Reduced Corneal Sensitivity With Neuronal Degeneration is a Novel Clinical Feature in Wolfram Syndrome

Abstract

Purpose: To evaluate corneal sensitivity and corneal nerve morphology among patients with Wolfram syndrome (WFS).

Design: An observational clinical case series with confirmatory experiments.

Methods: We included a group of 12 patients with biallelic mutations in the WFS1 gene and a control group composed of 30 individuals with type 1 diabetes (T1D). All participants (n = 42) underwent a complete ophthalmic examination, esthesiometry, and retinal nerve fiber layer assessment using optical coherence tomography. Morphologic assessment of corneal neuropathy by in vivo corneal confocal microscopy was conducted in 11 patients with WFS (both eyes) and 1 WFS patient (1 eye) as well as in 24 patients with T1D (both eyes in 6 patients and 1 eye in 18 patients). Additionally, corneas from Wfs1KO mice and their wild-type littermates were subjected to laser scanning confocal microscopy.

Results: Corneal sensitivity was significantly reduced in patients with WFS compared with patients with T1D (4.50 cm [interquartile range, 3.50-5.50 cm] vs 6.00 cm [interquartile range, 6.00-6.00 cm]; P < 10^-5). Additionally, corneal nerve fiber and branch density as well as nerve fiber length were low among patients with WFS. Corneal sensitivity correlated with macular average thickness (R = 0.6928; P = .039) and best-corrected visual acuity (R = -0.61; P = .002) in the WFS group. Similarly, Wfs1 knockout mice also presented corneal neurodegeneration changes when corneal nerve fiber density and length were measured using laser scanning confocal microscopy.

Conclusions: Decreased corneal sensitivity and corneal nerve degeneration are observed in WFS. Corneal sensitivity is linked with the degree of disease progression as measured by visual acuity and retinal thinning.

Keywords: Corneal nerves; WFS1; Wolfram syndrome; corneal sensitivity; diabetes; diabetic neuropathy; in vivo confocal microscopy; wolframin.