Progression of Friedreich ataxia: quantitative characterization over 5 years

Abstract

ObjectiveFriedreich ataxia (FRDA) is a progressive neurodegenerative disorder of adults and children. This study analyzed neurological outcomes and changes to identify predictors of progression and generate power calculations for clinical trials.MethodsEight hundred and twelve subjects in a natural history study were evaluated annually across 12 sites using the Friedreich Ataxia Rating Scale (FARS), 9‐Hole Peg Test, Timed 25‐Foot Walk, visual acuity tests, self‐reported surveys and disability scales. Cross‐sectional outcomes were assessed from recent visits, and longitudinal changes were gaged over 5 years from baseline.ResultsCross‐sectional outcomes correlated with measures of disease severity. Age, genetic severity (guanine‐adenine‐adenine [GAA] repeat length), and testing site predicted performance. Serial progression was relatively linear using FARS and composite measures of performance, while individual performance outcomes were nonlinear over time. Age strongly predicted change from baseline until removing the effects of baseline FARS scores, when GAA becomes a more important factor. Progression is fastest in younger subjects and subjects with longer GAA repeats. Improved coefficients of variation show that progression results are more reproducible over longer assessment durations.InterpretationWhile age predicted progression speed in simple analyses and may provide an effective way to stratify cohorts, separating the effects of age and genetic severity is difficult. Controlling for baseline severity, GAA is the major determinant of progression rate in FRDA. Clinical trials will benefit from enrollment of younger subjects, and sample size requirements will shrink with longer assessment periods. These findings should prove useful in devising gene therapy trials in the near future.

A non-synonymous single nucleotide polymorphism in SIRT6 predicts neurological severity in Friedreich ataxia

“…It is plausible that the N to S amino acid change in SIRT6 changes the enzymatic properties of SIRT6, which could modulate Frontiers in Molecular Biosciences frontiersin.org downstream pathways differently between the two genotypes. This possibility, however, is also not supported by our data or others' (Patel et al, 2016); others have found no difference in enzymatic activity, and we found no difference in expression, albeit with small sample sizes, between the two SIRT6 variants. We cannot rule out the possibility of a subtle effect on SIRT6 activity by the presence of N to S amino acid change that may compound over time or a difference in regulation or localization of SIRT6 activity in a specific situation.…”

Cardiopulmonary exercise testing on adaptive equipment in children and adults with Friedreich ataxia

“…This result is similar to the lack of decline in peak VO 2 over the course of 24 and 48 weeks previously reported in a larger cohort of individuals with FRDA who completed arm ergometry studies 22 . Other studies have likewise shown that the rate of progression for many disease manifestations in FRDA, including neurological outcomes, is overall slow, and only detectable with larger sample sizes, in particular in those who may be more mildly affected 23 . These prior studies also suggest slower disease progression in individuals who are older and/or with more established disease.…”

A Clinical and Epidemiological Prevalence Study on Friedreich’s Ataxia in Latium, Italy

“…Conversely, patients with late-onset disease had a milder phenotype and slower disease progression [25]. The association between age-at-onset and the number of GAA repeats in the shorter or the longer allele is in accordance with the data reported by the largest collaborative studies (the European Friedreich's Ataxia Consortium for Translational Studies [EFACTS] and the Friedreich's Ataxia-Clinical Outcome Measure Study [FA-COMS]) [25][26][27]. The frequency of compound heterozygote FRDA patients (4.7%) is in agreement with data reported from other populations [28][29][30].…”