Leber’s Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations

Leber’s congenital amaurosis (LCA), one of the most severe inherited retinal dystrophies, is typically associated with extremely early onset of visual loss, nystagmus, and amaurotic pupils, and is responsible for 20% of childhood blindness. With advances in molecular diagnostic technology, the knowledge about the genetic background of LCA has expanded widely, while disease-causing variants have been identified in 38 genes. Different pathogenetic mechanisms have been found among these varieties of genetic mutations, all of which result in the dysfunction or absence of their encoded proteins participating in the visual cycle. Hence, the clinical phenotypes also exhibit extensive heterogenicity, including the course of visual impairment, involvement of the macular area, alteration in retinal structure, and residual function of the diseased photoreceptor. By reviewing the clinical course, fundoscopic images, optical coherent tomography examination, and electroretinogram, genotype-phenotype correlations could be established for common genetic mutations in LCA, which would benefit the timing of the diagnosis and thus promote early intervention. Gene therapy is promising in the management of LCA, while several clinical trials are ongoing and preliminary success has been announced, focusing on RPE65 and other common disease-causing genes. This review provides an update on the genetics, clinical examination findings, and genotype-phenotype correlations in the most well-established causative genetic mutations of LCA.

GUCY2D mutations in retinal guanylyl cyclase 1 provide biochemical reasons for dominant cone–rod dystrophy but not for stationary night blindness

Mutations in the GUCY2D gene coding for the dimeric human retinal membrane guanylyl cyclase (RetGC) isozyme RetGC1 cause various forms of blindness, ranging from rod dysfunction to rod and cone degeneration. We tested how the mutations causing recessive congenital stationary night blindness (CSNB), recessive Leber's congenital amaurosis (LCA1), and dominant cone–rod dystrophy-6 (CORD6) affected RetGC1 activity and regulation by RetGC-activating proteins (GCAPs) and retinal degeneration-3 protein (RD3). CSNB mutations R666W, R761W, and L911F, as well as LCA1 mutations R768W and G982VfsX39, disabled RetGC1 activation by human GCAP1, -2, and -3. The R666W and R761W substitutions compromised binding of GCAP1 with RetGC1 in HEK293 cells. In contrast, G982VfsX39 and L911F RetGC1 retained the ability to bind GCAP1 in cyto but failed to effectively bind RD3. R768W RetGC1 did not bind either GCAP1 or RD3. The co-expression of GUCY2D allelic combinations linked to CSNB did not restore RetGC1 activity in vitro. The CORD6 mutation R838S in the RetGC1 dimerization domain strongly dominated the Ca2+ sensitivity of cyclase regulation by GCAP1 in RetGC1 heterodimer produced by co-expression of WT and the R838S subunits. It required higher Ca2+ concentrations to decelerate GCAP-activated RetGC1 heterodimer—6-fold higher than WT and 2-fold higher than the Ser838-harboring homodimer. The heterodimer was also more resistant than homodimers to inhibition by RD3. The observed biochemical changes can explain the dominant CORD6 blindness and recessive LCA1 blindness, both of which affect rods and cones, but they cannot explain the selective loss of rod function in recessive CSNB.

Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins

Accumulation of misfolded and mistrafficked rhodopsin on the endoplasmic reticulum of photoreceptor cells has a pivotal role in the pathogenesis of retinitis pigmentosa and a subset of Leber’s congenital amaurosis. One potential strategy to reduce rhodopsin misfolding and aggregation in these conditions is to use opsin-binding compounds as chemical chaperones for opsin. Such molecules have previously shown the ability to aid rhodopsin folding and proper trafficking to the outer cell membranes of photoreceptors. As means to identify novel chemical chaperones for rhodopsin, a structure-based virtual screening of commercially available drug-like compounds (300,000) was performed on the main binding site of the visual pigment chromophore, the 11-cis-retinal. The best 24 virtual hits were examined for their ability to compete for the chromophore-binding site of opsin. Among these, four small molecules demonstrated the ability to reduce the rate constant for the formation of the 9-cis-retinal-rhodopsin complex, while five molecules surprisingly enhanced the formation of this complex. Compound 7, 13, 20 and 23 showed a weak but detectable increase in the trafficking of the P23H mutant, widely used as a model for both retinitis pigmentosa and Leber’s congenital amaurosis, from the ER to the cell membrane. The compounds did not show any relevant cytotoxicity in two different human cell lines, with the only exception of 13. Based on the structures of these active compounds, a series of in silico studies gave important insights on the potential structural features required for a molecule to act either as chemical chaperone or as stabiliser of the 11-cis-retinal-rhodopsin complex. Thus, this study revealed a series of small molecules that represent a solid foundation for the future development of novel therapeutics against these severe inherited blinding diseases.

Multiple retinal astrocytic hamartomas in siblings with lebers congenital amaurosis: a case series and review of literature

Background Leber’s congenital amaurosis (LCA) is a known inherited retinal disease (IRD) associated with severe visual loss, nystagmus, amaurotic pupils, oculo-digital sign and markedly reduced or absent electroretinograms (ERG). Retinal astrocytic hamartomas (RAH) is a benign vascularized glial tumor of the retina. There is no known association of these two entities, more so in siblings. Case presentation A pair of siblings diagnosed as LCA who presented with RAH with no extraocular symptoms or signs of phakomatosis were imaged. Multimodal imaging was performed and are elaborately described in this article. Conclusion LCA in siblings with multiple RAHs is an extremely rare association. Recent advances in retinal imaging tools have aided in diagnosing even subtle and early RAH with high sensitivity using Infrared imaging (IRI) and Optical coherence tomography (OCT).

Intraocular Lens Dislocation into the Anterior Chamber because of Repeated Eye-Poking in a Patient with Leber’s Congenital Amaurosis

The dislocation of a posterior chamber intraocular lens (PC IOL) because of constant eye rubbing is unusual and has never been reported in a child with Leber’s congenital amaurosis (LCA). A 4-year-old full-term girl with an ocular history of LCA presented to the emergency room with a single-piece PC IOL dislocated into the anterior chamber (AC) of the left eye. There was no history of trauma or any other surgical intervention. A specific behavior known as Franceschetti’s oculo-digital sign is a characteristic feature of LCA; this sign consists of repeated pressing, poking, and rubbing of the eyes with knuckles and fingers to stimulate the photoreceptors. This behavior caused the dislocation of the PC IOL into the AC. The dislocated IOL was explanted, and the patient was provided with aphakic glasses.