Researchers note decreased corneal sensitivity and corneal nerve degeneration in patients with Wolfram syndrome (WFS), according to the results of a study published in the American Journal of Ophthalmology. The investigators suggest that corneal sensitivity predicts the degree of disease progression as measured by visual acuity and retinal thinning.

In the current observational clinical case series with confirmatory testing, investigators examined 12 patients with biallelic mutations in the WFS1 gene, as well as a control group consisting of 30 individuals with type 1 diabetes.

They found that corneal sensitivity was significantly decreased in WFS patients vs type 1 diabetes patients (4.50 (3.50-5.50) cm vs 6.00 (6.00-6.00) cm; P <10-5). Corneal nerve fiber/branch density and nerve fiber length were decreased in patients with WFS.


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In those with WFS, corneal sensitivity was correlated with macular-average thickness and best corrected visual acuity. In knockout-mouse models, the investigators observed corneal neurodegeneration changes when corneal nerve fiber density and length were assessed.

This study, however, is the first to indicate corneal neurodegeneration in WFS patients. Mechanistically, there could be a link between neurodegeneration and endoplasmic reticulum (ER) stress and mitochondrial dysfunction evident in cells lacking wolframin as a consequence of biallelic mutation in the WFS1 gene.

“We found that corneal sensitivity and corneal nerves were affected in WFS, indicating much deeper processes of corneal neurodegeneration than in the age- and sex-matched group of patients with type 1 diabetes serving as controls,” according to the report. “Since long-term diabetes might cause corneal neuropathy, our study design enabled us to separate this effect in the WFS group.”

The investigators found that corneal sensitivity was associated with the age at diagnosis of diabetes and age at optic atrophy. Age at diagnosis of diabetes and age at optic atrophy could be interpreted as surrogates for the severity of impairment of WFS1 mutation, according to the researchers.

The team notes limitations to their study, such as small sample size, the evaluation of only the central cornea vs the peripheral cornea, and a lack of autonomic-function assessment to assess autonomic innervation. 

Reference

Waszczykowska A, Zmyslowska AZ, Bartosiewicz K, et al. Reduced corneal sensitivity with neuronal degeneration is a novel clinical feature in Wolfram syndrome. Am J Ophthalmol. Published online October 25, 2021. doi:10.1016/j.ajo.2021.09.030