What is McArdle's Disease?

Causes and symptoms
PYGM gene
Diagnosis and treatment
Further reading

​​​​McArdle's disease, also known as Glycogen Storage Disease Type V, or GSD5, is a congenital disorder of muscle metabolism. It occurs when the body loses its ability to break down glycogen leading to characteristic symptoms like fatigue, muscle pain, and cramps. McArdle's disease is a genetic disorder due to mutations of the PYGM (myophosphorylase or glycogen phosphorylase) gene, which has an autosomal recessive inheritance.

Due to the rarity of the condition and the variable signs and symptoms, McArdle's disease is often difficult to diagnose. Treatment primarily focuses on lifestyle changes to improve the symptoms in patients.

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The first case of McArdle's disease was reported in 1951 by B. McArdle. The patient was a 30-year-old man experiencing muscle pain, stiffness, and weakness while exercising. The symptoms gradually improved after rest. Exercise did not affect blood lactate levels, indicating that the patient could not convert muscle glycogen to lactate. Mommaerts et al. (1959) determined that the absence of muscle phosphorylase and a glycogenolytic deficiency in the muscle were the root causes of the disease. In the same year, Schmid and Mahler also identified this association.

The "second wind" phenomena, which Pearson et al. (1961) initially mentioned concerning this condition, was investigated by Braakhekke et al. in 1986. The three patients they studied experienced gradual muscle weakening and tiredness during the first 15 minutes of exercise, followed by a swift and complete recovery (adaptation phase). All three patients could continue working out without problems (the "second wind" phase). Increased cardiac output, modifications to the metabolic pathways, and an increase in EMG activity were among the events during the "second wind" phase. These events likely represented the recruitment of additional motor units to make up for a failure of force generation in the muscle fibers.

Causes and symptoms

McArdle disease typically occurs from mutations in the glycogen phosphorylase enzyme (PYGM), which is found on chromosome 11q13 and is exclusive to muscles. The myophosphorylase deficit caused by the PYGM mutation prevents glycogenolysis in voluntary muscles by reducing glycogen breakdown.

McArdle's disease is classified as a myopathy, predominantly affecting the muscular tissue. Physical exercise intolerance continues to be the most frequently mentioned symptom. Other signs include aching muscle cramps, weariness, and weakness. Painful contractures can occasionally result from muscle discomfort and stiffness. These symptoms are considerably more noticeable right after commencing exercise, and the symptoms eventually improve once exercising is stopped. In severe episodes, myoglobinuria is observed, turning the urine to be red or brown. Myoglobinuric McArdle's disease patients are thought to have a 50% chance of developing fatal renal failure. Four percent of patients have been reported to experience seizures.

 In McArdle disease, clinical heterogeneity is frequently observed. Some patients have very minor symptoms, such as fatigue without cramping. On the other side, around the sixth or seventh decade of life, increasing weakening sets in.

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To date, about 150 different disease-causing variants in PYGM have been reported. About half of the disease-causing variants in PYGM are missense variants, 18% are deletions, 13% are nonsense variants, 11% are splice site variants, and the remaining variants are duplications or insertion/deletion variants. The majority of variations, which are mostly found within exons, all cause the myophosphorylase enzyme activity to be drastically diminished or missing, frequently as a result of nonsense-mediated decay. Hotspots for mutations are particularly evident in exons 1 and 17.

PYGM gene

The PYGM gene contains the instructions required to manufacture the myophosphorylase enzyme. Only in muscle cells can one find this enzyme, which converts glycogen into the less complex molecule glucose-1-phosphate. Glucose-1-phosphate is transformed into glucose through additional processes, a simple molecule that serves as the majority of cells' primary energy source.

Mutations in the PYGM gene restrict myophosphorylase from efficiently metabolizing glycogen. As a consequence, muscle cells are unable to produce adequate energy and gradually become fatigued. The main characteristics of GSDV are caused by decreased energy synthesis in muscle cells.

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Epidemiological information on McArdle's disease is scarce. The disease affects people of both sexes at a mean age of 44 and is expected to have a prevalence of 1 per 100000 to 167000 people. In the United States, the prevalence of McArdle disease appears to range from 1 in 50,000 to 1 in 200,000. According to genetic data, the incidence of McArdle disease in some regions of the USA, such as the Dallas/Fort Worth area, is estimated to be 1/100000. As per a Spanish study, there are roughly 1 in 139543 diagnosed instances overall. McArdle's disease presents a variable incidence in different regions of the world. Concerning gender, the condition is prevalent in a 1:1 ratio in the United Kingdom. Spain and Italy have reported incidences of 55:45 and 65:35 in men and women, respectively.

Diagnosis and treatment

Early diagnosis is crucial since it will benefit patient care. The condition has always been known to show significant clinical heterogeneity. Using a phenotypic scale, McArdle patients are divided into four groups: classes 0, 1, 2, and 3. Patients in class 0 exhibit mild exercise intolerance and are asymptomatic (or paucisymptomatic). They do not experience restrictions on everyday activities. Class 1 consists of classical presentations with limits in everyday activities. Exercise intolerance, recurrent cramps, myalgia, and myalgia without myoglobinuria are also observed. Patients in class 2 have a classical presentation with myoglobinuria. Class 3 involves the classical presentation with myoglobinuria and fixed muscle weakness, which significantly restricts everyday activities. Muscle biopsy and/or PYGM genetic testing can be used to diagnose based on the clinical signs and symptoms, along with high baseline serum creatine kinase levels.

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The main focus of treatment is avoiding physical activities that make symptoms worse. Although patients may learn to avoid exercise, this could worsen their condition as serum CK rises with decreased aerobic capacity. The therapeutic benefits of moderate-intensity graded aerobic exercise are of utmost importance in managing the symptoms of McArdle's disease. With this technique, patients reported less significant exercise discomfort and an earlier onset of a second wind. In some people, a balanced weightlifting strategy reduces the intensity of symptoms. Consumption of a sugary meal before a planned workout is one dietary modification that has positive results. Comparatively, a diet high in carbohydrates yields far better benefits than one high in protein.

The key moderator of the clinical course of McArdle disease appears to be exercise. Eighty-one percent of physically active patients moved down a disease severity class during four years, according to one study. Patients can increase their fitness levels almost as effectively as healthy people if they commit to a supervised, progressive exercise regimen. To increase their commitment to regular exercise, patients are advised to select a pleasurable form of exercise. Light- to moderate-intensity exercise (especially if it is preceded by carbohydrate ingestion) is currently the only effective therapy for this condition, and the findings of prior research demonstrate the viability and advantages of tailored, professionally supervised exercise regimens. Further epidemiological research can shed more light on the global prevalence of the disease.


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Last Updated: Sep 2, 2022

Written by

Aimee Molineux

Aimee graduated from Oxford University with an undergraduate degree in Japanese and Korean Studies, with an exchange year at Kobe University in Hyogo, Japan. Throughout her studies, Aimee took part in various internships, gaining an interest in marketing and editorial work along the way.In her personal time, Aimee can be found either attempting to cook, learning how to code, doing pilates, as well as regularly updating her pet hamster’s Instagram account.

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