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McArdle disease (glycogen storage disease type V, OMIM database number 232600) may provide the ultimate model of exercise intolerance in humans, and thus is of great interest in the sports medicine setting. The condition is an autosomal recessive disorder of muscle glycogen metabolism originally described in 1951 by Brian McArdle.1 Patients have pathogenic mutations in both alleles of the PYGM gene, which encodes myophosphorylase, the skeletal muscle isoform of glycogen phosphorylase.2 As a result, myophosphorylase activity is totally absent. Because this enzyme initiates the breakdown of muscle glycogen leading to liberation of glucose-1-phosphate, patients are unable to obtain energy from their muscle glycogen stores. Hence this disease is arguably the paradigm of exercise intolerance in humans.2 Exercise is the trigger for symptom occurrence in McArdle patients; as such, they tend to be averse to exercise and have often been advised by clinicians to refrain from exercise.
McArdle disease and exercise
Men and women are equally affected and symptoms usually begin during childhood, typically in the school playground or physical education classes.3 The clinical presentation is dominated by exercise intolerance in the form of acute crises of early fatigue and contractures, which are often accompanied by exertional rhabdomyolysis, as indicated by marked increases in serum levels of creatine kinase (CK) activity and myoglobinuria.3 Rhabdomyolysis can sometimes be so severe as to cause acute renal failure. A typical feature of the disease is the so-called ‘second wind’ phenomenon, that is, marked improvement in the tolerance of aerobic, dynamic, large muscle mass exercise (walking or cycling) after ∼ 10 min.4 Owing to blocked glycogenolysis, exercise intolerance is most marked during activities relying on anaerobic glycolysis for ATP production, that is, typically isometric exercise (handgrip exercise, carrying weights), but also dynamic exercise of high intensity (climbing stairs, sprinting to catch a bus).2,5 Another main characteristic of the disease is a high baseline serum level of CK activity even in the absence of heavy exercise in the previous few hours or days, which would theoretically reflect an ongoing state of muscle damage.2 ,3 Thus, fixed muscle weakness, frequently accompanied by muscle wasting and affecting mostly proximal upper limb and axial muscles, is prevalent in patients aged ≥40 years.3 ,6 There is heterogeneity in the severity of the disease, for example, 8% of Spanish patients belong to the lowest severity group (virtually asymptomatic, with no functional limitation in any daily life activity) whereas 25% can be included in the most severe group (reporting recurrent exertional myoglobinuria, fixed muscle weakness, and severe limitations on exercise and most daily life activities).3
An unexpected finding – exercise as treatment!
There is no prospect of a definitive cure (genetic therapy) for this disease in the foreseeable future. Yet there are two feasible interventions for alleviating patient's exercise intolerance: (1) pre-exercise carbohydrate ingestion (400–500 ml of most commercially available sport drinks) to ‘protect’ the muscle (especially at the start of exertion, because blood glucose, especially when available in high amounts can enter muscle fibres and by-pass the metabolic blockade)2; and mostly (2) regular, moderate-intensity aerobic exercise. Individual differences in patients' physical activity (PA) levels largely explain the aforementioned heterogeneity in disease severity. Physically active patients are more likely to improve their clinical course (ie, move to a lower severity group of patients) over a 4-year period compared with their peers (OR: 225; 95% CI: 20.3 to 2496.7).3 Levels of PA are also positively associated with patients' functional capacity, as assessed by peak oxygen uptake (VO2peak) determination. This is an important consideration because the VO2peak (a strong, independent health indicator and mortality risk predictor) is usually very low in inactive patients, especially in women, where it barely reaches the limit (∼4METs) necessary for independent living.3 However, some physically active patients have a VO2peak level ≥ 8METs (which is the minimum threshold for optimal health), with one reaching ∼11METs despite having, like all ‘typical’ patients, no myophosphorylase activity in his muscle.3 The VO2peak values of these physically active patients are higher than those recently reported (∼7METs) in two atypical patients described in the literature, in whom there was a ‘mild’ or variant form of McArdle disease. In these two cases, there was a small amount of residual myophosphorylase activity, owing to the presence of an intronic splice mutation in one of the two PYGM alleles.7 (Note that permanent restoration of myophosphorylase activity, even at below normal levels, would be an ideal outcome of eventual gene therapy).
Most neurologists are unaware that McArdle patients with appropriate exercise habits can be almost as aerobically fit as unaffected people. We previously reported the case of a 38-year old patient who, after gradual, supervised training, could run regularly and cover 10 km in ∼ 60 min with no health problems.8 With regards to his performance, the average time for recreational runners (joggers) to complete a 10 km race generally falls between 75 and 80 min. There is also preliminary data from interventional research (using non-controlled designs) showing that McArdle patients adapt to regular exercise just like anyone else, for example, with a significant increase in VO2peak after even light-intensity supervised aerobic exercise.9 ,– ,11 Haller et al 9 showed a 36% increase in the cycle-ergometer peak work capacity of 8 patients after a 14-week training programme (4 sessions/week (duration: 30–40 min) of cycling exercise at 60–70% of peak heart rate), whereas Maté-Muñoz et al 10 reported a 44% increase in the VO2peak of 9 patients with an 8-month programme (5 weekly sessions (duration ≤60 min) of walking or cycling exercise at 60% of peak heart rate). No dietary intervention was included in the study by Haller et al whereas in the report by Maté-Muñoz et al patients ingested a meal containing ∼ 100 g of complex carbohydrates (pasta, rice, bread) 1 h before each session and a commercialised sports drink during warm-up (330 ml solution containing ∼30 g of simple carbohydrates (glucose and fructose)). Pre-exercise carbohydrate ingestion might not be strictly necessary, at least in those patients who are more habituated to exercise. However, in our experience with Spanish patients, especially in those who start a training programme, ingestion of a sports drink prior to exertion is useful to increase the patients' adherence to the programme. Indeed, it decreases their ‘fear of exercise’ by minimising the risk of ‘muscle crises’ and attenuating the feelings of early fatigue and discomfort during the first minutes of a training session.
Adaptation to exercise training should be a very gradual process, especially in those patients belonging to the highest severity class, that is, reporting recurrent exertional myoglobinuria, and severe limitations on exercise and most daily life activities, as mentioned above. In general, we believe that vigorous dynamic exercise (ie, at a level that does not permit normal talking) should only be performed by the more habituated patients. Very intense exercises, particularly those involving high loads on low muscle mass (eg, static muscle contractions such as handgrip exercise, heavy weightlifting), should be discouraged. Clinicians should also instruct their patients to record the incidence myoglobinuria (the latter being referred to by the latter as ‘dark urines’) in order to prevent excessive training loads, that is, inducing severe rhabdomyolysis.
In the BJSM blog (http://blogs.bmj.com/bjsm/), we present some examples (self-reports) of exercise accomplishments by McArdle patients that we entitled ‘McArdle Olympians – lessons from patients’ own experiences'. They provide ‘success stories’ to motivate patients with McArdle disease, and educate clinicians.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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