Iron levels are markedly low in Friedreich’s ataxia patients: Study
Frataxin deficiency results in toxic buildup of nutrient in cells
Levels of iron in the blood, along with iron stored in the liver and spleen, are significantly lower in adults with Friedreich’s ataxia (FA) relative to healthy adults, and the more severe the FA-causing mutation, the lower the iron in blood and organs, a study shows.
The findings highlight “a previously unrecognized iron starvation signature at systemic [whole-body] and cellular levels in FA patients,” and “argue against the use of surrogate measures of iron reduction as [outcome measures] in clinical trials,” the researchers wrote in “Genetic Determined Iron Starvation Signature in Friedreich’s Ataxia,” which was published in Movement Disorders.
FA is caused by mutations in the FXN gene that consist of the excessive repetition of a trio of DNA building blocks, or nucleotides — one guanine (G) and two adenines (A). The number of GAA repeats is associated with disease features, with more repeats linked to an earlier disease onset, more severe symptoms, and faster progression.
Excessive GAA repeats in the FXN gene result in the deficient production of frataxin, a protein that’s important for the function of mitochondria, the cell’s powerhouses. Given that frataxin helps mitochondria use iron, a nutrient that’s needed for many crucial biological processes, its deficiency leads to the toxic buildup of iron inside cells.
While this is believed to be one of the key biochemical mechanisms that drive FA’s progression, “the role of iron in the [disease mechanisms] of FA remains unclear,” the researchers wrote. “It is currently of crucial importance to address this issue, because iron-related therapeutic strategies, such as [suppression of iron-dependent cell death], are in development.”
Systemic iron levels are tightly controlled, with hepcidin, a hormone produced in the liver, playing a key role. When hepcidin is high, iron release from liver, intestinal cells, and certain immune cells is suppressed by promoting the breakdown of ferroportin, the only iron-exporting protein, at their surface. Low hepcidin signals the release of iron from cells and tissues into circulation.
The balance of iron levels in FA
But “investigations on systemic iron homeostasis [balance] in FA patients … are lacking,” wrote researchers at the Medical University of Innsbruck, Austria who analyzed levels of iron-related molecules in blood samples from 40 adults (21 men, 19 women; mean age, 39) with genetically confirmed FA and 40 age- and sex-matched healthy adults who served as controls.
Compared with healthy controls, FA patients had significantly lower levels of circulating iron (mean, 14.8 vs. 20.5 micromoles/L) and lower transferrin saturation (mean, 22.5% vs. 29.8%), results showed. Transferrin saturation indicates how much iron is bound to transferrin, the main protein in the blood that binds and transports it throughout the body.
While group differences in blood levels of ferritin, the major iron storage protein, and hepcidin didn’t reach statistical significance, lower levels of either molecule were significantly associated with more GAA repeats.
Because iron is a key component of hemoglobin, the protein in red blood cells (RBCs) responsible for transporting oxygen through the body, the researchers evaluated RBC production. No significant differences were observed between FA patients and controls in mean hemoglobin levels and RBC counts. However, lower amounts of hemoglobin in RBCs and smaller RBCs were each significantly associated with more GAA repeats, meaning patients with more severe disease produced smaller RBCs and with less hemoglobin.
Thirty-six FA patients had an abdominal MRI to quantify the iron stored in tissues and the findings were compared with a new group of 41 age- and sex matched healthy controls who had significantly higher levels of circulating ferritin than the FA patients (mean, 194 vs. 127 micrograms/L).
The FA group showed significantly less stored iron in the liver and spleen relative to the controls, even after adjusting for blood ferritin levels. And lower levels of stored iron in the liver and spleen were each significantly linked to a higher number of GAA repeats.
Liver fat content was comparable between FA patients and controls (6.4% vs. 6.2%), but the patients showed a slightly, but significantly, stiffer liver.
An analysis of iron metabolism in certain immune cells, called peripheral blood mononuclear cells (PBMCs), showed the activity of genes coding for a ferritin subunit and divalent metal transporter 1, a protein involved in iron transport, was significantly reduced in FA patients relative to controls.
In addition, there was a significant association between more severe disease (more GAA repeats) and increased iron uptake and mobilization.
Finally, PBMCs of FA patients showed a significantly higher proportion of iron in mitochondria over controls (29% vs. 24%).
“Overall, the present findings provide an indispensable clinical ground for the development of iron-targeting therapeutics in FA,” the researchers wrote. “They furthermore show that a stratification according to the [genetic profile] is necessary when addressing iron metabolism in FA.”
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