Marco Luigetti

Introduction Hereditary 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). Methods Late‐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. Results Forty 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. Conclusions Our 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.

In the present study, through a case series, we highlighted the role of magnetic resonance (MR) in the identification and diagnosis of peripheral neuropathies. MR neurography allows the evaluation of the course of nerves through 2D and 3D STIR sequences with an isotropic voxel, whereas the relationship between nerves, vessels, osteo-ligamentous and muscular structures can be appraised with T1 sequences. Currently, DTI and tractography are mainly used for experimental purposes. MR neurography can be useful in detecting subtle nerve alterations, even before the onset of symptoms. However, despite being sensitive, MR neurography is not specific in detecting nerve injury and requires careful interpretation. For this reason, MR information should always be supported by instrumental clinical tests.