Prospective Cohort Study Identifies Critical Predictors of Survival in Friedreich Ataxia

Newly published in Movement Disorders, a prospective cohort study using the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS; NCT02069509) registry revealed key factors that influence survival in patients with Friedreich ataxia (FA), a rare multisystemic disorder.¹ These results led to the development of a survival prognostic score which can potentially identify patients who may benefit from early monitoring and therapy.

Over a 12-year observation period, 44 patients of the 631 enrolled died (mean age, 39 [±14]; after a median follow-up of 6 years) and 119 terminated the study for other reasons. Overall, there was an 87% 10-year cumulative survival rate for the cohort (n = 512). In a multivariable analysis, investigators observed that the disability stage (HR, 1.51; 95% CI, 1.08-2.12; P = .02), history of arrhythmic disorder (HR, 2.93; 95% CI, 1.34-6.39; P = .007), and diabetes mellitus (HR, 2.31; 95% CI, 1.05-5.10; P = .04) were independent predictors of survival in FA. Notably, researchers did not observe GAA repeat lengths as an independent predictor of survival in the multivariable model.

Top Clinical Takeaways

Disability stage, history of arrhythmic disorder, and diabetes mellitus emerged as independent predictors of survival among patients with Friedreich ataxia.
A survival prognostic score based on 4 predictors showed potential for identifying patients with FA who may benefit from early monitoring and therapy.
Limitations of the study include its focus on adults, incomplete genetic information, and limited cardiological evaluation, suggesting avenues for future research and validation.

“The diagnosis of arrhythmic disorder emerged as the solely independent cardiac predictor of survival in the multivariable model,” senior author Sylvia Boesch, MD, MSc, neurologist at the University Hospital Innsbruck in Austria, and colleagues wrote.¹“The predictive role of GAA repeat lengths in the univariable model was not confirmed in the multivariable analysis and no correlation was found between this parameter and the age of death. These differences are not explained by the clinical characteristics of our cohort, which are indeed comparable with those of the [previous] studies.”

Investigators enrolled patients with genetically confirmed FA from the EFACTS registry2 between September 2010 and March 2017 at 11 tertiary centers and followed up with them in yearly intervals. The study assessed overall survival by application of the Kaplan-Meier method, life tables, and log-rank test. Authors investigated prognostic factors by applying Cox proportional hazards regression and subsequently built a risk score, which evaluated for discrimination and calibration performance. Of note, the median age at inclusion for patients was 31 years old (range, 6-76).

Based on the deaths reported in the study, investigators selected 4 predictors in a stepwise backward regression and put them into a prognostic model. These predictors included disability stage, history of arrhythmia, diabetes mellitus, and left ventricular systolic dysfunction. Researchers had the disability stage factor transformed into a categorical variable with threshold of at least 6 based on distribution of events across worsening ranking. Then, authors randomly assigned each predictor 1 point to calculate the final sum score.

Authors noted that increasing the sum scores enabled them to discriminate between different prognostic trajectories with stepwise increasing risk, as demonstrated on Kaplan–Meier curves (log-rank test P <.001). The cumulative 10-year survival rate was estimated at 96% with a sum score of 0, 84% with a sum score of 1, 70% with a sum score of 2, and 42% with a sum score at least 3. Additionally, researchers noted that the discriminatory ability of the risk score was confirmed by the receiver operating characteristic analysis (AUC 0.75) and its calibration by the Hosmer–Lemeshow test (χ2 < 0.01, df = 1, P = 1).

All told, the study was limited by the fact that EFACTS comprised of mostly adults and a large proportion of patients at an advanced disease stage. Authors recommended a global registry study, including pediatric patients and adults patients, with reliable genetic information on the precise repeat length on both alleles for FA research. Another limitation was that cardiological evaluation in EFACTS encompassed only widely assessable parameters because of the multicentric nature of the study. In addition, since exact circumstances of death were not obtained in many patients included in the study, authors reported the limitation of assumption to the cause of mortality in FA.

“We propose a simple predictive score which allows stratification of prognostic trajectories based on the presence of relevant predictors. This tool awaits external validation in further prospective FA cohorts. Collectively our findings have relevant implications for disease monitoring, risk stratification, and development of future therapeutic strategies in FA,” Boesch et al noted.¹