Natural history of patients with autosomal dominant pathogenic variants associated with sensorineural hearing loss and optic atrophy.

Objective: Autosomal dominant pathogenic variants in the WFS1 gene can cause a broad spectrum of WFS1-related disorders. These disorders present with a range of phenotypic manifestations, including isolated low-frequency sensorineural hearing loss, optic nerve atrophy accompanied by low- to mid-frequency sensorineural hearing loss, isolated diabetes mellitus, and early-onset cataracts. In general, WFS1-related disorders represent a milder spectrum of conditions linked to pathogenic WFS1 variants, except for Hattersley-Urano syndrome, which is characterized by early-onset diabetes mellitus, optic nerve atrophy, cataracts, hypotonia, intellectual disability, and developmental delay. By contrast, autosomal recessive WFS1 variants result in Wolfram Syndrome type 1, a rare neurodegenerative disorder characterized by early-onset diabetes mellitus, optic nerve atrophy, arginine vasopressin deficiency, hearing loss, and cerebellar and brainstem atrophy. Although WFS1-related disorders have been increasingly recognized, additional data are needed to understand their clinical progression and long-term outcomes. Our study aims to expand knowledge on the severity and progression of WFS1-related disorders by reviewing clinical data from patients with autosomal dominant pathogenic WFS1 variants.

Approach: We obtained clinical data from the Washington University International Registry and Clinical Study for Wolfram Syndrome and related disorders and the Endoplasmic Reticulum Disease Patient Registry and Biorepository. We included participants with autosomal dominant WFS1 pathogenic variants who were diagnosed with optic nerve atrophy and sensorineural hearing loss. Eleven participants with autosomal dominant WFS1 variants meeting these criteria were identified.

Results: The 11 cases included five distinct autosomal dominant WFS1 variants: c.923C>G (p.Ser308Cys), c.2051C>T (p.Ala684Val), c.2389G>T (p.Asp797Tyr), c.2456A>C (p.Gln819Pro), and c.2590G>A (p.Glu864Lys). Among these, the p.Gln819Pro variant has not been previously reported in the literature. The median age of optic atrophy diagnosis was 10 years (quartiles: 6.0 and 19.0 years). Visual acuity did not significantly differ between the left (OS) and right (OD) eyes (p = 0.8901). The least square best-corrected visual acuity (BCVA) mean for the right eye was 0.2114 ± 0.01903 and for the left eye, 0.2153 ± 0.01903. Age was not significantly related to best eye BCVA (p = 0.9196), with an estimated change of -0.0002 (95% CI [-0.003, 0.003]) per year. Patient age was also not correlated with binocular BCVA (p = 0.5994), with an estimated change of 0.00075 (95% CI [-0.0021, 0.0036]) per year. Mean retinal nerve fiber layer (RNFL) thickness was not significantly related to age (p = 0.1604), with an estimated annual change of 0.1486 (95% CI [-0.659, 0.363]). However, removing an influential outlier resulted in a significant relationship between RNFL thickness and age (p = 0.0160), with an estimated change of 0.2114 (95% CI [0.045, 0.377]) per year. Hearing loss diagnoses occurred at a median age of 2.0 years (quartiles: 1.5 and 2.0 years). All participants used hearing aids (11/11); six (6/11) had cochlear implants, while three (3/11) used external hearing aids. The median time between hearing loss diagnosis and hearing aid use was 4.0 years (quartiles: 2.5 and 8.0 years).

Conclusion: This study contributes to the growing understanding of WFS1-related disorders caused by autosomal dominant WFS1 variants. In particular, it highlights two clinical phenotypes of a novel WFS1 variant and provides valuable insights into the progression of optic nerve atrophy and hearing loss management.