Retinitis Punctata Albescens and RLBP1-Allied Phenotypes: Phenotype-Genotype Correlation and Natural History in the Aim of Gene Therapy

Ophthalmol Sci. 2021 Aug 17;1(3):100052. doi: 10.1016/j.xops.2021.100052. eCollection 2021 Sep.

Abstract

Purpose: To identify relevant criteria for gene therapy based on clinical and genetic characteristics of rod-cone dystrophy associated with RLBP1 pathogenic variants in a large cohort comprising children and adults.

Design: Retrospective cohort study.

Participants: Patients with pathogenic variants in RLBP1 registered in a single French reference center specialized in inherited retinal dystrophies.

Methods: Clinical, multimodal imaging, and genetic findings were reviewed.

Main outcome measures: Age of onset; visual acuity; ellipsoid line length; nasal, temporal, and foveal retinal thickness; and pathogenic variants and related phenotypes, including Newfoundland rod-cone and Bothnia dystrophies (NFRCDs), were reappraised.

Results: Twenty-one patients (15 families) were included. The most frequent form was NFRCD with 12 patients (8 families) homozygous for the recurrent deletion of exons 7 through 9 in RLBP1 and 5 patients (4 families) with biallelic protein-truncating variants (2 novel: p.Gln16∗ and p.Tyr251∗). A novel combination of the p.Arg234Trp Bothnia variant with a nonsense variant in trans led to Bothnia dystrophy in 2 sisters. One proband carrying the p.Met266Lys Bothnia variant and in trans p.Arg121Trp and a second, with the p.Arg9Cys and p.Tyr111∗ combination, both demonstrated mild retinitis punctata albescens. Independently of genotype, all patients showed a visual acuity of worse than 20/200, an ellipsoid line width of less than 1000 μm, and a mean foveal thickness of less than 130 to 150 μm, with loss of both the interdigitation and ellipsoid lines.

Conclusions: The eligibility for RLBP1 gene therapy first should be determined according to the biallelic variant combination using a robust classification as proposed herein. An ellipsoid line width of more than 1200 μm and a central thickness of more than 130 to 150 μm with detectable ellipsoid and interdigitation lines should be 2 prerequisite imaging indicators for gene therapy.

Keywords: BD, Bothnia dystrophy; Bothnia dystrophy; CRALBP; CRALBP, cellular retinaldehyde-binding protein; EZ, ellipsoid zone; GVF, Goldmann visual field; IRD, inherited retinal dystrophy; IZ, interdigitation zone; NFRCD, Newfoundland rod–cone dystrophy; NMD, nonsense-mediated mRNA decay; Newfoundland rod–cone dystrophy; RCD, rod–cone dystrophy; RLBP1; RPA, retinitis punctata albescens; RPE, retinal pigment epithelium; SD, spectral-domain; gene therapy; retinitis punctata albescens; spectral-domain OCT; variant classification; visual cycle; white dots.