The Broadening Clinical Spectrum of Friedreich's Ataxia


Source: Dürr A, et al. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med 1996;335: 1169-1175.

Friedreich's ataxia (FA) is the most common of the inherited ataxias. FA typically has onset during the second decade of life, then progresses slowly over approximately a 20-year period. In its full manifestation, FA features areflexia in the upper and lower limbs, along with pyramidal tract signs (most commonly extensor plantar responses) and ataxia. A high proportion of patients with FA develop diabetes and/or cardiomyopathy, highlighting the systemic nature of this autosomal recessive disorder.

Earlier this year, Campuzano and associates (Science 1996;271:1423-1427) demonstrated that patients with clinically typical FA have an abnormal intronic trinucleotide (GAA) expansion within a novel gene, termed frataxin. Thus, FA is another "Type II trinucleotide repeat disorder," similar to Fragile X and myotonic dystrophy in that the trinucleotide expansion is not expressed in the structural protein frataxin (in contrast to "Type I trinucleotide repeat disorder" Huntington disease, in which abnormal exonic CAG repeats do result in an expansion of polyglutamine residues in the disease gene product, huntingtin). Normally, there are 8-22 GAA intronic repeats in frataxin. Most patients with clinically typical FA have homozygous (i.e., both frataxin alleles) expansion to 120-1700 repeats. Rare patients with clinically typical FA are heterozygous for such repeats; in at least one such family, a point mutation in the frataxin gene has also been detected, so that it is likely that two mutant frataxin alleles are necessary for the expression of clinically typical FA, consistent with autosomal recessive inheritance.

It is well known that there are patients with autosomal recessively inherited ataxia but without development of areflexia or extensor plantar responses. Could some of these patients be a forme fruste of FA (i.e., might they also have evidence of homozygous frataxin gene mutations)? To address this, Dürr and coworkers examined the status of the frataxin gene in 187 patients from 147 pedigrees who had progressive ataxia with suspected or proven autosomal recessive inheritance. They considered such patients to have "typical FA" if they met all of the following criteria: 1) onset before age 25; 2) progressive ataxia of gait and limbs; 3) absent knee and ankle jerks; and 4) extensor plantar responses. Of the 187 patients studied, 74 (almost 40%) lacked one or more of the above criteria despite a duration of progressive ataxia for five or more years. Among these 74 patients with "atypical FA," 46% were found to have homozygous intronic GAA expansions of greater than 120, at least six-fold higher than normal; 51% lacked such mutations, and two patients had heterozygous mutations. Furthermore, the authors showed that patients with higher homozygous frataxin GAA repeat numbers had an earlier onset of disease, and were more likely to display areflexia, extensor plantar responses, pes cavus, scoliosis, and cardiomyopathy.


This study demonstrates that the clinical spectrum of FA is broader than previously believed. FA must still be considered a likely diagnosis in a progressive ataxia that is possibly recessively inherited, even if the onset of illness is in adulthood and certain "cardinal signs" of FA are absent. As is typical of trinucleotide repeat diseases, patients with larger repeat numbers appear to have a more severe phenotype, suggesting that a study of frataxin GAA repeat numbers may have both diagnostic and prognostic value in the evaluation of patients with progressive ataxia. It is important to note that patients with phenotypic features closely resembling FA but with normal frataxin gene structure have been reported; in these patients, a genetic deficiency in vitamin E metabolism should be suspected.