Presenters: Rossella D’Aloisio, (ITALY)

The youngest brother (case 1): a male, 31 years old, with a progressive vision loss during childhood, progressive night blindness and previous clinical diagnosis elsewhere of Leber’s Hereditary Optic Neuropathy.

Case Summary:

Two brothers were referred to our retina unit for a consultation.

The youngest brother (case 1): a male, 31 years old, with a progressive vision loss during childhood, progressive night blindness and previous clinical diagnosis elsewhere of Leber’s Hereditary Optic Neuropathy. At our ophthalmogical examination a decreased vision loss was detected, anterior segment was unremarkable. Posterior segment: pale optic disc and retinal vessel attenuation. On fundus autofluorescence: hyperfluorescent ring in both eyes. Visualization of retinal vessels of reduced caliber, leakage and pooling in macular area on FA and ICGA in both eyes.

The oldest brother (case 2): a male, 42 years old, with sudden vision loss at 21 years old with a clinical diagnosis elsewhere of Leber’s Hereditary Optic Neuropathy not genetically confirmed and treated firstly with corticosteroids and then with ubiquinone; rod-cone dystrophies clinically excluded. Onset of cystoid macular edema treated with carbonic anhydrase inhibitors for 1 year without benefits. At our ophthalmogical examination: nystagmus, hand motion in both eyes, anterior segment was unremarkable. Posterior segment: pale optic disc, retinal vessel attenuation and ’bone spicule’ pigmentary deposits in the peripheral retina.

Visualization of retinal vessels of reduced caliber, leakage and pooling in macular area, hypofluorescence areas corresponding to bone spicules on FA and ICGA in both eyes. OCT showed in case 1 cystoid macular edema and perifoveal loss of photoreceptor layer structure with central preservation of photoreceptors and the transitional zone, and in case 2 cystoid macular edema and thinning of the outer retina with EB and ELM disappearance.

Electrophysiology testing: rod and cone ERG responses reduced in both brothers. We therefore hypothesized retinitis pigmentosa (RP). Molecular genetic testing of entire exome using next- generation sequencing (NGS) in both brothers and in their mother revealed an unusual heterozygous mutation: LRP5 gene (NM_002335), exon 19, variant c.4025G>C p.(Arg1342Pro).

Mutations in the gene LRP5 have been shown to be responsible for both familial exudative vitreoretinopathy (FEVR) and osteoporosis-pseudoglioma syndrome. Heterozygous mutations of LRP5 have not been identified in RP before.One single case has been reported in literature caused by novel digenic heterozygous mutations in a chinese family, but it was different from our case because of the co-existence of EYS c.7723+1G>A and LRP5 c.3361 A>G.

Retinitis pigmentosa is really exceptionally heterogeneous in terms of genetic, allelic, phenotypic and clinical presentation; this heterogeneity can be confusing to patients and clinicians and can be a confounding factor in diagnosis. Nowadays, many RP cases are still not associated with any gene. We still do not know if such unusual mutation we found is the real responsible of RP in our case. We speculate that in all retinitis pigmentosa and related photoreceptor dystrophies (RPRPD) some new mechanisms may be involved, probably epigenetic changes in promoters of genes required for photoreceptor development and of genes associated with RP during retinal progenitor cells differentiation into cone and rod photoreceptors.

Undoubtedly, more cases are needed to further understand the mutation spectrum of RP.

References:

Mastropasqua R, D’Aloisio R, De Nicola C, et al. Widefield Swept Source OCTA in Retinitis Pigmentosa. Diagnostics. 2020
SP Daiger, LS Sullivan, and SJ Bowne. Genes and mutations causing retinitis pigmentosa. Clin Genet. 2013
Gao F-J, Zhang S-H, Chen J-Y, et al. Digenic heterozygous mutations in EYS/LRP5 in a Chinese family with retinitis pigmentosa. Int J Ophthalmol. 2017
Dvoriantchikova G, Lypka KR, Ivanov D. The Potential Role of Epigenetic Mechanisms in the Development of Retinitis Pigmentosa and Related Photoreceptor Dystrophies. Frontiers in Genetics. 2022