branches of glycogen, leading to liberation of glucose-1-phosphate (Figure 1). In healthy individuals, glucose-1-phosphate is converted into glucose-6-phosphate, which subsequently undergoes glycolysis, resulting in pyruvate production. Muscle pyruvate can be converted to lactate (e.g. in hypoxic conditions), which is then released to the blood at a rate proportional to its production, but most of the pyruvate crosses the mitochondrial membrane where it is converted into acetyl-CoA, which then enters the citric acid, or Krebs, cycle. As a consequence of deficient myophosphorylase activity, patients with McArdle disease are unable to obtain energy from their muscle glycogen stores.⁷

Figure 1 Schematic representation of skeletal muscle glycogen metabolism.

The figure indicates the steps in the pathway that are affected in various glycogen storage diseases that cause defects in skeletal muscle function, leading to exercise intolerance. Abbreviation: GSD, glycogen storage disease; UDP, uridine diphosphate.

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In view of the fact that glycolysis is blocked upstream, the skeletal muscle fibers of patients with McArdle disease can still take up glucose from the blood and convert it into glucose-6-phosphate, which then enters the downstream steps of glycolysis. Muscle glycolysis is not, therefore, totally impaired in these patients, and pre-exercise ingestion of carbohydrates can markedly improve their exercise tolerance.⁸ Some patients exhibit diurnal variations in their degree of exercise intolerance, depending on the timing of their last meal and its carbohydrate content. Fasting periods lasting several hours lead to hypoglycemia and a probable decrement in muscle function in these patients, owing to the low availability of glucose to working muscles.

Epidemiology

There is individual variability in the clinical manifestation of McArdle disease, even between affected relatives. The time of onset of the typical disease symptoms (early or late childhood, and sometimes adulthood) and the degree of exercise intolerance both vary between patients. In rare cases, patients are oligosymptomatic and are correctly diagnosed only because they have an affected relative; in other patients, the disease can be profoundly incapacitating.¹² The first reported patient with the disease (in 1951) was a 30-year-old male,² and he was a good example of extreme phenotype manifestation. He reported severe exercise intolerance in almost all types of physical activities and myalgia in any muscle involved in a given task (including, sometimes, masticatory muscles when chewing gum), together with muscle weakness and stiffness.

One reason for clinical heterogeneity might lie in different dietary regimens (e.g. low vs high carbohydrate content, especially before exercise) and lifestyles, with more-physically active individuals exhibiting better functional capacity than those with a more sedentary lifestyle.⁴ Another factor that might contribute to phenotypic heterogeneity is the patient's sex, with women generally being more severely affected than men, at least in our experience.^{13, 14} In some women, peak cardiorespiratory capacity is barely high enough to sustain the metabolic cost of physical activities of daily living.¹⁴ This might explain why we recently observed a higher degree of physical limitation in women than in men during common daily activities, such as housework.¹³ Among the middle-aged patients whom we studied, proximal muscle wasting and weakness was more frequent in women than in men; in some cases, the severity was such that the patients had to use an electric toothbrush as they easily became fatigued when brushing their teeth manually. In addition, the few adult patients in whom respiratory muscles have been shown to be affected have all been women.^{15, 16}

Genetic variants of several candidate genes that modulate human responses to exercise can also have a role in determining the severity of the McArdle disease phenotype. One such example is the insertion–deletion polymorphism of the angiotensin-converting enzyme (ACE) gene. The insertion allele, which is associated with reduced enzyme activity, improves cardiovascular function and higher uptake of blood glucose into skeletal muscle fibers¹⁷ and favors a less-severe clinical presentation of the disease;^{12, 13} in women, this genotype also results in improved exercise capacity.¹⁸ By contrast, the coexistence in the same individual of McArdle disease and homozygous^{12, 19} or even heterozygous mutations in the gene encoding muscle adenylate deaminase (AMPD1), an important regulator of muscle metabolism during intense exercise, might account for a more-severe phenotypic manifestation of the disease.²⁰

Natural history and precautions

In the past, McArdle disease has rarely been diagnosed before adulthood, possibly because the relevant medical information and diagnostic tools (in particular, molecular genetics) were not widely available until relatively recently. In our series (currently 110 patients), however, most individuals remember having had painful symptoms associated with severe exercise since early childhood, during physical education classes for example.²¹ It is possible that McArdle disease could have been the cause of (or at least contributed to) severe respiratory insufficiency and death in a 13-year-old girl described in a case report in 1978.²²

Besides the typical symptom of exercise intolerance, around a third of patients with McArdle disease also develop fixed weakness and wasting (affecting more proximal than distal muscles) with aging.^{3, 7} In addition to aggravated exercise intolerance over the years, proximal muscle weakness and wasting could be the fate of some patients at an advanced age because of the long-term effects of the disease itself, which is frequently associated with 'chronic' muscle damage even under resting conditions, and a lifetime of sedentary habits. We recently studied an elderly patient (now 81 years old and sedentary since childhood) with marked exercise intolerance and proximal muscle atrophy and fixed weakness.²³

McArdle disease is not usually a life-threatening condition, although there are some exceptions. Continuing to exercise in the presence of severe pain (which, as well as being an unpleasant symptom, is also a physiological, self-protective mechanism) might increase the risk of myoglobinuria and subsequent acute renal failure. Myoglobinuria occurs in about 50% of patients after intense exercise, and about 50% of these patients also develop acute renal failure, which is almost always reversible but, nevertheless, requires emergency treatment.²⁴ Patients should, therefore, be advised to refrain from any exercise that induces severe pain, especially if it involves static muscle contractions; however, as further explained below, medically prescribed dynamic exercise of low to moderate intensity is a safe, recommended therapeutic option for these patients. Another potential problem in these patients is myogenic hyperuricemia. Owing to impaired ATP production, muscular exertion can induce overproduction of AMP, with accelerated liberation of the metabolites ammonia, inosine, hypoxanthine and xanthine to the blood.^{25, 26} These purine metabolites subsequently serve as substrates for the synthesis of uric acid, leading to hyperuricemia.²⁶

Although McArdle disease does not seem to cause severe perioperative problems in routine anesthetic care, measures for preventing muscle ischemia and rhabdomyolysis should be kept in mind, as should the potential of patients with this condition to develop postoperative fatigue, myoglobinuria and renal failure.²⁷ In pregnant patients, we propose that vaginal delivery is probably a better option than cesarean section, so as to prevent any potential problem associated with anesthesia, although more data are required to confirm the validity of this approach. To ensure appropriate and safe management of the patient after delivery, and to avoid partum-induced rhabdomyolysis and myoglobinuria, obstetricians should be well briefed by neurologists on the characteristics of McArdle disease and its potential risks.

The use of statins could exacerbate rhabdomyolysis in patients with McArdle disease; therefore, it is important to exercise caution when prescribing such drugs to these individuals.²⁸

Diagnosis

Initial suspicion: features indicative of McArdle disease

In view of the fact that McArdle disease is mainly associated with exercise intolerance, in the form of acute episodes of reversible 'muscle crisis', neurologists must be attentive to their patients' self-reports of exercise intolerance, as well as to the occurrence of dark urine following heavy exertion. Patients typically describe myoglobinuria as urine looking like cola, marsala, or red wine.

The main diagnostic tools for McArdle disease are summarized in Table 1. In particular, four features that are present in the great majority of patients should set the initial basis for a correct diagnosis. The first feature is exercise intolerance, usually since childhood, with or without actual fixed muscle weakness at the moment of evaluation. The patient might also report improved exercise tolerance after ingesting carbohydrates (e.g. pasta, rice, sports drinks). Another classic feature is a high serum level of total creatine kinase (CK) activity, even at rest, that is, in the absence of heavy exercise in the previous hours or days. In one of our series,¹⁴ a mean CK activity of about 3,200 U/l was recorded in 24 men, and a mean of about 1,600 U/l was recorded in 22 women at rest. A third characteristic of the disease is one or more previous episodes of hyper-CK-emia (several thousand U/l, indicating marked rhabdomyolysis) after intense exercise. The fourth feature, as we will discuss below, is the 'second wind' phenomenon.

Table 1 Main tools for correct diagnosis of McArdle disease and differential diagnosis with other myopathies.

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Treatment

Despite previous, valuable efforts,^{53, 54} no effective gene therapy is expected to be available in the forseeable future to replace myophosphorylase deficiency in humans. Adenovirus type V and adeno-associated virus type II can transiently restore myophosphorylase activity in sheep muscle⁵⁴—a promising result given that the corporal mass of the sheep is similar to that of humans—but permanent restoration of enzyme activity is the ultimate goal in patients. More than 90% of patients with McArdle disease have mutations that produce a premature termination codon (PTC). This leads to nonsense-mediated messenger RNA decay, a cellular protective mechanism that eliminates the majority of messenger RNA transcripts containing nonsense and frameshift mutations.⁵⁵ An investigational new drug, PTC124, has been shown to translate genes with a PTC into full-length protein in cystic fibrosis and Duchenne muscle dystrophy.⁵⁶ In patients with McArdle disease, however, short-term treatment (10 days) with gentamicin, a drug that also has the potential to read through PTCs, failed to normalize ³¹P-MRS indicators of myophosphorylase deficiency in muscle.⁵⁷

Several randomized, placebo-controlled trials (each with more than five patients) have been conducted in patients with McArdle disease; both pharmacological interventions (ACE inhibitors⁵⁸ or dantrolene sodium,⁵⁹ a drug normally used for the prevention of anesthetic-induced rhabdomyolysis) and nutritional interventions (D-ribose⁶⁰ or creatine^{61, 62} supplementation, a carbohydrate-rich diet,⁶³ pre-exercise oral administration of branched-chain amino acids⁶⁴ or sucrose^{8, 65} or pre-exercise intravenous infusion of glucose³⁰) have been investigated. These approaches are reviewed by Quinlivan et al.⁶⁶ in a recent Cochrane update. Low-dose creatine supplementation (60 mg/kg per day for 4 weeks) can increase tolerance to ischemic exercise in patients with McArdle disease,⁶¹ but higher doses (150 mg/kg per day) might actually exacerbate myalgia.⁶² Given the susceptibility of patients to recurrent muscle injury, it is important to ensure a sufficient intake of protein in the diet, as this could theoretically improve the potential for muscle repair. Uncontrolled case studies have suggested an improvement in the exercise capacity of two patients with McArdle disease who were given a high-protein diet,^{67, 68} but randomized controlled trials investigating the short-term⁶⁴ or long-term⁶⁹ effects of branched-chain amino acids administered before exercise showed no benefit;⁶⁹ in fact, short-term administration resulted in a decrement in performance.⁶⁴

At present (and keeping in mind the need for further research in the field), the most beneficial intervention for patients with McArdle disease, in combination with aerobic conditioning, consists of ensuring that sufficient blood glucose (derived from high hepatic glycogen stores) is constantly made available to patients' working muscles during the daytime. This is achieved by adopting a diet with a high proportion (65%) of complex carbohydrates (such as are found in vegetables, fruits, cereals, bread, pasta and rice) and a low proportion (20%) of fat,⁶³ and through ingestion of simple carbohydrates (30–40 g of glucose, fructose or sucrose in adults,^{14, 65} which translates to around 440 ml of most commercially available sport drinks, and 20 g in children²¹) about 5 min before engaging in strenuous exercise, such as brisk walking,¹⁴ or physical education classes in the younger patients.²¹

We have detailed the exercise recommendations for patients with McArdle disease in Table 2 and Box 1. Paradoxically, the main enemy of these patients, acute exercise, can become their ally if carefully prescribed and performed on a regular basis. Aerobic, dynamic exercise involving large muscle mass (e.g. cycling or walking) at low to moderate intensities (i.e. at a level that permits talking after some build up) is a safe and recommended therapeutic option for these patients.^{14, 70} Notably, this intervention markedly improves (by around 44%) their maximum cardiorespiratory capacity (VO_2peak), which usually falls well below 25 ml O₂/kg per min (the minimum threshold for optimal health in humans), even after pre-exercise carbohydrate ingestion.¹⁴ This is an important consideration, as VO_2peak reflects peak muscle oxidative capacity and is arguably the best indicator of health and predictor of all-cause mortality in humans. Furthermore, serum CK levels decrease with training, suggesting that the stimulation of muscle growth prompted by exercise training might partially counterbalance muscle damage and wasting in patients with McArdle disease.¹⁴

Table 2 Exercise therapy in patients with McArdle disease: recommendations and precautions.

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In general, vigorous dynamic exercise (i.e. at a level that does not permit normal talking) should be performed only by the more-fit patients (after months of gradual habituation) and should be combined with pre-exercise carbohydrate ingestion. Very intense exercises, particularly those involving high loads on low muscle mass, are strongly discouraged in these patients.

Conclusions

McArdle disease, a disorder associated with a block in muscle glycogenolysis caused by an inherited deficiency of myophosphorylase, is arguably the paradigm of the exercise intolerance syndrome in humans. This syndrome is characterized by acute exercise-induced crises, consisting of excessive, premature muscle fatigue and contractures, frequently accompanied by rhabdomyolysis and sometimes myoglobinuria. No effective gene therapy is expected to be available in the short term. Until a definitive cure is found, carefully supervised aerobic, gentle physical activities, combined with 'muscle protection' by pre-exercise ingestion of carbohydrate drinks, can help to improve the functional capacity of patients with McArdle disease. Controlled, randomized therapeutic trials, possibly involving numerous research centers and hospitals in view of the rarity of the disease, will be needed to uncover additional nutritional and/or exercise interventions that might be of benefit to these patients.

Acknowledgments

Research relating to McArdle disease by A Lucia and M Pérez is supported by the Health Research Fund of the Spanish Ministry of Health (FIS, ref. #PI061183). Research for the Spanish consortium for the study of McArdle disease is supported by the Health Research Fund (FIS, ref. #PI040487, PI041157, PI040362) and the Spanish Centre for Biomedical Network Research on Rare Diseases (CIBERER). Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Subject areas under which this article appears: Neuromuscular disease