June is Myasthenia Gravis Awareness Month

McArdle’s Disease: The Right Diagnosis Can Lighten the Load

When Michael Marino, 47, of Selden, N.Y., was a child, his parents thought he was lazy and sent him to a nautical military school to straighten him out. It didn’t.

He had his first muscle cramps at age 9 or 10, from the extreme sit-up regimen, and couldn’t straighten up for two days.

“I thought the pain meant I was building muscle, but now I know I was damaging it.”

Kelly Webb, 36, of Demopolis, Ala., collapsed without warning while swimming and almost drowned when she was 5 or 6. Tests at the hospital revealed she had an elevated CK level (CK, or creatine kinase, is an enzyme that leaks into the blood from damaged muscle tissue).

Later, as a cheerleader, she made another trip to the hospital after lifting weights. She was given shots for the pain and sent home.

It would be many years before Webb and Marino would find out the reason she could never ride a bike, and why he was always the “rotten egg”: McArdle’s disease.

Oh, what a relief it is

McArdle’s, also known as phosphorylase deficiency, is one of 10 metabolic diseases of muscle in MDA’s program. These rare disorders occur when gene mutations create problems in the way muscle cells process food for energy.

Because of its rarity, people with McArdle’s often live with unexplained muscle cramps and weakness for many years before getting a correct diagnosis.

But diagnosis is improving and, on another positive note, experts’ observation and ongoing research show that behavioral factors can help people with McArdle’s keep the worst of the disease symptoms under control.

People with McArdle’s almost never receive diagnoses in childhood because doctors are rarely concerned about complaints of tiring easily, says MDA researcher Ronald Haller, professor of neurology and director of the Neuromuscular Center at the University of Texas Southwestern Medical Center Institute for Exercise and Environmental Medicine in Dallas.

“They all have unbelievable stories of how they have had to cope. They have had to bear a tremendous psychological and emotional burden,” he says. Sometimes the burden goes on for decades.

And when they find out that “It’s not me, it’s the disease,” they feel a tremendous sense of relief.

What is McArdle’s disease?

One of the processes of metabolism, transforming food into energy, depends upon breaking down glycogen, a form of stored energy, in muscle cells.

In normal muscle cells, glycogen is like energy in the bank vault, and phosphorylase takes it to the teller. Glycogen is a long-chain molecule of identical sugars (glucoses). When the enzyme phosphorylase adds phosphorus to the last glucose on the chain, a glucose molecule is released, ready to be spent in the energy chain.

The actual currency of energy is ATP (adenosine triphosphate), which then can be used for muscle work, the contraction of the muscle fibers.

The fastest way to generate ATP is by anaerobic (non-oxygen-requiring) glycolysis. In this process, the glucose from glycogen can be immediately converted to ATP and a by-product, lactic acid, without the presence of oxygen.

When muscles are working at top speed, the free glucose and then the glycogen get used up quickly, and lactic acid builds up (that’s when you “feel the burn”). That’s why you can’t sprint forever.

For sustained activity the muscle has to rely instead on aerobic (oxygen requiring) metabolism, a system of energy production that occurs in the mitochondria, the cells’ powerhouses. Pyruvate, a glucose by-product of glycolysis, moves into the mitochondria.

Then, when the muscle has exhausted the available glycogen, it calls for other sources of energy to be sent via the bloodstream. These other sources include free fatty acids (FFAs), free glucose (from the liver) and sometimes even protein, broken down into amino acids.

The reserves (glucose, FFAs and amino acids) start to arrive in 5 to 10 minutes. Once the body has made the switch to using FFAs, it can sustain activity for quite a while.

In McArdle’s disease, named for Brian McArdle, a British pediatrician who in 1951 was the first to describe a patient with the symptoms of the disease, muscles can’t convert muscle glycogen into glucose because their muscle phosphorylase is missing. They have to rely solely on blood-transported fuels.

There are many different phosphorylases. In McArdle’s glycogen phosphorylase, specifically the skeletal muscle form (myophosphorylase), is absent. McArdle’s disease is thus also called myophosphorylase deficiency (MPD).

The period until aerobically produced energy from blood-borne fuels becomes available is critical for a muscle cell affected by McArdle’s. Because the phosphorylase is missing, the glycogen in the cell just sits around, hoarding all of its glucose.

Phase 1 of the energy system thus breaks down because the muscle cell can’t get to the energy stored in the glycogen. The muscle stops functioning until it gets its “second wind” from fuels from outside the cell.

Because of the problem of metabolizing glycogen, McArdle’s disease is called a metabolic myopathy, glycogen storage disease type 5.

Who’s on third?

McArdle’s disease results from defects (mutations) in genes.

Researchers have so far discovered three separate mutations of the myophosphorylase gene on chromosome 11. This may account at least in part for the variability in symptoms among people with McArdle’s.

Haller finds the similarities more significant than the differences. People with McArdle’s give similar answers to questions about their childhoods, he says.

“If you hit the ball and run as fast as you can, can you run the bases?” No, they generally answer, they can never make it beyond second base.

Severity of symptoms may also be based on past activity and pattern of injury, he says.

The baseball question also touches on the differences between men and women with McArdle’s.

More men than women have McArdle’s. Women can use FFAs better than men, perhaps because of hormonal regulation. That might be one reason why fewer women have McArdle’s, and why they tend to do better with it than men.

There may be a cultural explanation as well.

MDA grantee Mark Tarnopolsky of the Neurology Department of McMaster University Medical Center in Hamilton, Ontario, thinks women have an easier time getting by without strength and are less likely to hurt themselves.

“More men get pushed into hockey and other high-intensity sports and end up damaging themselves,” Tarnopolsky says.

Muscles can repair small damaged areas. But when more of the cell is damaged, part or all of it dies (necrosis). When many muscle cells die, the breakdown is called rhabdomyolysis, which can result in increased CK levels or even myoglobinuria.

Other, as yet unknown factors can also affect symptoms.

MDA grantee George Karpati of the Montreal Neurological Institute at McGill University has seen some people who, 20 to 30 years after diagnosis, are doing more poorly than expected, even using motorized wheelchairs. He’s exploring the possibility that they have additional disease factors.

Tarnopolsky agrees. Several other genetic factors can influence a person’s aerobic capacity, and in people with these factors, the muscles may just become overwhelmed more easily, he says.

He warns that statin drugs such as Lipitor, which are often prescribed for heart problems, could precipitate more muscle damage, and should be used very cautiously.

There for the asking

Tarnopolsky and Karpati agree that the clinical aspects of McArdle’s are quite distinctive. In fact a careful history taken by a doctor who’s familiar with the disease is likely to produce a diagnosis.

However, because of the rarity of McArdle’s, most doctors aren’t alert to it as a possibility. Misdiagnosis or missed diagnosis frequently appear as chapters in the stories that people with McArdle’s recount. That’s why it’s a good idea to see a specialist at an MDA clinic if a diagnosis of McArdle’s is suspected.

“I had one patient who had been going to doctors for 20 years,” Tarnopolsky relates. “They finally sent him to our clinic. Within 20 seconds my resident said, ‘It’s either McArdle’s disease or another storage disease.’”

Several signals might point an examining physician toward McArdle’s.

Marino had myoglobinuria after he overworked his legs on workout equipment at age 15. The physician tested his urine for blood, did some X-rays and sent him home. Sixteen years later a muscle biopsy confirmed McArdle’s disease.

Keith Stout, 42, of Edmund, Okla., actually had a muscle biopsy, but without the standard stain for myophosphorylase. Later, when his sister was having similar problems, he had a second biopsy that finally led to his diagnosis.

In some cases McArdle’s disease has been confused with polymyositis, Tarui’s disease (another glycogen storage disease) or forms of muscular dystrophy. Suspicions raised are usually resolved by a combination of case history and diagnostic tests.

Blood tests that reveal elevated CK levels indicate the presence of damaged muscle, which necessitates narrowing the range of diseases possible.

Tissue taken in a muscle biopsy can be stained for myophosphorylase; its absence, rather than its presence, indicates McArdle’s.

An ischemic forearm test might also be ordered (ischemia means no blood flow). In this test, blood flow to the forearm is cut off while the patient exercises the forearm muscles. If a blood test doesn’t show the lactic acid buildup that normally occurs in a muscle worked anaerobically, McArdle’s disease is a likely diagnosis.

McArdle’s is transmitted as a recessive genetic disease, which means that each parent must contribute an affected gene to produce symptoms. DNA testing can determine the presence of these genetic defects.

More or less?

People with McArdle’s disease have to think carefully about what they eat and the exercise they do. Diets high in protein and a controlled amount of exercise can keep many symptoms at bay.

In physical activity, they learn to perform a balancing act between moving muscles the right way and using energy the right way.

“Start slowly, move slowly and rest, and gradually increase the intensity and duration of your exercise,” recommends Tarnopolsky.

On the one hand, rapid or intense exercises should be avoided because they can only cause damage — these include anything anaerobic, such as weight lifting, squats, arm wrestling, sprinting, standing on tip-toe or pull-ups. And anything that restricts blood flow, such as squatting, kneeling or sitting cramped for long periods of time, will force the affected muscle into an anaerobic mode.

Minimizing emotional stress is also important because extreme stress may even cause myoglobinuria.

On the other hand, some exercise is beneficial. Tarnopolsky admonishes, “All that hurts ain’t always McArdle’s,” and Haller reminds us, “The less you do, the less you are able to do.”

In the course of a meal

Nutrition, providing sources of energy to the body, is the other important element in the balancing act for someone with a metabolic disorder.

Doctors differ somewhat in their diet recommendations. As Tarnopolsky remarks, “There is rarely a definitive answer in rare disorders.”

Alfred Slonim of the Department of Pediatrics at North Shore University Hospital in Manhasset, N.Y., suggested in the 1980s a high-protein diet for McArdle’s patients, with regular, easy exercise such as walking. He’s studying the benefits, and recommends a diet of 25-30 percent protein, 30-35 percent carbohydrates and 35-40 percent fat.

Slonim cautions against cutting back sharply on carbohydrates, since they’re important in keeping up the liver glycogen. In the “low-carb” diets, carbohydrates are greatly restricted in the first phase, one purpose of which is to deplete the liver (and muscles) of the stored glycogen.

When people with McArdle’s who follow these diets then become active, hypoglycemia (low blood sugar) can occur if the liver can’t provide enough circulating glucose.

That’s what happened to Marino, who tried the low-carb Atkins diet for weight loss. Webb started the Atkins diet, too, but felt worse than usual and stopped it.

“I couldn’t do it. I really liked the energy I was getting from sugar.” Her body was telling her something important and she listened.

Slonim, Tarnopolsky and Haller agree that severely restricting carbohydrates might put people with McArdle’s at risk for muscle damage.

Tarnopolsky’s diet recommendations are slightly different from Slonim’s — 30 percent protein, 40 percent carbohydrates, 30 percent fat. He says the high protein provides amino acids such as leucine, which can enhance the use of free fatty acids. Haller also says high protein is important, especially because muscle constantly needs those extra amino acids for muscle repair.


A couple of dietary supplements can also affect muscle function for those with McArdle’s.

Some 80 percent of the body’s store of vitamin B6 (pyridoxine) is normally bound to myophosphorylase. Without that stockpile, people with McArdle’s may be deficient in B6, which is an important co-factor in amino acid metabolism. While studies haven’t convincingly shown that B6 improves muscle function, its short supply may work in subtler ways. Tarnopolsky recommends it as a supplement, and other experts agree it can’t hurt.

Oral creatine therapy hasn’t been shown to improve the effects of exercise. An early study claimed to show a minor improvement in anaerobic exercise capacity in some subjects who took creatine phosphate orally. Later, though, a higher dose showed a worsening of pain and fatigue, causing some to recommend against it.

Tarnopolsky suggests a low dose (5 grams a day) of creatine monophosphate. It can be a useful buffer during that critical time of transition from anaerobic to aerobic muscle activity, he says. Haller agrees.

All of the experts advise having a sugar-rich drink or candy bar before strenuous exercise, to help prevent damage and to ease into the “second wind.” Of course, sugar intake should be moderated so it won’t lead to weight gain.

Haller and John Vissing, his collaborator at the Copenhagen Muscle Research Center in Denmark, gave people with McArdle’s a sweetened drink (75 grams of sucrose) 30 to 40 minutes before they exercised on a stationary bicycle for 15 minutes. Those who had the drink didn’t feel tired during the exercise, and their heart rates reached a steady level.

Haller calls that steady transition the “induced second wind.”

The blood levels of FFAs, however, were reduced with the sucrose drink. FFAs are the preferred fuel for extended exercise, but the test didn’t examine how the subjects would have done on a longer exercise. Some evidence exists that glucose enhances fatty acid use for muscle energy, a hypothesis Haller is researching.

In addition to the different kinds of phosphorylases found in the body’s diverse tissues, a fetal form is found in immature muscle. A possible avenue of future research might focus on what would happen if more muscle cells could be “tricked” into turning on their “babyhood” enzymes.

Perhaps gene therapy will be able to deliver myophosphorylase-making machinery to every muscle cell. Karpati, in collaboration with researchers in Australia, is exploring gene replacement in McArdle’s disease, and hopes to have it in clinical trials soon.

Eat, think and be merry

“Your muscles pain you more when you don’t exercise,” says Kelly Webb. She was a cheerleader in high school and has always had high energy. She wants to start running again, something she used to do before life got in the way — she’s working on her master’s degree in elementary music education — but “it takes time to build up.”

Michael Marino doesn’t let false pride get in the way of telling someone he needs a breather. For Marino, who worked with a carpenter in his 20s, “Constantly moving kept me on a level plane.” But once he was told he had McArdle’s, he started to restrict his activities and put on a little weight.

Marino is now a building maintenance manager for a local community college. He misses the days before he knew, because he was more active and actually felt better then. But he plans on taking good care of himself so he can run around with his kids for the next few years.

If you do the things that work for you, there are a variety of safe activities available.

Brad Calcagni, 60, of Rye Brook, N.Y., has enjoyed the outdoors all his life, but he had to quit hang gliding and whitewater kayaking because they brought on cramps. The flat-water kayaking he does now lets his body reach its second wind.

“You start out in the harbor on an easy paddle, and it builds up as you go.”

While snow skiing may have caused myoglobinuria in the early days, exercise is still important to Keith Stout.

“Keep in shape. Otherwise it’s a vicious spiral downward.”

McArdle’s Disease Symptoms

Fatigability or weakness — Starting a normal exercise activity and tiring quickly, usually within the first minute or two.

Myalgia — Muscle pain when performing a strenuous activity. Depending on a person’s fitness, the provoking activity could be vigorous, such as swimming, weight lifting, skiing, rowing or sprinting; or just taxing, such as climbing stairs or lifting bags of groceries. 

Stiffness — The muscles often seem stiff or hard, especially after unaccustomed exercise.

Cramps — During strenuous exercise, a muscle “locks up” in excruciating pain. These aren’t normal cramps, signaled by the nerves, that you can relax with stretch or massage. These are contractures, and may take hours or even a day to relax. 

Myoglobinuria — Especially after a contracture, the damaged muscle contents leak out of the torn cell and enter the bloodstream — myoglobinemia —and pass through the kidneys and out as cola-colored urine — myoglobinuria. People with McArdle’s may have a persistent low level of myoglobin in the blood due to ongoing muscle damage and repair, which the kidneys process and recirculate. 

Overloading the kidneys can damage them. An extreme or prolonged bout of myoglobinuria could cause kidney failure and even require a person to go on dialysis, though rarely permanently. At the first sign of myoglobinuria, drinking lots of fluids and getting prompt medical attention can prevent permanent damage. 

“Second wind” — After an initial 5 to 10 minutes of fatigue, a person exercising at a low level will experience a surge in energy that will permit him or her to continue exercising normally.

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