Detecting touch, temperature may help predict FAP onset
Symptoms between ages 30-50 considered early-onset; after 50, late-onset
Testing the ability to sense temperatures and mechanical forces could help predict when symptoms will appear for people who carry mutations that cause familial amyloid polyneuropathy (FAP).
That’s according to “Quantitative sensory testing and skin biopsy findings in late-onset ATTRv presymptomatic carriers: Relationships with predicted time of disease onset (PADO),” which was published in the Journal of the Peripheral Nervous System. The study was funded by Alnylam Pharmaceuticals, which markets the FAP treatments Onpattro (patisiran) and Amvuttra (vutrisiran).
FAP, also called hereditary transthyretin amyloidosis polyneuropathy, or ATTRv-PN, is caused by mutations in the gene that gives instructions for making the transthyretin protein. The mutations cause an abnormal form of the protein to be produced that forms toxic clumps that damage nerves.
The mutations are present from the moment a person is conceived, but most people with FAP don’t start to have overt symptoms until adulthood. People who develop symptoms between the ages of 30 and 50 are considered to have early-onset FAP. The onset of symptoms after 50 is called late-onset.
“Presymptomatic follow-up tests able to timely identify the disease onset have become a matter of study and debate, especially for their implications in the early initiation of disease-modifying therapies,” the researchers wrote.
Studies have shown that “small nerve fiber involvement occurs early in ATTRv-PN,” the researchers wrote, with reports of “small nerve fiber loss and dysfunction” in people carrying FAP-causing mutations, but not yet showing any disease symptoms (presymptomatic). “However, no biomarker is currently validated to follow up presymptomatic carriers and to predict the transition from presymptomatic to clinically evident disease, thus helping therapeutic decision making.”
Testing for when FAP symptoms might appear
Scientists in Italy evaluated several clinical tests to see if they could reliably identify early signs of FAP to predict the onset of symptoms. The study included 40 presymptomatic adults (22 women, 18 men) who carried FAP-causing mutations and whose affected family members showed late-onset FAP.
Their median age was 49 and nearly two-thirds (65%) carried Val30Met, the most common FAP-causing mutation. Their predicted age of disease onset (PADO) was 63 years and time-to-PADO, 13.5 years. Those with Val30Met had a significantly lower PADO relative to those without such a mutation (60 vs. 65 years).
Each person underwent a battery of tests. Skin biopsies evaluated the density of nerves in the skin, while nerve conduction velocity studies measured how fast an electrical impulse moved through the nerve.
Participants also underwent quantitative sensory testing (QST), wherein a person is exposed to different standardized sensations (hot or cold temperatures, pressure, etc.) and asked how well they can feel each sensation.
Half the participants had lower than normal nerve density and 11 (27.5%) showed abnormalities in their ability to detect hot and/or cold temperatures. Eight (20%) showed abnormalities in pain sensation and five (13%) had abnormalities in the ability to detect a mechanical force (e.g., pushing or poking the skin).
Notably, 17.5% of presymptomatic carriers showed both sensory problems regarding cold and/or hot temperatures and altered nerve density in a skin biopsy.
“We found that small fiber impairment, as detected by skin biopsy and/or QST thermal thresholds … the reference standard diagnostic tests for small fiber neuropathy [nerve damage] diagnosis, was a frequent finding in [FAP] presymptomatic carriers,” the researchers wrote.
With these data, the researchers conducted statistical tests for factors with significant associations with the predicted age of onset, which was calculated according to a previously established method based on each patient’s mutation type and other clinical factors. Participants predicted to have symptoms sooner tended to have more difficulty sensing cold temperatures or mechanical forces, as well as less electrical activity of assessed sensory nerves.
While abnormalities on a skin biopsy were common, they didn’t show a clear association with the predicted age of onset.
“Our findings suggest that sensory threshold assessment by QST, in particular [evaluation of the ability to detect cold and mechanical forces], may be a valuable tool for monitoring nerve function in presymptomatic carriers,” the scientists wrote, adding “serial combined QST and [nerve conduction study] evaluation could be useful in [FAP] presymptomatic carriers’ follow-up, also given their noninvasiveness, cost-effectiveness, and easy repeatability over time.”
The researchers emphasized the study was limited to a small group of patients assessed at a single point in time, so future work should assess how these tests may be used over time to help predict the clinical course for those carrying FAP-causing mutations.
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