Children younger than age 8 with symptoms of Friedreich’s ataxia are at a higher risk of faster disease progression and earlier loss of walking abilities, a single-center natural history study in Belgium reported.
The findings were consistent with previous results from another natural history study, and may help to guide treatment and the design of clinical trials in this disease.
The study, “Neurologic outcomes in Friedreich ataxia: Study of a single-site cohort,” was published in the journal Neurology Genetics.
Longer GAA repeats have been associated with earlier disease onset and more severe disease.
With the increasing number of potential therapies for FA entering clinical trials, there is an urgent need to identify who, among the small number of these ataxia patients, will enable best monitoring of disease progression. Finding the most sensitive and robust measures and biomarkers to track the disease is also a priority.
Achieving these goals would allow more efficient trial design, including the smallest number of patients possible without compromising a reliable evaluation of a therapy’s effectiveness.
Analyses of two ongoing natural history studies in FA, the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS; NCT02069509) and Friedreich’s Ataxia – Clinical Outcome Measures Study (FA-COMS; NCT03090789), showed that patients with earlier disease onset have faster disease progression.
However, they failed to clearly define a rapidly progressive patient subgroup — even in terms of age at disease onset — and the best outcome measures to detect disease progression, as each study is using a different clinical scale. (Both studies are still enrolling, for more information, please click on their NCT identifiers.)
Massimo Pandolfo, MD, EFACTS’ principal investigator in Belgium, set out to identify the most rapidly progressing subset by analyzing the clinical, demographic, and genetic data of 54 FA patients (27 males and 27 females) registered in EFACTS in that country as of Oct. 25, 2019.
Mean age at symptom onset was 13.6, with 17 patients developing the disease before age 8. Twenty developed FA between ages 8 and 14, and the remaining 17 at age 15.
Patients’ mean disease duration was 16.9 years (range, 3–42 years). Data from the first 20 years of the disease were available for 49 participants, equally distributed across the age of onset groups. The same number of patients had information on GAA repeat length.
Results showed that SARA scores effectively detected disease progression in the first 20 years of the disease and in patients who could walk, but not after they lost their walking ability.
The finding suggested that “more sensitive measures of neurologic functions that keep worsening in wheelchair-bound patients are needed,” Pandolfo wrote.
He then evaluated whether the rate of disease progression could be used to predict patients more likely to have faster disease progression. SARA scores for the previous one or two years could not predict FA progression for the following year.
“Age at onset turned out to be the major determinant of the SARA progression rate in the first 20 years of disease, with those with onset [before] 8 years showing significantly more rapid worsening,” the researcher wrote.
The faster disease progression seen in these patients was associated with a significantly earlier loss of ambulation (15 years after symptom onset), compared with those with later disease onset — 17 years for the intermediate age at onset group, and more than 20 years for the older age at onset group.
Notably, needing occasional or constant support to walk was a strong predictor of ambulation loss in the two subsequent years.
Interestingly, the length of GAA repeats did not predict progression rate as accurately as age at onset, “possibly because the latter reflects the combination of all factors that modify disease severity, of which [GAA repeat length] is only one,” Pandolfo wrote.
“A recent analysis of the FA-COMS cohort reached very similar conclusions,” he added, “showing that patients with earlier symptom onset also had faster progression and earlier loss of ambulation, which was heralded by inability to stand without support.”
Similar to SARA, the Activities of Daily Living (ADL) score also worsened more rapidly in patients with earlier disease onset, supporting its use as a co-primary or secondary outcome in clinical trials for Friedreich’s ataxia, the scientist said.
Based on these findings, Pandolfo added that ambulatory patients with disease onset before age 8 and less than 20 years of disease duration may be the most appropriate patient group to evaluate a therapy’s potential effectiveness in clinical trials.
He also suggested that, in addition to disease progression measured by the SARA and the ADL score, loss of ambulation may be a relevant trial outcome in this high-risk patient group.
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