Neurofilament Light Chain May Be Biomarker of FA Severity in Younger Patients

Neurofilament light chain may be a new blood biomarker to monitor disease severity and response to treatment among people with Friedreich’s ataxia (FA), particularly younger ones, a study suggests.

The study, “Neurofilament light chain as a potential biomarker of disease status in Friedreich ataxia,” was published in the Journal of Neurology.

Biomarkers that help inform about disease severity are valuable tools to objectively measure the effectiveness of treatments, but few such biomarkers exist for FA patients.

Neurofilament light chain (NfL) is a protein whose levels in the blood are elevated in many neurodegenerative diseases, including FA. The increase is believed to result from nerve cell death, though researchers think the rise in FA instead may be a consequence of the nerve fiber remodeling that occurs in early stages of disease.

Researchers at the University of Pennsylvania and BioMarin Pharmaceutical set out to investigate whether NfL levels could be used to diagnose and monitor disease severity in FA patients.

They examined 117 individuals, including 85 patients, 13 carriers of FXN gene mutations (parents or siblings of patients), and 19 controls who were not tested for FXN mutations, but were presumed to be non-carriers due to the lack of relatives with FA.

Results showed that patients had significantly higher average levels of NfL — 18.2 picograms (pg)/ml — than both carriers (7.96 pg/ml) or controls (7.86 pg/ml), who had about the same levels of the marker.

The findings were confirmed in another group including four patients, four carriers, and 40 controls. In this sample, both carriers and controls had much lower levels of the biomarker than patients.

In parallel, BioMarin developed an exploratory biomarker study to understand changes over time in NfL levels. This part included 32 individuals with FA, who had repeat blood draws for about a year, and findings revealed that NfL levels remained stable over time.

Likewise, the same results were seen in the second group of patients, two of whom had four monthly repeat collections.

The researchers then examined factors that correlated with NfL levels. In patients, higher levels of the biomarker correlated with younger age of FA onset, shorter disease duration, less neurological dysfunction — measured with the Friedreich Ataxia Rating Scale — lower activities of daily living scores, and less functional disability.

Altogether, the results suggested that besides differentiating FA patients from controls, NfL levels could be used to identify patients with more severe disease.

The team found, however, that NfL levels did not correlate with sex or with the number of GAA repeats in the FXN gene — a genetic feature linked to disease severity.

Also, the results showed that the biomarker significantly increased with age in controls and carriers, but decreased with age in patients. By age 40, levels of this biomarker in all three groups overlapped.

“In present study, we have demonstrated that NfL levels are elevated in [FA] compared with carriers and controls, particularly in younger subjects,” the researchers wrote.

“The combined elevation of NfL in [FA] disease, and the relative stability in [FA] patients over the timeframe of 1 year are favorable to implement NfL as a physiological measure of disease burden in patients in clinical studies of candidate therapies,” they concluded.