In recessive Ataxias
Michel Koening, MD
Friedreich's ataxia is the most frequent recessive ataxia occuring among white populations. But there are other recessive ataxias as well, they include:
- ataxia telanglectasia
- familial vitamin E deficiency
- refsum diseases
- infantile onset spinocerebellar ataxia, or IOSCA
- spastic ataxia of Charlevoix-Saguenay
Other rare ataxias that don't have a name because they are not well characterized.
In recessively inherited ataxias only the ataxia patient manifests the disease because he/she has 2 copies of the ataxian defect or mutation, one received from each parent. The parents of the patient are not affected because they carry only one copie. For all recessive diseases, the frequency of healthy carries is much higher than the frequency of patients, because the risk that 2 carries of the same ataxia mutation marry is relatively low. For example, for Friedreich's ataxia, the frequency of healthy carries is 1 in 120 while the frequency of patients is 1 in 40,000. We have shown that almost all Friedreich's ataxia carriers and patients have the same ancestor (who lived most likely more than 10,000 years ago). This explains why Friedreich's ataxia is more prevalent in white populations and is almost non-existent among Japanese and black African populations.
The mutations lie en gene, which serve to make proteins, the building blocks of all living matter. The identification of the Friedreich's ataxia gene showed that the mutation is te same in almost every patient (in agreement with the fact that they are the descendants of a same ancestor). It is an expansion of a repetition of the trinucleotide GAA. Unlike the trinucleotide expansions found in dominant ataxias, the GAA expansion is very large ands does not contain the information to make the protein (called frataxin). How then does this expansion cause the disease?
The expansion causes much less frataxin to be made, about 10 to 20 times less. The important point here is that there is still a little bit of frataxin made. This distinguishes the expansion mutation from other mutations, referred to as truncating mutations and frequently found in other recessive diseases, which completely alter the production of the protein. The identification of the Friedreich's ataxia gene now allows the study of the function offrataxin, which should shed light on ahow its reduction causes the disease. Frataxin is a protein of the mitochondria, the structures of a cell where its fuel is produced from food. This energy conversion requires electron transport with iron containing proteins.
Frataxin is present in tissues that are rich in mitochondria, which include the tissues that are affected in patients (dorsal cord, heart..). Frataxin is present in every living organism, including fungi and yeast, because they also contain mitochondria. In yeast, complete absence of frataxin causes iron accumulation within the mitochondria.
In Friedreich's ataxia patients, a similar defects is also likely to apply, but to a lesser extent since there is still some residualfrataxin present. Evidence of this are iron deposits and defect of some iron containing proteins and heart of patients. Mitochondrial iron accumulation seems therefore to be the culprit, since excess of iron is well known to stimulate the production of toxic compounds called free radicals or reactive oxygen species. The toxic process is called oxydative stress.
Some drugs and vitamins, called anti-oxidants, protect against oxidative stress. One of them is vitamin E, therefore suggesting that reduction of frataxin or of vitamin E may cause ataxia through a final common mechanism. The use of anti-oxidants appears attractive but should be approached with caution, since some anti-oxidants, may have an effect opposite to the one intended. The use of animal models is vitually important here, in order to assess the affectiveness of different therapeutic approaches.
A knockout mouse has been specially bred, its DNA altered to inhibit frataxin production and so mimic Friedreich's ataxia. The difficulty here is to create a mutation in the mouse that would have the same consequence as the expansion mutation in patients: a reduction but not a complete extinction of frataxin expression. An alternative therapeutic approch would be to prevent the expansion mutation from reducing frataxin production. The faulty process here seems to lie in the reading of the gene (elongation of transcription), and more precisely the reading of the expansion of the GAA repeat, as shown by the groups of Pandolfo (Montreal) and P. Patel (Houston). More work is warranted on this aspect of the disease.