RDH5 and RLBP1-Associated Inherited Retinal Diseases: Refining the Spectrum of Stationary and Progressive Phenotypes

To investigate the clinical, functional, and imaging characteristics in patients affected by inherited retinal diseases associated with RDH5 and RLBP1 gene variants, and to report novel genotype-phenotype correlations.

Retrospective single-center cohort study.

Twenty-two patients with molecularly confirmed RLBP1-associated retinopathy and 5 with RDH5-associated retinopathy. Medical records were reviewed to obtain data on family history and ophthalmologic examinations, including retinal imaging and full-field electroretinography (ffERG). Genotype was determined by targeted next-generation sequencing followed by confirmation and familial segregation by Sanger sequencing.

The median (interquartile ranges) age at baseline for the RDH5 and RLBP1 cohort was 44.6 (38.2-67.9) years and 36.9 (23.1-45.2) years, respectively. Macular atrophy (MA) was found in approximately 80% of eyes from both cohorts. The RLBP1 genotype was associated with a lower macular volume by 0.28 mm³ (95% CI, -0.46 to -0.11; P = .005) compared to the RDH5 genotype. In both genotypic cohorts, we found a significant annual rate of macular volume loss, estimated at -0.007 mm³/y (95% CI, -0.012 to -0.001; P = .02), without any significant difference between the two genotypes. Three unrelated patients homozygous for the c.361C>T p.(Arg121Trp) RLBP1 variant showed minimal impairment of both the rod and cone systems function on ffERG and absence of MA.

Progressive MA in addition to congenital night blindness can be identified in adult patients with RDH5-associated retinopathy. Vice versa, hypomorphic RLBP1 variants may cause milder retinal phenotypes rather than the typical severe rod-cone dystrophy with MA. These findings could prove beneficial to improve the prognostication of patients and help in designing future interventional trials.