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MODERATE EXERCISE IN METABOLIC MYOPATHIES

Ronald Haller

It may seem odd to ask if exercise can benefit people with a disorder in which the main symptom is exercise intolerance, but Haller is looking for answers.

"We don't know what to tell many of our patients with these diseases with respect to exercise," Haller says. "That's one of the things we're interested in — trying to determine whether exercise helps or hurts."

To get at this question, Haller has studied the effects of moderate supervised exercise in people with phosphorylase deficiency. Eight people in a recent study were "trained" on a stationary bicycle over a period of 14 weeks. Each person was given a heart monitor so that the level of exercise could be limited to that producing a submaximal heart rate.

At the end of the study, all eight people experienced increases in work capacity, with the person initially in the worst condition showing the most improvement. In addition, many of the participants reported an improved quality of life with the training.

Although the results may seem surprising, Haller had originally hypothesized that regular training should result in an improvement in work capacity for people with phosphorylase deficiency. To see why, it's important to understand how and when the body uses different fuels during exercise.

Haller explains that when a person begins exercising, the muscles rely on readily available sources of energy like phosphocreatine (an energy storage molecule, similar to ATP) and glycogen (a complex carbohydrate), both stored in the muscle. Gradually, as exercise continues, the muscles shift to fuel sources that are brought in from the blood, including glucose and fatty acids.

People with myophosphorylase deficiency experience difficulty at the beginning of a period of exercise because their muscles can't break down glycogen for energy. However, when the shift to blood-borne fuels occurs, many of these people experience a phenomenon known as a second wind, which provides a substantially increased work capacity. If the shift to blood-borne fuels could be improved, people who can't use glycogen for fuel might obtain an earlier and more robust increase in exercise capacity.

"There are two key considerations," Haller says. "First, if you are more aerobically fit [better able to do oxygen-requiring exercises like walking or cycling], your cardiovascular system will be better adapted to deliver the blood-borne fuels on which people with McArdle's disease are dependent. Second, if you are more physically fit, you will be able to use fats [rather than glycogen] as the primary source of muscle energy at any level of exercise.

"So the more deconditioned you are, the more you require carbohydrates for fuel. This is true of a normal person, but we reasoned that people with phosphorylase deficiency will have a 'double whammy' — the less they do, the more they depend on this source of energy that they can't use because of the enzyme defect. So the less they do, the less they will be able to do. And that leads to the rationale for 'training' people with phosphorylase deficiency."

Haller concluded from the study that inactivity has an important downside in genetic disorders that interfere with carbohydrate metabolism, but regular moderate activity can improve matters.

On the other hand, people with CPT2 deficiency, who can't utilize fats, experience difficulties with prolonged exercise exactly because of this shift to fatty acid metabolism. Haller describes a patient who experienced a first attack of myoglobinuria after walking around all day delivering packages during the Christmas holidays. Prolonged exercise, combined with not eating, is a recipe for disaster in those with CPT2 deficiency.

"For the most part," Haller says, "adults with CPT2 deficiency do well by just recognizing that they can't undertake prolonged exercise without paying attention to eating — taking carbohydrate snacks and making sure that their fuel tanks, presumably their glycogen fuel tanks, are full. We haven't strictly studied exercise in these patients because, in general, they haven't had to restrict their exercise."

RESEARCH IN METABOLIC MYOPATHIES

Because the primary cause of metabolic myopathies is the genetically induced lack of a key enzyme or molecule, some researchers are trying to figure out how to treat these disorders by replacing the missing component in the body. Except for carnitine deficiency, these disorders are caused by the lack of an enzyme, a protein that "encourages" a specific chemical reaction to occur.

One problem that's encountered when trying to deliver an active enzyme to all the muscle cells in the body is that enzymes are made of protein and, as such, can't be taken orally. The stomach sees no difference between the protein in steak and a vitally needed enzyme; it happily breaks them both down into tiny pieces. Researchers are left with two choices: The missing enzymes can be injected into the bloodstream (bypassing the destructive digestive tract), a tactic called enzyme replacement therapy, or a person's own cells can be given the DNA sequence to manufacture a fully operational enzyme on site within each cell, a tactic called gene therapy.

Acid Maltase Deficiency

In acid maltase deficiency, both of these strategies are being explored. Currently, there are two clinical trials underway for enzyme replacement in infants who have a severe and usually fatal form of acid maltase deficiency. The hope is that, if these trials are successful, they'll eventually be expanded to include all age groups. One is headed by MDA grantee Y.T. Chen of Duke University in Durham, N.C., while the other is being conducted in Europe by Pharming Pharmaceuticals.

In addition, a number of MDA grantees are completing preclinical experiments in animals to develop gene therapy for acid maltase deficiency. Andrea Amalfitano of Duke University, Paul Kessler of Johns Hopkins University in Baltimore (in collaboration with Barry Byrne of the University of Florida in Gainesville) and Frank Martiniuk of New York University are among those working in this area.

Muscle Phosphorylase Deficiency (McArdle's Disease)

Meanwhile, other researchers are pursuing a gene therapy strategy for muscle phosphorylase deficiency. These efforts are led by a group that includes MDA grantees George Karpati and Eric Shoubridge of the Montreal Neurological Institute in Canada, Salvatore DiMauro of Columbia University in New York, and John Howell of Murdoch University in Australia. In the October issue of Neurology, the group reported the successful use of a disabled adenovirus to deliver the phosphorylase gene and restore near normal levels of activity to cultured muscle cells obtained from both people and sheep with the disease. The group plans to switch to the safer adeno-associated virus for gene delivery and will test the technique in phosphorylase-deficient sheep in preparation for eventual human trials.

CPT2 Deficiency

In addition to developing therapies for metabolic disorders, researchers are working on better ways to diagnose them. MDA grantee Georgirene Vladutiu, director of the Robert Guthrie Biochemical Genetics Laboratory of Children's Hospital of Buffalo (N.Y.), has recently developed a simple blood test for CPT2 deficiency that's specific, sensitive, inexpensive and rapid compared to prior techniques.

Vladutiu thinks CPT2 deficiency is probably underdiagnosed and is interested in screening high-risk groups (athletes and armed services recruits) to see how common the disorder actually is. She suspects that people considered "carriers" because they have only one defective gene for CPT2 may also have symptoms of the disease that can be unmasked by participation in extreme sports, such as marathons, or by the presence of other, unrelated diseases.

"An important point to consider in CPT2 deficiency," Vladutiu says, "is that the functional enzyme is actually made up of four subunits. If you have one normal copy of the gene and one mutant copy, or if you have a different mutation in each of your two CPT2 genes, these subunits may come together in many different combinations. Depending on how the defective and normal CPT2 subunits combine, you may get varying degrees of enzyme deficiency, resulting in variable symptoms."

Vladutiu suggests that this variability, combined with other unknown factors, may produce a "threshold effect" in which a person doesn't experience symptoms until challenged by one or more combinations of triggers. Ultimately, she's interested in identifying genetic factors that contribute to symptoms of CPT2. 

Acid Maltase Deficiency
A Problem With Storage, Not Energy

Although acid maltase deficiency is caused by a defect in the glycogen breakdown pathway, the disorder doesn't cause an energy shortage. The real problem appears to be that too much glycogen accumulates in the lysosomes of the cells. As the lysosomes fill with glycogen, they gradually swell and take over all of the space in the cell, eventually destroying it. The disorder causes heart, respiratory and liver complications in infants and children, and is frequently fatal in the infantile form.

Tom Albrecht and his wife Carlene

Adults with acid maltase deficiency are affected more mildly, but experience symptoms in the form of generalized muscle weakness instead of exercise intolerance. Because the pattern of weakness seen in adult-onset acid maltase deficiency may resemble that of limb-girdle muscular dystrophy (LGMD), many people are first misdiagnosed with LGMD.

This was the case for Tom Albrecht of Pueblo West, Colo., who received a diagnosis of LGMD in his early 40s when he had trouble climbing onto railroad cars for his job. After he began having respiratory problems, the diagnosis was changed to acid maltase deficiency. The respiratory and heart muscles are often affected in acid maltase deficiency and specialists familiar with this disorder should be consulted to monitor these organs.

Now Albrecht uses assisted ventilation at night to help with his breathing. He also uses an electric scooter to help get around.

"The most frustrating thing about it," Albrecht says, "is not being able to do what I used to do. But you know, you've got to look at it this way: The sun comes up every day and I like to see the sun come up!"

Albrecht is interested in talking to others with adult-onset acid maltase deficiency, and has developed several ingenious solutions to dealing with his muscle weakness that he'd be glad to share with interested parties via e-mail. He can be reached at talbrecht@rmi.net.

Special Considerations in Metabolic Myopathies

Myoglobinuria: Rust-colored urine caused by the presence of myoglobin. When overexertion triggers acute muscle breakdown (rhabdomyolysis), muscle proteins like creatine kinase and myoglobin are released into the blood. Myoglobin, which is reddish-brown in color, ultimately finds its way into the urine. In addition to being an indicator of acute muscle damage, myoglobinuria can cause permanent damage to the kidneys. Severe cases of rhabdomyolysis should be treated as emergencies and may require the introduction of intravenous fluids to avoid renal failure.

Emergencies: The metabolic myopathies are such rare disorders that emergency room staffs are frequently unfamiliar with them. For this reason, some people carry a "protocol," composed by their treating neurologists, containing pertinent phone numbers and addresses of the patient's physicians, current medications, dietary considerations and guidelines for handling emergency situations. Another solution is to wear a MedicAlert bracelet. Emergency physicians can call the number on the bracelet and obtain information about the patient. For information, call 800-IDALERT or visit www.medicalert.org/home.asp.

Anesthesia: People with metabolic myopathies are at high risk for a potentially fatal reaction to common general anesthetics (typically combinations of halothane and succinylcholine). This reaction, called malignant hyperthermia, can be avoided by using lower-risk anesthetics. However, it's a good idea to wear a MedicAlert bracelet stating this susceptibility in case you require emergency surgery.

Diet: People with CPT deficiency are particularly sensitive to fasting and may be helped by frequent carbohydrate snacks during the day. Eating cornstarch dissolved in water is a quick and easy way to supply the body with carbohydrates to burn in place of fat.

Cardiac Care: Debranchor enzyme deficiency, carnitine deficiency and acid maltase deficiency can lead to heart failure. In the case of primary carnitine deficiency, the only symptom may be heart failure; however, this disorder responds very well to carnitine supplementation. (See "Carnitine and CoQ10" in Quest, vol. 6, no. 1.) In acid maltase deficiency and CPT2 deficiency, a cardiologist who's familiar with your disorder should monitor heart function regularly.

RESOURCES

CPT2

CPT Net
www.321website.com/members/home/data/dianem/
A Web site, maintained by an individual with CPT2 deficiency, that contains information, recipes and a chat room for those with the disorder.

The Spiral Notebook
www.spiralnotebook.org
A newsletter edited by free-lance writer Barbara Seaman and researcher Georgirene Vladutiu that contains information, links, research news and interactive surveys about CPT2 deficiency. Copies are available by mail by sending e-mail to the managing editor at wheatchild@sunflower.com.

Exercise and Metabolic Myopathies
www.texashealth.org/nmc/
The Web site of the Neuromuscular Center of the Institute for Exercise and Environmental Medicine at Presbyterian Hospital of Dallas, directed by Ronald Haller, contains plentiful information on the different metabolic myopathies, including symptoms, inheritance patterns and mechanisms of harm.

Glycogen Storage Disorders

Glycogen Storage Disease Net
The GSDNet is an e-mail list devoted to glycogen storage disorders. To join, send an e-mail message to LISTSERV@MAELSTROM.STJOHNS.EDU with the following words in the body of the message: SUBSCRIBE GSDNET. You'll receive instructions about posting and unsubscribing to the list.

The Association for Glycogen Storage Disease (UK)
www.agsd.org.uk
The AGSD Web site has information on all of the glycogen storage diseases.

Two sites on muscle phosphorylase deficiency (McArdle's disease) are maintained by individuals with the disorder: http://members.aol.com/itsgumby/ and http://mcardles.web-page.net.