Phenotypic variability in friedreich ataxia: Role of the associated GAA triplet repeat expansion

Abstract

We studied genotype-phenotype correlations in a group of 100 patients with typical Friedreich ataxia (FRDA), and in three groups of patients with atypical clinical presentations, including 44 Acadian FRDA, 8 late-onset FRDA (LOFA), and 6 FRDA with retained reflexes (FARR). All patients, except 3 with typical FRDA, carried two copies of the FRDA-associated GAA triplet repeat expansion. Overall, the phenotypic spectrum of FRDA appeared to be wider than defined by the currently used diagnostic criteria. Our study indicated the existence of several sources of variability in FRDA. Patients with larger GAA expansions tended to have earlier onset and were more likely to show additional manifestations of the disease. Mitotic instability of the expanded GAA repeats may partially account for the limited degree of correlation between expansion sizes as determined in lymphocytes and clinical parameters. Some clinical variants associated with specific FRDA haplotypes, such as Acadian FRDA and FARR, turned out to be unrelated to expansion sizes. No polymorphism in the frataxin coding sequence could be associated with these clinical variants.

Selected missense mutations impair frataxin processing in Friedreich ataxia

“…FRDA is most commonly caused by an expansion of a GAA repeat tract in the first intron of the FXN gene on both alleles, and less commonly by a GAA repeat on one allele accompanied by a point mutation in the other FXN allele. In typical FRDA, the length of the shortest GAA expansion correlates with disease severity; longer GAA expansions result in earlier onset and a faster progression 5, 6, 7. The phenotype of patients who carry a GAA expansion on one allele and a missense mutation on the other allele cannot be predicted with certainty; these patients can have a mild or severe clinical outcome,8 creating a unique platform to understand clinical and genetic heterogeneity.…”

Clinical and molecular studies in five Brazilian cases of Friedreich ataxia

“…As many other cases with retained reflexes and/or with late-onset were diagnosed by molecular analysis as FRDA 10,12 , the existence of other forms of autosomal recessive cerebellar ataxia without biological markers, such as EOCA, is doubtful. They probably represent FRDA variants with lateonset (LOFA) or with retained reflexes (FARR).…”

Hereditary optic neuropathies

“…Evidence of optic neuropathy is present in up to two-thirds of cases of Friedreich's ataxia, although severe visual loss is uncommon. [168][169][170][171][172][173][174] A condition resembling Friedreich's ataxia associated with decreased vitamin E levels has been localized to chromosome 8, and also includes some patients with optic atrophy. 175 Vitamin E supplementation of these patients may be efficacious early in the course of the disease.…”