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

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Abstract

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 (R2 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 (R2 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 R2 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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Fig. 1

Data availability

The data that support the findings of this study are available from author D.R.L., upon reasonable request.

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Acknowledgements

We acknowledge Agilent Technologies Inc. for the loan of an Agilent 6495 C triple quadruple mass spectrometer and financial support from NIH Grants U01NS114143 and 5P30ES013508.

Author information

Authors and Affiliations

  1. Penn/CHOP Friedreich Ataxia Center of Excellence, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    David R. Lynch, Teerapat Rojsajjakul, Medina Keita, Clementina Mesaros & Ian A. Blair

  2. Departments of Pediatrics and Neurology, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    David R. Lynch & Medina Keita

  3. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Teerapat Rojsajjakul, Clementina Mesaros & Ian A. Blair

  4. Department of Neurology, University of Florida, Gainesville, FL, 32608, USA

    S. H. Subramony

  5. Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA

    Susan L. Perlman

  6. Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, 502F Abramson Research Center, 3615 Civic Center Blvd, Philadelphia, PA, 19104-4318, USA

    David R. Lynch

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  1. David R. Lynch
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Correspondence to David R. Lynch.

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Ethical standard statement

All procedures were approved by the Children’s Hospital of Philadelphia (CHOP) IRB and conducted in line with the ethical rules for data collection.

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Lynch, D.R., Rojsajjakul, T., Subramony, S.H. et al. Frataxin analysis using triple quadrupole mass spectrometry: application to a large heterogeneous clinical cohort. J Neurol 271, 1844–1849 (2024). https://doi.org/10.1007/s00415-023-12118-x

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