Genetic Determined Iron Starvation Signature in Friedreich's Ataxia

Manuel Grander; David Haschka; Elisabetta Indelicato; Christian Kremser; Matthias Amprosi; Wolfgang Nachbauer; Benjamin Henninger; Ambra Stefani; Birgit Högl; Christine Fischer; Markus Seifert; Stefan Kiechl; Günter Weiss; Sylvia Boesch

doi:10.1002/mds.29819

Genetic Determined Iron Starvation Signature in Friedreich's Ataxia

Mov Disord. 2024 Apr 30. doi: 10.1002/mds.29819. Online ahead of print.

Authors

Manuel Grander¹, David Haschka¹, Elisabetta Indelicato^{2

3}, Christian Kremser⁴, Matthias Amprosi^{2

3}, Wolfgang Nachbauer^{2

3}, Benjamin Henninger⁴, Ambra Stefani³, Birgit Högl³, Christine Fischer¹, Markus Seifert¹, Stefan Kiechl^{3

5}, Günter Weiss¹, Sylvia Boesch^{2

3}

Affiliations

¹ Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria.
² Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
³ Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
⁴ Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria.
⁵ VASCage, Centre on Clinical Stroke Research, Innsbruck, Austria.

PMID: 38686449
DOI: 10.1002/mds.29819

Abstract

Background: Early studies in cellular models suggested an iron accumulation in Friedreich's ataxia (FA), yet findings from patients are lacking.

Objectives: The objective is to characterize systemic iron metabolism, body iron storages, and intracellular iron regulation in FA patients.

Methods: In FA patients and matched healthy controls, we assessed serum iron parameters, regulatory hormones as well as the expression of regulatory proteins and iron distribution in peripheral blood mononuclear cells (PBMCs). We applied magnetic resonance imaging with R₂*-relaxometry to quantify iron storages in the liver, spleen, and pancreas. Across all evaluations, we assessed the influence of the genetic severity as expressed by the length of the shorter GAA-expansion (GAA1).

Results: We recruited 40 FA patients (19 women). Compared to controls, FA patients displayed lower serum iron and transferrin saturation. Serum ferritin, hepcidin, mean corpuscular hemoglobin and mean corpuscular volume in FA inversely correlated with the GAA1-repeat length, indicating iron deficiency and restricted availability for erythropoiesis with increasing genetic severity. R₂*-relaxometry revealed a reduction of splenic and hepatic iron stores in FA. Liver and spleen R₂* values inversely correlated with the GAA1-repeat length. FA PBMCs displayed downregulation of ferritin and upregulation of transferrin receptor and divalent metal transporter-1 mRNA, particularly in patients with >500 GAA1-repeats. In FA PBMCs, intracellular iron was not increased, but shifted toward mitochondria.

Conclusions: We provide evidence for a previously unrecognized iron starvation signature at systemic and cellular levels in FA patients, which is related to the underlying genetic severity. These findings challenge the use of systemic iron lowering therapies in FA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Friedreich's ataxia; MRI relaxometry; hepcidin; iron; liver.

Abstract

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