Unconventional tests detect FAP in 12 of 38 asymptomatic carriers
Blood and eye tests, biopsy among approaches allowing for early treatment
Diagnostic tests outside those considered standard for familial amyloid polyneuropathy (FAP) detected FAP in 12 of 38 people who carried disease-causing mutations but were asymptomatic, or without evident FAP symptoms, a study reported.
The assessment methods, which identified FAP features when standard tests did not, included modified nerve condition studies, skin biopsies, eye exams, and blood tests. A conversion to active disease also was identified in four other carriers using standard tests.
Findings demonstrate the “need for broadening the neurological diagnostic workup,” the researchers wrote, which is “fundamental to detect disease onset at the earliest convenience.”
The study, “Early detection of nerve involvement in presymptomatic TTR mutation carriers: exploring potential markers of disease onset,” was published in the journal Neurological Sciences.
Standard tests for a FAP diagnosis include electromyography, nerve conduction
FAP, also called hereditary transthyretin amyloidosis polyneuropathy, is caused by inherited mutations in the TTR gene that encodes for the transthyretin (TTR) protein. Such mutations result in an abnormal TTR protein that clumps together, forming toxic deposits in peripheral nerves, those outside the brain and spinal cord. The heart, kidneys, and eyes also can be affected.
Although these mutations are present from conception, symptoms usually manifest between the ages of 20 and 80. As such, specialists recommend an annual follow-up of presymptomatic TTR mutation carriers starting a decade before the predicted age of disease onset.
Because of the clinical benefits associated with early FAP treatment, “strict monitoring of presymptomatic carriers, especially of those close to the predicted age of disease onset (PADO), is indeed essential to maximize the effectiveness of treatment,” wrote a team of researchers in Italy.
Standard tests to detect conversion from asymptomatic to overt illness include electromyography to assess the health of nerves and the muscles they control. Nerve conduction studies also are given to measure the degree of nerve damage by the strength and speed of electrical signals.
More recently, nonstandard — or unconventional, meaning not yet validated — methods to detect early symptom onset have been investigated. This included testing patients’ ability to sense temperatures and mechanical force or monitoring changes in the nerve fibers of the cornea, the transparent, protective outer layer of the eyes.
Researchers compared standard diagnostic tests for FAP to a series of unconventional ones in 38 presymptomatic carriers (53% men). Their goal was to evaluate the ability of such methods to detect FAP early and allow timely treatment. Carriers were identified via genetic screening.
Before regular monitoring, clinical assessments and nerve conduction studies showed no abnormal nerve findings across all study participants. During follow-up, 14 (36.8%) reported potential FAP symptoms, mainly abnormal touch sensations and/or burning or prickling sensations.
Based on standard nerve conduction tests alone, four of the 38 patients (10.5%) had a confirmed diagnosis of symptomatic FAP during follow-up and began treatment. Their mean age of conversion to symptomatic disease was 58.5, and in three cases, conversion was detected up to 25 years before their PADO.
As a nonstandard test, nerve conduction was applied to the dorsal sural nerve of the lower leg. This detects damage to large nerve fibers, which carry signals to the muscles to control movements and detect some sensations, such as touch, vibration, and balance. Despite normal standard nerve conduction results in all patients tested, 10 (33.3%) had abnormal findings in the modified test of their dorsal sural nerve.
To assess small nerve fibers, which send messages about pain and itch, hot and cold, researchers applied a cutaneous silent period test. Here, altered muscle responses to electrical stimulation using rings around nondominant hand fingers indicated small nerve fiber damage. However, only two of the 30 patients who underwent this test showed abnormal findings.
Skin biopsies taken on 19 patients found a reduced density of nerve fibers within the skin of the thighs and legs in 11 of them (57.9%). One patient showed abnormal biopsy findings about 20 years before their predicted age of disease onset.
Corneal confocal microscopy was applied to 14 eyes of seven carriers to assess nerve fibers of the cornea. All eyes examined (100%) showed signs of nerve damage and a reduced density of nerve fiber branches.
Overall, adding these unconventional diagnostic tests to standard exam findings resulted in 16 of these 38 people (42.10%) moving from a presymptomatic to FAP disease stage, including the four cases diagnosed using standard tests alone.
“A diagnosis of disease onset could have been reached in [a] further 12 cases” (nearly 32%) via unconventional testing, and in five cases the diagnosis was given up to 21 years before their PADO, the researchers noted.
Blood tests also showed that nine of these 16 so-called converted carriers had elevated levels of neurofilament light chain (NfL), an indicator of nerve damage. In comparison, none of the presymptomatic carriers with no disease evident in any test had elevated NfL levels. These individuals also were significantly younger than converted carriers (mean of 50 vs. 61 years).
“Long-term follow-up of carriers and further longitudinal [over time] studies on large and diversified cohorts are needed to define the best combination of tests to be employed to reach the highest diagnostic accuracy,” the researchers concluded.
Notably, in many cases, the conversion occurred up to 25 years before PADO, “supporting the importance of starting monitoring even before the 10-year cut-off,” they added.
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