Friedreich's ataxia and frataxin: 
Molecular genetics, evolution and pathogenesis.

Palau F.

Instituto de Biomedicina de Valencia, 
CSIC, 46010 Valencia, Spain.
Int J Mol Med 2001 Jun;7(6):581-9


Friedreich's ataxia is an autosomal recessive neuro-degenerative disorder involving both central and peripheral nervous system. Patients also show a systemic clinical picture presenting heart disease and diabetes mellitus or glucose intolerance. The disease is caused by mutations in the FRDA gene mapped on chromosome 9q13.  The product of the gene is frataxin, an 18 kDa soluble mitochondrial protein with 210 amino acids. Crystal structure suggests a new, not previously reported, protein fold.  The most frequent mutation is the expansion of a GAA trinucleotide repeat located within the first intron of the gene, and represents 98% of the mutations. Point mutations are described in compound heterozygous subjects with one expanded allele.  A two-step model of GAA normal alleles towards premutation alleles, which might generate further full expanded mutations in the population with Indo-European ancestry, has been postulated.  Clinical phenotype is variable and an inverse correlation with the GAA expansion size has been observed.  Analysis of the GAA triplet is a strong molecular tool for clinical diagnosis, genetic counselling and prenatal diagnosis.  Friedreich's ataxia patho-genesis is not solved yet.  Substantial data from organism models, such the S. cerevisae yeast and more recently conditioned knock-outs in mouse, and studies in heart biopsies and fibroblast cultures from patients suggest an important role of mitochondrial iron in the development of the disease. Iron is accumulated in the mitochondrial matrix of both the yeast frataxin deficient mutant and the patient fibroblasts.  It has been postulated that iron-induced oxygen radical affects the oxidative phosphorylation in frataxin deficiency states favouring the disease pathology.  A second hypothesis postulates a direct role of frataxin in the mitochondrial energy activation and oxidative phosphorylation.  Iron chelator drugs and antioxidant drugs have been postulated for Friedreich's treatment.  No results from clinical trials are available yet, but idebenone, a short-chain quinone, seems to reduce the size of hypertrophic cardiomyopathy and levels of oxidative stress molecules in patients.

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