Cutaneous nerve biomarkers in transthyretin familial amyloid polyneuropathy

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...

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Published in:	Annals of neurology Vol. 82; no. 1; pp. 44 - 56
Main Authors:	Ebenezer, Gigi J., Liu, Ying, Judge, Daniel P., Cunningham, Kelly, Truelove, Shaun, Carter, Noel D., Sebastian, Blessan, Byrnes, Kelly, Polydefkis, Michael
Format:	Journal Article
Language:	English
Published:	United States Wiley Subscription Services, Inc 01-07-2017
Subjects:	Adolescent Adult Aged Aged, 80 and over Amyloid - metabolism Amyloid Neuropathies, Familial - genetics Amyloid Neuropathies, Familial - metabolism Amyloid Neuropathies, Familial - pathology Amyloidosis Axons Biomarkers Biomarkers - metabolism Biopsy Birefringence Case-Control Studies Clinical trials Collagen Correlation analysis Diabetes mellitus Diabetic Neuropathies - metabolism Diabetic Neuropathies - pathology Diabetic neuropathy Diagnosis Diagnostic systems Disease control Female Glands Heterozygote Humans Limbs Male Middle Aged Mutation Mutation - genetics Nerve Fibers - pathology Patients Peripheral neuropathy Pili Polyneuropathy Prealbumin - genetics Severity of Illness Index Skin Skin - metabolism Skin - pathology Staining Sweat Sweat gland Sweat Glands - metabolism Transthyretin Young Adult β-Amyloid
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Summary:	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
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0364-5134 1531-8249
DOI:	10.1002/ana.24972