Tiny skin biopsies may help diagnose transthyretin amyloidosis: New study
Scientists show for first time that such testing is possible in living patients
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Minimally invasive skin biopsies may be used to diagnose transthyretin amyloidosis and guide treatment in people with the rare progressive disease, according to the findings of a new study from Switzerland.
A team of scientists was able to identify the exact molecular structure of disease-driving toxic protein clumps using tiny amounts of skin collected from the ankle and thigh of a patient with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) — demonstrating, for the first time, that it’s possible to do this type of molecular analysis in a living patient.
This result “validates non-invasive skin biopsy as a diagnostic tool” for transthyretin amyloidosis and other neurodegenerative conditions, the researchers wrote.
Further, “being able to study the structure of deposits directly in living patients profoundly changes our ability to understand these diseases and assess the effect of treatments,” Andreas Boland, PhD, an associate professor at the University of Geneva and one of the study’s corresponding authors, said in a university news story.
The study, “Structure of ATTRv-F64S fibrils isolated from skin tissue of a living patient,” was published in the journal Nature Communications.
Transthyretin amyloidosis encompasses hATTR-PN, which is characterized by damage to the nerves found outside the brain and spinal cord, as well as transthyretin amyloid cardiomyopathy (ATTR-CM), which is marked by heart damage.
Both disorders are driven by the buildup of toxic clumps of the protein transthyretin (TTR). hATTR-PN is caused by mutations in the gene that encodes the TTR protein, while ATTR-CM can be caused by mutations in the same gene or occur as a result of aging.
Testing TTR protein clumps in tissue from a living patient
Previous studies have deduced the specific molecular structure of TTR protein fibrils, or clumps, in tissues taken from patients who had died. Now, scientists wanted to see if they could do the same type of analysis using tissue from a living patient.
To that end, the team collected tiny amounts of skin from a person with hATTR-PN that was caused by a specific mutation called F64S. The scientists noted that no prior study had specifically evaluated the molecular structure of TTR protein fibrils associated with this particular mutation.
After the biopsy, the team analyzed the skin samples using a battery of advanced molecular techniques, including cryogenic electron microscopy, a cutting-edge imaging technique that enables researchers to visualize molecules down to almost the level of individual atoms.
The researchers found they could indeed determine the exact structure of this patient’s TTR fibrils using only the skin biopsy sample.
“Our structure of [TTR] fibrils derived from a skin biopsy of a living patient demonstrates that sufficient quantities of amyloid fibrils can be extracted from minimal amount of skin tissue (between 5-10 milligrams),” the scientists wrote.
[These findings] further [corroborate] skin biopsy as a minimally invasive test for detecting, typing and determining the structure of [TTR] fibrils.
Previous studies using tissues from the heart and nerves of deceased patients have shown that TTR fibrils tend to form an angular shape that scientists have described as looking like a spearhead. Here, the team noted that the TTR fibrils seen in their skin biopsy samples retained the same general shape as those in other tissues of people with other disease-causing mutations.
“Our findings suggest that [F64S-mutant TTR] fibrils derived from skin tissue are nearly identical to other [TTR] fibrils across different tissues and different genetic variants,” the scientists wrote.
The fact that protein clumps detected in skin seem to be essentially the same as those found elsewhere in the body “further corroborates skin biopsy as a minimally invasive test for detecting, typing and determining the structure of [TTR] fibrils,” the researchers wrote.
Scientists hope skin biopsies could be new approach to support care
The scientists are hopeful that their study could pave the way for new approaches using skin biopsies to support the medical care of hATTR-PN and ATTR-CM. For example, the researchers noted that skin biopsies might be used to help diagnose the disease, and could be taken regularly over time to help monitor disease progression.
According to Xuefeng Zhang, PhD, a postdoctoral researcher at the University of Geneva’s Faculty of Science and a study cofirst author, “the minimally invasive nature of the skin biopsy also opens new avenues for studying the disease directly in patients.”
Zhang added that “it is now possible to observe how fibrils evolve over time, at different clinical stages, or in response to treatments that may alter the course of the disease.”
Being able to determine the structure of a patient’s disease-driving protein clumps may also help guide the development of individualized treatment approaches, according to the scientists. The team speculated that it might be possible someday to determine the structure of a patient’s specific protein clumps, then administer a treatment tailored to that molecular structure.
