Longitudinal natural history study of dominant retinitis pigmentosa due to RHO gene mutations

Abstract

Purpose : To perform detailed longitudinal phenotyping of autosomal dominant retinitis pigmentosa (RP) caused by mutations in the RHO gene in a large Italian cohort.

Methods : In this retrospective, single-center, longitudinal observational study, a cohort of 71 patients (mean age: 33.8±16.7 years) from 27 unrelated families with a diagnosis of RHO-related RP was evaluated over a mean follow-up of 5.9±7.2 years. At each visit, patients underwent best-corrected visual acuity (BCVA) assessment, Goldmann visual field (GVF), optical coherence tomography (OCT), and full-field electroretinography (ERG).

Results : The mean BCVA was 0.6±0.8 logMAR. Night blindness was the most frequently reported symptom (50 patients, 70.4%). Typical RP fundus was found in 60 patients (84.5%), while 7 (9.9%) showed sine pigmento RP and 4 (5.6%) had pericentral RP. OCT, available in 38 patients, revealed cystoid macular edema in 45 eyes (59.2%), whereas epiretinal membranes and vitreomacular tractions were observed in 13 (17.1%) and 6 eyes (7.9%), respectively. The mean central retinal thickness (CRT) was 232±47 µm and the mean EZ band width was 2420±1283 µm. ERG was non-recordable in 47 patients (66.2%); 22 (31%) showed rod-cone pattern ERG responses. Significant correlations were found between BCVA (B: 0.014 logMAR/year; p<0.001) and CRT (B: -17.4 µm/year; p=0.002) with age. BCVA was better in patients with atypical RP (p=0.007) and detectable ERG (p<0.001). BCVA and CRT decreased at a mean rate of 0.037 logMAR/year (p=0.015) and -2.6 µm/year (p=0.038), respectively. On the basis of mutation location and its functional impact on Rhodopsin, the cohort was stratified into 3 classes: Class 1) Post-Golgi trafficking impairment; Class 2) Misfolding, endoplasmic reticulum retention, and instability; Class 3) Vesicular trafficking and endocytosis disruption. Class 2 had milder and slower BCVA decline (p<0.001), reaching mean BCVA <0.3 logMAR at 62.5 years on average, about 15 years later than Class 1 (48.7 years) and Class 3 (46.3 years). Detectable ERG was more frequent (p=0.001) in Class 2 (9/13; 69.2%) compared to Class 1 (2/16; 12.5%) and Class 3 (2/16; 12.5%).

Conclusions : Patients with RHO-related autosomal dominant RP displayed a composite spectrum of disease progression. Mutations causing misfolding, endoplasmic reticulum retention, and instability of Rhodopsin were associated with a milder disease phenotype.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.