Nerve cell damage marker may aid in early FAP diagnosis: Study

Findings add to evidence NfL protein may be a FAP biomarker

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A dropper hovers next to three vials of blood.

A study of people carrying mutations known to cause familial amyloid polyneuropathy (FAP) found that those with disease symptoms had significantly higher levels of neurofilament light chain (NfL) — a protein that’s a marker of nerve cell damage — in their blood than those who hadn’t shown symptoms, indicating NfL’s potential use as an aid in early diagnosis.

The findings, from a team of researchers in Spain, add to accumulating evidence that NfL, which gets released into the blood and other bodily fluids when nerve cells become damaged, may be a marker of disease onset, disease progression, and response to treatment in FAP.

The study, “Biomarkers of axonal damage to favor early diagnosis in variant transthyretin amyloidosis (A-ATTRv),” was published in Scientific Reports.

FAP, also called hereditary transthyretin amyloidosis with polyneuropathy, occurs when a mutation in the TTR gene leads to the production of an abnormal transthyretin protein that forms clumps and builds to toxic levels in the body’s tissues, leading to damage.

In FAP patients, these clumps mainly accumulate in the nerves that branch out from the brain and spinal cord. Patients experience a wide range of symptoms, including loss of sensation or weakness in the extremities. The first symptoms may not appear until late in adulthood.

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Early FAP diagnosis ‘challenging’

“Early diagnosis, monitoring of disease progression, and response to treatment can be challenging,” the researchers wrote. Current methods can only measure damage that has already occurred and fail to detect the disease at its early stages, they noted.

“A number of [FAP] biomarkers have been postulated, but none has yet reached clinical practice,” the researchers wrote, adding that “the most promising biomarker is neurofilament light chain (NfL).”

To find out if NfL might help in the early diagnosis of FAP, the researchers checked NfL blood levels in 60 people who carried a copy of Val30Met, the most common FAP-causing TTR mutation, and 30 healthy people.

They also analyzed levels of an enzyme called matrix metalloproteinase 1 (MMP1), which is part of a family of enzymes produced in response to degradation of nerve cell fibers. These enzymes have been shown to have potential as FAP biomarkers.

Among TTR mutation carriers, 29 had symptoms of FAP. Another 31 were asymptomatic carriers, meaning they had not yet developed symptoms. Of those with FAP symptoms, 72.4% were in an early stage of disease, and 75.9%  were receiving FAP treatment.

Four of the untreated patients, or 66.6%, had heart symptoms, which occur when transthyretin clumps build up in the heart, and two, or 33.3%, had advanced FAP.

Median levels of NfL in the blood, measured using a common lab test called the enzyme-linked immunosorbent assay (ELISA), were significantly higher in FAP patients (116 picograms per milliliter (pg/mL) than in asymptomatic carriers and healthy people (less than 33 pg/mL for each).

The cut-off level for differentiating patients from asymptomatic carriers was 93.55 pg/mL, with a sensitivity of 79% and a specificity of 87%. Here, sensitivity refers to how well NfL can correctly identify FAP patients, and specificity refers to how well the marker can correctly exclude those without symptoms.

The level differentiating patients from healthy people was 92.6 pg/mL, with a sensitivity of 79% and a specificity of 80%.

While blood NfL levels were significantly higher in patients with early-stage disease (FAP stage 1) than in asymptomatic carriers or patients with heart symptoms, no significant differences were observed between FAP stage 1 patients and those with more severe disease.

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Treatment can lower NfL levels

As most patients receive treatment, “disease progression may be halted and thus NfL levels may be reduced,” the team wrote. “Previous work has shown how treatment can reduce NfL levels and therefore how these biomarkers could be used to monitor treatment response,” they wrote.

The study found that the higher NfL level, the higher the Neuropathy Impairment Score (NIS). In patients, the median NIS was 8 on a scale ranging from 0 to 96, where a higher score reflects greater FAP-related disability burden.

Adjusted analyses for potential influencing factors showed that the higher the levels of NfL, the lower the levels of estimated glomerular filtration rate (eGFR), a measure of kidney health in which lower levels reflect worse function.

No significant differences in MMP1 levels were detected among the three groups of participants.

“ELISA appears to be a reliable and available technique for [NfL] quantification,” the researchers wrote, though they added that “decreased eGFR may influence NfL circulating levels.”

While the study looked at a relatively small number of people with varied clinical pictures, “it was sufficient to find differences between carriers and patients, allowing us to use NfL for early diagnosis,” the researchers wrote.