Some consensus, much controversy about diet in three metabolic diseases
Mark Tarnopolsky, a professor of pediatrics and medicine at McMaster University in Hamilton, Ontario, remembers clearly a patient he saw more than a decade ago, when he first began specializing in metabolism and nutrition.
The patient was an 8-year-old boy who had rapidly become weak and eventually almost completely paralyzed after exercising. His muscles were breaking down, spilling a protein known as myoglobin into the blood and threatening the survival of the boy’s kidneys, if not of the child himself.
Fortunately, before too much time elapsed, Tarnopolsky was able to come to the right diagnosis. The child had a deficiency of a metabolic enzyme called carnitine palmityl transferase 2 (CPT2), which normally allows fats to be broken down and used for energy.
Specifically, CPT2 escorts molecules known as fatty acids from the main part of a muscle cell into cellular energy “factories” known as mitochondria.
After intravenous infusions of water and sugar, the child recovered his strength and returned to his normal activities, now armed with a special diet and advice to avoid exercise during periods of stress, such as when he had a cold or the flu.
“We put him on a high-carbohydrate diet and had him drink from a juice bottle every 20 to 30 minutes,” says Tarnopolsky, who had MDA research funding between 2000 and 2003.
“He’s now about 20 years old and is a competitive cross-country cyclist. He’s on a dietary regimen involving carbohydrate gels and sports drinks. Other than one minor episode a few years after the diagnosis, he has not had any further problems.”
Carnitine palmityl transferase deficiency is one of 11 metabolic diseases of muscle covered by MDA, in which the body’s ability to break down carbohydrates or fats for fuel is impaired. The main symptom of most of the metabolic muscle diseases is difficulty with exercise.
Nutritional strategies for regulating these diseases are based on substituting fuel sources people can use for those they can’t. Although this sounds simple enough, in practice it can be complicated.
Carbs — first choice for energy
Carbohydrates, fats and protein are the three basic sources of energy. Normally, muscles are very efficient at getting the fuel they need from these sources, utilizing carbohydrates first, and then moving to fat and then to protein, if necessary.
Carbohydrates are sugars and starches. Sugar, in the form of glucose, is transported by the bloodstream to muscle cells, enters muscle cells, and is trapped inside by the addition of a phosphate group (a phosphorus atom attached to four oxygen atoms).
When a person is exercising, sugar that comes into the cell this way is immediately broken down for energy. But if the person is resting, the sugar is likely either to be combined with other glucose molecules and stored in the muscle cell as glycogen, or turned into fat.
Proteins called enzymes, which allow chemical reactions to take place, take apart this stored glycogen and separate it into its component glucose molecules, each of which then goes through more enzymatic treatments and further modifications.
Each step in the process of breaking down glucose for immediate energy or building it up as storage molecules of glycogen requires specific enzymes.
“When you start exercising, glycogen is the key fuel. It’s really critical for going from rest to maximal exertion,” says Ron Haller of the Institute for Exercise and Environmental Medicine at University of Texas Southwestern Medical Center in Dallas. Haller has been awarded seven MDA grants for research projects on muscle metabolism since 1989.
Normally, when people attempt very rapid or hard exercise, glycogen metabolism in the main part of the cell kicks in right away, immediately yielding some energy itself, and at the same time supplying pyruvate, the final product of glycogen breakdown, for a more constant, “maintenance” type of energy supply.
This maintenance kind of energy, also known as oxidative or aerobic metabolism, takes place inside mitochondria, which are bacteria-like structures (organelles) inside cells.
After glycogen molecules have been broken down and then modified to become pyruvate molecules, they can enter the mitochondria.
There, the aerobic pathway can produce about 12 times more energy per molecule of glucose (or glucose unit of glycogen) than just breaking down glycogen can. But it can’t do it as quickly.
Cellular recycling centers provide backup power source
There’s yet another pathway for breaking down glycogen, and it’s located in cellular organelles called lysosomes.
Lysosomes are usually thought of as part of a disposal system that cells use to rid themselves of things they don’t want or need, such as bacteria, worn-out cell structures, excess glycogen and other molecules.
But lysosomes also play an important role as providers of new raw materials for energy production, says Alfred Slonim, a metabolic endocrinologist and a clinical professor in the Molecular Genetics Division of Columbia University in New York.
Slonim’s research (he was funded by MDA in 1989-90 and 1999-2001) suggests that there’s a continuous breakdown of excess glycogen in lysosomes that frees phosphorylated glucose for energy production. The contribution of lysosomal glycogen breakdown to total energy production is small compared to that from other pathways, but still significant, Slonim says. (Others disagree, and this remains an area of debate.)
The main glycogen breakdown path, outside the lysosomes, responds only to exercise demands. But in the lysosomal pathway, “there’s a continuous release of glucose from the lysosomes that goes on day and night,” Slonim says, whether or not a person is exercising.
“It’s a wastebasket,” Slonim says of the lysosome, “and it does dispose of some of the substances. But it also breaks down a complex substance [such as glycogen or protein] to a very simple substance, which is then reutilized. If you’re not reutilizing it, then you’re missing out on a fuel source.”
Fat — an unpredictable energy supplier
Although carbohydrates are the body’s preferred source of energy, fats and, if necessary, protein also can be used.
“When you eat fat, like the fat around a steak, you’re eating triglycerides,” Tarnopolsky says, noting that a triglyceride is three fatty acid molecules stuck to a glycerol molecule. An enzyme from the pancreas, called lipase, breaks down the triglycerides into fatty acids, which then enter muscle cells and then the mitochondria to be burned for fuel.
“At lower levels of exercise, we can [metabolize] those through the mitochondria,” Tarnopolsky says. “You can get energy from fat, but fat absorption is much slower than carbohydrate absorption and is more unpredictable.”
|In Pompe disease (1), the lysosomes can’t break down excess glycogen, which builds up and interferes with cellular function. Some experts believe there is normally some energy production from the lysosomes and that it too is lacking in Pompe disease.
In McArdle disease (2), the main carbohydrate breakdown pathway is blocked, interfering with energy production from this source.
In CPT2 deficiency (3), fats can’t enter the mitochondria and can’t be used for energy production.
A boost from protein
Normally, a small amount of protein in the form of amino acids is used for metabolism, Haller says. These amino acids, the building blocks of protein, can be routed to the mitochondria.
“During endurance activity [such as running], you can combine amino acids with oxygen, and these can be taken up and used in the mitochondria,” Tarnopolsky says. “Normally, at most, you get maybe 4 percent to 8 percent of your energy from amino acids.”
Muscle itself is mostly protein, and it can be broken down for use as fuel in an emergency, when no other fuels are available.
Avoiding that process, which resembles chopping up the furniture to heat the house, is a major goal of nutritional strategies in metabolic disease. The other is avoiding a buildup of substances such as glycogen or fat that can’t be broken down and can become toxic to cells.
A person who can’t use all the usual food sources for energy has to concentrate on those he or she can use.
Bypassing the glycogen freeway in McArdle disease
A classic example of a metabolic muscle disorder is muscle phosphorylase deficiency, also known as McArdle disease. In this condition, people lack an enzyme that’s needed to break down glycogen in the main part of the cell.
Haller says that, in his experience, people with McArdle disease have trouble doing hard exercise under any circumstances because they can’t break down glycogen, which normally yields fuel for aerobic as well as anaerobic metabolism.
But they may have particular problems during the first few minutes of attempted exercise, because it takes a little time for some compensatory glucose to arrive at muscle tissue from the liver via the bloodstream.
Taking in any kind of sugar (they all get converted to glucose in the body) helps provide energy in McArdle disease, because sugar can join the carbohydrate energy pathway below the point where glycogen is normally utilized.
“You’re bypassing a blocked pathway,” Tarnopolsky says, comparing the glycogen metabolism pathway to a freeway that normally feeds most of its cars onto a road several miles down. “If the main freeway is shut off, you can increase a couple of feeder lanes downstream,” he explains. Starting at glucose metabolism to get around a glycogen traffic jam is taking that approach.
|Exercise training, combined with proper diet, keep muscles as fit as possible.|
“If you have McArdle and can’t break down glycogen, if you take a chunk of glucose [such as a candy bar], it gets into the blood and goes down glycolysis [glucose metabolism] perfectly fine,” he says.
Unfortunately, it can also be turned into fat. “The downside is, if you take in tons of sugar, four months later, you’ve gained 20 pounds. You have to match your sugar intake to your caloric expenditure,” something that usually requires close supervision by a dietician or doctor who knows a lot about nutrition.
Another problem is that glucose that isn’t immediately burned up for energy can get stored as glycogen, which the person with a glycogen-processing disorder can’t use.
Haller recommends exercise training and a diet adequate in carbohydrates in McArdle disease. He notes that, even though McArdle patients can’t break down glycogen in muscle, they can do so in the liver, and the resulting glucose can then travel to the muscles through the circulation.
Slonim disagrees. Taking in sugar “in the initial phase for the first five to 10 minutes of exercise is supplying glucose at a critical period, and that’s very helpful,” he says.
But in his view, long-term treatment of McArdle disease should involve a high-protein diet. “When you give adequate protein, you can deal with what’s happening under these unusual conditions,” he says.
Raising protein intake may spare muscle tissue in acid maltase deficiency
In its most severe form, in which virtually no functional acid maltase is available, the lysosomes quickly fill up with indigestible glycogen, causing them to burst and spill their contents into the muscle fiber.
Muscle fibers in this form of Pompe disease, which was nearly universally fatal in infancy until recently, die from this lysosomal spillage and clogging of cellular structures with excess glycogen. (Last year, Myozyme, a laboratory-developed replacement acid maltase enzyme, was approved for treatment of Pompe disease, markedly improving the prognosis in this condition.)
In its less severe form, however, where some acid maltase activity remains, there really isn’t much glycogen buildup or bursting of lysosomes, Slonim says. Instead, in his view, the problem is lack of fuel supply that normally would come from breakdown of glycogen in lysosomes during periods of inactivity. (Not everyone agrees on this.)
“Because there’s an interference with glycogen breakdown [in the lysosomes] and fatty acids can only come in later on, the only other source of fuel is amino acids,” Slonim says. These amino acids, he says, if not adequately supplied in the diet, are “stolen away” from muscle tissue itself, adding to the weakness caused by the enzyme deficiency in late-onset Pompe disease.
Slonim recommends a high-protein, low-carbohydrate diet for people with Pompe disease, accompanied by a moderate level of exercise. The protein in the diet, he says, provides amino acids for energy production and keeps muscle from being broken down for this purpose.
But carbohydrate intake is a controversial area, and people with Pompe disease seem to vary in their response to carbs. Patients describe a range of reactions to sugar and sugary soda, from feeling an energy boost to feeling drunk and weighed down.
Using carbs in CPT deficiency
Short- and medium-chain fatty acids can enter mitochondria on their own, but long ones can’t. They need a transport system that relies on a carrier molecule called carnitine and two enzymes called carnitine palmityl transferase (CPT) 1 and 2. Carnitine deficiency and carnitine palmityl transferase deficiency prevent people from using long-chain fatty acids.
The answer to this problem can be as simple as giving carnitine supplements to patients who are deficient in carnitine.
But for those with deficits in CPT1 or CPT2, things get more complicated. At first glance, it seems as if ingesting only the shorter types of fatty acids would be a solution. But those, Tarnopolsky notes, aren’t well tolerated.
“It’s difficult to get enough medium- or short-chain fatty acids in without getting cramps and diarrhea,” he says.
Most of them are also oily and unpalatable. Butter is a short-chain fatty acid, but eating enough of it leads to serious gastrointestinal problems.
CPT-deficient patients, like the one described on page 42, are those who really benefit from a high-carbohydrate diet, Tarnopolsky says. “That’s probably where I see the most dramatic benefit. In CPT deficiency, you eat a high-carb diet to maintain glycogen stores and ingest carbs before and during exercise. Several nice studies have recently shown the benefit of these strategies in patients with CPT2 deficiency.”
Maintaining body mass is critical — even if it means a G-tube
Any metabolic disease that interferes with getting energy from dietary sources puts people at risk for eating into their fat and muscle stores for energy.
|A G-tube goes directly into the stomach, not down the throat. Newer types allow detachment of the tube between feedings.|
While some people with a neuromuscular disease have trouble keeping their weight low enough for comfort and appearance, when metabolism is abnormal, people often have trouble keeping weight on.
“I learned my lesson about 12 years ago with a late-onset acid maltase deficiency [AMD] patient,” says Slonim. “He was fine until his mid-50s, and then he lost a lot of weight, quite rapidly, for reasons nobody really understood at the time. We had him exercising, and we had him on a high-protein, low-carbohydrate diet. Despite that, his respiratory insufficiency progressed, and nobody was able to reverse it.”
What was happening, Slonim says, is that “his BMI [body mass index] was decreasing, and his muscles, including his respiratory muscles, were being depleted.”
Why that happens in AMD and certain other muscle diseases is something that needs further investigation, Slonim says, although he thinks it’s a combination of the metabolic breakdown of muscle for energy, and weak chewing and swallowing muscles causing people to eat less.
BMI is considered a reliable indicator of body fatness. For adults 20 and older, a BMI of 18.5 to 24.9 is considered within the normal range. Below 18.5 is considered underweight, 25 to 29.9 overweight, and 30 and above, obese.
(For details, or to calculate your BMI, go to the Centers for Disease Control and Prevention Web site at www.cdc.gov and enter “body mass index” in the search box.)
“As far as we can gather, anybody who has a BMI of under 18 is really in danger of increasing their muscle degradation,” Slonim says. “They’re utilizing their protein sources from their own muscles. Enzyme replacement therapy or other therapy will not be effective, because they’re progressively losing body mass. The best way to try to prevent or reverse that process is to give them supplemental nutrition.”
For people with Pompe disease who can’t maintain a BMI of at least 18 on a high-protein diet, Slonim recommends supplemental nutrition through a gastrostomy tube (G-tube), which is surgically inserted into the stomach from outside the body (not down the throat).
“It’s by far the most convenient for the patient and others, and it’s also reversible,” he says. He usually prescribes overnight G-tube feedings of about a third of the patient’s total caloric requirement.
“I didn’t like the way I looked, but I swore up and down I would never get a G-tube,” says Hillary Gibson of Norfolk, Va., who has late-onset Pompe disease and once weighed 95 pounds despite a height of 5 feet 10 inches.
But four years ago, at age 25, she gave in to Slonim’s pressure to do so and says she’s now “really glad I did.” She now weighs 130 pounds, which she attributes in part to the tube. “I feel much better,” she says, “and I look much better too.”
Staying fit for future therapies
Since the development of Myozyme, which replaces missing acid maltase, doctors and patients have had high hopes for similar therapies, using either proteins or genes, to treat other metabolic diseases.
But even if such medications come along, Slonim says, adults and children who already have a metabolic disease need to keep their muscles in good shape, so that they can make use of any therapies the future may bring.
For specific advice on nutrition in metabolic muscle disease, ask your MDA clinic physician for a referral to a dietician or nutritionist.
To read interviews with Hillary Gibson and two other people with Pompe disease who have successfully used nutritional strategies but have different responses to carbohydrates, see "People with Pompe Disease Speak Out on Nutrition, Exercise."