Electrophysiological Monitoring of Asymptomatic Transthyretin Mutation Carriers

Abstract

Introduction/aims: It is imperative to screen asymptomatic carriers of transthyretin (TTR) mutations to initiate treatment early. The protocol for repeated electrodiagnostic (EDX) assessments over time lacks standardization. Our aim was to report the electrophysiological evolution of a cohort of asymptomatic carriers and to determine which biomarkers were most sensitive to change.

Methods: We performed a retrospective review of medical records of asymptomatic carriers identified by screening families with amyloid neuropathy. Carriers who underwent two EDX assessments with a minimum 1-year interval between studies were selected. EDX included analysis of median, ulnar, tibial, fibular and sural nerves, motor unit number index (MUNIX), electrochemical skin conductance, sympathetic skin response, and heart rate variability on deep breathing. Measurements were compared at first and second examinations.

Results: Twenty-three carriers were included with a median age of 49 years (interquartile range 37-58). Median time between examinations was 3 years (2-4). Compound muscle and sensory nerve action potential (CMAP and SNAP) amplitudes, nerve conduction velocities, autonomic small fiber testing and MUNIX remained stable except for motor distal latency of the median nerve (+0.07 ms/year) and CMAP duration of the ulnar (+0.10 ms/year) and fibular (+0.12 ms/year) nerves. The CMAP duration of the ulnar nerve was the most sensitive biomarker to change when performed within 10 years preceding the age of the youngest case in the family, with a standardized response mean of 0.91.

Discussion: Nerve conduction parameters remain relatively stable in asymptomatic TTR carriers. Changes can only be detected using multimodal and extensive electrophysiological tests.

Keywords: asymptomatic carriers; electrophysiological monitoring; familial amyloid polyneuropathy; small fiber testing; transthyretin.

FIGURE 1

Electrophysiological data varying significantly between two examinations in asymptomatic carriers. CMAP, compound muscle action potential.

FIGURE 2

Variation of the CMAP duration of the ulnar nerve. Variation of the duration of the CMAP of the ulnar nerve CMAP duration in ms/year is not correlated with TTR V30M mutation (full circles), delay between measurements (size of circles) and age at first measurement. Circles to the right of the vertical dotted line are asymptomatic carriers for whom the first examination was carried out in the 10 years prior to or at any time following the age of the youngest case in the family (n = 8). Circles above the horizontal dotted line correspond to a variation greater than the 99th percentile of the variation observed in healthy control subjects. CMAP, compound muscle action potential.

FIGURE 3

Variation of electrophysiological data in asymptomatic carriers evaluated in the 10 years preceding or at any time following the age of the youngest case in the family. Variations in ulnar CMAP duration remain significant.

FIGURE 4

Variation of the CMAP duration of the ulnar nerve between two different examinations in asymptomatic TTR mutation carriers, symptomatic TTR mutation carriers, and healthy controls. Median time between two EDX was 3 years. The bars represent the medians.