Skin Biopsy May Help Diagnose FAP in Early Stages for Treatment
A skin biopsy may help speed up the diagnosis of familial amyloid polyneuropathy (FAP), including for asymptomatic people with disease-causing mutations who are at higher risk of developing full-blown disease, according to a single-center retrospective study.
This would allow patients, especially those with the Val30Met mutation, to receive treatment early, increasing their likelihood of successful outcomes.
Also called hereditary transthyretin amyloidosis with polyneuropathy, FAP is caused by mutations in the TTR gene. These mutations lead to the buildup of abnormal protein deposits called amyloids, in different tissues and organs over time, causing a series of problems, including neuropathy (nerve damage).
The diagnosis of people suspected of having FAP typically involves a biopsy of affected tissues, such as a nerve or abdominal fat tissue, to test for the presence of amyloid deposits.
Taking a skin biopsy, however, is a simple and less invasive procedure. Moreover, it can help detect changes in nerve fibers and serve as a potential marker of disease severity.
In this study, a team led by researchers at the Referral Center for Familial Amyloid Polyneuropathy and other rare peripheral neuropathies in France reviewed clinical data from patients with a confirmed FAP diagnosis and carriers — individuals with TTR mutations but no nerve disease — who had a skin biopsy at the center between January 2012 and February 2019.
People who were referred for a skin biopsy in the same period of time for other reasons were also included as controls.
The researchers reviewed data from skin biopsies of 183 symptomatic FAP patients (mean age of 60.7 years at biopsy), 36 asymptomatic carriers (mean age of 33.7 years at biopsy), and 537 controls (mean age of 56.2 years at biopsy). In the control group, 524 were suspected of having small nerve fiber damage, while the remaining 13 individuals had a confirmed diagnosis of amyloidosis (other than FAP).
Skin biopsy confirmed the presence of amyloid deposits in most (80%) symptomatic FAP patients. Skin samples were collected from three different body parts — thigh, ankle, and wrist — in 158 FAP patients. Amyloid deposits were more commonly detected in ankle samples.
Skin amyloid deposits were found in 75% of early-stage FAP patients, and in 14% (five of 36) of asymptomatic carriers. All five patients were carriers of the Val30Met mutation and had reduced density of intra-epidermal nerves — those responsible for perceiving changes in temperature, pain, and itch in the skin.
No amyloid deposits were detected in skin biopsies of control subjects suspected of having small nerve fiber damage.
The density of intra-epidermal nerves was reduced in ankle skin samples in all of the 183 FAP symptomatic patients (100%) and in 34 (94%) asymptomatic carriers.
Reduced density of skin nerves in ankle, thigh, and wrists correlated with worse disabilities, as assessed by the modified polyneuropathy disability (PND) scoring system, a method broadly used to classify FAP patients based on their neurological health and walking ability. The system includes five stages, with higher stages associated with more severe symptoms and a poorer quality of life.
Only reduced nerve fibers in the ankle correlated with longer disease duration.
On the day of their skin biopsy, 98 symptomatic FAP patients were evaluated for sweat gland function in their feet using Sudoscan, a device that uses electrochemical skin conductance (ESC), which measures how well electrical signals travel through the skin. The presence of amyloid deposits impairs ESC.
Results showed that in patients with amyloid deposits in the ankle, ESC was significantly lower. Also, foot ESC correlated with nerve fiber density at the ankle and wrist, as well as with disease duration and modified PND staging.
Based on these observations, the researchers argued that “skin biopsy represents a simple, minimally invasive, reliable, effective tool for the detection of amyloid deposits and small-nerve fiber loss” in FAP patients.
Skin amyloid deposits can be used as a marker of disease onset and may help identify patients at early stages of the disease, when “early initiation of disease modifying therapies could be particularly beneficial,” they wrote.