Onset of FAP symptoms may be marked by higher blood NfL levels

Blood levels of neurofilament light chain (NfL) — a marker of nerve cell damage — can separate people with symptoms of forms of hereditary ATTR amyloidosis (hATTR), including familial amyloid polyneuropathy (FAP), from those who haven’t developed symptoms yet.

That’s according to a study in Italy that also showed blood NfL levels were higher in people with hATTR than in healthy people, suggesting it could help detect the shift toward manifesting symptoms.

“Further longitudinal studies [those done over time] are needed to confirm such a role and determine whether it could equally represent a biomarker of disease progression and response to therapy,” the researchers wrote in “Serum neurofilament light chain: a promising early diagnostic biomarker for hereditary transthyretin amyloidosis?” in the European Journal of Neurology.

In all forms of hATTR, mutations in the TTR gene cause an abnormal version of the transthyretin (TTR) protein to be produced that forms toxic clumps that accumulate in the body’s tissues, disrupting their normal function.

The nerves outside the brain and spinal cord, or peripheral nerves, are mainly affected in FAP, also called hereditary transthyretin amyloidosis with polyneuropathy. In another form, called hATTR with cardiomyopathy, TTR accumulates mainly in the heart. People with hATTR may also have a mixed clinical profile or phenotype, with both the peripheral nerves and the heart affected.

NfL as a nerve damage biomarker

The age at which the disease begins to manifest varies widely and symptoms may not appear until late in adulthood. TTR clump “deposition starts long before the onset of symptoms,” the researchers wrote, meaning damage may already have occurred “by the time the disease becomes clinically evident.”

There’s an urgent need to identify “sensitive biomarkers [that can] detect disease onset at a subclinical stage,” given that therapeutic approaches have been developed that may delay or even prevent the disease from progressing, especially when given early in the disease course, the researchers wrote.

NfL provides structural support to nerve cells, helping them maintain their shape. When nerve cells become damaged, NfL is released into bodily fluids and it has been proposed as a marker of disease progression and response to treatment in FAP.

To find out if NfL might also be a sensitive biomarker of peripheral nerve damage, or polyneuropathy, in hATTR, researchers in Italy collected blood samples from 111 adults (71 men, 40 women) with a disease-causing TTR mutation. Among the participants, 61 had symptoms for a median of five years (symptomatic group) and 50 were not yet showing symptoms (presymptomatic group). In both groups, about half carried Val30Met, the most common hATTR-causing mutation.

Among the symptomatic patients, most (78.7%) had a mixed phenotype, 11.5% had mainly nerve damage (neuropathic profile), and 9.8% had a cardiomyopathic phenotype. Most patients with evidence of polyneuropathy (mixed and neuropathic phenotype) had mild disease, as assessed with the FAP stage and the polyneuropathy disability (PND) score.

Blood samples were collected at a median age of 72 in symptomatic patients, most of whom were on approved treatments, and a median age of 47 in presymptomatic patients. The study also included 50 healthy volunteers (25 men, 25 women) without any neurologic, heart, or autoimmune disease, with samples taken at a median age of 52.5.

NfL levels and disease symptoms

Mean blood NfL levels were significantly higher in symptomatic patients than in presymptomatic carriers (74 vs. 13.14 picograms per milliliter, or pc/mL) and in healthy controls (17.70 pg/mL). No significant differences were found between the presymptomatic and control groups.

Also, symptomatic patients with more severe polyneuropathy based on the FAP stage or the PND score generally had significantly higher blood NfL levels than those with less severe disease.

“Conversely, no statistically significant difference was found when stratifying [hATTR] patients based on [TTR mutation], phenotype or treatment at the time of sample collection,” the researchers wrote. “This might suggest that even patients with a pure [cardiomyopathic] phenotype could have a subclinical neurological involvement.”

Statistical models showed a blood NfL level of 37.1 pg/mL could discriminate between symptomatic patients and presymptomatic carriers with a sensitivity of 81.4% and a specificity of 100%. Similar findings were obtained when comparing symptomatic patients against controls. Sensitivity refers to the percentage of symptomatic patients being correctly identified, whereas specificity refers to the percentage of presymptomatic carriers being correctly ruled out.

This cutoff value “could discriminate between still-asymptomatic carriers and symptomatic patients with high diagnostic accuracy, sensitivity and specificity,” the researchers wrote. “The detection of such a threshold could thus represent a red flag for ‘disease conversion,’ calling for more attention toward those carriers and pushing further investigation with more advanced diagnostic tests.”

A threshold of 57.7 pg/mL was also able to discriminate between early symptomatic patients and those with more advanced disease stages — both based on PND scores — with a sensitivity of 82.4% and a specificity of 73.7%. Polyneuropathy severity, as assessed with the neuropathy impairment score (NIS), was found to be the only significant predictor of blood NfL levels among patients with mixed or neuropathic phenotypes.

Further studies are needed to confirm whether NfL “might become a reliable, objective measure to detect the transition from the presymptomatic stage to the onset of symptomatic disease,” the researchers said.