Glycogen is a form of stored energy. The main stores in the human body are in skeletal muscle and in the liver. People with Type V GSD are deficient in an enzyme called myophosphorylase (muscle phosphorylase) which plays a vital role in the break-down of glycogen into glucose so that it can be utilized to power the muscles.
The use of muscle glycogen is particularly important in the early stages of activity, after the first few seconds and up to about eight or ten minutes. It is also used in all intense (anaerobic) activity. So it is in these two situations that people with GSD V may have great difficulty and are exposed to the risk of muscle pain, cramps and contractures (muscle that is “locked up”, swollen and extremely painful).
The clinical presentation of myophosphorylase deficiency was first described in 1951 by Dr. Brian McArdle, whose name is now associated with the condition. The onset is almost always in childhood with repeated presentation to general practitioners around the ages of 5 to 10. Children are often dismissed as lazy, unfit or having ‘growing pains’. It is rare to be diagnosed before adulthood and many people are not diagnosed until their 30s, 40s and even older. Men and women are equally affected.
Individuals present with painful muscle cramps within a minute or two of commencing activity, which ease with rest if activity is ceased soon enough. All skeletal muscle is affected. These cramps can be associated with such routine tasks as cleaning teeth or hanging up clothes. People with Type V GSD experience a ‘second wind’ phenomenon, whereby symptoms experienced during exercise such as walking improve slightly after about 8 to 10 minutes. This is due to other fuel sources coming into use, particularly fat metabolism and glucose released from the liver’s glycogen stores. People with McArdle Disease have great trouble lifting and carrying heavy items, squatting, climbing stairs/hills and walking or running fast. These activities can lead to a muscle contracture, a painful muscle spasm that causes muscle damage (rhabdomyolysis). These activities should be strictly limited to 6 seconds of maximal effort, or avoided altogether.
The physical exam is often normal, although older people over the age of 40 years may notice weakness of the trunk and shoulder muscles. People with McArdle’s may have muscular legs but in older people the shoulders can appear thin and wasted. They may experience dark red or red brown urine (myoglobinuria) after there has been muscle damage (rhabdomyolysis) from cramps or contractures. The myoglobin (red muscle protein) comes from the breakdown of skeletal muscle and is excreted in the urine.
The typical clinical presentation described above is by far the most common; however, variations are well known. At one end of the spectrum, a patient with Type V GSD who has lost aerobic fitness or accumulated years of muscle damage may be a regular wheelchair user. Whereas at the other end of the spectrum a patient who has learned to manage their condition and has achieved a high level of aerobic fitness, may have no symptoms other than when something unexpected happens and they have a severe episode of muscle breakdown.
Any person with painful muscle cramps during exercise should be evaluated for a diagnosis of GSD V. A blood test for serum creatine kinase (CK or CKP, a muscle enzyme) will usually show an abnormally high level. A functional test, such as a 12-minute walk test or static cycle test, can demonstrate the symptoms and the ‘second wind’ phenomenon described above. These are strong clues to the diagnosis.
Some medical centers may perform a forearm exercise test for diagnosis. In this test the person is asked to squeeze a rubber ball tightly on and off for several minutes. Each minute a blood sample is taken for lactate and ammonia. In healthy people the lactate increases four-fold and the ammonia does not rise, whereas in people with McArdle Disease the lactate does not rise, and sometimes evenfalls, and there is a marked rise in ammonia.
Genetic testing will usually confirm the diagnosis. Caucasians from Northern America and Northern Europe have a high chance of carrying one of two very common genetic mutations (R50X and G205S). Testing for these two mutations can diagnose 80% of people in this ethnic group. For people from other ethnic backgrounds full sequencing of the gene may be required.
Ultimately, a patient may need a muscle biopsy to test for the deficiency of the enzyme myophosphorylase and for the presence of raised levels of glycogen in the muscle.
Although there is no specific medical treatment for McArdle’s, regular aerobic exercise following a warm up into the ‘second wind’ has been shown to be safe and is increasingly proven to be beneficial.
It is very important to avoid maximal activity such as sprinting and isometric (static) activities such as weight lifting or squatting because they can cause muscle breakdown (acute rhabdomyolysis) resulting in dark urine (myoglobinuria). This is a potentially serious complication as it may cause temporary kidney failure. If the urine looks like coca cola, patients should go to hospital. The treatment is intravenous fluids to flush out the myoglobin. Blood tests will be required to monitor kidney function. If there is evidence of compartment syndrome an urgent surgical referral may be needed.
The long-term outlook is good. The prognosis is enhanced by an early diagnosis, expert advice and good self-management by the patient. However, a small number of patients have developed significant muscle problems (myopathies) later in life, usually muscle atrophy (wasting) through avoidance of activity or accumulated muscle damage through repeated episodes of rhabdomyolysis.
Research in Type V GSD has demonstrated an improved exercise tolerance after high carbohydrate intake (sugar equivalent to a soft drink just before exercise), or with aerobic training. The high carbohydrate intake makes sense as more energy would be available in the blood supply going to the muscle. However, some people anecdotally report doing better on high protein diet and others on high fat. Patients may usefully consult with their medical doctor to see what diet works best for them.
McArdle Disease is inherited in what is known as an autosomal recessive pattern. This means that both parents will have been carriers and their children each had a 25% chance of getting McArdle’s, a 50% chance of being a carrier and a 25% chance of being completely clear of the condition. The parents are unlikely to have been aware that they were carriers, as carriers have no symptoms.
The single gene responsible for myophosphorylase is the PYGM gene on chromosome 11. To date about 150 mutations of this gene have been identified and nearly all result in a total absence of myophosphorylase. These days DNA-based diagnosis and carrier detection is possible in most cases, without the need for a muscle biopsy.
The children of people with McArdle Disease will all be carriers as they will inherit one of the mutated copies of the gene from their affected parent. However, there is only a risk of them getting McArdle Disease, if the other parent is a carrier. It is believed that the number of carriers is around 1 in 160. If a Type V GSD patient and a carrier have children together there is a 50% risk of their children having McArdle’s. The normal pattern is for McArdle Disease to appear in one generation, with no family history of the disease, and then disappear again for many generations.
There is a YouTube Channel ‘AGSDUK’ and Facebook Groups ‘McArdle’s Disease’ and ‘McArdle parents’. Advice is available in the book ‘101 Tips for a Good Life with McArdle Disease’ and information for the patient’s GP and other doctors is available in ‘McArdle Disease: medical overview’. The ‘McArdle Disease Handbook’ is useful for details of the medical and scientific research into McArdle Disease. These and other McArdle’s Resources are from the AGSD [U.K.]