Key Points
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Of the glycogenolytic and glycolytic disorders (GSDs), McArdle disease (GSD V) is the most common (prevalence 1 in 100,000–167,000), and β-enolase deficiency is the rarest, with only three cases identified to date
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The GSDs result from autosomal or X-linked recessive mutations, resulting in a specific enzyme deficiency that leads to the inability to utilize muscle glycogen as an energy substrate
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The main features of the GSDs include exercise intolerance, hyperCKaemia and myoglobinuria; paradoxically, when appropriately prescribed, exercise can improve work capacity, reduce health risks, ameliorate symptoms and improve quality of life
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Exercise intolerance and, hence, avoidance can lead to secondary health threats from a sedentary lifestyle, increase health risks generally, and further impair quality of life
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Additional clinical features, such as dysmorphic features, haemolysis, neurological features, liver disease, skin lesions and/or cardiomyopathy, can help to pinpoint the specific enzyme deficiency
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Potential therapies for McArdle disease are being explored through the use of animal models of the disease (cattle, sheep and mice), and through dietary manipulation and speculative drug therapy in humans
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A European database (EUROMAC) has been established to pool and transfer knowledge regarding McArdle disease and other rare diseases of carbohydrate metabolism more effectively
Abstract
Skeletal muscle disorders of glycogenolysis and glycolysis account for most of the conditions collectively termed glycogen storage diseases (GSDs). These disorders are rare (incidence 1 in 20,000–43,000 live births), and are caused by autosomal or X-linked recessive mutations that result in a specific enzyme deficiency, leading to the inability to utilize muscle glycogen as an energy substrate. McArdle disease (GSD V) is the most common of these disorders, and is caused by mutations in the gene encoding muscle glycogen phosphorylase. Symptoms of McArdle disease and most other related GSDs include exercise intolerance, muscle contracture, acute rhabdomyolysis, and risk of acute renal failure. Older patients may exhibit muscle wasting and weakness involving the paraspinal muscles and shoulder girdle. For patients with these conditions, engaging with exercise is likely to be beneficial. Diagnosis is frequently delayed owing to the rarity of the conditions and lack of access to appropriate investigations. A few randomized clinical trials have been conducted, some focusing on dietary modification, although the quality of the evidence is low and no specific recommendations can yet be made. The development of EUROMAC, an international registry for these disorders, should improve our knowledge of their natural histories and provide a platform for future clinical trials.
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Acknowledgements
We wish to acknowledge the European Union for funding the EUROMAC network and NHS England for funding our nationally commissioned service. We wish to thank the Association for Glycogen Storage Disease UK (AGSD-UK) for their continuing support, as well as Muscular Dystrophy UK (MDUK), which is currently funding a trial of valproate in McArdle disease.
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Godfrey, R., Quinlivan, R. Skeletal muscle disorders of glycogenolysis and glycolysis. Nat Rev Neurol 12, 393–402 (2016). https://doi.org/10.1038/nrneurol.2016.75
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DOI: https://doi.org/10.1038/nrneurol.2016.75
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