X連鎖性網膜分離症の進行：定量的バイオマーカーとその遺伝子治療への影響を定義する縦断的研究

To delineate age-related changes in visual, structural, and electrophysiologic measures in X-linked retinoschisis (XLRS) and to assess automated cyst-cavity volume (CCV) as a quantitative biomarker.

Single-center mixed retrospective-prospective cohort study.

This study included 440 visits from 107 individuals with clinically diagnosed XLRS and confirmed pathogenic RS1 variants. Comprehensive ophthalmic evaluations were performed at baseline and during follow-up, including visual acuity (VA), fundus examination, electroretinogram (ERG), and spectral-domain optical coherence tomography (SD-OCT), with microperimetry (MP) conducted in a subset of patients. Among SD-OCT parameters, CCV was automatically quantified using self-developed DEEP-OCT-CCSEG system. Annual progression rates were estimated using restricted cubic spline or linear regression models, and interocular agreement was evaluated with Bland-Altman and intraclass correlation analyses.

In this cohort, 70% patients presented by age 10. The median age at first examination was 7.3 years (range, 1.9-78.5) over a mean follow-up of 1.9 years. Baseline means were: VA 0.82 ± 0.47 logMAR, central foveal thickness (CFT) 495 ± 186 µm, and CCV 1.54 ± 1.16 mm³. Genetic analysis identified 64 distinct RS1 variants, including 5 that were novel. Longitudinally, visual acuity followed a triphasic pattern: slight improvement in childhood, a prolonged plateau through mid-adulthood, and a more rapid decline thereafter, with Kaplan-Meier analysis projecting 40% of patients will be blind by age 60. Scotopic ERG a- and b-wave amplitudes peaked in early childhood before declining with age, while the b/a ratio gradually decreased. In OCT, CFT showed a modest, significant age-related decrease. In contrast, CCV followed a non-linear age-related pattern, increasing to a peak in the third decade of life before progressively declining.

In this XLRS cohort, most patients showed gradual structural and functional decline beginning in the second decade of life, suggesting an optimal therapeutic window within early adulthood. By applying CCV as a quantitative biomarker in a large-scale longitudinal setting for the first time, this study quantitatively characterized three-dimensional retinal remodeling and delineated age-related structural changes in XLRS. These findings refine the understanding of XLRS natural history and provide a robust framework for therapeutic evaluation and clinical trial design.