Systematic study of ophthalmological findings in 10 patients with PEX1-mediated Zellweger spectrum disorder

This cross-sectional study describes the ophthalmological and general phenotype of 10 patients from six different families with a comparatively mild form of Zellweger spectrum disorder (ZSD), a rare peroxisomal disorder. Ophthalmological assessment included best-corrected visual acuity (BCVA), perimetry, microperimetry, ophthalmoscopy, fundus photography, spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) imaging. Medical records were reviewed for medical history and systemic manifestations of ZSD. Nine patients were homozygous for c.2528 G > A (p.Gly843Asp) variants in PEX1 and one patient was compound heterozygous for c.2528 G>A (p.Gly843Asp) and c.2097_2098insT (p.Ile700TyrfsTer42) in PEX1. Median age was 22.6 years (interquartile range (IQR): 15.9 – 29.9 years) at the most recent examination, with a median symptom duration of 22.1 years. Symptom onset was variable with presentations of hearing loss (n = 7) or nyctalopia/reduced visual acuity (n = 3) at a median age of 6 months (IQR: 1.9–8.3 months). BCVA (median of 0.8 logMAR; IQR: 0.6–0.9 logMAR) remained stable over 10.8 years and all patients were hyperopic. Fundus examination revealed a variable retinitis pigmentosa (RP)-like phenotype with rounded hyperpigmentations as most prominent feature in six out of nine patients. Electroretinography, visual field measurements, and microperimetry further established the RP-like phenotype. Multimodal imaging revealed significant intraretinal fluid cavities on SD-OCT and a remarkable pattern of hyperautofluorescent abnormalities on FAF in all patients. This study highlights the ophthalmological phenotype resembling RP with moderate to severe visual impairment in patients with mild ZSD. These findings can aid ophthalmologists in diagnosing, counselling, and managing patients with mild ZSD.

本项横断面研究描述了来自六个不同家庭的10名患有相对温和型塞尔韦格谱系障碍（ZSD）患者的眼科及一般表型，ZSD是一种罕见的过氧化物酶体疾病。眼科评估包括最佳矫正视力（BCVA）、视野检查、微视野检查、眼底镜检查、眼底摄影、频域光学相干断层扫描（SD-OCT）及眼底自发光（FAF）成像。通过审查病历，对ZSD的病史及全身症状进行了分析。9名患者为PEX1基因c.2528G>A（p.Gly843Asp）变异的纯合子，1名患者为PEX1基因c.2528G>A（p.Gly843Asp）和c.2097_2098insT（p.Ile700TyrfsTer42）复合杂合子。最近一次检查时的中位年龄为22.6岁（四分位间距（IQR）：15.9–29.9岁），症状持续的中位时间为22.1年。症状出现时间不一，其中7名患者表现为听力丧失，3名患者表现为夜盲或视力下降，中位发病年龄为6个月（IQR：1.9–8.3个月）。BCVA（中位数为0.8 logMAR；IQR：0.6–0.9 logMAR）在10.8年内保持稳定，所有患者均为高度近视。眼底检查显示9名患者中6名存在类似视网膜色素变性（RP）的表型，其中以圆形色素沉着最为突出。电生理视网膜电图、视野测量和微视野检查进一步证实了RP样表型。多模态成像显示所有患者SD-OCT上存在显著的视网膜内液腔，FAF上呈现出显著的过度自荧光异常模式。本研究突出了在轻度ZSD患者中，类似于RP且具有中至重度视力障碍的眼科表型。这些发现有助于眼科医生在诊断、咨询和管理轻度ZSD患者方面提供支持。