FRIEDREICH'S ATAXIA

Friedreich's Ataxia — the most common inherited ataxia, now with the first FDA-approved treatment after decades of supportive care, where expansion size determines disease course and repeat length guides treatment decisions.

Whole genome sequencing accurately sizes GAA repeat expansions in both FXN alleles — detecting compound heterozygous cases (GAA expansion + point variant) that standard PCR-based tests never identify, and providing the baseline expansion length that informs prognosis.

About this condition

Friedreich's Ataxia

Friedreich's ataxia (FRDA) is the most common hereditary ataxia in individuals of European descent, affecting approximately 1 in 50,000, with a carrier frequency of approximately 1 in 100. It is caused by autosomal recessive loss-of-function of frataxin (encoded by FXN on chromosome 9q21.11), a mitochondrial protein involved in iron-sulfur cluster assembly. Frataxin deficiency leads to mitochondrial iron accumulation, oxidative stress, and progressive neurodegeneration. FRDA is characterized by progressive cerebellar and sensory ataxia, cardiomyopathy (present in >90% of cases and the leading cause of death), diabetes mellitus (developing in approximately 10-20%), and skeletal deformities (scoliosis, pes cavus).

The molecular cause of FRDA is unusual: approximately 96-98% of pathogenic alleles are GAA trinucleotide repeat expansions in intron 1 of FXN. Normal alleles contain 5-33 GAA repeats; full expansion alleles contain 66 to over 1,000 repeats, with premutation alleles in the 34-65 range conferring stability risk but not causing disease at that size. Expansion length correlates meaningfully with clinical phenotype: larger expansions in the shorter allele correlate with earlier age of onset and more severe cardiomyopathy. Approximately 2-4% of FRDA cases are compound heterozygous — one GAA expansion allele and one conventional pathogenic point mutation (missense, nonsense, splice site) on the other allele. These compound heterozygous cases are completely missed by PCR-based tests that detect only GAA expansion length.

The first disease-modifying therapy for FRDA was approved by the FDA in February 2023: omaveloxolone (Skyclarys), an Nrf2 activator that improves mitochondrial function and reduces oxidative stress. This approval marks a historic milestone after decades during which management was purely symptomatic. With an approved treatment available, early diagnosis and precise molecular characterization — including expansion sizing and compound heterozygous detection — becomes directly therapeutic in determining eligibility and monitoring treatment response.

2-4% of FRDA cases are compound heterozygous: one GAA expansion + one point mutation on the other allele. Standard GAA-PCR assays report the shorter allele as 'normal' in these cases, creating a false-negative result that leaves patients undiagnosed.

Gene locus: FXN (9q21.11)

Standard GAA expansion testing by PCR detects homozygous expansion — the common case — but misses compound heterozygous FRDA (expansion + point mutation). Whole genome sequencing identifies both mechanisms simultaneously.

Compound heterozygous FRDA is invisible to standard PCR — leaving 2-4% of patients undiagnosed

PCR-based GAA repeat testing — the standard first-line FRDA diagnostic test — measures the size of GAA repeats on both alleles. In compound heterozygous patients (one expanded allele + one allele with a point mutation), the standard PCR assay detects the expansion on one allele but reports a normal repeat count on the other. This creates a result that appears to show heterozygous GAA expansion — often interpreted as 'carrier' rather than 'affected' — and leads to an incorrect or delayed diagnosis. FXN gene sequencing must be performed on all apparent 'heterozygous expansion' results to rule out compound heterozygosity. Whole genome sequencing performs both the repeat expansion measurement and complete FXN gene sequencing in a single analysis.

Precise GAA expansion sizing determines prognosis and guides omaveloxolone treatment decisions

GAA repeat length in the shorter (allele 1) expansion is the strongest predictor of age of onset in FRDA — each additional 100 GAA repeats is associated with approximately one year earlier onset. Patients with shorter alleles in the 66-400 repeat range tend toward later onset (teenage to adult) with slower neurological progression but may still have significant cardiomyopathy. Patients with allele 1 expansions above 700 repeats tend toward earlier onset and more severe disease. This expansion size information guides prognostic counseling, cardiac surveillance intensity, and — with omaveloxolone now approved — informs the benefit-risk discussion of initiating therapy at different disease stages.

Friedreich's Ataxia — the most common inherited ataxia, now with the first FDA-approved treatment after decades of supportive care, where expansion size determines disease course and repeat length guides treatment decisions.