"Keeping Up' With Metabolic Myopathies"

by Sharon Hesterlee

For many people dealing with metabolic myopathies, disorders that interfere with the extraction of energy from specific types of food, the pre-diagnosis days are a "living nightmare" of self-doubt and frustration. The good news is that symptoms of these disorders are often manageable through diet and exercise, and new research holds promise for better diagnostic tests and for treatments.

Remember that kid at school who always brought up the rear? The one who would make up any excuse to get out of gym class/field trips/camping trips. The kid that well-meaning coaches and parents tried to "toughen up."

[photo: Keith Stout]
Keith Stout

Keith Stout of Edmond, Okla., knew that kid in himself. He particularly remembers having to run up a hill and around a stump at the end of Little League baseball practice. The last one back would have to run up the hill again.

"I was always the last one back," he says. "Even my brother, who was two years younger, could run faster than me!"

Later, Stout found gym classes tough and hated every minute of them. "The coach would always think up some insane torture like climbing a rope, lifting weights or running a mile or two. The best thing that ever happened was when I broke my arm in eighth grade and got to spend six weeks in the library — it was heaven! Everyone thought I was just lazy, especially the teachers and coaches. After awhile, you begin to think the same thing."

Finally, in his late 20s, Stout's inadequacy in gym class was given a name: muscle phosphorylase deficiency. Also known as McArdle's disease, muscle (or myo-) phosphorylase deficiency is an "inborn error of metabolism" — a genetic defect that interferes with the breakdown of glycogen, a form of carbohydrate that's stored in the muscle. No matter how much carbohydrate Stout consumed in his diet, his muscles were unable to use this important fuel source to perform work. As a result of this block in energy availability, he didn't have the stamina of his peers. Stout, now an office manager for a highway-design firm, has learned to modify his lifestyle to cope with the disorder.

"As an adult, I still try to keep up with everyone else, but I have had to learn to say 'no' to people when they want me to do physical activities that can hurt me. This is difficult to do because I look perfectly normal on the outside. People look at you and you can see the doubt in their eyes."

Although getting a specific diagnosis can be an immense boost to self-confidence, metabolic myopathies still require a special set of solutions for day-to-day living. Stout says that one of the major problems faced by people with phosphorylase deficiency is obtaining accurate information about it.


The metabolic myopathies covered in MDA's program include muscle phosphorylase deficiency (McArdle's disease), debrancher enzyme deficiency (Cori's or Forbes' disease), phosphofructokinase deficiency (Tarui's disease), phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, acid maltase deficiency (Pompe's disease), myoadenylate deaminase deficiency, carnitine deficiency and carnitine palmityl transferase deficiency. Each is caused by a specific genetic defect in the various pathways involved in food metabolism in the cell (see illustration).

The major sources of fuel used by our muscles are carbohydrates (in the form of glucose and glycogen) and fats. Carnitine deficiency and carnitine palmityl transferase deficiency (CPT) interfere with fat metabolism by preventing the passage of fatty acids through the inner membrane of the mitochondria, energy-processing centers of cells. The remaining disorders, except for myoadenylate deficiency, are all defects in the carbohydrate pathway.

Defects in protein metabolism also occur in humans, but because protein isn't a major fuel source for muscle, these disorders aren't manifested as muscle disorders. Finally, myoadenylate deaminase deficiency can theoretically reduce energy production from any source because it interferes with the recycling of the cell's energy molecule, ATP, but researchers say that, in reality, myoadenylate deaminase deficiency rarely produces symptoms.

Although each myopathy listed above has its own set of symptoms depending on the particular metabolic pathway that's blocked, two major problems can occur in all of them. First, tissues can suffer from a lack of energy, and, second, toxic metabolites may build up and destroy the tissue. With most metabolic myopathies, the biggest problem seems to be the inability to use specific fuel sources for energy. Two exceptions are carnitine deficiency and acid maltase deficiency, in which unused fat and glycogen, respectively, build up in the muscle (see "Acid Maltase Deficiency: A Problem With Storage, Not Energy").

Many of these disorders have different forms that may begin in infancy, childhood or adulthood. The infantile-onset forms tend to be the most severe and many are fatal. At the other end of the spectrum, the adult-onset forms of the metabolic myopathies are usually less severe, but still encompass a wide range of symptoms and rates of progression.


When metabolic myopathies interfere with the extraction of energy from food, the main result is the inability to perform some types of ordinary exercise, a situation called exercise intolerance. People with exercise intolerance become fatigued easily, either at the onset of exercise or after sustained exercise. When children and adults with these types of myopathies push themselves in physical activities, overexertion may be accompanied by acute episodes of muscle breakdown (rhabdomyolysis), producing skyrocketing creatine kinase levels, myoglobinuria (myoglobin in the urine that turns it a cola color) and intense muscle pain. Although many people describe this muscle pain as a "cramp," in reality, it's not a true cramp (spasmodic muscle contraction) and can, in fact, be more painful.

Because these acute attacks can be so painful and may produce significant muscle injury and myoglobinuria-induced kidney damage, a major goal in living with this form of metabolic myopathy is to prevent attacks. In response, many people have learned to avoid activities that they know will trigger an attack, and have made dietary modifications designed to circumvent the blocked metabolic pathway.


Some think the standard warnings against "strenuous" exercise in metabolic myopathies understate the problem. Last June, Stout squatted down for a second and triggered an attack of rhabdomyolysis that cost him 10 percent of the muscle mass in both his thighs. He cites a list of other activities that could trigger problems in people with phosphorylase deficiency, including squatting, standing on tiptoes, and lifting, pushing or pulling heavy objects. Each of these activities involves "isometric" exercise, or strength exercise.

MDA research grantee Ronald Haller, director of the Neuromuscular Center of the Institute for Exercise and Environmental Medicine at Presbyterian Hospital of Dallas, points out that intense isometric muscle contractions constrict blood vessels and cut off blood flow to the muscles. Thus, during isometric exercise, the muscles must depend on anaerobic metabolism for energy (an anaerobic pathway is one that doesn't require oxygen to make ATP). Because the main fuel source for anaerobic metabolism is glycogen, those with defects in glycogen metabolism can develop significant muscle injury during this type of exercise.

"That warning needs to be there up front," Stout says. "I didn't have a clue that squatting would be a high-risk activity, but my CK [creatine kinase] count topped out at 82,000. I should have been hospitalized — my doctor didn't know how to treat me, and I ended up getting some IVs at the doctor's office."

[photo: Tamara Moore]
Tamara Moore

Tamara Moore of Paradise, Calif., has carnitine palmityl transferase II deficiency (CPT2 deficiency), a condition caused by the inability to metabolize certain kinds of fats in the muscle (CPT1 deficiency causes the same problem in liver cells). For Moore, attacks of rhabdomyolysis are accompanied by severe pain that causes her to lose her breath "as if the wind had been knocked out of me." Although most people with CPT2 deficiency experience attacks infrequently after exercising for a long time, or exercising without eating, Moore's attacks are somewhat unpredictable. She lists activity in general, fasting, illness, stress, cold weather, menstruation and not getting enough sleep as potential triggers. For the most part, Moore has learned to avoid attacks by subconsciously avoiding things that may trigger them.

An important observation about the metabolic myopathies is that they can vary in severity — the degree of exercise intolerance may be different from one person to the next, as may be specific situations that trigger rhabdomyolysis. Also, although many people with adult-onset metabolic myopathy may be told that their conditions aren't progressive, repeated episodes of rhabdomyolysis, combined with the effects of aging, may eventually lead to some degree of chronic muscle weakness, in addition to exercise intolerance.


Defects in muscle carbohydrate or fat metabolism cause problems for the skeletal, or voluntary, muscles because this active tissue normally depends on both these fuel sources to produce ATP.

Some researchers have experimented with diet manipulation in an attempt to compensate for the pathway that's inactive. For instance, a person who can't draw energy from carbohydrates may benefit from a high-protein diet. Although protein isn't usually a major source of energy for muscle, when there's an energy shortage, the muscle will use it instead of carbohydrate. On the other hand, people with CPT deficiency, who have trouble metabolizing fats, may benefit from a low-fat, high-carbohydrate diet.

These are vast generalizations about a very complex process. If you're interested in trying diet manipulation to manage your metabolic myopathy, you should seek out a physician or dietician who's familiar with your metabolic disorder to design a supervised, custom diet. One such physician who has pioneered extensive studies on diet manipulation and metabolic myopathies is pediatrician Alfred Slonim of North Shore University Hospital in Manhasset, N.Y.

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