A one day meeting concerning advances in research in Friedreich Ataxia was held on the 30th August in Adelaide. This meeting brought together people working in the field of Friedreich Ataxia from a number of countries as well as the related fields of iron metabolism and triplet repeat diseases. Some of the information presented has not been accepted for publication in the scientific literature and therefore will not be detailed in this report. This meeting highlighted not only the cooperatively of the Australian researchers but that this also occurs in the international arena. Through informal discussions and meetings over the past year or so, a concerted effort has been made not to waste resources duplicating research efforts apart from areas where it is essential to confirm exciting findings. This has ensured that we have made the best progress possible and as you will see from the meeting report we aim to continue in this collaborative cooperative manner.

A bit of background first. Friedreich ataxia is due to faults in the gene known as FRDA, which produces the protein frataxin. Most of the genetic alterations are an expansion of a GAA repeat (three letters of the genetic code) in intron 1 of this gene but point mutations have also been found in some patients where a single letter of the genetic code for frataxin is altered. Last year it was found that if the yeast equivalent of frataxin is knocked out in the yeast, iron accumulates in the mitochondria. Mitochondria are the energy sources for cells. Other evidence for the involvement of mitochondrial iron include the abnormalities in enzymes from the mitochondria in heart muscle from people with Friedreich ataxia as well as the finding of iron deposits in heart muscle. These tissues are known to be affected in patients with FRDA but are not readily accessible from patients to check the effect of therapies.

The first presentation was from Professor Massimo Pandolfo from Montreal who laid the foundation for the rest of the meeting. He elegantly summarised the current status of research findings and highlighted areas where further work was required to confirm preliminary results. A particular focus was a discussion about the evidence for mitchondrial iron build up underlying Friedreich ataxia. His laboratory found clearly increased levels of iron in the mitochondria of heart muscle from one person with FRDA but not in fibroblasts (skin cells).

Dr Martin Delatycki (Melbourne) spoke about his findings looking at fibroblasts, which are skin cells from people with Friedreich ataxia. He did find a small but significant difference in iron levels in mitochondria from people with FRDA compared to controls. These experiments have been performed in order to determine if there is a readily accessible tissue that shows a biochemical phenotype. Then it may be possible to both test the effects of therapeutic measures and monitor it during a trial.

Mouse models for human diseases offer the opportunity to examine the way that the gene fault causes the disease. Once it has been confirmed that the mouse has a similar clinical picture to humans, then the mouse can be used to test possible therapeutic interventions. Dr Michel Koenig from Strasbourg in France who along with Professor Pandolfo found the gene which is faulty in Friedreich ataxia, talked about a mouse model for Friedreich ataxia that they are generating where the gene is disrupted. The first litter has only just been born and is currently being investigated.

Other forms of mouse models are being generated in the Melbourne and Montreal labs. Professor Pandolfo is looking at making a mouse that has the expanded GAA repeat in the gene. Dr. Kate Elliott (Melbourne) spoke of the mouse being developed there which will have the G130V point mutation. These mice have not been produced yet and discussion centred around how the presence of these gene faults would affect the mice.

Dr. Koenig then spoke about his work in looking at proteins which interact with frataxin which may then give a better understanding of how the deficiency of frataxin leads to Friedreich ataxia. The interacting protein he found, mitochondrial processing peptidase b, causes maturation of frataxin into its fully functional form. This unfortunately does not shed further light into how frataxin functions. Work to find further partners is continuing in both the Montreal and Strasbourg laboratories.

Another avenue for investigation of frataxin function was suggested by Dr Des Richardson from the University of Queensland. In order to understand the role of frataxin in mitochondrial iron overload, knowledge of the iron metabolism of the mitochondrion is crucial. He presented some of his finding in examining how iron gets to the mitochondria in red blood cell precursors which might provide clues that may be important in understanding the role of frataxin in other cells.

Phillipa Lamont, a neurologist from Perth, talked about possible therapies based on the current understanding of the underlying problem in Friedreich ataxia. It is believed that the build up of iron in mitochondria leads to the production of free radicals which damage the cells. Therefore, potential therapeutic options include drugs to remove iron from the mitochondria (iron chelation) or drugs to mop up the free radicals produced (antioxidants). There are many different antioxidants including co enzyme Q10 which may have a role in the treatment of Friedreich ataxia.

The only approved drug which removes iron from cells is the iron chelator, desferrioxamine. This has been used extensively in iron overload conditions such as thalassaemia. It is unclear whether this drug removes iron from the mitochondria. It was universally agreed at the meeting that it was not appropriate to use this drug to treat Friedreich ataxia because it removes iron from cells so effectively causing depletion of iron from where it is required within the cell.

Erica Becker who is a PhD student with Des Richardson in Queensland discussed various new iron chelators which have the potential to be used in Friedreich ataxia. She demonstrated that some of these can be used to remove iron from mitochondria although they also removed iron from cells. It needs to be emphasised that these chemicals are very much at an early laboratory research level.

Professor Bob Williamson, the Director of the Murdoch Institute discussed gene therapy and possible ways that this may be used in the future for treating Friedreich ataxia. He then summed up the meeting and put into context just how far research into Friedreich ataxia had come in the two years since the gene responsible for the condition was discovered.

Samantha Dixon from NSW spoke on behalf of the support groups who met at the same time as the scientific meeting. She raised the issue of availability of educational material for families, their support network including families and clinicians. The overriding concern was the desire to have treatment trials set up in Australia. She asked whether potential therapies could be combined

The ensuing discussion began with Dr Garth Nicholson, a neurologist from NSW, pointing out the importance of doing such trials in a proper manner which requires significant funding. The issue of how to monitor the benefit or otherwise of medications in the trial was also discussed. If a drug slows the progression of Friedreich ataxia this may be very difficult to detect by the usual clinical methods. Therefore, important areas of research include those which look for methods of detecting benefits from drugs in a more subtle fashion that is currently available. Information from a London group involved in the use of specialised technique called magnetic resonance spectroscopy presented at the neuromuscular meeting which followed on from the Friedreich ataxia meeting may prove to be useful in this respect. Professor Pandolfo pointed out the possible use of biochemical markers such as erythrocytic protoporphirin IX, which is above normal in all FA patients, and possibly plasma malonaldheyde (no data yet) for monitoring the response to various therapies.

The meeting from a scientific perspective was very successful in that it allowed open discussion regarding research results and a clearer picture regarding the cause and possible therapies for Friedreich ataxia was presented.

The organisers of the meeting would like to again thank those who helped financially with the meeting including the Theresa Byrne Foundation and the Friedreich Ataxia Associations of Victoria and NSW.


Medical Geneticist Head Scientist, Gene Discovery





This summary is provided through the co-operation of The Murdoch Institute, Melbourne, Australia and contributors to the proceedings of the Conference. It represents a lay person's analysis of the main points and is presented with a view to providing an overview of the current state of research into Friedreich's Ataxia.

The Program:

The Frataxin Story

Dr Massimo Pandolfo

Understanding Frataxin Gene Function and Mutation Analysis

Dr Michel Koenig
Dr Sue Forrest
Dr Martin Delatycki
Dr Kate Elliott


Dr Des Richardson
Dr Michael Koenig
Dr Martin Delatycki

Therapeutic Strategies

Dr Phillipa Lamont
Ms Erika Becker
Professor Bob Williamson

Dr Pandolfo's presentation set the scene for much of the subsequent discussion and the later presentations. It would appear from yeast studies that there is an excess of iron in the mitochondria, that is, within the structures containing respiratory enzymes and which are responsible for producing energy. In the yeast model, developed by Kaplan and his associates, lack of expression of the gene results in an excess of iron in the mitochondria. One salient issue is whether frataxin acts as an exporter of iron from the mitochondria. It is believed that excess free iron in the mitochondria generates highly toxic free radicals.

In the human, frataxin is a mitochondrial protein which has no direct interaction with the membrane.. Vulnerable cells require a high level of frataxin and Friedreich's patients exhibit a profound deficiency of frataxin in these. Conversely, there does not seem to be a change in the fibroblasts, which are cells obtained from a skin biopsy, or iron-related aspects in fibroblasts amongst patients.

There is deficiency of iron-sulphur enzymes in the heart but not in skeletal muscles or fibroblasts. This appears to be due to the sensitivity of these enzymes to free radicals. Mitochondrial DNA is not depleted in the heart, spinal cord, brain or muscle of patients.

One might conclude that Friedreich's Ataxia results in a frataxin deficiency leading to an increase in mitochondrial iron and free radicals. This results in cell damage and cell death in specific tissues such as dorsal root ganglia resulting in that person having Friedreich's ataxia.

Dr Koenig stated that FA is a Caucasian disease and that there is a correlation between expansion size and severity of the illness. There also appears to be a correlation between age of onset of FA and the size of the expansion. FA is caused by a reduction of frataxin, not a complete obliteration of it. This has important and positive implications for future treatment. Dr Koenig is currently finalising work on a knockout mouse model.

The Murdoch group provided interesting insights into the relationship between point mutations and severity of illness. While FA normally results from an atypical expansion of the GAA repeat on both alleles, between one and five per cent of cases are caused by a single nucleotide change in the gene. Some point mutations result in severe Friedreich's ataxia whist others cause milder FA. This gives insight into which parts of frataxin are important for function. Of interest here was Koenig's presentation of a variety of FA patients with lengthy repeats on two alleles, but whose physical characteristics appeared relatively normal.

The Murdoch group is currently involved in developing a mouse model that imitates a milder form of FA.

Research at the University of Queensland's Department of Medicine could have significant implications for FA. Papers presented by Dr Des Richardson and Ms Erika Becker provided insights into the nature of mitochondrial iron transport and iron overload, as well as the development of new iron chelators.

In previous research Richardson demonstrated that haem synthesis in the mitochondrion was inhibited through the intervention of a specific inhibitor (succinylacetone) resulting in an iron accumulation because iron continued to be transported into the mitochondrian despite the lack of a facility for binding it. When the binding facility is added, or when the inhibitor is removed, iron is incorporated to form haem which is transported out of the mitochondrion.

Richardson believes that iron accumulation in the mitochondrion in FA patients could be the result of a defect in mitochondrial iron release. He postulates that since frataxin could be involved in regulating iron uptake by the mitochondrion it becomes necessary to investigate the pathway of iron uptake from the endosome to the mitochondrion.

Ms Becker pointed out the problems attaching to iron chelators, particularly given their serious side effects and the unavailability of orally administered chelators. She referred to the capacity of arolhydrazone chelators to remove iron from iron-loaded mitochondria in erythroid cells.

Becker's current research attempts to identify chelators that are more efficient than desferrioxamine. She has identified three as having greater activity than desferrioxamine and intends examining the usefulness of these in removing iron from mitochondria. It is very important to realise that this work is in the very early laboratory research stage and is not immediately applicable to therapy for FA.

Dr Phillipa Lamont from Royal Perth Hospital in Western Australia presented an overview of potential therapies for FA. She referred to the problems associated with the currently available iron chelators, indicating that these may not remove iron from the mitochondrion although they are effective in depleting iron from cells in general. Any depletion of such cytosolic iron could well lead to iron deficiency.

The Lamont paper suggested that antioxidants aimed at reducing free radicals in cells provided a safer and more beneficial effect than the present chelation therapy.

Professor Bob Williamson, Director of the Murdoch Institute, presented an overview of the present state of the art in gene therapy as it relates to FA. Work on mouse models is proceeding apace and, while gene therapy is still not available to FA patients, more is being found out about its possibilities. FA is regarded as a good candidate for gene therapy and research on adeno associated viruses as a delivery system is moving ahead quickly.

The possibility of early trials with accepted antioxidants should be considered now. It is imperative that these be conducted under controlled conditions. While sufferers and carers are understandably frustrated at the delay in determining a treatment, it should be realised that great advances have been made in the two brief years since the discovery of the FA gene. It is also encouraging that there are now clinicians with an understanding of FA and its effects in every Australian state. Moreover, the study of FA amongst researchers has increased dramatically worldwide.

Peter Rousch
September 1998