Cutaneous Nerve Biomarkers in Transthyretin Familial Amyloid Polyneuropathy

Abstract

Objective: 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) TTR-FAP (N=20), 2) TTR mutation carriers without neuropathy (TTR-noPN, N=10), 3) healthy controls (N=20), 4) diabetic neuropathy disease controls (N=20) and 5) patients with 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-LL (NIS-LL) were evaluated.

Results: IENFD, SGNFD, and PMNFD were all significantly reduced in TTR-FAP patients vs. healthy controls while 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 and 2/10 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.

Conclusion: 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.

Annals of Neurology 2017