High blood NfL levels appear to be early sign of FAP nerve damage
Study in patients and disease carriers supports testing of protein's levels
Rising levels of a protein called neurofilament light chain (NfL) in the blood may indicate nerve damage due to familial amyloid polyneuropathy (FAP) even before the disease manifests, a study in 65 people reports.
These findings suggest that testing for NfL levels could be used to detect nerve damage early in people who carry FAP-causing mutations but are not yet showing symptoms.
They also add to an increasing number of studies supporting NfL as a nerve damage marker of symptom onset, and to monitor disease progression and response to FAP treatment.
The study, “Longitudinal analysis of serum neurofilament light chain levels as marker for neuronal damage in hereditary transthyretin amyloidosis,” was published in the journal Amyloid by researchers in the Netherlands.
NfL, a protein, is released into the blood when nerves are damaged
Transthyretin amyloidosis, also called ATTR amyloidosis, refers to any disease marked by a buildup of toxic clumps, called amyloid fibrils, made up of unstable transthyretin protein in various tissues and organs.
A type of hereditary ATTR amyloidosis, FAP is caused by mutations in TTR, the gene that codes for the transthyretin protein. Toxic transthyretin aggregates accumulate in the peripheral nerves (those outside the brain and spinal cord) of patients, causing such FAP symptoms as numbness and weakness.
Due to available FAP treatments being more effective when initiated early in the disease course, regular monitoring of asymptomatic carriers “to identify early stages of disease is recommended to improve the prognosis,” the researchers wrote.
Asymptomatic carriers are people with FAP-causing TTR mutations who do not have evident disease symptoms.
Current tests to monitor peripheral nerve damage can be of limited help to asymptomatic carriers, the team noted, either by being less sensitive in early disease stages or by looking at a particular subset of nerves.
NfL is a protein released into the blood and other bodily fluids when nerves are damage. While growing evidence points to NfL as a nerve health marker in FAP, it remains unknown how blood NfL levels change over time in asymptomatic carriers who progress to develop polyneuropathy, or damage to multiple peripheral nerves.
A team of researchers at University Medical Center Groningen tracked blood NfL levels for up to two years in 20 persistently asymptomatic carriers and seven other carriers who went on to develop polyneuropathy. Among the persistently asymptomatic group, 12 patients had no evidence of amyloid fibrils, while the remaining eight did.
Their study also included 20 FAP patients with polyneuropathy who were being treated with a TTR stabilizer, seven with a TTR silencer, and 11 with both.
TTR stabilizers, such as Vyndaqel (tafamidis meglumine), prevent transthyretin from aggregating, whereas TTR silencers like Onpattro (patisiran) or Tegsedi (inotersen) interfere with transthyretin production. Vyndaqel is approved for FAP in the European Union, but not in the U.S.
NfL levels rose in asymptomatic carriers with amyloid fibrils in fat tissue
Over the course of two years, blood NfL levels remained unchanged in persistently asymptomatic carriers without amyloid fibrils. However, these levels showed a significant increase, from a median of 7.1 to 11.1 picograms per milliliter (pg/mL), in persistently asymptomatic carriers with evidence of amyloid fibrils in fat tissue under the skin.
In carriers who went on to develop polyneuropathy, blood NfL levels also significantly increased, from 8.4 to 49.8 pg/mL, up to the moment of symptom onset.
NfL’s presence in the blood may indicate “early neuronal damage in ATTRv [hereditary transthyretin] amyloidosis already before the onset of polyneuropathy,” the researchers wrote.
In FAP patients with polyneuropathy symptoms and treated with a TTR stabilizer, blood NfL levels remained generally stable over about two years. Notably, NfL levels significantly decreased in those on a TTR silencer, dropping from 61.2 to 37.7 pg/mL after a mean follow-up of 14 months, or just over a year.
“Our data support the use of sNfL [serum NfL levels] in screening TTRv [TTR variant] carriers and in monitoring disease progression and effect of treatment in ATTRv amyloidosis patients,” the researchers wrote.
“Larger studies are warranted to confirm and specify the results presented here and to investigate sNfL in relation to [clinical and genetic disease features],” they concluded.
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