Nerve damage patterns seen on conduction tests vary in early FAP

More uniform signs of polyneuropathy with more advanced disease, study finds

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The electrical signaling patterns associated with polyneuropathy, or damage to nerves outside the brain and spinal cord, vary in a first nerve conduction study given people in earlier stages of familial amyloid polyneuropathy (FAP).

That’s according to a small study in Italy, which also found that signs of polyneuropathy are more uniform at later disease stages, equally affecting sensory and motor signals in both the upper and lower limbs, and resulting exclusively from damage to nerve cell fibers known as axons.

Given that nerve conduction studies are part of the FAP diagnostic process, these findings help to shed light on why reaching a diagnosis “is so challenging” in clinical practice, leading to delays in  disease treatment, the researchers wrote.

The study, “Heterogenous electrophysiological features in early stage of hereditary transthyretin amyloidosis neuropathy,” was published in Neurological Sciences.

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A form of hereditary transthyretin amyloidosis (ATTRv), FAP is characterized by the accumulation of an abnormal version of the transthyretin protein (TTR) due to mutations in the TTR gene.

This form of TTR mainly accumulates in and damages the peripheral nerves, which transmit sensory and motor signals between the brain and the rest of the body, leading to progressive disease symptoms.

As a rare disease, diagnosing FAP can be challenging, with many patients facing misdiagnoses or diagnostic delays.

“In the era of different disease modifying treatments, a proper and early diagnosis is essential to limit the disability burden and assure the halting of disease progression,” the researchers wrote.

While a conclusive diagnosis can only be made via genetic testing for TTR mutations, nerve conduction scans can help to identify signs of polyneuropathy. This test evaluates nerve cells’ health by measuring their electrical activity in response to stimulation; the speed at which they send signals often is slower with FAP.

Researchers at the University of Naples examined the electrical signaling patterns of neuropathy, or nerve damage, in 33 FAP patients given a first conduction test between 2011 and 2013. They also sought to identify potential distinguishing features that could improve diagnosis.

Patients, 27 men and six women, underwent this evaluation at a mean age of 63.9, after living with FAP for a mean of 2.8 years.

More than half of the patients (60.6%) were in FAP stage 1, nearly one-quarter (24.2%) in stage 2, and five (15.2%) in stage 3, with higher stages indicating more severe disease. Their mean Neuropathy Impairment Score (NIS) was 47.6 on a scale ranging from zero to 244; a higher NIS score reflects a greater neuropathy-related disability burden.

Results showed that nerve conduction slowing most commonly resulted from damage to axons, reported in 87.8% of patients. Damage associated with a loss of myelin, the fatty substance surrounding nerve cells that protects them and speeds the transmission of their electrical signals, were detected in 6.1%.

The remaining 6.1% of cases were an intermediate type, where signs of axonal damage were lacking and signs of myelin loss failed to reach establishing criteria.

In most cases, nerves with both sensory and motor functions were equally affected (75.8%), whereas sensory nerves were predominately affected in 18.1% of patients and motor nerves in 6.1%.

Significant differences seen between patients in earlier, later FAP stages

For nearly half of patients (48.5%), nerves in both the upper and lower limbs were equally impacted, known as neuronopathic-like neuropathy. In other cases, either those in the lower (30.3%) or upper limbs (9.1%) were more affected.

The remaining patients (12.1%) showed signs of multi-neuropathy, where damage affects one side of the body more or there is variable involvement of two contiguous nerves.

Neuropathy features significantly changed between patients with early and later stage disease, the analysis showed. Those in early stages, with a mean disease duration of 1.8 years, had a mean NIS score was 23.2, whereas patients in later stages (mean disease duration of 5.2 years) had an NIS score of 103.8.

At later disease stages, neuropathy was exclusively axonal, equally affected sensory and motor nerves, and showed a neuronopathic-like distribution pattern.

In contrast, neuropathy features were much more variable at earlier stages, “including intermediate [nerve conduction slowing], sensory and/or motor predominant nerve fiber involvement and variable distribution pattern,” the team wrote.

Although the study was small and retrospective (looking at previously recorded data), its findings indicate that “neuropathy may present at first NCS [nerve conduction study] in variable way and it changes over the course of disease,” the researchers wrote. “It can rapidly evolve in[to] a severe polyneuropathy characterized by a sensory-motor axonal involvement with a neuronopathic-like pattern.”

For this reason, “clinicians should perform the TTR genetic analysis in patients with neuronopathic-like polyneuropathy, while in patients with other type of polyneuropathy, they have to look for [other symptoms] in order to suspect [FAP] and thus perform an early diagnosis,” they added.

Findings also could have important implications for carriers of FAP-causing mutations not yet showing overt symptoms, because “if an extensive NCS is not performed (bilaterally upper and lower limb nerves), [peripheral nervous system] involvement may be missed, resulting in a delay of treatment,” the scientists concluded.