Retinal Pigment Epitheliopathy due to Sub-Optimal Recycling of Vitamin A (RESORVA): A Novel RDH11 -Related Phenotype.

Retinol dehydrogenases (RDHs) catalyze multiple steps in the visual cycle to regenerate 11-cis-retinal, a critical component in rod phototransduction. The structural homology between RDHs enables functional redundancy; yet Mendelian disorders are linked to RDHs. Variants in RDH12 and RDH5 cause non-syndromic inherited retinal dystrophy (IRD), whilst variants in RDH11 cause syndromic IRD. RDH11 is a minor isoenzyme catalyzing two reactions: (i) reduction of all-trans-retinal in rod photoreceptors alongside RDH12 and RDH8, and (ii) oxidation of 11-cis-retinol in the retinal pigment epithelium (RPE) alongside RDH5 and RDH10. Prior cases with RDH11 demonstrated a generalized photoreceptor dystrophy, similar to RDH12-retinopathy. We describe a visually asymptomatic 7-year-old boy carrying a homozygous null variant in RDH11 [NM_016026.4:c.216C>A:p.(Cys72*)] with autism, dysmorphic features, oligodontia, microcephaly and a novel IRD. This retinopathy consisted of yellow deposits and hyperpigmentation within the RPE with absent autofluorescence and a normal electroretinogram implying sub-optimal oxidation of 11-cis-retinol. These features are reminiscent of RDH5-retinopathy but milder. We termed this phenotype Retinal pigment Epitheliopathy due to Sub-Optimal Recycling of Vitamin A (RESORVA). We propose that the divergence in retinal phenotypes among RDH11 cases is likely due to variant-specific protein effects on paralogous gene functioning, such as differences in activation of transcriptional adaptation.