Metabolic Markers May Help in FA Diagnosis, Therapeutic Development

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Some molecules involved in metabolism — all daily operations run by cells — are found in different amounts in patients with Friedreich’s ataxia (FA) versus healthy individuals and may be used as both diagnostic biomarkers and therapeutic targets, a small study suggests.

The study, “Metabolomics analysis reveals dysregulation in one carbon metabolism in Friedreich ataxia,” was published in the journal Molecular Genetics and Metabolism.

Patients with FA do not make enough frataxin (FXN), a protein that helps control the cells’ reservoir of iron and sulfur. The protein is found in mitochondria, which are the small structures inside cells responsible for energy production. As a result, iron builds up inside the cells, which in turn results in the production of toxic forms of oxygen that trigger damage.

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When there is not enough FXN, proteins in mitochondria that rely on iron and sulfur can no longer work, and this can turn down energy production. A shortage of FXN also makes cells more sensitive to damage from reactive molecules called free radicals.

For successful drug discovery, biomarkers that represent the altered processes characteristic of FA and reflect treatment effects are still needed.

The biomarker study

A team of researchers at Indiana University School of Medicine in the U.S. set out to identify a set of biomarkers that could speed up the development of new treatments.

“Multiple therapeutic approaches are in development, but a key limitation is the lack of biomarkers reflecting the activity of FXN in a timely fashion,” the researchers wrote. They focused on metabolites, which are molecules made or used in metabolism.

The study included 10 patients with FA (five men and five women) with a mean age of 23.3 years. As controls, there were 11 healthy individuals with a mean age of 28.0 years.

Seven (70%) patients took medications to decrease the heart’s workload and lower blood pressure. Six (60%) took idebenone or selegiline to address FA’s neurologic symptoms. None of the controls were on these medications.

The researchers used techniques called mass spectrometry and nuclear magnetic resonance to find which molecules — and how much of each — were in samples from patients versus controls.

There were 59 metabolites found in either higher or lower amounts in patients versus controls.

When the researchers tried to group them in clusters of molecules that operate together toward a specific goal, they identified a dense network of 10 metabolites. Half of them — formate, sarcosine, hypoxanthine, choline, and homocysteine — are known to be involved in one-carbon (1C) metabolism.

1C metabolism involves the transfer of methyl groups in cells, which are basic building units containing one single carbon atom, and their use to build larger molecules. Many of these reactions occur in mitochondria.

However, “the mechanisms by which this dysregulated pathway impacts the disease state, including mitochondrial dysfunction and ultimately heart failure, are completely unexplored,” the researchers wrote.

To know if the 59 metabolites could help tell patients with FA from healthy individuals, the researchers looked at how many patients could be diagnosed based on their levels. The test identified over 90% of the patients with FA and had a specificity of nearly 80%, which reflects how many individuals tested negative.

“The metabolic perturbations, especially those related to 1C metabolism, may serve as a valuable biomarker panel of disease progression and response to therapy,” the researchers concluded, adding that “the identification of dysregulated 1C metabolism may also inform the search for new therapeutic targets related to this pathway.”