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

IntroductionHereditary transthyretin amyloidosis polyneuropathy (ATTRv‐PN) presymptomatic carriers often show preclinical abnormalities at small fiber‐related diagnostic tests. However, no validated biomarker is currently available to use for presymptomatic 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 presymptomatic carriers and to evaluate whether they correlated with predicted age of disease onset (PADO).MethodsLate‐onset ATTRv presymptomatic carriers were consecutively enrolled and underwent NCS, QST, and skin biopsy with intraepidermal nerve fiber 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 fiber neuropathy‐related symptoms. PADO and time‐to‐PADO (delta‐PADO) were estimated for each carrier, and correlations with diagnostic test measures were analyzed.ResultsForty presymptomatic 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 = .416, p = .004), and z‐values of QST parameters like CDT (r = .314, p = .028), WDT (r = −.294, p = .034), and mechanical detection threshold (MDT; r = −.382, p = .012). Simple linear regression models showed a linear relation between delta‐PADO and sural SAP, CDT, and MDT.ConclusionsOur findings confirm that IENFD reduction and QST abnormalities may occur early in ATTRv presymptomatic 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 presymptomatic carriers' follow‐up.