Levels of frataxin protein in blood correlate with clinical status: Study
Findings: Triple quadrupole mass spectrometry may assess treatment efficacy
Levels of the frataxin protein in the blood correlate with disease progression and disability status in Friedreich’s ataxia (FA) patients, a study reports.
The findings suggest a technique called triple quadrupole mass spectrometry could help assess the effectiveness of treatments in clinical trials.
The study, “Frataxin analysis using triple quadrupole mass spectrometry: application to a large heterogeneous clinical cohort” was published in the Journal of Neurology.
FA is caused by mutations in the FXN gene, which carries the information for making frataxin. As a result, people with FA lack the protein.
The mutations most often consist of the excessive repetition of a trio of nucleotides — DNA building blocks — namely, one guanine (G) and two adenines (A). Having more GAA repeats correlates with an earlier onset of disease, more severe symptoms, and faster disease progression.
The frataxin protein exists in at least two forms: a mature form, or frataxin-M, that supports the function of mitochondria (the so-called powerhouses of the cell) in most cells and isoform E (FXN-E), which is largely found in red blood cells.
Measuring frataxin levels
As frataxin is decreased in the tissues of FA patients, measuring its levels “in unaffected tissue can serve in some therapeutic approaches as a marker of levels in affected tissues,” wrote a team led by researchers at the Perelman School of Medicine at the University of Pennsylvania who evaluated triple quadrupole mass spectrometry to detect both forms of frataxin in blood samples of a large group of FA patients. Mass spectrometry can identify and quantify molecules based on their mass-to-charge ratio. Frataxin levels were correlated with clinical parameters.
In total, 106 patients (age range, 11-68; 59% females) enrolled in two natural history FA studies were included in the analysis. The number of GAA repeats among patients varied from 101 to 1,000. Natural history studies are meant to track disease progression.
Levels of frataxin-M and frataxin-E correlated highly with age of disease onset and the number of GAA repeats. Frataxin-E also showed a small correlation with sex, with females having lower levels.
In statistical analyses, levels of both frataxin-M and frataxin-E correlated significantly with the GAA repeat length, in that patients with more repeats had less frataxin. Also, older age associated with high frataxin levels, with predictions of a 1% annual increase for frataxin-M and a 2% increase for frataxin-E.
Both frataxin-M and frataxin-E levels predicted clinical severity, as measured by the modified Friedreich’s Ataxia Rating Scale and functional disability stage scores, two scales that assess disease progression. The same was seen with age, but not with sex.
Since blood has several cell types, this may contribute to variability in frataxin levels. Normalizing measurements to the blood-specific protein hemoglobin, which is responsible for transporting oxygen in red blood cells, improved the predictive power of both frataxin-M and frataxin-E. Including hemoglobin in the analysis removed the effect of sex, “suggesting that the effect of sex is mediated by differences in hemoglobin levels between men and women,” the investigators wrote.
Overall, measuring the levels of frataxin-M and frataxin-E with triple quadrupole mass spectrometry “predicted neurological outcomes, demonstrating their utility as a potential biomarker of disease status,” the researchers said. “The present data show that assay of FXN-M and FXN-E levels in blood provides an appropriate biofluid for assessing their repletion in particular clinical contexts.”