Cutaneous nerve biomarkers in transthyretin familial amyloid polyneuropathy

Ebenezer, Gigi J.; Liu, Ying; Judge, Daniel P.; Cunningham, Kyle W.; Truelove, Shaun; Carter, Noel D.; Sebastian, Blessan; Byrnes, Kelly; Polydefkis, Michael

doi:10.1002/ana.24972

Cited by 66 publications

(90 citation statements)

References 43 publications

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“…Several invasive and non‐invasive biomarkers have been assessed in ATTRm amyloidosis to aid in early diagnosis. Intraepidermal nerve fibre density (IENFD) and in vivo laser scanning confocal microscopy (IVCM) of the cornea sensitively detect small fibre dysfunction in patients with ATTRm and correlate with clinical severity measures . IENFD is a quantitative, albeit invasive marker that would limit its use for repeated measurements and while IVCM is a non‐invasive, rapid procedure, depending on the quantification method used, the results can be examiner dependent.…”

Section: Discussionmentioning

confidence: 99%

“…5 However, the absence of a difference in the mean pNfL concentration between neurologically asymptomatic patients with ATTRm sures. 10,11 IENFD is a quantitative, albeit invasive marker that would limit its use for repeated measurements and while IVCM is a non-invasive, rapid procedure, depending on the quantification method used, the results can be examiner dependent. High-resolution magnetic resonance neurography (MRN) has been shown to quantitatively identify peripheral nerve impairment in sural nerves of asymptomatic and symptomatic ATTRm patients.…”

Section: Discussionmentioning

confidence: 99%

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Plasma neurofilament light chain concentration is increased and correlates with the severity of neuropathy in hereditary transthyretin amyloidosis

Kapoor

Foiani

Heslegrave

et al. 2019

J Peripheral Nervous Sys

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Hereditary transthyretin amyloidosis (ATTRm) causes a disabling peripheral neuropathy as part of a multisystem disorder. The recent development of highly effective gene silencing therapies has highlighted the need for effective biomarkers of disease activity to guide the decision of when to start and stop treatment. In this study, we measured plasma neurofilament light chain (pNfL) concentration in 73 patients with ATTR and found that pNfL was significantly raised in ATTRm patients with peripheral neuropathy compared to healthy controls. Furthermore, pNFL correlated with disease severity as defined by established clinical outcome measures in patients for whom this information was available. These findings suggest a potential role of pNfL in monitoring disease activity and progression in ATTRm patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Plasma neurofilament light chain concentration is increased and correlates with the severity of neuropathy in hereditary transthyretin amyloidosis

Kapoor

Foiani

Heslegrave

et al. 2019

J Peripheral Nervous Sys

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“…To demonstrate amyloids, we stained skin sections using the conventional Congo red (pH = 11.0) protocol . This was in contrast to the Congo red (pH = 8.0) protocol, which did not reveal amyloids, but sweat glands for SGII(PGP9.5) quantification .…”

Section: Methodsmentioning

confidence: 99%

“…Nerve fibers of different categories and functions in mutant TTR carriers can be examined with various tests, such as magnetic resonance neurography, nerve excitability tests, neurophysiological studies, and skin biopsies . Except for skin biopsies and autonomic functional tests, all of these mainly evaluate deficits in large‐diameter nerves, which usually follow impairments of small‐diameter nerves over the natural course of FAP . Reduced sensitivity to nociceptive stimuli and autonomic dysfunctions are early and major presentations of FAP .…”

mentioning

confidence: 99%

“…However, it is not clear whether the skin innervation reflects the progression of FAP, a critical indicator and prognostic factor in FAP treatment . Because amyloid is a pathognomonic sign of FAP, a further critical issue is to examine amyloid deposition in the skin biopsies quantitatively and to analyze its relationships to skin nerve degeneration during the course of FAP stages.…”

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confidence: 99%

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Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy

Chao

Hsueh

Kan

et al. 2019

Annals of Neurology

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Objective: Small-fiber sensory and autonomic symptoms are early presentations of familial amyloid polyneuropathy (FAP) with transthyretin (TTR) mutations. This study aimed to explore the potential of skin nerve pathologies as early and disease-progression biomarkers and their relationship with skin amyloid deposits. Methods: Skin biopsies were performed in patients and carriers to measure intraepidermal nerve fiber (IENF) density, sweat gland innervation index of structural protein gene product 9.5 (SGII[PGP9.5]) and peptidergic vasoactive intestinal peptide (SGII[VIP]), and cutaneous amyloid index. These skin pathologies were analyzed with clinical disability assessed by FAP stage score (stage 0-4) and compared to neurophysiological and psychophysical tests. Results: There were 70 TTR-mutant subjects (22 carriers and 48 patients), and 66 cases were TTR-A97S. Skin nerve pathologies were distinct according to stage. In carriers, both skin denervation and peptidergic sudomotor denervation were evident: (1) IENF density was gradually reduced from stage 0 through 4, and (2) SGII(VIP) was markedly reduced from stage 1 to 2. In contrast, SGII(PGP9.5) was similar between carriers and controls, but it declined in patients from stage 2. Skin amyloids were absent in carriers and became detectable from stage 1. Cutaneous amyloid index was correlated with SGII(PGP9.5) and stage in a multivariate mixed-effect model. When all tests were compared, only IENF density, SGII(PGP9.5), and cutaneous amyloid index were correlated with stage, and IENF density had the highest abnormal rate in carriers. Interpretation: Biomarkers of sensory and sudomotor innervation exhibited a stage-dependent progression pattern, with sensory nerve degeneration as the early skin nerve pathology.

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Cutaneous amyloid is a biomarker in early ATTRv neuropathy and progresses across disease stages

Freeman

González‐Duarte

Barroso

et al. 2022

Ann Clin Transl Neurol

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Objective To determine the sensitivity and specificity of cutaneous amyloid deposition in relation to patient‐reported measures in the earliest disease stage of hereditary ATTR amyloidosis (ATTRv). Methods In a cross‐sectional study, we analyzed 88 individuals with TTR mutations, 47 of whom were in the earliest disease stage and without clinically evident neuropathy, 12 healthy controls, and 13 disease controls with diabetes. All participants' neuropathy symptoms and signs were assessed using validated patient and clinician‐reported measures and 3‐mm skin punch biopsies were immunostained using protein gene product 9.5 and Congo Red. Results Amyloid can be detected in the earliest disease stages in up to 86% of patients with ATTRv amyloidosis. Amyloid was not detected in healthy individuals or individuals with diabetic peripheral neuropathy supporting a sensitivity of 86% and a specificity of 100%. The cutaneous deposition of amyloid correlates with neuropathy sensory symptoms, measured with the Neuropathy Total Symptom Score‐6 ( R = 0.46, p < 0.01); pain measured with the Brief Pain Symptom Inventory ( R = 0.44, p < 0.05); autonomic symptoms, measured with the Boston Autonomic Symptom Questionnaire ( R = 0.38, p < 0.05); and quality of life measured with the Norfolk Diabetic Neuropathy Quality of Life Questionnaire ( R = 0.44, p < 0.05). Individuals with amyloid deposition were more likely to have sensory symptoms, pain, autonomic impairment, and reduced quality of life than ATTRv patients without amyloid deposition. Interpretation These findings have implications for understanding the earliest manifestations of the clinical phenotype of ATTRv‐associated neuropathy, for the pathophysiological construct of disease staging, and for timing the introduction of disease‐modifying therapy.

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Cutaneous nerve biomarkers in transthyretin familial amyloid polyneuropathy

Cited by 66 publications

References 43 publications

Plasma neurofilament light chain concentration is increased and correlates with the severity of neuropathy in hereditary transthyretin amyloidosis

Plasma neurofilament light chain concentration is increased and correlates with the severity of neuropathy in hereditary transthyretin amyloidosis

Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy

Cutaneous amyloid is a biomarker in early ATTRv neuropathy and progresses across disease stages

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