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Diseases can affect the power in our cells

By Judy Foreman, 6/17/2003

n retrospect, it was clear from the moment Samantha Fargo was born six years ago that something was very wrong -- and very strange. At first, she was too weak to breast-feed. By five weeks, she could drink from a bottle, but had such bad reflux (in which food backs up into the esophagus from the stomach) that her parents, Justine and Bill Fargo of Medford, had to keep her semi-upright all the time. She didn't walk until she was 18 months old. Worse yet, the poor kid never seemed to have much energy.

This spring, she developed gastroparesis, in which her stomach and intestines stopped functioning, prompting a long hospitalization. She is now fed via a tube in her stomach and another in a vein.

Yet, it wasn't until she was 4 that Samantha's symptoms gelled into a diagnosis -- mitochondrial disease, an often-underdiagnosed genetic condition that may shed light on far-more-common problems, including lack of energy as people get older and other disorders of later life such as Alzheimer's, Parkinson's, diabetes and heart disease.

Conservatively, mitochondrial disease is believed to affect between 40,000 and 70,000 Americans, said Christopher Rice, executive director of the United Mitochondrial Disease Foundation.

But, in reality, the disorder may be ''extremely common'' and frequently missed by doctors, said Doug Wallace, a mitochondrial DNA geneticist who heads the new Center for Molecular and Mitochondrial Medicine at the University of California at Irvine.

Mitochondria are the powerhouses of the cell, little ''organelles'' -- 1,000 per cell -- that, in the presence of oxygen, convert the energy stored in the hydrogen bonds in fat and sugar into the kind of energy the body can use, a substance called adenosine triphosphate, or ATP.

If the mitochondria don't work properly, the result is a lack of energy and, ultimately, cell death. But mitochondrial disease can be tough to diagnose because lack of energy is a symptom of many diseases. And unlike diseases that attack one main organ, mitochondrial dysfunction can affect multiple organs, especially the brain and muscles.

In some cases, mitochondrial dysfunction can be caused by drugs, including the cholesterol-lowering drugs called statins, and certain AIDS drugs, according to Dr. Bruce Cohen, a neurologist at the Cleveland Clinic Foundation in Ohio.

Over the course of a lifetime, free radicals, destructive oxygen molecules, also damage the mitochondria.

This a major reason why scientists suspect that mitochondrial damage underlies many of the diseases of later life, said Wallace of UC-Irvine. Indeed, a recent study by Howard Hughes Medical Institute investigators at Yale University found that a decline in mitochondrial function is linked to insulin resistance, a precursor to diabetes.

But perhaps the most dramatic instances of mitochondrial disease are those caused in children by genetic defects. The exact figure is unknown, but mitochondrial disease is believed to occur in one in 2,500 to 4,000 births, noted Dr. Mark Korson, associate chief of the metabolism service at the Floating Hospital for Children, part of Tufts-New England Medical Center.

There are two ways to inherit mitochondrial disease -- via defects in the mitochondrial DNA itself, or by defects in genes in the nucleus that act in the mitochondria. The former can only be inherited through defects in the mother's mitochondrial DNA. (Samantha's mother, for instance, has a mild form of the disease herself.) The latter can come from defects in either parent's nuclear DNA.

But within any given cell, some mitochondria may be normal and some sick, a state called heteroplasmy. Depending on how the mitochondria sort themselves out during cell division, some of the new cells may get a lot of bad mitochondria while others do not. This explains why some siblings, even identical twins, can end up with mitochondrial problems of vastly differing severity.

There are no high-tech cures for mitochondrial diseases, but some low-tech remedies, chiefly vitamin supplements, can help, though much of the data on this is anecdotal.

In theory, one might think that giving people ATP, the substance produced by mitochondria used to fuel cells, would correct the low-energy problem. Unfortunately, this doesn't work because ATP is such a short-lived molecule that a person would have to consume several times his or her body weight in ATP every day.

A better solution is what doctors call a ''mito cocktail,'' said Dr. Richard Kelley, director of metabolism at the Kennedy Krieger Institute at Johns Hopkins University in Baltimore.

One ingredient of this cocktail is coenzyme Q-10, an enzyme that, in natural form, drives energy production in the mitochondria. Depending on which stage of energy production in the mitochondria is affected, boosting coenzyme Q-10 levels may help.

Vitamins such as thiamine (B1) and riboflavin (B12) may help, too, as can the antioxidant vitamins C and E, and another supplement, lipoic acid.

At the University of Florida, Dr. Peter Stacpoole, director of the general clinical research center, has been exploring other approaches. One is a drug called DCA (dichloroacetate) that may block the buildup of lactic acid. Elevated lactic acid levels are often used as a marker for potential mitochondrial disease. Another, based on the idea that sick mitochondria can't process carbohydrates properly, is placing patients on a high-fat ''ketogenic'' diet, in which the body, in particular the brain, uses fat instead of carbohydrate for fuel.

For the moment, though, except for the ''mito cocktails'' and common-sense measures such as eating a nutritious diet, it's still an uphill battle for families like the Fargos. When things flare up, things get ''pretty awful,'' said Samantha's mother, Justine. ''I wish I had more hope that scientists will come up with a cure soon.''

This story ran on page C3 of the Boston Globe on 6/17/2003.
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