Glycogen storage disease type V is a rare inherited condition that affects the muscles’ ability to break down stored energy. When muscle cells cannot access the fuel they need during physical activity, people experience fatigue, pain, and cramping. Though symptoms often appear in childhood, many individuals don’t receive a correct diagnosis until decades later, leading to years of uncertainty and mismanagement.

Understanding the Condition

Glycogen storage disease type V, also known as McArdle disease, is a genetic disorder that disrupts how muscles produce energy. The condition gets its name from Dr. Brian McArdle, a British physician who first described it in 1951. This disease belongs to a group of metabolic disorders where the body cannot properly store or break down glycogen, which is the stored form of glucose that serves as fuel for muscle cells.^[1]

When you eat, your body converts excess glucose into glycogen and stores it in muscles and liver for later use. During physical activity, muscles normally break down this stored glycogen to release glucose for energy. In people with glycogen storage disease type V, an important enzyme needed for this process is missing, so muscles cannot access their stored fuel. This missing enzyme is called myophosphorylase, which is found only in muscle cells.^[1]

The disease primarily affects skeletal muscles, which are the muscles that allow you to move your body. Unlike some other glycogen storage diseases that affect the liver or other organs, type V specifically targets the muscles used for movement and exercise. Without the ability to convert glycogen to glucose, these muscles become easily fatigued and can suffer damage during physical activity.^[2]

How Common Is This Disease

Glycogen storage disease type V is a rare condition. While the exact number of affected individuals worldwide remains unknown, studies conducted in specific regions provide some insight into how often it occurs. In the Dallas-Fort Worth area of Texas, where researchers have specifically studied this disease, it is estimated to affect approximately 1 in 100,000 people.^[1]

Other estimates suggest the condition may affect anywhere from 1 in 50,000 to 1 in 200,000 people in the United States.^[6] The disease affects people of all ethnic backgrounds and both sexes equally, though some genetic variations may be more common in certain populations. Because the condition can present with mild symptoms or go unrecognized for many years, the true prevalence may be higher than currently estimated.

What Causes Glycogen Storage Disease Type V

This condition is caused by mutations in the PYGM gene, which provides instructions for making the enzyme myophosphorylase. This enzyme has a specific and crucial job: it breaks down glycogen stored in muscle cells into a simpler sugar called glucose-1-phosphate. Through additional chemical processes in the body, glucose-1-phosphate is then converted into glucose, which is the primary energy source that muscles need to function.^[1]

When mutations occur in the PYGM gene, the enzyme myophosphorylase either doesn’t work properly or isn’t produced at all. As a result, glycogen accumulates in muscle tissue because it cannot be broken down effectively. Without access to this stored energy, muscles cannot produce enough fuel to sustain activity, leading to rapid fatigue and the characteristic symptoms of the disease.^[1]

Researchers have identified 179 different variants that can affect the PYGM gene.^[6] The severity and specific symptoms can vary depending on which mutation a person carries, though all mutations ultimately interfere with the muscle’s ability to use stored glycogen for energy.

The disease follows an autosomal recessive inheritance pattern. This means that to develop the condition, a person must inherit two copies of the mutated gene—one from each parent. Parents who carry one copy of the mutated gene typically do not show any signs or symptoms of the disease themselves. When both parents are carriers, each of their children has a 25% chance of inheriting both mutated genes and developing the condition.^[1]

Who Is at Risk

The primary risk factor for developing glycogen storage disease type V is having a family history of the condition. If both biological parents carry one copy of a mutated PYGM gene, their children are at risk of inheriting both copies and developing the disease. Parents who are carriers typically have no symptoms and may not know they carry the gene mutation until they have an affected child.^[4]

Because this is a genetic condition present from birth, there are no lifestyle factors or environmental exposures that increase or decrease the risk of developing it. The mutations are inherited and cannot be caused by diet, exercise habits, injuries, or infections. However, certain activities and circumstances can increase the risk of experiencing symptoms or complications once a person has the disease.

While the genetic risk is established at conception, the expression of symptoms can vary widely. Some people with the condition experience severe symptoms from early childhood, while others may have such mild symptoms that they remain undiagnosed for decades. A family history of unexplained muscle problems, exercise intolerance, or similar symptoms in relatives may suggest an increased likelihood that other family members could be affected.^[3]

Recognizing the Symptoms

The hallmark symptom of glycogen storage disease type V is exercise intolerance, which means getting tired very quickly during physical activity. People with this condition typically experience fatigue, muscle pain, and cramps during the first few minutes of exercise. Activities like weight lifting, jogging, climbing stairs, or any sustained movement usually trigger these symptoms. The discomfort generally improves with rest, and many affected individuals find they can resume activity after a brief pause with less discomfort—a phenomenon known as the “second wind.”^[1]

The second wind phenomenon is quite distinctive. After resting for a few minutes when symptoms first appear, many people find they can continue exercising with little or no discomfort. This happens because after a few minutes of rest, the body begins to use alternative fuel sources, such as fatty acids and blood glucose, instead of relying solely on muscle glycogen stores.^[4]

Common symptoms experienced by people with this condition include muscle cramps that can be quite painful, muscle stiffness that makes movement difficult, generalized weakness particularly during or after physical activity, and profound fatigue that seems disproportionate to the level of exertion. Between episodes of physical activity, people with glycogen storage disease type V usually feel normal and do not experience symptoms at rest.^[6]

While most people can tolerate light to moderate exercise like walking on level ground, strenuous physical activity or exercises that involve holding muscles in a contracted position without movement—such as lifting heavy objects, squatting, or standing on tiptoes—can cause significant muscle damage.^[6]

The symptoms of this disease can vary dramatically from person to person. Some individuals experience mild symptoms such as poor stamina or getting tired more easily than others. In rare cases, some people with the genetic mutations show no symptoms at all. The features of glycogen storage disease type V typically begin appearing in a person’s teens or twenties, though they can emerge anytime from infancy to late adulthood.^[1]

In about 25% of affected individuals, fixed muscle weakness develops over time, typically affecting the muscles closest to the body’s center, such as those in the shoulders and hips. This weakness is more common in older individuals and can progress with age. However, in about one-third of people with the condition, muscle weakness remains stable rather than worsening.^[4]

The median age when symptoms first appear is approximately 3 years old. However, there is often a significant delay before a correct diagnosis is made. Studies show that the median time between first symptoms and diagnosis is 29 years, meaning many people live with unexplained symptoms for decades before learning they have this condition.^[3]

Diagnostic Challenges and Delays

One of the most significant problems with glycogen storage disease type V is the substantial delay in diagnosis. Misdiagnosis is overwhelmingly common, with approximately 90% of patients receiving incorrect diagnoses initially. About 62% of people receive multiple different misdiagnoses before finally getting the correct one.^[3]

This prolonged diagnostic delay has serious consequences. Being misdiagnosed or receiving multiple wrong diagnoses, or being given inappropriate exercise advice such as “ignore the pain” or “avoid all exercise,” severely impacts quality of life both physically and mentally. Many people spend years thinking their symptoms are due to lack of fitness, laziness, or psychological problems, leading to frustration, anxiety, and depression.^[3]

The difficulty in diagnosing this condition stems partly from the fact that symptoms can be vague and easily dismissed, especially in children. Muscle pain and fatigue during exercise might be attributed to normal childhood experiences or lack of conditioning. Additionally, because the symptoms can vary widely in severity and some people have periods where they feel relatively normal, healthcare providers may not immediately suspect a metabolic muscle disorder.

How the Disease Affects the Body

To understand what happens in glycogen storage disease type V, it helps to know how muscles normally produce energy. Muscles need a constant supply of glucose to work properly. When you eat carbohydrates, your digestive system breaks them down into glucose, which enters the bloodstream. Any glucose not immediately needed for energy is converted into glycogen through a process called glycogenesis and stored primarily in muscles and the liver.^[12]

When muscles need more fuel—such as during exercise—the body breaks down stored glycogen back into glucose through a process called glycogenolysis. This process requires several different enzymes working in sequence. In people with glycogen storage disease type V, the enzyme myophosphorylase is missing or doesn’t function properly. This enzyme catalyzes one of the first and most important steps in breaking down glycogen.^[2]

Without functional myophosphorylase, glycogen cannot be broken down effectively in muscle cells. As a result, glycogen accumulates in the muscles, but more importantly, the muscles cannot access this stored energy. It’s like having money in a locked bank account—the resource is there, but you cannot use it when you need it.

The muscles can still use glucose that comes directly from the bloodstream after eating, and they can use other fuel sources like fatty acids. However, these alternative sources take longer to mobilize and are less efficient for intense or sustained muscle activity. This is why people with the condition can sometimes exercise after a brief rest—the body has had time to activate these backup energy pathways, creating the “second wind” effect.^[4]

When muscles don’t have enough energy to sustain activity, several things happen. First, the muscles fatigue very quickly because they’re running on limited fuel. Second, the lack of adequate energy can trigger muscle cramping and pain. Third, in severe cases or with prolonged exertion, muscle cells can begin to break down in a process called rhabdomyolysis. This breakdown releases intracellular proteins, particularly myoglobin, into the bloodstream.^[1]

Myoglobin is normally contained within muscle cells and helps them store and use oxygen. When released into the blood in large quantities, it can be toxic to the kidneys. As the kidneys try to filter out the myoglobin, it can clog the filtering units and cause acute kidney damage or even kidney failure. It is estimated that about half of those individuals with glycogen storage disease type V who experience myoglobinuria (myoglobin in the urine) will develop life-threatening kidney failure.^[1]

Preventing Complications

While glycogen storage disease type V cannot be prevented because it is an inherited genetic condition, steps can be taken to prevent symptoms and serious complications once the diagnosis is made. Early diagnosis is crucial because proper management can significantly improve quality of life and reduce the risk of muscle damage and kidney problems.^[4]

For families with a history of glycogen storage disease type V, genetic counseling can be valuable. When the specific PYGM gene mutations are known in a family, testing can identify whether other family members are affected or are carriers. Early detection in relatives ensures proper management from childhood, preventing muscle injury and helping individuals develop healthy exercise habits appropriate for their condition.^[4]

Understanding personal physical limitations is essential for people with this condition. Learning to recognize early warning signs of muscle fatigue or pain and responding by resting can prevent progression to more serious muscle damage. Warming up gently before exercise and avoiding activities that are too intense or prolonged are important preventive strategies.^[5]

Adequate nutrition plays a role in managing symptoms. Eating enough protein helps support muscle health. Some people find that consuming simple carbohydrates or sugary drinks before exercising can help prevent muscle symptoms. This works because it provides glucose directly to the bloodstream, giving muscles an alternative fuel source when they cannot access stored glycogen.^[5]

Certain types of exercise should be avoided or approached with caution. Intense isometric exercises—where muscles contract without movement—and maximal aerobic exercise can trigger cramps and potentially cause rhabdomyolysis. Instead, moderate-intensity aerobic activities like walking or gentle bicycling are generally better tolerated and can actually improve overall fitness and exercise capacity over time.^[4]

Staying hydrated is also important, particularly during and after exercise. Good hydration helps the kidneys function properly and may reduce the risk of kidney damage if muscle breakdown does occur. Avoiding extremely hot weather or taking precautions when exercising in heat can help prevent excessive stress on muscles.