By David N. Leff

It's been 136 years since a German neurologist, Nikolaus Friedreich (1825-1882), described in 1863 the crippling, fatal disease that his name has since immortalized.

Neurodegeneration of the spinal cord causes Friedreich ataxia (FRDA). This brings on a progressive array of physical deformities - from clumsiness and slow, slurred speech in childhood to a lurching, unsteady gait, with constant danger of falling, to tremors in the arms and head, to general muscle weakness and in most victims life-threatening enlargement of the heart.

FRDA is the commonest of all ataxias. It strikes about 20 people per million in the population, typically young children and adolescents. By their 20s, most patients are in wheelchairs, with death intervening in the 30s, usually from heart failure. It's a congenital ailment, inherited when both parents carry the mutated FRDA gene, which resides on the long arm of human chromosome 9.

Until the 1990s, the etiology and mechanism of Friedreich ataxia were riddles wrapped in a mystery inside an enigma. Now, the gene is known, as well as the protein it encodes, frataxin - but its function in the body remains unknown. One key clue to that function came to light three years ago, when cell biologist/geneticist Jerry Kaplan at the University of Utah in Salt Lake City announced in Science dated June 13, 1997, that a gene in the genome of brewer's yeast (Saccharomyces cerevisiae) had a lot of homology in common with the just-discovered but as yet unpublished human FRDA gene. "They're the same genes that affect the same metabolic processes," Kaplan told BioWorld Today. That Science paper's title: "Iron accumulation by . . . a putative homolog of frataxin."

Kaplan went on: "Many of the same genes that work in yeast and C. elegans [the round worm] also work in humans. So in the future when you want to study a disease, you can just pick the species that's most convenient. His finding also said, 'Look! This is a disease of mitochondria.' That, I think, is one of the major outcomes of genomic studies."

Kaplan grants, "The counter-argument is that yeasts are not humans. There are significant differences. For example, human beings can't live without mitochondrial respiration; yeast can."

Now, a report in the current Proceedings of the National Academy of Sciences, (PNAS), dated Sept. 28, 1999, carries the exploration of Friedreich's ataxia into living human victims. Its title is: "Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia." The article's senior and lead authors, respectively, are Anthony Schapira at the University of Oxford in Cambridge, UK, and Raffaele Lodi at the University of Bologna, Italy. The two have long collaborated in prying open the black box of the disease. Kaplan contributed a Commentary to their paper, titled, "Friedreich's ataxia is a mitochondrial disorder."

Live-Action Human Research Subjects

Among the 12 FRDA patients the PNAS co-authors studied, four could walk without support, three with assistance; three could stand with support; and two were wheelchair cases. All 12 had inherited their mutated FRDA gene from both parents, which meant that their chromosomes contained expanded triplet repeats of the GAA (guanine-adenine-adenine) codon, which is the genomic hallmark of Friedreich ataxia. The number of these stuttering DNA nucleotide in those subjects ranged from 290 to 900 repeats. That's about one hundred-fold more GAAs than the normal healthy human carries.

While subjecting their patients to various levels of exercise exertion, the co-authors charted the rate at which energy was generated by their mitochondria. "Our findings," they reported, "demonstrate that the GAA triplet repeat expansion in FRDA is associated with a profound deficit of skeletal muscle mitochondrial ATP [adenosine triphosphate] production, and strongly support mitochondrial involvement in the pathogenesis of FRDA." (ATP is the product of mitochondrial energy synthesis.)

The PNAS data also "may suggest a link between degree of mitochondrial respiration deficit and clinical expression of the disease in other tissues." On this score, Kaplan noted, "The heart, which is tremendously affected by Friedrich's ataxia, gets most of its energy from mitochondrial respiration. Skeletal muscles get less."

Among a chain of metabolic depredations, the paper indicted oxygen free-radical toxicity. An excess of oxygen radicals attack DNA in mitochondrial proteins, which brings on deficits of the organelle.

Kaplan said, "Vitamin E is an antioxidant. If you have a normal level of antioxidants, and now decrease that level, you'd generate more oxygen radicals. There's a rare genetic disease called congenital vitamin E deficiency. It looks exactly like FRDA. That disease can be managed by giving those patients vitamin E. But there's no evidence that increased vitamin E has any effect on FRDA patients."

The PNAS paper concluded: "In contrast to other neurodegenerative disorders FRDA can be diagnosed by genetic analysis either presymptomatically or in the early stage of disease, before central nervous system and cardiac damage become established. Our findings provide a very strong rationale for treatments aimed to enhance mitochondrial function and reduce toxic radical production in these patients."

At Long Last, Hints Of Therapies To Come

"It's not so easy to isolate mitochondria from living patients," Kaplan observed. "Their study suggests that in fact there is a deficit in mitochondria. I think it confirms the yeast work, and allows it to be extended, because now you have a non-invasive way of looking at FRDA patients. Also, it offers a mechanism for evaluating therapeutic interventions."

As more and more light illuminates the FRDA picture, its research devotees are experimenting with a range of plausible treatments, applicable to clinical practice, such as increased antioxidants, gene manipulation to replace the mutated version, and approaches to limiting buildup of iron in the mitochondrion.

"One open question that needs research," Kaplan pointed out, "is, 'What is the mechanism of the mitochondrial disorder?' The yeast work has made a suggestion. Can this be verified on humans - or mammals? We're all working on these things, with everything we've got." As for mammals, he added, "The most critical attempt right now is to make an animal model of FRDA. We, like other people, are working on that. In our lab it would be a mouse that expressed decreased levels of frataxin."