OBJECTIVE: To determine the utility of skin biopsies as a biomarker of disease 
severity in subjects with amyloid neuropathy.
METHODS: Five groups of patients were studied: (1) transthyretin (TTR) familial 
amyloidotic polyneuropathy (FAP; n = 20), (2) TTR mutation carriers without 
peripheral neuropathy (TTR-noPN; n = 10), (3) healthy controls (n = 20), (4) 
diabetic neuropathy disease controls (n = 20), and (5) patients with light-chain 
(AL) amyloid (n = 2). All subjects underwent neurological examination and 3mm 
skin biopsies. Sections were stained with anti-PGP9.5, anti-TTR, and Congo red. 
Intraepidermal (IENFD), sweat gland (SGNFD), and pilomotor nerve fiber densities 
(PMNFD) were measured. Correlations between the amount of amyloid present 
(amyloid burden), fiber subtype, and Neuropathy Impairment Score in the Lower 
Limbs (NIS-LL) were evaluated.
RESULTS: IENFD, SGNFD, and PMNFD were all significantly reduced in TTR-FAP 
patients versus healthy controls, whereas TTR-noPN subjects had intermediate 
reductions. Lower nerve fiber densities were associated with NIS-LL (p < 0.001). 
Congo red staining revealed brilliant red amyloid deposits confirmed by 
apple-green birefringence within dermal collagen, sweat glands, and arrector 
pili that engulfed axons. The diagnostic sensitivity and specificity to detect 
amyloid in skin were 70% and 100%. Both AL amyloidosis and 2 of 10 TTR-noPN 
subjects were Congo red-positive. Amyloid burden correlated with IENFD 
(r = -0.63), SGNFD (r = -0.67), PMNFD (r = -0.50), and NIS-LL (r = -0.57). 
Wild-type TTR staining was less prominent in TTR-FAP patients.
INTERPRETATION: Cutaneous amyloid was detected in 70% of TTR-FAP and 20% of 
TTR-noPN subjects. Amyloid burden correlated strongly with reductions in IENFD, 
SGNFD, PMNFD, and NIS-LL. Skin is an attractive tissue to establish an amyloid 
diagnosis, and amyloid burden has potential as a biomarker to detect treatment 
effect in TTR-FAP drug trials. Ann Neurol 2017;82:44-56.