Genetic detection of two novel LRP5 pathogenic variants in patients with familial exudative vitreoretinopathy.

BACKGROUND: Familial exudative vitreoretinopathy (FEVR) is a genetic eye disorder that leads to abnormal development of retinal blood vessels, resulting in vision impairment. This study aims to identify pathogenic variants by targeted exome sequencing in 9 independent pedigrees with FEVR and characterize the novel pathogenic variants by molecular dynamics simulation. METHODS: Clinical data were collected from 9 families with FEVR. The causative genes were screened by targeted next-generation sequencing (TGS) and verified by Sanger sequencing. In silico analyses (SIFT, Polyphen2, Revel, MutationTaster, and GERP + +) were carried out to evaluate the pathogenicity of the variants. Molecular dynamics was simulated to predict protein conformation and flexibility transformation alterations on pathogenesis. Furthermore, molecular docking techniques were employed to explore the interactions and binding properties between LRP5 and DKK1 proteins relevant to the disease. RESULTS: A 44% overall detection rate was achieved with four variants including c.4289delC: p.Pro1431Argfs*8, c.2073G > T: p.Trp691Cys, c.1801G > A: p.Gly601Arg in LRP5 and c.633 T > A: p.Tyr211* in TSPAN12 in 4 unrelated probands. Based on in silico analysis and ACMG standard, two of them, c.4289delC: p.Pro1431Argfs*8 and c.2073G > T: p.Trp691Cys of LRP5 were identified as novel pathogenic variants. Based on computational predictions using molecular dynamics simulations and molecular docking, there are indications that these two variants might lead to alterations in the secondary structure and spatial conformation of the protein, potentially impacting its rigidity and flexibility. Furthermore, these pathogenic variants are speculated to potentially influence hydrogen bonding interactions and could result in an increased binding affinity with the DKK1 protein. CONCLUSIONS: Two novel genetic variants of the LRP5 gene were identified, expanding the range of mutations associated with FEVR. Through molecular dynamics simulations and molecular docking, the potential impact of these variants on protein structure and their interactions with the DKK1 protein has been explored. These findings provide further support for the involvement of these variants in the pathogenesis of the disease.

Impact of anti-VEGF therapy on distinctive retina layers in patients with macular edema secondary to branch retinal vein occlusion.

BACKGROUND: To explore the impact of anti-vascular epithelial growth factor (ant-VEGF) on the thickness of each retinal layer in patients with macular edema (ME) secondary to the branch retinal vein occlusion (BRVO). METHODS: This retrospective study included patients with ME secondary to monocular BRVO who received anti-VEGF therapy in Ningxia Eye Hospital between January-December 2020. RESULTS: Forty-three patients (25 males) were included, with 31 showed > 25% reduction in central retinal thickness (CRT) after anti-VEGF therapy (response group), and the others showed a ≤25% reduction in CRT (no-response group). The response group showed significantly smaller mean changes in the ganglion cell layer (GCL) (after 2 months) and inner plexiform layer (IPL) (after 1, 2, and 3 months) and significantly greater mean changes in the inner nuclear layer (INL) (after 2 and 3 months), outer plexiform layer (OPL) (after 3 months), outer nuclear layer (ONL) (after 2 and 3 months), and CRT (after 1 and 2 months) (all P < 0.05) as compared to the no-response group. The mean change in the thickness of each retinal layer IPL (P = 0.006) between the two groups was significantly different after controlling for a time and with a significant time trend (P < 0.001). Additionally, patients in the response group were more likely to have an improvement in IPL (43.68 ± 6.01 at 1 month and 41.52 ± 5.45 at 2 months vs. 39.9 ± 6.86 at baseline) after anti-VEGF therapy, while those in no response group might show improvement in GCL (45.75 ± 8.24 at 1 month, 40.00 ± 8.92 at 2 months, and 38.83 ± 9.93 at 3 months vs. 49.67 ± 6.83 at baseline). CONCLUSIONS: Anti-VEGF therapy might help restore the retinal structure and function in patients with ME secondary to BRVO, and those who have a response after anti-VEGF therapy are more likely to improve IPL, while those having no response might show improvement in GCL.

Factors correlated with the resolution of macular oedema after one dose injection of intravitreal triamcinolone acetonide treatment in branch retinal vein occlusion.

OBJECTIVE: To investigate the predictive baseline factors for a successful outcome following one dose of intravitreal triamcinolone acetonide (IVTA) in patients with macular oedema (ME) caused by branch retinal vein occlusion (BRVO). METHODS: This retrospective study enrolled patients with ME (macular retinal thickness [MRT] ≥ 300 µm) due to BRVO who still had ME 3 months after grid laser photocoagulation. Patients were divided according to treatment into an IVTA group and a laser-only group. The resolution of ME was documented at months 3 and 6. RESULTS: A total of 154 eyes with ME were investigated: IVTA group (90 eyes) and laser-only group (64 eyes). Predictive factors for successful IVTA treatment were younger age, shorter duration of ME, initial onset ME, accompanied by serous retinal detachment, few concomitant systemic diseases and nonischaemic BRVO. A broken foveal capillary ring was related to a poor treatment outcome. Eyes with cystoid spaces in the outer plexiform layer were more likely to have a good treatment response. CONCLUSION: IVTA is effective for resolving ME due to BRVO after grid laser photocoagulation treatment.