Quantitative sensory testing and skin biopsy findings in late‐onset ATTRv pre‐symptomatic carriers: relationships with predicted time of disease onset (PADO)

Introduction: Hereditary transthyretin amyloidosis polyneuropathy (ATTRv-PN) pre-symptomatic carriers often show preclinical abnormalities at small fibre related diagnostic tests. However, no validated biomarker is currently available to use for pre-symptomatic carriers' follow-up, thus helping therapeutic decision making. Our study aimed at assessing nerve conduction study (NCS), quantitative sensory testing (QST), and skin biopsy parameters in a large cohort of late-onset ATTRv pre-symptomatic carriers, and to evaluate whether they correlated with predicted age of disease onset (PADO). Methods: Late-onset ATTRv pre-symptomatic carriers were consecutively enrolled and underwent NCS, QST, and skin biopsy with intraepidermal nerve fibre density (IENFD) evaluation from a distal and a proximal site. Douleur Neuropathique-4 (DN4) and Small Fiber Neuropathy-Symptoms Inventory (SFN-SIQ) were used to assess painful and small fibre neuropathy related symptoms. PADO and time-to-PADO (delta-PADO) were estimated for each carrier, and correlations with diagnostic test measures were analysed. Results: Forty pre-symptomatic ATTRv subjects were enrolled. Twenty carriers (50%) had distal IENFD reduction, with a non-length dependent distribution in 73% of cases. Eleven subjects (27.5%) had cold and/or warm detection threshold (CDT and/or WDT) abnormalities at QST. Delta-PADO positively correlated with sural sensory nerve action potential (SNAP) amplitude (r = 0.416, p = 0.004), and z-values of QST parameters like CDT (r = 0.314, p = 0.028), WDT (r = -0.294, p = 0.034), and mechanical detection threshold (MDT) (r = -0.382, p = 0.012). Simple linear regression models showed a linear relation between delta-PADO and sural SAP, CDT, and MDT. Conclusions: Our findings confirm that IENFD reduction and QST abnormalities may occur early in ATTRv pre-symptomatic carriers, often with a non-length dependent pattern. However, only sural SAP amplitude and QST parameters correlated with delta-PADO, suggesting that serial combined QST and NCS evaluation could be useful in ATTRv pre-symptomatic carriers' follow-up. This article is protected by copyright. All rights reserved.