Peroxisome Biogenesis Disorders in the Zellweger Spectrum: Ophthalmic Findings from a New Natural History Study Cohort and Scoping Literature Review

BackgroundZellweger Spectrum Disorder (ZSD) is caused by bi-allelic defects in any of 13 PEX genes, resulting in failure to form functional peroxisomes. Individuals manifest a wide spectrum of clinical phenotypes and severity, but almost all have retinal degeneration leading to blindness. The onset, extent and progression of retinal findings has not been well-described and there are no therapies for treating vision loss. With expanding research and trials on retinal gene therapy for genetic disorders, it is now crucial to understand the natural history of vision loss in ZSD for defining reliable endpoints for upcoming interventional trials. Here we describe ophthalmic findings in the largest number of ZSD patients to date. MethodsWe reviewed ophthalmology records from our retrospective longitudinal cohort of 66 patients, and cross-sectional ophthalmic findings from 79 patients reported in the literature. We divided patients by severe, intermediate or mild disease based on genotypes or their reported disease severity. ResultsWe found that visual acuity (VA) declines slowly (+0.01 Logmar/year) with a mean of 0.93 Logmar (0 = normal vision, 1 = legal blindness) in all 53 intermediate-mild patients with available data. Longitudinal VA data revealed slow loss over time and legal blindness onset at average age 7.8 years. Fundoscopy 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. Electroretinogram (ERG) tracings were diminished in 93% of patients, 40% of which were extinguished. ERG responses did not change over time in patients with multiple ERGs. Optical coherence tomography (OCT), reported only in milder patients, revealed cystoid macular edema or macular schisis in 16/21 (age 1.8-30 years). Serial OCTs showed evolution or stable macular edema. ConclusionsAlthough limited by retrospective data, we highlight several useful conclusions (1) VA slowly deteriorates and is without clear association with disease severity, (2) serial ERGs are not useful for documenting vision loss progression and (3) intraretinal cysts may be common in ZSD. This study indicates that systematically reporting multiple measures will be required for accurately assessing visual function in the ZSD population, including measures of functional vision.