BackgroundEarly studies in cellular models suggested an iron accumulation in Friedreich's ataxia (FA), yet findings from patients are lacking.ObjectivesThe objective is to characterize systemic iron metabolism, body iron storages, and intracellular iron regulation in FA patients.MethodsIn 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).ResultsWe 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.ConclusionsWe 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.

中文翻译：

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弗里德赖希共济失调中遗传决定的铁饥饿特征

背景细胞模型的早期研究表明弗里德赖希共济失调 (FA) 中存在铁积累，但缺乏来自患者的研究结果。目的目的是表征 FA 患者的全身铁代谢、体内铁储存和细胞内铁调节。方法在 FA 患者和匹配的健康人中进行作为对照，我们评估了血清铁参数、调节激素以及调节蛋白的表达和外周血单核细胞 (PBMC) 中的铁分布。我们应用磁共振成像右2*‐松弛测定法可量化肝脏、脾脏和胰腺中的铁储存量。在所有评估中，我们评估了遗传严重性的影响，以较短的 GAA 扩展 (GAA1) 的长度表示。结果我们招募了 40 名 FA 患者（19 名女性）。与对照组相比，FA 患者的血清铁和转铁蛋白饱和度较低。 FA 中的血清铁蛋白、铁调素、平均红细胞血红蛋白和平均红细胞体积与 GAA1 重复长度呈负相关，表明随着遗传严重性的增加，铁缺乏和红细胞生成的可用性受到限制。右2*‐松弛测量显示 FA 中脾脏和肝脏铁储存减少。肝脏和脾脏右2* 值与 GAA1 重复长度呈负相关。 FA PBMC 显示铁蛋白下调以及转铁蛋白受体和二价金属转运蛋白 1 mRNA 上调，特别是在 GAA1 重复次数 > 500 的患者中。在 FA PBMC 中，细胞内铁没有增加，而是向线粒体转移。结论我们为 FA 患者的全身和细胞水平上以前未被识别的铁饥饿特征提供了证据，这与潜在的遗传严重程度有关。这些发现对 FA 中全身降铁疗法的使用提出了挑战。 © 2024 作者。运动障碍由 Wiley periodicals LLC 代表国际帕金森和运动障碍协会出版。