Blood test may help detect nerve damage in hereditary ATTR-PN

Measuring blood levels of a protein called neurofilament light chain (NfL) may help identify nerve damage in people with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) caused by the Val30Met mutation, the most common mutation associated with the disease, a study shows.

However, although median NfL levels were numerically higher in people who carried the Val30Met mutation but had not developed symptoms than in healthy people without the mutation, the difference was not statistically significant.

The findings contrast with earlier studies suggesting that elevated NfL may help detect nerve damage from hATTR-PN even before symptoms develop.

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The study, “Evaluation of serum neurofilament light chain, GFAP, and peripherin as biomarkers in hereditary transthyretin amyloidosis,” was published in Scientific Reports by researchers in Sweden.

In hATTR-PN, also known as familial amyloid polyneuropathy, mutations in the TTR gene cause the transthyretin (TTR) protein to become unstable and break apart. This faulty protein is prone to form toxic clumps called amyloid deposits that build up in peripheral nerves — those outside the brain and spinal cord — and may also affect other parts of the body.

Damage to multiple nerves, or polyneuropathy, can cause a wide range of neurological symptoms that vary depending on the type of mutation involved. “The degree of polyneuropathy varies between TTR variants, and early diagnosis is essential to prevent irreversible nerve damage,” the researchers wrote, noting that treatment is most effective before severe nerve damage develops.

“There is therefore a growing need for novel, minimally invasive biomarkers to assist early diagnosis and disease monitoring,” the researchers wrote.

The researchers examined whether blood levels of three proteins — NfL, glial fibrillary acidic protein (GFAP), and peripherin (PRPH) — could help detect nerve damage related to hATTR-PN.

When nerve fibers are damaged, the structural protein NfL can be released into the bloodstream, with higher levels potentially reflecting greater nerve damage. GFAP is a structural protein found mainly in nerve-supporting cells called astrocytes, while PRPH is found primarily in peripheral nerve fibers. The researchers therefore examined whether the proteins might reflect different aspects of nervous system damage.

Study compares patients, symptom-free carriers, healthy adults

The study included 34 adults with hATTR-PN caused by the Val30Met mutation, 17 adults who carried the mutation but had not yet developed any symptoms, known as presymptomatic carriers, and 35 healthy controls.

Neurological symptoms were the first signs of disease in most patients (91.2%). Many also experienced digestive symptoms (76.5%) and heart involvement (67.6%). Nineteen patients (55.9%) could walk without assistance, while the remaining 15 (44.1%) had difficulty walking.

Blood NfL levels were about threefold higher in patients than in healthy controls, a statistically significant difference. Levels were also 1.6-fold higher in patients than in presymptomatic carriers, but that difference was not statistically significant, meaning the study could not rule out chance as an explanation.

There was also no statistically significant difference between presymptomatic carriers and healthy controls, suggesting that NfL levels may become clearly elevated only after symptoms begin.

Among patients, higher NfL levels were also linked to more severe disease. Those with stage 2 or 3 polyneuropathy disability (PND), meaning they experienced difficulty with walking, had significantly higher NfL levels than those with stage 1 PND, who may experience abnormal sensations but no walking difficulties.

However, blood NfL levels were similar in newly diagnosed patients and those who had been living with the disease longer.

Unlike NfL, blood levels of GFAP and PRPH were comparable between the three groups, suggesting that these two proteins may not be useful for diagnosing hATTR-PN.

“NfL represents a promising non-invasive biomarker for assessment of early symptomatic disease and monitoring of disease progression,” the researchers wrote. However, “further longitudinal studies with larger [patient groups] are required to establish prognostic cut-offs and to evaluate its responsiveness to emerging disease-modifying therapies.”