Predictors of loss of ambulation in Friedreich's ataxia

Abstract

Background: Friedreich's ataxia (FRDA) is a characterized by progressive loss of coordination and balance leading to loss of ambulation (LoA) in nearly all affected individuals. While transition to becoming fully wheelchair bound is a critical milestone in the disease course, it presents a particularly challenging prediction, mostly due to variability in inter- and intra-subject severity and progression. For these reasons, LoA or potential surrogates have been impractical as outcomes in clinical trials.

Methods: We studied progressive features leading to LoA in participants enrolled into the Friedreich's Ataxia Clinical Outcome Measures Study (FA-COMS), a natural history study with currently 4606 yearly follow up visits in 1021 patients. Loss of specific functions related to walking and standing of the neurological Friedreich Ataxia Rating Scale (FARS) exams were evaluated using time to event methods. To account for different severities, patients were stratified by age of disease onset.

Findings: Early onset FRDA patients (<15y of age) typically become fully wheelchair dependent at a median of 11.5y (25th, 75th percentiles 8.6y, 16.2y) after the onset of first symptoms. Further time to loss of function analyses revealed a unique pattern of function loss, in particular in stance/balance items of the FARS exam. Each step in this typical sequence predicts future risk of LoA and can be used to rank patients in their individual progression.

Interpretation: We propose a stratification paradigm for time to LoA in FRDA. Concurrently, each step in a sequence of events represents a surrogate measure for future LoA. This will facilitate patient selection and stratification in clinical trials, and potentially enable study of LoA as a direct clinical outcome.

Funding: This work was funded by the Friedreich's Ataxia Research alliance (FARA), www.curefa.org.

Keywords: Balance; Cerebellar ataxia; Friedreich's ataxia; Gait; Loss of ambulation.

Fig. 1

FARS E item results at enrolment (baseline). Bars are coloured from minimal (light green) to maximum (dark green) item score, respectively: (A) stance items. (B) items measuring walking, sitting and FRDA Disease Staging (FDS).

Fig. 2

Estimated proportion of ambulant participants over disease duration. Vertical dotted lines indicate the median disease duration at LoA by onset group.

Fig. 3

Sequence of events prior to LoA in participants with early onset FRDA (<15y of age): E5, E4 and E3B are lost prior to diagnosis (blue line), followed by E2B, E3A, E2A and eventually LoA (E7, red line). See Fig. 1 for item coding.

Fig. 4

Kaplan Meyer analysis for Time from Enrolment in FA-COMS to LoA, stratified by ability to stand at baseline (onset <15y).