Friedreich's Ataxia & Iron Accumulation This article submitted by on 11/8/97. FRIEDREICH'S ATAXIA: FRATAXIN AND IRON ACCUMULATION IN THE MITOCHONDRIA Fraser J. Goodmurphy, London, Canada Massimo Pandolfo, Centre de Recherche Louis-Charles Simard, Montreal, Canada In the 8 March 1996 issue of SCIENCE, Doctor Massimo Pandolfo and his colleagues in Houston, Texas and around the world announced that they had cloned the gene responsible for Friedreich's Ataxia (FRDA), a recessively inherited neurodegenerative disorder characterized by a wide range of symptoms including cardiac, muscular-skeletal, and metabolic complications. Its cause has remained a mystery and has been untreatable since it was first identified by Nicholaus Friedreich, a Professor of Medicine in Heidelberg, Germany, over 120 years ago. Since relocating to Montreal, Canada, Doctor Pandolfo and a number of laboratories in Canada, the United States, France, Italy, and Belgium have clarified how lack of FRATAXIN - the protein expressed by the FRDA gene X25 - appears to cause FRDA and how this cause MIGHT eventually be treated. Although the connection between the role of Frataxin and the cause of FRDA is based on THEORY and OBSERVATION at the moment, it may eventually lead to a clinical trial. NO drugs are currently available to safely and effectively treat or cure the cause of this disorder but this research remains a significant breakthrough. It offers us a new and valid reason to hope that a treatment to halt or slow the progression of FRDA might be on the horizon. During the past year, laboratories around the world have observed that Frataxin is apparently a mitochondrial protein, concentrated in the tiny structures inside cells which convert food into energy. When Doctor Jerry Kaplan and his colleagues at the University of Utah "knocked out" a gene in Baker's Yeast (Yeast Frataxin Homologue 1, YFH1) which is genetically similar to X25, iron accumulates in the mitochondria causing mitochondrial disfunction, possibly by catalyzing the production of free radicals; by "chemically helping" the formation of unstable molecules which destroy nerves and organs. These observations, which appear in the Friday 13 June 1997 issue of SCIENCE in an article co-authored by Doctor Pandolfo, suggest that the process of iron accumulation in the mitochondria could be studied within FRDA cells grown in a test tube, and if the accumulation appears to cause the degeneration characteristic of FRDA, the efficacy of iron chelators - drugs which remove iron from cells - could be evaluated for protecting these cells. If the relationship proves to be valid and reliable, an investigation of the therapeutic benefits of iron chelating drugs alone or in combination with antioxidants such as Vitamin E among individuals who have been diagnosed with FRDA may be considered. While this news is very exciting, a number of caveats about the hypothesis itself and the method in which it ought to be tested need to be addressed before it can be applied, especially among humans. Obviously, our cells are infinitely more complicated than Yeast cells. Because we cannot live without functional mitochondria and because our cells contain a varying amount of them, unlike yeast, the connection between iron accumulation and the degeneration characteristic of FRDA may not be as straightforward as it first appears. Furthermore, as all of us who have been diagnosed with FRDA express some amount of residual Frataxin no matter how much our DNA differs from the norm, observations drawn from Yeast cells may not be entirely compatible with the processes that cause FRDA in humans. A number of laboratories around the world are diligently working on developing a "transgenic" model of FRDA in mice in order to study how Frataxin functions in organisms that are closer to humans but none of them have published results to date. Although a published result indicates that a single individual has been successfully treated for Aceruloplasminemia, an autosomal-recessive neurodegenerative disorder characterized by iron overload in the Central Nervous System, with an iron chelator, the particular drug has a number of drawbacks. It is very expensive, it is not overly effective in children, and occasionally it has some toxic side effects. Furthermore, it is not administered orally, but injected or infused by a small pump. An oral medication is currently in Clinical Trials in Canada and Europe but evidence of its safety and effectiveness in chelating iron - eliminating it from iron-overloaded cells - remains inconclusive. The problem of measuring the extent of iron overload and free radical damage among those of us with FRDA is equally complicated. Minerals cannot be easily visualized by non-invasive investigative techniques such as Magnetic Resonance Imaging (MRI), which actually images structures according to their difference in water content. Similarly, free radical production and damage are impossible to quantify in living organisms at the moment. Procedures may be developed, however, to increase the sensitivity of MRI to iron, and experiments aimed at extending free radical assessment beyond tissue samples and cultured cells to those of us with FRDA are currently underway. These latter concerns need to be addressed because the severity and symptoms of FRDA vary so much. Before anyone who has been diagnosed with FRDA can be treated with an iron chelator or an antioxidant, we need to confirm beyond a reasonable doubt that iron accumulation in the mitochondria is indeed the primary cause of the progression of FRDA, and that this kind of treatment is safe and effective. A number of circumstances however, warrant optimism. Another Neurologist at the University of Sherbrooke in Quebec observed iron accumulation in the mitochondria of the heart cells among those of us with FRDA almost 20 years ago. Up to this year, the cause of the accumulation remained a mystery - until genetic science advanced far enough to reveal that the protein expressed by X25 appears to cause the iron accumulation which seems to produce FRDA. At the recent First International Symposium on Inherited Ataxias held in Montreal, Doctor Pandolfo took the names of over 20 Neurologists and Geneticists from Canada, the United States, England, Italy, Spain, France, Germany, Australia, and Russia who are interested in investigating the possibilities of treating this accumulation with iron chelators and antioxidants. This global committee needs to meet a number of critical aims before rushing into Clinical Trials: development of a working model of FRDA in mice, development of a safe and effective iron chelator, selection of an appropriate antioxidant, and development of meaningful measurements of effects. According to Doctor Pandolfo, the committee wants to "do this right". They urge you to refrain from asking your Doctor for any sort of iron chelator, and they advise you not to attempt to completely eliminate iron from your diet because iron deprivation directly causes a number of other disorders which are just as serious as FRDA. We have all been waiting a long time for this news. Encouraging results may be published sooner than you might expect. In the meantime, because FRDA research is not well supported, you may want to consider helping fund this project by donating your time or money to one of the organizations which fund Ataxia research in your country. Speaking as someone who has been coping with FRDA for 20 years, I believe that we all have a valid reason to be optimistic about the possibility of a viable treatment becoming available in the near future. -- Permission is granted to reproduce this material for noncommercial use provided that the text, author's names, and copyright statement are not changed.