ABSTRACT
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
ABSTRACT
PURPOSE: To assess the longitudinal vision-related quality of life among patients with CRB1-associated inherited retinal dystrophies. METHODS: In this longitudinal questionnaire study, the National Eye Institute Visual Function Questionnaire (39 items, NEI VFQ-39) was applied at baseline, two-year follow-up, and 4-year follow-up in patients with pathogenic CRB1 variants. [Correction added on 20 November 2023, after first online publication: The preceding sentence has been updated in this version.] Classical test theory was performed to obtain subdomain scores and in particular 'near activities' and 'total composite' scores. The Rasch analysis based on previous calibrations of the NEI VFQ-25 was applied to create visual functioning and socio-emotional subscales. RESULTS: In total, 22 patients with a CRB1-associated retinal dystrophy were included, [ ] with a median age of 25.0 years (interquartile range: 13-31 years) at baseline and mean follow-up of 4.0 ± 0.3 years. [Correction added on 20 November 2023, after first online publication: The preceding sentence has been updated in this version.] A significant decline at 4 years was observed for 'near activities' (51.0 ± 23.8 vs 35.4 ± 14.7, p = 0.004) and 'total composite' (63.0 ± 13.1 vs 52.0 ± 12.1, p = 0.001) subdomain scores. For the Rasch-scaled scores, the 'visual functioning' scale significantly decreased after 2 years (-0.89 logits; p = 0.012), but not at 4-year follow-up (+0.01 logits; p = 0.975). [Correction added on 20 November 2023, after first online publication: In the preceding sentence, " after 4 years " has been corrected to " after 2 years " in this version.] The 'socio-emotional' scale also showed a significant decline after 2 years (-0.78 logits, p = 0.033) and 4 years (-0.83 logits, p = 0.021). CONCLUSION: In the absence of an intervention, a decline in vision-related quality of life is present in patients with pathogenic CRB1 variants at 4-year follow-up. Patient-reported outcome measures should be included in future clinical trials, as they can be a potential indicator of disease progression and treatment efficacy.
ABSTRACT
Purpose: Heavy pigmentation is known to be a prognostic risk factor in uveal melanoma (UM). We analyzed whether genetic tumor parameters were associated with tumor pigmentation and whether pigmentation should be included in prognostic tests. Design: Retrospective comparison of clinical, histopathological, and genetic features and survival in UM with different pigmentation. Participants: A total of 1058 patients with UM from a White European population with diverse eye colors enucleated between 1972 and 2021. Methods: Cox regression and log-rank tests were used for survival analysis; the chi-square test and Mann-Whitney U test were used for correlation analysis. Main Outcome Measures: Uveal melanoma-related survival based on tumor pigmentation and chromosome status, correlation of tumor pigmentation with prognostic factors. Results: The 5-year UM-related mortality was 8% in patients with nonpigmented tumors (n = 54), 25% with lightly pigmented tumors (n = 489), 41% with moderately pigmented tumors (n = 333), and 33% with dark tumors (n = 178) (P < 0.001). The percentage of tumors with monosomy 3 (M3) or 8q gain increased with increasing pigmentation (31%, 46%, 62%, and 70% having M3 [P < 0.001], and 19%, 43%, 61%, and 63% having 8q gain [P < 0.001] in the 4 increasing pigment groups, respectively). BRCA-associated protein 1 (BAP1) loss (known for 204 cases) was associated with increased tumor pigmentation (P = 0.001). Cox regression analysis on survival showed that when chromosome status and pigmentation were both included, pigmentation was not an independent prognostic indicator. Preferentially expressed antigen in melanoma (PRAME) expression was a significant prognostic marker in light tumors (P = 0.02) but not in dark tumors (P = 0.85). Conclusions: Patients with moderately and heavily pigmented tumors showed a significantly higher UM-related mortality than patients with unpigmented and light tumors (P < 0.001), supporting prior reports on the relation between increased tumor pigmentation and a worse prognosis. Although we previously showed that a dark eye color was associated with tumor pigmentation, we now show that the tumor's genetic status (chromosome 3 and 8q/BAP1 status) is also related to tumor pigmentation. When pigmentation and chromosome 3 status are both included in a Cox regression analysis, pigmentation is not an independent prognostic factor. However, evidence from this and previous studies shows that chromosome changes and PRAME expression have a stronger association with survival when they occur in light tumors than in dark ones. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.
