Nerve Function Drop Predicts FAP 2 Years Out for Val30Met Carriers
An annual decline in sensory nerve function — one greater than 25% — occurs as long as two years before the onset of familial amyloid polyneuropathy (FAP) in people carrying Val30Met, the most common disease-causing mutation in FAP, a study shows.
Such drops in function, as measured by non-invasive nerve conduction tests, highlight sensory nerve function damage and thus can serve as a potential early predictor of FAP symptom onset, the researchers said.
These findings may be used to identify Val30Met carriers — people with FAP-causing mutations, but no overt symptoms — who are at risk of conversion to full-blown disease, according to the researchers, who note that treating these patients early on could help to prevent further damage.
“Given the … 1.92 increase in risk of conversion after an annual decline greater than 25% in [nerve testing], we propose that this magnitude of change could be used as a red flag in the evaluation of … asymptomatic carriers,” the researchers wrote.
The study, “Changes in Nerve Conduction Studies predates clinical symptoms onset in early onset Val30Met hereditary ATTR amyloidosis,” was published in the European Journal of Neurology.
FAP is a form of hereditary transthyretin (ATTR) amyloidosis that is marked by progressive peripheral and autonomic neuropathy — with damage to the sensory, motor, and autonomic nerves that control involuntary bodily functions — and variable involvement of other organs, such as the heart.
It is caused by mutations in the TTR gene that result in the production of a faulty TTR protein that aggregates, or clumps together, and forms toxic deposits in different tissues and organs.
Given FAP’s progressive and life-threatening nature, and the availability of disease-modifying therapies, early diagnosis and treatment are key to preventing irreversible nerve and organ damage.
However, determining disease onset among carriers of the Val30Met TTR mutation “is challenging due to the preferential involvement of small nerve fibers at early disease stages,” the researchers wrote.
Small nerve fibers are thin fibers of peripheral nerves — those found outside the brain and spinal cord — whose damage is more difficult to detect through conventional, non-invasive nerve conduction tests.
A nerve conduction study or NCS primarily measures the speed at which an electric signal travels along nerve fibers. It also can determine the intensity of the signal.
Importantly, degeneration of nerve fibers results in a signal intensity reduction.
Now, a team of researchers in Portugal, where the Val30Met variant is the cause of virtually all FAP cases, assessed whether changes in NCS preceded overt clinical symptoms. The goal was to determine if such changes could therefore be used as an early disease marker in Val30Met carriers.
The team retrospectively analyzed clinical and NCS data from 69 adults (43 women and 26 men) with the Val30Met mutation who were followed for four years at a single center in Lisbon. NCS tests were performed annually, and included scores of electrical signal intensity for sensory, motor, and autonomic skin nerve fibers in both the upper and lower limbs.
Most carriers (91%) had at least three of the five nerve conduction assessments.
The results showed that 38 carriers (55.1%) developed FAP symptoms over the four-year follow-up period, while 31 (44.9%) remained without symptoms, or asymptomatic. There were no significant differences in terms of sex and age between converters and non-converters.
Notably, a significant reduction in sensory nerve scores relative to the first assessment (baseline) was detected in the converted group, but not among carriers who remained asymptomatic. No significant changes were observed for motor and autonomic nerve scores.
After adjusting for potential influencing factors, including age, sex, and initial score values, the converters were found to have had a significantly greater decline in sensory nerve scores relative to the non-converters. These declines started about two years before symptom onset.
In addition, the proportion of carriers showing a greater than 25% annual reduction in sensory nerve scores gradually and significantly increased in the converted group over time, in contrast to the asymptomatic group.
Carriers with a more than 25% annual sensory score drop on the last assessment had a nearly two times higher risk of developing symptoms, while those with such a reduction in any of the two previous years had a 1.48 times increased risk.
These results suggest that this decline in sensory nerve function can predict the onset of FAP symptoms by as much as two years in carriers of the Val30Met mutation, “allowing a timely diagnosis and management of symptomatic disease,” the researchers wrote.
Based on these findings, and the fact that most Val30Met carriers have nerve conduction values within a normal range at the time of symptom onset, the team proposed that an annual decline greater than 25% in sensory nerve scores be used as “a red flag” when evaluating Val30Met carriers not yet showing symptoms.
“Changes in the follow-up assessments of NCS, a technique known to be reproducible, non-invasive, painless, and relatively easy to perform, could provide an invaluable contribution for the early identification of carriers at-risk,” the team wrote.
Since the study only included people with the Val30Met mutations, its findings may not be generalized to the overall FAP patient population, the researchers noted.
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