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GSD V (McArdle disease)
This inherited disorder primarily affects skeletal muscles, leading to exercise intolerance, muscle pain, and cramping. It is caused by changes in the PYGM gene and typically becomes apparent in childhood or adolescence.
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Overview
Glycogen Storage Disease Type V (GSD V), also known as McArdle disease, is a rare genetic condition that primarily affects how muscle cells produce energy. Individuals with GSD V have difficulty using stored glycogen, a complex sugar, as fuel for their muscles, especially during physical activity. This leads to a range of symptoms, most notably exercise intolerance and muscle discomfort [PMID:30137549].
The condition is present from birth but symptoms often become noticeable during childhood or adolescence. It is one of several types of glycogen storage diseases, which are a group of inherited disorders affecting the body's ability to store or use glycogen properly.
While GSD V can significantly impact daily life, it is generally not considered a progressive muscle-wasting disease. Management strategies focus on understanding exercise limits and avoiding activities that trigger severe symptoms.
Symptoms & clinical features
The primary symptoms of GSD V are related to muscle function and energy production. Individuals typically experience exercise intolerance, meaning they find it difficult to sustain physical activity. Early signs can include fatigue, muscle stiffness, and cramping during exercise.
Often, there's a phenomenon known as the 'second wind', where symptoms improve after a short rest period, allowing for further activity, though this is not always the case. In some instances, severe muscle activity can lead to rhabdomyolysis, a breakdown of muscle tissue, which can result in dark, reddish-brown urine (myoglobinuria) and, in rare cases, kidney problems [PMID:30137549].
Symptoms can vary in severity. Some individuals may have mild symptoms that only appear with strenuous exercise, while others experience more significant limitations in their daily activities. Very rarely, severe rhabdomyolysis can lead to acute kidney injury, which requires urgent medical attention.
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Affected organs
GSD V predominantly affects the skeletal muscles, which are the muscles responsible for movement. These muscles are unable to break down glycogen effectively to generate the energy needed for activity. The heart muscle (cardiac muscle) is generally not affected in GSD V.
In severe episodes of muscle breakdown (rhabdomyolysis), waste products from damaged muscle cells can be released into the bloodstream. These can sometimes affect the kidneys, potentially leading to kidney damage if not managed appropriately.
Risks & severity
The severity of GSD V symptoms can vary considerably between individuals. While most experience exercise intolerance, muscle pain, and cramping, the degree to which these impact daily life differs. Symptoms typically begin in childhood or adolescence, but some individuals might not experience noticeable issues until adulthood. The condition is not generally life-threatening, but episodes of severe rhabdomyolysis carry a risk of acute kidney injury, which requires prompt medical intervention [PMID:20301376].
Unlike some other muscle disorders, GSD V does not typically cause progressive muscle weakness or wasting. With careful management and understanding of one's limits, individuals can often maintain a good quality of life. The exact prevalence of GSD V is estimated to be around 1 in 100,000 people, but this might be an underestimate due to milder cases potentially going undiagnosed.
Genetic causes
GSD V is caused by pathogenic variants in the PYGM gene. This gene provides instructions for making an enzyme called muscle glycogen phosphorylase. This enzyme is crucial for the first step in breaking down glycogen, the stored form of glucose, into a usable form of energy specifically within muscle cells [PMID:20301376].
When there are changes in the PYGM gene, the muscle glycogen phosphorylase enzyme either works incorrectly or is not produced in sufficient quantities. This means that muscle cells cannot efficiently access their stored glycogen for energy, especially during physical activity when demand is high. The inability to break down glycogen leads to the build-up of glycogen in muscle cells and insufficient energy production, causing the characteristic symptoms of GSD V.
- PYGM glycogen phosphorylase, muscle associatedThe PYGM gene encodes myophosphorylase, an enzyme essential for glycogen breakdown in muscle cells, with pathogenic variants causing Glycogen Storage Disease Type V (GSD V).
Inheritance pattern
GSD V has an autosomal recessive inheritance pattern. This means that an individual must inherit two copies of a pathogenic variant in the PYGM gene - one from each parent - to develop the condition. People who inherit only one pathogenic variant are known as carriers. Carriers typically do not show symptoms of GSD V because their one working copy of the PYGM gene is usually sufficient to produce enough functional enzyme.
If both parents are carriers of a pathogenic PYGM variant, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two copies of the variant and develop GSD V. There is a 50% (1 in 2) chance that their child will be a carrier, and a 25% chance that their child will inherit two working copies of the gene and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
A diagnosis of GSD V is often suspected based on an individual's clinical symptoms, particularly exercise intolerance, muscle pain, and sometimes myoglobinuria. Blood tests may show elevated levels of creatine kinase (CK) after exercise, which indicates muscle damage [PMID:30137549].
Confirmation of GSD V typically involves genetic testing, which looks for pathogenic variants in the PYGM gene. This type of testing falls under the NHS National Genomic Test Directory with an R-code, meaning it is available through the NHS Genomic Medicine Service. Referrals for genetic testing are usually made by a specialist, such as a neurologist or a clinical geneticist, often following initial assessment by a GP. A muscle biopsy, which examines a small sample of muscle tissue, can also be used to look for the absence of muscle glycogen phosphorylase activity or for glycogen accumulation, although genetic testing is now the preferred diagnostic method.
Management & lifestyle
The management of GSD V focuses on symptom control, preventing severe complications like rhabdomyolysis, and improving quality of life. There is currently no cure for GSD V, but strategies include understanding and managing physical activity levels. Individuals are often advised to avoid intense, sustained exercise that triggers severe muscle pain or cramping.
The 'second wind' phenomenon can be used strategically; a brief rest period at the onset of symptoms can sometimes allow for continued, less intense activity. Dietary modifications, such as a high-protein diet or specific carbohydrate timing, have been explored, but evidence of consistent benefit is variable and should be discussed with a healthcare professional [PMID:20301376].
It is important to stay well-hydrated, especially during any physical activity, to help protect the kidneys. Genetic counselling is often recommended to help individuals and families understand the inheritance pattern and implications of GSD V. Regular follow-up with a neurologist or metabolic specialist is usually part of the ongoing care pathway within the NHS.
UK care pathway
In the UK, individuals suspected of having GSD V typically enter a care pathway that begins with their GP. They may be referred to a specialist, such as a neurologist or a metabolic consultant, for further assessment. If GSD V is suspected, genetic testing can be requested under the NHS National Genomic Test Directory (typically via an R-code, such as R189 for muscle disorders). This testing confirms the diagnosis by identifying pathogenic variants in the PYGM gene.
Following diagnosis, care is usually coordinated by a specialist team, which may include neurologists, dietitians, and genetic counsellors. Genetic counsellors play a crucial role in explaining the condition, its inheritance pattern, and options for family planning. Support groups and patient organisations can also provide valuable information and peer support.
Frequently asked questions
Can children with GSD V participate in sports?
Children with GSD V can often participate in sports, but it's important to understand their individual limits. Activities that involve short bursts of intense effort followed by rest may be better tolerated than prolonged, strenuous exercise. Working with a doctor to find suitable activities is key.
Is GSD V a progressive disease?
GSD V is generally not considered a progressive muscle-wasting disease. While symptoms like exercise intolerance and muscle pain are lifelong, they do not typically worsen over time, and muscle strength usually remains normal outside of exercise-induced episodes.
What is the 'second wind' phenomenon?
The 'second wind' is a characteristic feature of GSD V where individuals might experience muscle pain and weakness early in exercise, but after a short rest, they feel an improvement and can continue exercising, often at a lower intensity, with reduced symptoms. This occurs as their body adapts to using alternative fuel sources like fats.
Are there any dietary changes that can help with GSD V?
Some dietary approaches, such as consuming carbohydrates before exercise or following a high-protein diet, have been explored. However, the effectiveness of these strategies can vary, and it's best to discuss any potential dietary changes with a dietitian or specialist healthcare professional.
What happens if I experience dark urine during exercise?
Dark, reddish-brown urine during or after exercise can be a sign of rhabdomyolysis, which is muscle breakdown. This symptom requires immediate medical attention as it can lead to kidney problems. You should contact your doctor or seek urgent care if this occurs.