Arrhythmias, Neurologic Disability, and Diabetes Mellitus Lead to Greater Mortality in Friedreich Ataxia


After following patients for more than 10 years, arrhythmias were considered the most important cardiac predictor of survival, with progressive neurologic disability and diabetes mellitus identified as further major contributors.

Sylvia Boesch, MD, MSc, a senior staff member at the Medical University of Innsbruck

Sylvia Boesch, MD, MSc

Using data from a prospective registry of patients with Friedreich ataxia (FA), recently published findings indicated that progressive neurological disability, history of arrhythmic disorder, and diabetes mellitus all influence the overall survival in FA. Consequently, the study investigators proposed a simple predictive score, which needs further external validation, that allows stratification of prognostic trajectories based on the presence of relevant predictors.1

Published in Movement Disorders, the trial enrolled 631 generically confirmed patients with FA from 2010 to 2017 and followed them in yearly intervals to investigator predictors of survival. Until December 2022, 44 patients died and 119 terminated the study for other reasons. Using a multivariable analysis, 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.

Senior investigator Sylvia Boesch, MD, MSc, a senior staff member at the Medical University of Innsbruck, and colleagues documented a cumulative survival rate of 87% across a 10-year stretch for the whole cohort. Death occurred at a mean age of 39 (±14) years after a median follow-up of 6 (range, 3-10) years. Cardiovascular issues, a common concern for patients with FA, was the cause of death in 13 of the 44 patients who passed. Of the 9 patients carrying an implantable cardioverter/pacemaker, 5 died during follow-up, after a range of 6-28 years after implantation. In this group, death occurred because of heart failure in 4 patients and because of pneumonia in 1 patient.

In the analysis, no significant correlation was found between GAA repeat lengths and the age at death. Overall, GAA repeat lengths were not an independent predictor of survival in the multivariable model. “Disease burden” metric, which encompasses both GAA repeat lengths and disease duration, showed a strong association with survival in the univariable analysis (HR, 1.08; 95% CI, 1.05-1.11; P <.001) but not in the multivariable one (HR, 1.03; 95% CI, 0.99-1.07; P = .1).

For the deaths observed, 18 cases had an unknown cause, 5 were from pneumonia, and 2 patients had death ascribed to a general, progressive deterioration. In addition, 2 patients died because of cancer (metastatic bladder cancer: n = 1; acute leukemia: n = 1), 2 by means of euthanasia, 1 patient succumbed to a traumatic neck injury, and 1 died following thrombosis.

READ MORE: FDA Removes Partial Clinical Hold on Nomlabofusp Program for Friedreich Ataxia

For the prognostic model, the study authors selected 4 predictors of survival: disability stage, history of arrhythmia, diabetes mellitus, and left ventricular systolic dysfunction. Disability stage was transformed in a categorical variable with at least a 6 threshold based on the distribution of events across worsening ranking. Following that, each predictor was assigned 1 point to calculate a final sum score.

Using this model, cumulative 10-year survival was estimated at 96% (95% CI, 93.4%-99.4%) for those with a score of 0, 84% (95% CI, 77.4%-91.3%) with a sum score of 1, 70% (55.4%-83.8%) with a sum score of 2, and 42% (10.7%-74.1%) with a sum score of at least 3. The discriminatory ability of the risk score was confirmed by the ROC analysis (AUC, 0.75) and its calibration by the Hosmer-Lemeshow test (X2 <.01, df = 1; P = 1).

The study authors wrote, “This score may support clinical management by identifying high-risk patients who merit closer clinical surveillance and might benefit from early invasive therapies aimed at improving survival. Current recommendations include yearly transthoracic echocardiography and 12-lead ECG to monitor cardiomyopathy in FA. Holter ECG is listed as an optional examination only in symptomatic patients."

"Our findings support the introduction of systematic prolonged ECG monitoring, independently from symptoms, to tackle intermittent arrhythmias," they added. "In the era of digital biomarkers, portable devices may help accomplish this task in a home setting, especially in patients with advanced disease. To date, cardiac studies in FA have mostly been cross-sectional and focused on ultrasound biomarkers. We urgently need longitudinal natural history studies specifically investigating cardiac outcome and integrating both ultrasound and ECG biomarkers."

1. Indelicato E, Reetz K, Maier S, et al. Predictors of survival in Friedreich ataxia: a prospective cohort study. Mov Disord. 2024;39(3):510-518
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