Friedreich's ataxia (FRDA) is the most common early onset hereditary ataxia, caused by GAA repeat expansions in the FXN gene. The length of the shorter allele (GAA1) and age at onset are established determinants of disease severity, though additional biomarkers such as frataxin expression and neurofilament light chain (NfL) have been proposed. We conducted a 30-month prospective longitudinal study, including 25 FRDA patients and 16 heterozygous carriers, assessing clinical progression through SARA, FARS-ADL, INAS, EQ-5D, SCAFI, and CCFS scales. Baseline measures included GAA repeats, frataxin expression in fibroblasts, CSF NfL, and disease burden. Frataxin levels were significantly reduced in patients and correlated with GAA1 length and baseline severity. SARA, FARS-ADL, and INAS worsened significantly over time, while SCAFI and CCFS remained stable. GAA1 length and baseline SARA score emerged as the strongest predictors of progression. CSF NfL was elevated in younger patients and declined with age but did not correlate with severity or progression. These results support GAA1 length and baseline clinical status as robust predictors of progression and suggest limited utility of CSF NfL as a longitudinal biomarker particularly in later disease stages.
Manrique et al. (Thu,) studied this question.