Zellweger Spectrum Disorder: Ophthalmic Findings from a New Natural History Study Cohort and Scoping Literature Review

Purpose: Individuals with Zellweger spectrum disorder (ZSD) manifest a spectrum of clinical phenotypes but almost all have retinal degeneration leading to blindness. The onset, extent, and progression of retinal findings have not been well described. It is crucial to understand the natural history of vision loss in ZSD to define reliable endpoints for future interventional trials. Herein, we describe ophthalmic findings in the largest number of ZSD patients to date.

Design: Retrospective review of longitudinal data from medical charts and review of cross-sectional data from the literature.

Participants: Sixty-six patients with ZSD in the retrospective cohort and 119 patients reported in the literature, divided into 4 disease phenotypes based on genotype or clinical severity.

Methods: We reviewed ophthalmology records collected from the retrospective cohort (Clinicaltrials.gov NCT01668186) and performed a scoping review of the literature for ophthalmic findings in patients with ZSD. We extracted available ophthalmic data and analyzed by age and disease severity.

Main outcome measures: Visual acuity (VA), posterior and anterior segment descriptions, nystagmus, refraction, electroretinography findings, visual evoked potentials, and OCT results and images.

Results: Visual acuity was worse at younger ages in those with severe disease compared with older patients with intermediate to mild disease for all 78 participants analyzed, with a median VA of 0.93 logarithm of the minimum angle of resolution (Snellen 20/320). Longitudinal VA data revealed slow loss over time and legal blindness onset at an average age of 7.8 years. Funduscopy showed retinal pigmentation, macular abnormalities, small or pale optic discs, and attenuated vessels with higher prevalence in milder severity groups and did not change with age. Electroretinography waveforms were diminished in 91% of patients, 46% of which were extinguished and did not change with age. OCT in milder patients revealed schitic changes in 18 of 23 individuals (age range 1.8 to 30 years), with evolution or stable macular edema.

Conclusions: In ZSD, VA slowly deteriorates and is associated with disease severity, serial electroretinography is not useful for documenting vision loss progression, and intraretinal schitic changes may be common. Multiple systematic measures are required to assess retinal dystrophy accurately in ZSD, including functional vision measures.

Financial disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.