Frataxin analysis using triple quadrupole mass spectrometry: application to a large heterogeneous clinical cohort

Background Friedreich ataxia is a progressive multisystem disorder caused by deficiency of the protein frataxin; a small mitochondrial protein involved in iron sulfur cluster synthesis. Two types of frataxin exist: FXN-M, found in most cells, and FXN-E, found almost exclusively in red blood cells. T...

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Bibliographic Details
Published in:Journal of neurology Vol. 271; no. 4; pp. 1844 - 1849
Main Authors: Lynch, David R., Rojsajjakul, Teerapat, Subramony, S. H., Perlman, Susan L., Keita, Medina, Mesaros, Clementina, Blair, Ian A.
Format: Journal Article
Language:English
Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2024
Springer Nature B.V
Subjects:
Ataxia
Blood levels
Clinical trials
Epigenetics
Erythrocytes
Frataxin
Friedreich Ataxia - genetics
Friedreich's ataxia
Gene therapy
Hemoglobin
Humans
Iron-Binding Proteins - genetics
Iron-Binding Proteins - metabolism
Mass Spectrometry
Mass spectroscopy
Medicine
Medicine & Public Health
Mitochondrial Proteins - genetics
Neurology
Neuroradiology
Neurosciences
Original Communication
Protein deficiency
Proteins
Regression analysis
Scientific imaging
Mitochondrial protein
GAA repeat length
Friedreich Ataxia Rating scale
Disability status
Frataxin blood levels
ISSN:0340-5354, 1432-1459, 1432-1459
Online Access:Get full text
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Summary:Background Friedreich ataxia is a progressive multisystem disorder caused by deficiency of the protein frataxin; a small mitochondrial protein involved in iron sulfur cluster synthesis. Two types of frataxin exist: FXN-M, found in most cells, and FXN-E, found almost exclusively in red blood cells. Treatments in clinical trials include frataxin restoration by gene therapy, protein replacement, and epigenetic therapies, all of which necessitate sensitive assays for assessing frataxin levels. Methods In the present study, we have used a triple quadrupole mass spectrometry-based assay to examine the features of both types of frataxin levels in blood in a large heterogenous cohort of 106 patients with FRDA. Results Frataxin levels (FXN-E and FXN M) were predicted by GAA repeat length in regression models ( R 2 values = 0.51 and 0.27, respectively), and conversely frataxin levels predicted clinical status as determined by modified Friedreich Ataxia Rating scale scores and by disability status ( R 2 values = 0.13–0.16). There was no significant change in frataxin levels in individual subjects over time, and apart from start codon mutations, FXN-E and FXN-M levels were roughly equal. Accounting for hemoglobin levels in a smaller sub-cohort improved prediction of both FXN-E and FXN-M levels from R 2 values of (0.3–0.38 to 0.20–0.51). Conclusion 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.
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ISSN:0340-5354
1432-1459
1432-1459
DOI:10.1007/s00415-023-12118-x