Friedreich's ataxia (FA) is a complex disease involving the nervous system (mostly the sensory nerves), the heart and other organs. Many people with the disorder have diabetes or abnormalities in the eye's retina. The word "ataxia" means incoordination, and difficulty with balance and coordinated movements characterize the disorder. There may also be difficulty speaking.

The disease usually begins during adolescence, and most people with it need a wheelchair starting in their 20s. The age at which the disorder starts and its severity vary, and new genetic findings are beginning to explain this variation.

FA is a recessive genetic disease. To show symptoms, a person needs to have a genetic flaw on both of a pair of chromosomes.

In 1988, MDA-funded researcher Susan Chamberlain of St. Mary's Hospital in London was among researchers who mapped the FA gene to a small area of chromosome 9.

Then, in 1996, MDA grantee Dr. Massimo Pandolfo, then at Baylor College of Medicine in Houston, led a team that identified the gene for FA and two kinds of flaws (mutations) in that gene. (Pandolfo is now at the University of Montreal and McGill University, both in Montreal, Canada.)

By far the most common mutation in FA is an expanded section of DNA of a type known as a "GAA triplet repeat." The chemical sequence GAA is repeated between seven and 22 times in people without FA, but in FA, GAA sequences are repeated from about 200 to more than 1,000 times.

The expansion, the scientists believe, probably suppresses the production of a protein recently dubbed "frataxin."

To make matters a little more complicated, there are also other ways for the frataxin gene to be flawed. The expanded GAA repeats are the disease-causing mutation in 95 percent of the chromosomes studied. But, about 5 percent of the time, one of the chromosomes has a different kind of mutation. These other mutations also decrease frataxin production.

So far, there are no patients with FA who entirely lack the frataxin protein. They all have some, although probably to varying degrees. In general, researchers report, the larger the GAA repeat, the more severe is the disease and the earlier is its onset. Presumably, people with larger GAA repeats make less frataxin, but this remains to be proven.

So far, nearly all FA's patients studied have the extra repeated GAAs on both chromosome 9s, although the lengths of the repeated segments aren't the same on both chromosomes.

WHAT DOES FRATAXIN DO?

Since FA affects many tissues and systems in the body, doctors have long theorized that the protein made from this gene must be one that's needed in many kinds of cells. It turns out they're right.

Frataxin, it seems, is a protein normally found in the mitochondria (singular, mitochondrion), the "powerhouses" of the body's cells. Nearly all cells have mitochondria, vital miniature "organs" - they're actually called "organelles" -- that produce the cell's energy. They're especially important in nerve and heart cells. Some experts think mitochondria may once have been cells themselves, early in evolution, because they have many of the characteristics of independent cells.

This year, studies from Pandolfo's group and others around the world have confirmed that frataxin not only shows up in mitochondria, but that it plays a role in regulating how much iron is in the mitochondria.

Mitochondria need iron to do their work, and they get it from the cells they inhabit. Cells get their iron from the surrounding environment by transporting it across their membranes in response to signals that tell them how much to take in. Iron is constantly moving between "compartments" -- from the fluid around the cells to the interior of cells to the mitochondria inside cells. It's kept at the right concentration in each compartment by the cell's control systems.

Normally, once it's inside a cell, some of the iron ends up inside the mitochondria, where it's needed for energy production. Iron also has to leave the mitochondria and enter the main part of the cell, from which some of it will eventually be removed. Frataxin, Pandolfo believes, is probably one of the proteins involved in removing iron from the mitochondria and depositing it in the main part of the cell, where it can be transported back out into the surrounding fluid. No frataxin, no transport out of the cells' mitochondria, this theory says.

When scientists looked at yeast cells that completely lacked frataxin, they found severe damage to the mitochondria, probably caused by iron poisoning (iron overload is highly toxic to cells). But, Pandolfo says, yeast cells, unlike human cells, don't really need their mitochondria, so the problem isn't so serious.

"In yeast cells, as in humans, excess iron in the mitochondria leads to free radical formation," Pandolfo said. "The yeast cells will get rid of mitochondria if this happens. But human cells will not get rid of their mitochondria, which accumulate free radical damage." (Free radicals are chemicals that damage cells by reacting with a variety of substances. They're produced as byproducts in many chemical reactions.)

Unfortunately, damage to the mitochondria may be only part of the picture in human cells, Pandolfo believes. The ultimate insult may be a secondary effect. "Since iron is trapped in the mitochondria," he said, "the cell keeps incorporating iron from outside." It's as if the cell mistakenly "senses" a need to keep bringing in iron, Pandolfo speculated, because its sensors can't detect iron that's stuck in the mitochondria.

WHAT'S TO BE DONE?

Pandolfo said he isn't ready to start treating patients for iron overload but, if certain research studies prove his speculations correct, "it would not be a crazy idea to start a pilot study with patients to bind iron." He's encouraged by old research that shows there are iron deposits in the hearts of FA patients.

At an MDA-supported meeting in Montreal in May, Pandolfo and colleagues from around the world agreed to form a network of clinicians and researchers in FA. The ultimate goal is development of clinical trials to test treatments for this disorder.

For now, the first steps are 1) proving that human cells react the same way to frataxin deficiencies as the yeast cells do; 2) proving that iron accumulates both inside and outside the mitochondria in human cells; 3) proving that iron builds up in several tissues of the body in people with FA, not just in the heart.

There is an iron-binding drug already on the market, Pandolfo said, but it has to be injected. He said newer drugs, which bind iron but can be taken orally, are in development. Prospects for a drug trial are "encouraging," Pandolfo said, "but very preliminary.

GENETIC TESTING FOR FRIEDREICH'S ATAXIA

Commercial genetic testing to identify people who will develop Friedreich's ataxia or those who are carriers is close. Patents are pending. University testing is available at some centers, including Pandolfo's in Montreal. Call MDA at (800) 572-1717 to be referred for genetic testing at a university medical center.