Small Nerve Fiber Problems Can Precede Symptoms in Late-onset FAP

Responses differ in asymptomatic people with familial amyloid polyneuropathy

Somi Igbene, PhD avatar

by Somi Igbene, PhD |

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An illustration of stimulation being given to a person's hand.

Quantitative sensory testing (QST), a tool for monitoring nerve function, may help to detect problems in small nerve fibers in people with late-onset familial amyloid polyneuropathy (FAP) before symptoms start, a small study suggested.

Adults with disease-causing mutations for late-onset FAP but no disease symptoms had more abnormal responses to cold, warm, and painful stimuli than did healthy adults serving as a control group.

The study, “Quantitative sensory testing in late-onset ATTRv presymptomatic subjects: a single centre experience,” was published in the journal Biomedicines.

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Late-onset familial amyloid polyneuropathy usually affects large nerve fibers

FAP is a form of hereditary transthyretin amyloidosis (ATTRv) caused by mutations in the TTR gene, which carries instructions to make the transthyretin (TTR) protein. These mutations alter the protein’s structure, causing it to clump and form deposits of amyloid fibrils inside various tissues, especially the heart and nerves. These deposits can impair the function of peripheral nerves that control movement and sensation in the arms and legs, leading to peripheral neuropathy.

FAP can begin before (early-onset) or after (late-onset) the age of 50, depending on the type of TTR mutation a patient has. Early-onset FAP typically initially affects small nerve fibers responsible for sensing pain and temperature, while late-onset FAP primarily affects the large nerve fibers that are involved in movement, vibration, and touch.

However, some studies suggest that small nerve fiber damage may occur long before symptoms of large nerve fiber damage are evident in late-onset FAP.

QST is a tool that studies small nerve fiber function by monitoring an individual’s response to cold, warm, and tactile (touch) sensations.

Researchers used QST to determine if people with presymptomatic late-onset FAP — a group they called disease carriers — had small nerve fiber damage. They assessed nerve function in the foot, leg, thigh, and non-dominant hand in response to several types of stimuli, including tactile stimuli, milder cold and warm sensations, and painful cold and heat.

A total of 14 people — 11 men and three women, with a mean age of 51 — with late-onset FAP and no disease symptoms or signs, and 55 age-matched healthy adults were enrolled. Among FAP carriers, nine had the Val30Met mutation, the most common FAP-causing mutation, and five had the Phe64Leu mutation.

All had normal results in a nerve conduction study, a conventional test that primarily measures the speed at which an electric signal travels along nerve fibers. Damage to small nerve fibers can be difficult to detect through nerve conduction tests, especially in asymptomatic patients, the researchers noted.

Responses to thermal and pain sensations in FAP carriers differed significantly from controls, with the FAP group having higher thermal thresholds, meaning they were less sensitive to cold or warm temperatures. Tactile responses were similar in both groups.

“Our results support the notion that the smallest fiber dysfunction was evident, since all thermal thresholds were higher compared to the control group. These findings support that [small nerve fibers] are precociously involved compared to the larger … fibers (explored through tactile stimuli),” the researchers wrote.

Abnormal responses to milder cold and warm sensations and to painful cold were more frequent than responses to hot pain in the FAP group. These responses mainly occurred in the foot (62.3%) and leg (62.3%), and less frequently in the thigh (47.8%) and hand (44.9%).

Notably, abnormal responses to cold sensations, especially painful cold, were more frequent in individuals who were closer to their predicated age of disease onset (less than 10 years away) than in those who were further away (more than 10 years). The hand was the most sensitive site for detecting nerve fiber dysfunction in people who were closer to their predicted age of disease onset.

“Our work suggests that thermal QST, despite the limits of the methodology due to its subjective nature, can be useful in multidisciplinary evaluation of carriers given the high frequency of abnormal findings,” the researchers wrote.

“Moreover, the investigation of the hand may provide useful information in monitoring disease progression before the [predicted age to disease onset],” they added.