McArdle Disease

Introduction 

McArdle Disease, also known as Glycogen Storage Disease Type V, is an inherited muscular disorder characterised by an inability to properly break down glycogen, the body’s primary source of stored energy. More specifically, it is caused by a deficiency in the enzyme that breaks down glycogen. McArdle Disease leads to muscular and skeletal damage and, if left untreated, muscular wasting (muscular atrophy) and exhaustion during exercise. There are several defining symptoms, diagnostic methods, and treatment options for this rare disease. Not much is known about the disease’s prevalence according to the Rare Disease Database. 

About McArdle Disease

McArdle Disease, also known as Glycogen Storage Disease Type V (GSDTV), is a genetic condition characterised by a deficiency in the enzyme ‘muscle glycogen phosphorylase’.¹ It is an autosomal recessive disorder meaning that both of the individual’s parents must have mutations on the chromosome that code for the muscle glycogen phosphorylase (PYGM gene). Those who carry only one copy of the mutation typically will not have symptoms of the disease. 

Glycogen is a stored energy source for the body that is broken down when in need of energy. Individuals deficient in glycogen phosphorylase cannot break down glycogen, leading to the reduced ability of the body to use glycogen as a quick energy source. Glycogen breakdown is essential in muscles so they can perform their functions. Individuals with McArdle Disease typically experience muscular pain and exhaustion within the first few minutes of exercise.⁴ This is due to the body being unable to break down glycogen to support cellular nutrient demand during exercise. 

The onset of McArdle Disease typically occurs in childhood and the disease is characterised by elevated serum creatine kinase levels – an indicator of skeletal damage.³

Symptoms 

The most characteristic symptom of McArdle Disease is muscle pain following exercise. McArdle Disease symptoms vary between patients due to the level of deficiency that each may have. As the muscle glycogen phosphorylase enzyme is only found in muscle, most of the disease’s symptoms are muscle-related.³ Symptoms include:

• Muscle pain (Myalgia): Muscle pain is the most common symptom of McArdle Disease.⁴ Deficiencies in the glycogen phosphorylase leads to the inability to sufficiently break down glycogen, in turn, this leads to muscle cells not having enough energy and nutrient access to carry out their functions; thus, inducing pain. Muscle pain typically occurs after a few minutes of exercise due to the strain on the muscle cells.⁴ Muscle pain may also be in the form of muscle cramping and tightness.
• Muscle wasting (Atrophy): Muscle wasting typically occurs following long periods due to the overexertion of muscles and their cells. Muscle wasting is usually not seen in patients until they reach older age.⁵
• Abnormal coloured urine (Myoglobinuria): Myoglobinuria is is characterised as excessive myoglobin levels in the urine due to the breakdown of muscle.⁶ Myoglobin is a protein that is usually present in the blood; the breakdown of muscle cells leads to myoglobin being released into the bloodstream and excessive myoglobin within the blood leads to abnormal coloured urine.⁶ 
• Low stamina: Due to the great strain that exercise puts on patients with McArdle Disease, patients may have a low exercise tolerance due to muscles not having enough energy to sustain their activity.⁴ 
• Elevated serum creatine kinase levels: High levels of serum creatine kinase is a sign of muscle damage. Due to the damage that muscles sustain due to insufficient glycogen breakdown, serum creatine kinase levels can rise, indicating that a patient may have McArdle Disease or other diseases that cause muscle damage.^2,3

Causes and Risk Factors

McArdle Disease is caused by autosomal recessive mutations on the PYGM gene on the long arm of chromosome 11.⁷ The PYGM gene codes for the glycogen phosphorylase enzyme which breaks down glycogen to be used as an energy source. As of 2006, there are 67 PYGM known gene mutations that may lead to McArdle Disease if both of an individual’s parents carry one of them.¹ PYGM mutation leads to partial or total loss of the PYGM gene which then affects the severity of the disease. Mutations in PYGM prevent the glycogen phosphorylase enzyme from being able to break down glycogen for its use as a muscle energy source.¹ 

When individuals with McArdle Disease participate in anaerobic activities, such as weightlifting, uphill walking, and sprinting, their bodies are unable to break down glycogen sufficiently enough to support the physical activity they are engaging in.^3,7 This leads to the condition’s characteristic symptoms, such as muscle pain, abnormal urine colour, and low endurance. However, it should be noted that McArdle patients are typically able to perform exercise over long periods of time due to the “second wind phenomenon”.³ Longer periods of exercise lead to the use of alternative energy sources allowing individuals to perform an exercise without any of the uncomfortable symptoms of short-duration exercise.⁴ 

McArdle Disease onset is typically in childhood, before the age of 15. In children, the condition usually appears as exercise intolerance, muscle weakness, and significant fatigue following physical exertion.² This is specifically noted in children due to their great energy and sustained periods of running and other forms of physical activity.² 

Diagnosis of McArdle Disease

There are several diagnostic methods that can be used to determine if an individual has McArdle Disease. Diagnosis is based on biological investigations of specific causes that can reveal the absence or overproduction of certain biological factors. These include: 

• Blood tests: Muscle damage occurs in McArdle Disease due to strained muscles (during exercise) being unable to access sufficient sources of energy in the form of glycogen. Elevated levels of serum creatine kinase are typically a sign of muscle damage. Blood tests can be performed to check for elevated muscle enzyme levels, such as serum creatine kinase.⁴ 
• Electromyography: Electromyography is a diagnostic test that is used to test the muscle, and its associated nerves function. The test involves the placement of electrodes on the muscles that are being tested, the electrodes pick up nerve signals from muscles and transmit them to a computer for the nerve signals to be graphed for diagnosis.^8,10 
• Urine tests: Urine tests can be performed to test for abnormal proteins in the urine, such as myoglobin. Myoglobin is a protein that is released into the bloodstream following muscle breakdown. Myoglobin is excreted in the blood leading to the abnormal colour of the urine.^4,6 
• Muscle biopsy: Although invasive, muscle biopsies can be used to test the function and physiology of muscle. Muscle biopsy is typically performed on the bicep, where muscle tissue is removed from the bicep and then tested for high glycogen levels and absence of myophosphorylase.⁵ 
• Forearm Exercise Test: The forearm exercise test is one of the most common diagnosis methods for McArdle Disease. The procedure is performed by temporarily blocking the circulation of blood in the forearm. Patients with McArdle Disease will experience a decrease in lactate concentration in the blood and increased ammonia concentration. However, a forearm exercise test can pain and muscle cramps in the tested area.⁹ 
• DNA testing: This can be performed to confirm that a patient has the two copies of the PYGM gene mutations to confirm that they have McArdle Disease.⁴ 

Treatments for McArdle Disease

There is no cure for McArdle Disease, however, there are several ways to combine treatment options to ensure a patient’s ultimate comfort. Treatment usually involves actively making lifestyle choices that prevent the aggravation of an individual’s symptoms.⁴ Patients should avoid participating in activities that are too strenuous and/or too hard, as this can lead to unpleasnt symptoms. However, total avoidance of exercise can actually worsen McArdle’s symptoms as it leads to a rise in serum creatine kinase levels (a sign of muscle damage). Exercise avoidance also reduces muscle cells’ ability to use alternative energy sources for their functioning.⁴ 

There has been evidence that moderate exercise is a good treatment therapy. Exercising to experience the “second-wind phenomenon” can ease symptoms and is an excellent approach to prevent the total avoidance of exercise. McArdle Disease can also be treated with a diet rich in proteins and carbohydrates. A diet rich in these nutrients allows easy access to them as energy sources during exercise to prevent the characteristic symptoms of the disease.⁴ Creatine supplements have also been suggested as a potential treatment option, however, a clinical trial found that high levels of creatine lead to poor exercise tolerance and increase muscle pain during exercise.^5,6 The combination of healthy lifestyle and exercise choices allows patients with McArdle Disease to live relatively normal lives. 

Complications

If McArdle Disease is left untreated and is continuously exarberrated through high-intensity exercise, it can lead to several complications. When muscle breakdown in McArdle disease is left untreated and uncontrolled, it can lead to severe kidney injury.¹⁰ This is because the myoglobin that is released is more than the kidney can process and handle, thus leading to kidney injury. If the kidney injury is sustained it can lead to kidney failure, which is life-threatening due to the diverse functions that the kidneys perform in the body, such as blood filtering and the production of urine.^10,11 It should be noted that kidney involvement in McArdle Disease is extremely rare and the disease rarely progresses to this point. Seizures can also occur but their occurrence is extremely rare. The exact mechanism of seizure occurrence in McArdle Disease is unknown.¹⁰ 

Summary 

McArdle Disease is an autosomal recessive disorder that is characterised by the body’s inability to break down glycogen in muscle tissue.¹ It is caused by a patient having two copies of the PYGM gene mutation, as the PYGM gene is responsible for coding and guiding the activity of the muscle glycogen phosphorylase enzyme. McArdle disease is a very rare disease, although its exact prevalence is unknown. The characteristic symptom of McArdle Disease is muscle pain as muscle tissue is unable to break down glycogen into glucose to use as an energy source to fuel its activities.⁴ There are several diagnostic methods that can be used to diagnose this condition, specifically, the blood testing to evaluate for elevated protein levels in the blood and DNA testing to confirm the gene mutations. Despite there being no cure for the disease, there are several lifestyles and diet modifications that McArdle patients can implement to improve their comfort despite their diagnosis.⁸ Complications are rare but can be life-threatening.¹