Baseline structural and functional findings from a PRPH2(p.Gly208Asp) natural history study

Abstract

Purpose : Pathogenic variants in the peripherin-2 (PRPH2) gene result in PRPH2 associated retinal disease which encompass a broad phenotypic spectrum. Although ultra-rare, the c.623G>A (p.Gly208Asp) pathogenic PRPH2 variant has been reported commonly by a number of centers and laboratories (ClinVAR). The purpose of this study is to understand phenotypic heterogeneity at this locus and to perform baseline structural and functional testing as part of a natural history study.

Methods : The study had IRB approval from the UCSD review board and included patients heterozygous for the PRPH2 p.Gly208Asp pathogenic variant. Patients were imaged using spectral-domain optical coherence tomography and ultra-widefield fundus pseudocolor and autofluorescence for baseline studies. Functional testing was performed using best corrected visual acuity and microperimetry. Total retinal and choroidal thickness were manually segmented using Heidelberg HEYEX2 software and were compared with normal controls. The statistical analyses were conducted per subject eye level through Linear Mixed Effects modeling using R statistical software.

Results : Seven cases (Mean 60 years, SD 14.8 years, 5 females) and 7 controls (Mean 63.3 years, SD 2.6, 4 males) were included. Patients had a mean best corrected visual acuity of 0.7 SD 1.0. All patients had macular disease; 3 with central areolar chorioretinal dystrophy; 3 cone-rod dystrophy type and one with marked macular atrophy with a history of cone-rod dystrophy type. At baseline, mean retinal volume (6.40 (CI 5.78, 7.01) mm3) was significantly lower (p<0.003) in cases than in controls (8.06 (CI 7.44, 8.68) (Fig.1). The mean total choroidal volume (4.55 (CI 3.04, 6.06) mm3) was also significantly lower (p<0.021) in cases compared to controls (7.44 (5.92, 8.97) mm3)(Fig.1). Six cases completed microperimetry with a mean retinal sensitivity of 12.1 dB (SD 6.5).

Conclusions : Patients with PRPH2 (p.Gly208Asp) pathogenic variants had disease which was mainly confined to the macula. Structural macular studies showed that cases had significantly reduced macular volume compared to aged-matched controls and had
significantly reduced functional microperimetric mean sensitivity compared to similarly aged normal controls in the literature. Longitudinal studies are warranted to see if these structural and functional measures may help predict disease progression.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.