What is McArdle Disease?
McArdle disease, also known as glycogen storage disorder (GSD) type V, is a genetic disease that affects how the body processes glycogen, a form of sugar that provides energy to your muscles. Normally, an enzyme called muscle glycogen phosphorylase helps convert glycogen to glucose, a simpler form of sugar, in your muscles. However, in McArdle disease, this enzyme is either missing or not working well, causing glycogen to build up in tissues.
This disease mostly affects the muscles you control, like those in your arms and legs. Despite the systemic symptoms, which mean symptoms throughout the body, in some cases, the defect is restricted to certain tissues. In McArdle disease, the process of converting glucose to another molecule, glucose-6-phosphate (G6P), is only partially blocked, allowing muscle cells to receive some glucose downstream of the metabolic blockage.
While most patients with GSDs show symptoms in childhood, McArdle disease can also appear in adults. Unfortunately, there are no standard treatment options available now. However, changes in diet have been found to help reduce symptoms.
The disease was first recognized in 1951 by Dr. Brian McArdle from London. Later in 1959, the missing enzyme, myophosphorylase, was found to be responsible for the problem. And in 1984, scientists discovered the faulty gene that causes the disorder.
What Causes McArdle Disease?
McArdle disease is caused by changes or mutations in a gene responsible for an enzyme known as muscle-specific glycogen phosphorylase (PGYM). This enzyme helps in a process called glycogenolysis, which breaks down certain types of sugar stored in muscle fibers to release a molecule called glucose-1-phosphate. Glucose-1-phosphate is a vital source of energy for muscles. When this enzyme doesn’t work properly due to the gene mutations, the muscles can’t get energy from their stored sugars, causing various problems.
The gene that controls the production of the PGYM enzyme is found on a specific part of chromosome number 11 known as 11q13. If this gene is defective or mutated, the PGYM enzyme can’t perform its duty of energy generation from the muscle’s glycogen stores. Most of the mutations happen in specific parts of the gene, referred to as Exons 1 and 17, and often lead to the enzyme becoming inactive. The most common mutation in white individuals is known as p.Arg50Stop or R50X.
Researchers studying McArdle disease’s genetics have identified 179 different variants of these mutations, each of which affects the PGYM gene. The most common type of mutation found in European and US white populations is the missense mutation, constituting approximately 60% of all mutations. Regardless of the type of mutation – missense, nonsense, insertion, deletion, or splicing – most patients lack the myophosphorylase enzyme, which is the functioning form of PGYM. However, there are some exceptions in rare cases where the missense mutations do not totally inhibit the myophosphorylase activity, resulting in less severe symptoms.
Risk Factors and Frequency for McArdle Disease
McArdle disease, a rare disorder, is more common than previously thought. Though it differs by region, it’s estimated to affect between one in 50,000 and one in 200,000 people in the United States. This variation in prevalence is largely due to delayed diagnosis. Innovative approaches using gene frequency and next-generation sequencing have indicated that the prevalence may be as high as 1 in 7,650. In certain parts of the US, like Dallas/Fort Worth, genetic data puts the prevalence at 1 in 100,000. Meanwhile, in Spain, the prevalence of diagnosed cases is around 1 in 139,543.
- In Spain, the gender ratio of people with McArdle disease is 55:45, Men to Women.
- In Italy, the ratio is 65:35, Men to Women.
- In the UK, the ratio is 50:50, Men to Women.
Typically, the disease manifests in the second or third decade of life. However, there have been unique cases where it has been diagnosed in the patients as old as 73. Due to these atypical instances, medical professionals are urged to keep McArdle disease in mind regardless of a patient’s age.
Signs and Symptoms of McArdle Disease
McArdle disease is a disorder that causes muscle weakness and fatigue, especially during physical activity. Some common symptoms include muscle cramps, tiredness, and muscle stiffness, which can sometimes lead to painful muscle spasms. Usually, these symptoms become more noticeable shortly after starting an activity and reduce upon stopping the exercise.
In some rare but severe situations, during intense exercise, the muscles can be significantly damaged. This damage leads to the increased release of proteins such as creatinine kinase and myoglobin into the blood, and myoglobin into the urine, causing it to become dark colored. In extreme cases, this could lead to acute kidney failure and dangerously high blood potassium levels following a process known as rhabdomyolysis, or muscle breakdown.
An interesting detail about this disorder is a phenomenon called the “second-wind phenomenon.” This is a situation wherein symptoms improve after around 10 minutes of mild aerobic activity.
McArdle disease generally begins to show symptoms in the first or second decade of life. However, patients over 40 years old might experience muscle weakness and wasting. The severity and exact symptoms can vary greatly among patients. Some may only experience mild fatigue, while others may suffer from progressive weakness later in life. A more severe form of the disease can appear shortly after birth, known as fatal infantile McArdle syndrome. A small percentage of patients, about 4%, may also experience seizures.
The typical physical examination findings for classic McArdle disease include:
- Proximal muscle weakness, particularly after exercise
- Fixed limb weakness, usually in the proximal muscle groups
- Muscle wasting
The fatal infantile variant is characterized by:
- Hypotonia, or low muscle tone
- Diminished deep tendon reflexes
Testing for McArdle Disease
If your doctor thinks you may have a disease that affects how your body breaks down sugars stored in your muscles (a condition known as glycogen storage disease), they will start by giving you a simple arm exercise test. This exercise will help them measure the amount of lactate (a form of lactic acid) and ammonia that your body makes when your muscles work.
Normally, doing exercises makes the amount of lactate and ammonia in your body increase about three times. However, with conditions that affect how your body uses stored sugar, the increase in lactate will be much lower.
There are different types of exercise tests. One of them uses a blood pressure cuff, but this test is not commonly used anymore because it can cause undesirable outcomes like rhabdomyolysis (a condition where muscle tissue breaks down and releases a damaging protein into the blood) and compartment syndrome (a painful and potentially serious condition caused by pressure buildup from internal bleeding or swelling of tissues).
Most often, your doctor will use a non-ischemic forearm exercise test, where you do exercise without using a blood pressure cuff. This test is pretty good at identifying problems with how your body uses stored sugars, and if the test results are normal, you probably don’t have a glycogen storage disease.
Another important sign of a specific glycogen storage disease called McArdle disease is that patient’s blood will have higher levels of a specific enzyme, called creatine kinase (CK), all the time.
Your doctor might also have you do a graded exercise stress test. This test is useful for diagnosing McArdle disease as it can show a specific feature many patients with this disease experience, known as the “second wind” phenomenon.
Additionally, your doctor may choose to do a muscle biopsy, which involves taking a small sample of muscle tissue to look for certain physical signs of disease. They can also do genetic testing to look for specific mutations related to glycogen storage diseases.
Lastly, your doctor may find it useful to rule out other conditions or confirm a diagnosis by conducting tests such as measuring your uric acid level, checking your urine for certain substances, and doing an electromyography test (a test that measures the electrical activity of your muscles at rest and during contraction).
Treatment Options for McArdle Disease
The main approach to control the symptoms of the disease is lifestyle modification. This usually involves avoiding specific physical activities that can make the symptoms worse. However, limiting physical activity can actually worsen the disease because levels of a particular protein in your blood, known as creatine kinase (CK), can increase when your fitness level decreases. Cutting down on physical activity can also negatively affect your muscles’ ability to use alternative energy sources and may reduce the production of proteins needed for metabolism and balancing calcium levels in muscles that aren’t being exercised.
Research has shown that moderate, gradual aerobic exercise can help reduce symptoms. People who have tried this treatment reported less severe symptoms after exercise and being able to get their “second wind” more quickly while working out. Strength training, in which you slowly increase the weight you’re lifting, can also reduce the severity of symptoms for some individuals.
A study by Howell et al. suggested that a drug called sodium valproate might increase the production of an enzyme in your muscle called myophosphorylase. This could potentially be a new way to treat the disease, but more research needs to be done before confirming it as a treatment option.
Another treatment option that was explored is creatine, a natural substance found in the body that can be increased through supplements. It was thought that creatine might improve the body’s ability to store ATP (the main source of energy for our cells) and make it easier to do physical activities. However, a trial found that using high-dose creatine monohydrate led to poor exercise tolerance and more discomfort in the muscles during exercise. They believed this might be because the muscles were contracting more during exercise than they were supposed to, leading to increased symptoms.
Some dietary interventions may also have beneficial effects. Consuming a high-sugar meal before exercise (like a drink with 37 grams of sucrose) can reduce the early symptoms of exercise intolerance. A diet high in carbohydrates also leads to better outcomes compared to a high-protein diet. Other nutrients that were found to be helpful for some patients, but have not been proven to consistently help in scientific studies, include branched-chain amino acids, glucagon, verapamil, dantrolene sodium, vitamin B6, high dose D-ribose, and high-dose creatine.
What else can McArdle Disease be?
McArdle disease is a medical condition that doctors must distinguish from other similar disorders that can cause muscle problems, such as other glycogen storage disorders, fatty acid oxidation defects, and mitochondrial myopathies.
Typically, symptoms of McArdle disease emerge at the start of heavy physical exertion. In contrast, fatty acid oxidation defects (like carnitine palmitoyltransferase II deficiency) and mitochondrial myopathies (like medium-chain acyl-CoA dehydrogenase deficiency) exhibit their symptoms later and depend on a longer exercise duration. These defects are also likely to show symptoms under stress conditions like fasting, fever, and infections.
An intriguing characteristic of McArdle disease is the second-wind phenomenon, which means a decrease in discomfort after the initial symptoms onset. This phenomenon does not exist in other conditions that might resemble McArdle disease.
People with McArdle disease usually have persistently high levels of creatine kinase enzyme in their blood. Other disorders like glycogen storage diseases, fatty acid oxidation defects, and mitochondrial myopathies may or may not show elevated levels of this enzyme.
A notable fact is that a carbohydrate-loaded meal before exercise can decrease symptom intensity in McArdle disease and fatty acid oxidation defects. However, this dietary change doesn’t help in mitochondrial myopathies and can actually worsen symptoms in disorders relating to the sugar breakdown pathway.
Muscle biopsy and genetic testing provide more clarity in distinguishing these disorders. A biopsy of a muscle with McArdle disease would show a high level of glycogen, while one with carnitine palmitoyltransferase II deficiency would show increased fat, and a mitochondrial myopathy would show irregular red fibers and cytochrome oxidase negative fibers. Genetic tests can pinpoint specific mutations, with the most common ones being R50X for McArdle disease, S113L for fatty acid oxidation disorders, and m.3243A>G for mitochondrial defects.
What to expect with McArdle Disease
Most people with McArdle disease, a type of muscle condition, live normal lives and it doesn’t usually affect how long they live. It’s important to avoid a condition called rhabdomyolysis, where muscle breaks down quickly, because it can potentially lead to acute renal failure (sudden kidney failure) that could be life-threatening. Individuals with McArdle disease often adapt to their situation, using what is known as the ‘second wind’ phenomenon.
A small number of patients might experience symptoms that get worse as they get older, including muscle loss or weakening, especially in the muscles across the shoulders and back.
Recent research findings have shown a range in how severe the disease is in different people. For example, about 8% of people with McArdle disease have no symptoms in their daily life, and around 21% show signs of limitations in daily activities and permanent muscle weakness. The same research also emphasizes the importance of an active lifestyle for people with McArdle disease.
Various research studies have reported that McArdle disease doesn’t negatively alter the course of pregnancy or childbirth.
Possible Complications When Diagnosed with McArdle Disease
Rhabdomyolysis, a severe breakdown of muscle tissue, is a known complication associated with McArdle disease. After intense physical activity, the damaged muscles might start to leak a protein called myoglobin. When this enters the urinary system, it can lead to a condition known as acute kidney failure.
Similar to any person experiencing rhabdomyolysis, those suffering from McArdle disease should be closely observed for potential complications. These complications could include:
- Electrolyte abnormalities – an imbalance of minerals like sodium and potassium in the body.
- Compartment syndrome – a painful and dangerous condition caused by pressure buildup from internal bleeding or swelling of tissues.
- Metabolic encephalopathy – A brain disorder resulting from a chemical imbalance in the blood.
Preventing McArdle Disease
If you’re diagnosed with this condition, it’s crucial that you see a specialist known as a clinical geneticist or a genetic counselor. These experts will provide regular check-ups every year, including physical exams and dietary assessments. They will also advise you to avoid particular exercises such as hand grip exercises held for extended periods, lifting weights unless supervised by a specialist, competitive sports involving a ball, running, high intensity jumping activities, strenuous swimming, and cycling.
It’s important to modify or limit physical activities to prevent symptoms from appearing. This is because rhabdomyolysis, which is a serious condition where muscle tissue breaks down quickly, could be a potential issue.
There’s also a small risk of acute muscle tissue death caused by certain anesthetics generally used during surgical procedures. These anesthetics can include muscle relaxants and gases inhaled during the surgery. Doctors need to be mindful of this when treating patients with McArdle disease to prevent rhabdomyolysis from happening.