Longitudinal and cross-sectional study of retinal phenotypes and visual function in choroideremia carriers: a new...

Choroideremia is an X-linked chorioretinal dystrophy with well-characterized progression in affected males but variable phenotypes in female carriers. Understanding the phenotypic spectrum in female carriers is important for prognosis, monitoring, and trial design. This study aims to delineate the natural history of retinal phenotypes and visual function loss in female choroideremia carriers and establish an improved fundus grading system for disease stratification and prognostic prediction.

This single-center, longitudinal and cross-sectional, retrospective study included 64 genetically confirmed female choroideremia carriers. Clinical data included genotype, age, best-corrected visual acuity, color fundus photography, fundus autofluorescence, visual field testing, and full-field electroretinography. A novel fundus phenotypic grading system was proposed based on fundus autofluorescence and fundus color photographs, which included four types: granular (merged fine/coarse patterns), severe peripapillary atrophy (highlighting severe peripapillary atrophy as a crucial feature), localized atrophy, and widespread atrophy. The agreement between measurement-based grading and visual grading was assessed.

Visual acuity and fundus phenotypes showed moderate interocular symmetry, while visual field and electroretinography metrics showed high interocular symmetry. At baseline, phenotypes included granular (76.3%), severe peripapillary atrophy (7.5%), localized atrophy (10.8%), and widespread atrophy (5.4%). Longitudinally, the granular type remained stable, while other types progressed, with a mean atrophy expansion rate of 3.1 mm²/year. Age did not correlate with visual function decline, and neither age nor genotype was linked to the severe fundus phenotype. Baseline phenotype was the strongest predictor of prognosis. Excellent agreement (weighted κ = 0.93) was observed between the measurement-based and visual grading methods.

We proposed a novel fundus grading system for choroideremia carriers and demonstrated its strong clinical utility and prognostic value. The granular type confers a favorable prognosis, whereas the other three types exhibit progressive deterioration. Baseline phenotypic grading is the best indicator of long-term outcomes, underscoring its value in clinical monitoring and therapeutic trial design.