Ophthalmic Genetics最新文献

Stem cell-based therapy has gained importance over the past decades due to huge advances in science and technology behind the generation and directed differentiation of pluripotent cells from embryos and adult cells. Preclinical proof-of-concept studies have been followed by clinical trials showing efficacy and safety of transplantation of stem cell-based therapy, which are beginning to establish this as a modality of treatment. Disease candidates of interest are primarily conditions that may benefit from replacing dead or dying cells, including advanced inherited retinal dystrophies and age-related macular degeneration, and predominantly seek to transplant either RPE or photoreceptors, although neurotrophic approaches have also been trialed. Whilst a consensus has yet to be reached about the best stage/type of cells for transplantation (stem cells, progenitor cells, differentiated RPE and photoreceptors) and the methods of implantation (sheet, suspension), several CTs have shown safety. There remain potential concerns regarding tumorigenicity and immune rejection; however, with ongoing improvements in cell generation, selection, and delivery, these can be minimized. Earlier studies showed efficacy with immunosuppressive drugs to prevent rejection, and recent donor-matched transplants have avoided the need for immunosuppression. Retinal regenerative medicine is a challenging field and is in a nascent stage but holds tremendous promise. This narrative review delves into the current understanding of stem cells and the latest clinical trials of retinal cell transplantation.

Background: One of the conditions that might harm your eyesight is diabetic retinopathy (DR), DR may set in slowly but surely for those with long-term diabetes and poor glucose control. ‎.

Objective: To establish a connection between the various genotypes of the rs1800624 SNP and the rs80096349 SNP located in the AGER gene and DR patients. ‎.

Methods: The current case-control research examined one hundred thirty-four individuals diagnosed with type 2 diabetes and thirty-six healthy individuals who did not have DM. These samples were obtained from Amir Al-Muminin, a private hospital in Najaf, Iraq. The tetra primers ARMS-PCR method was utilized to determine the genotype of rs1800624 SNP of the AGER gene.

Results: A significant association was found between genotypes (AA, AG, and GG) and DR subgroups (NPDR & PDR) in patients (p = 0.001). The AG genotype of rs1800624 SNP is associated with a lowering the risk of developing NPDR (OR = 0.30; 95% CI = 0.12-0.74; p = 0.009 between controls and NPDR, OR = 0.36; 95% CI = 0.14-0.90; p = 0.029 between NDR and NPDR). HRM analysis verified the presence of only two genotypes in the samples: wild type (GG) and a heterozygous mutant (GA). However, a significant association between genotypes was observed when comparing DR status with controls and NDR (p = 0.031).

Conclusion: The rs1800624 SNP of the AGER gene is associated with the risk of NPDR and PDR in T2DM, and the polymorphism of the rs80096349 may be associated with retinopathy in the Iraqi population.

Background: Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive autoinflammatory disorder associated with systemic vasculitis and bone marrow failure. Reported ophthalmic findings in DADA2 include optic neuritis, retinal artery occlusion, uveitis, and optic atrophy. We report the case of a child found to have bilateral cataracts.

Case report: A three-year-old recent immigrant from Mexico with a diagnosis of DADA2 and transfusion-dependent anemia was referred to ophthalmology to screen for deferasirox-associated retinopathy in the setting of hemochromatosis. He was incidentally found to have bilateral posterior subcapsular cataracts with no other ophthalmic abnormalities. The child's lab findings were significant for chronic hyperferritinemia, and his history was significant for over a year of oral prednisone use in Mexico.

Conclusions: This is the first reported case of cataracts in a child with DADA2. While DADA2 is an autoinflammatory disorder, this child's lack of uveitis suggests a non-inflammatory etiology. Hyperferritinemia is a known cause of cataracts and is common in DADA2, but the child's history of oral steroid use in Mexico could also explain his cataracts. As pediatric cataracts have not otherwise been reported in DADA2, ophthalmologists should be aware of this possibility, especially in children with hyperferritinemia or a history of steroid use.

Purpose: To investigate whether genetic and clinical characteristics differ depending on generations using 326 patients (male/female, 259/67; mean age, 55.4 ± 12.5 years) with simple CSC.

Methods: All patients were diagnosed with simple CSC, defined as a retinal pigment epithelium alteration area equal to or smaller than 2-disc areas based on multimodal imaging at the initial presentation. We cross-sectionally evaluated clinical characteristics at the initial visit and genotyped CFH rs800292 and rs1329428 for all patients using TaqMan technology.

Results: As generations decreased, the proportion of males, subfoveal choroidal thickness, and prevalence of fibrin significantly increased (p < 0.001, p < 0.001, and p = 0.012, respectively), and the best-corrected visual acuity improved (p < 0.001); in contrast, the prevalence of pachydrusen significantly decreased (p < 0.001). The younger presentation was significantly associated with male and risk variants (T allele) of CFH rs1329428 (p = 9.1 × 10^-7 and p = 0.042, respectively), and patients were estimated to present 2 years younger per one T allele of CFH rs1329428 (p = 0.042, β = -1.95, stepwise regression analysis).

Conclusion: Clinical and genetic characteristics differed significantly among patients with simple CSC, depending on their generation.

Purpose: This study aims to estimate the potential causal relationship between genetically predicted levels of inflammatory cytokine and retinitis pigmentosa (RP) by performing Mendelian randomization (MR).

Methods: Single nucleotide polymorphisms (SNPs) were identified as instrumental variables (IVs) from publicly available genome-wide association study datasets. Inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were applied in this MR analysis. IVW and MR-Egger were used to confirm heterogeneity and pleiotropy of identified IVs. Leave-one-SNP-out analysis was used to identify SNPs with potential impact.

Results: IVW results revealed that elevated levels of Tumor Necrosis Factor Alpha (TNF-α), Macrophage Inflammatory Protein-1a (MIP1a), and Monokine Induced by Gamma Interferon (MIG) were associated with higher RP risk (OR = 2.358, p = 0.050; OR = 2.583, p = 0.013; OR = 1.851, p = 0.015), while elevated levels of Interleukin-16 (IL-16) were associated with reduced RP risk (OR = 0.723, p = 0.019). The results of heterogeneity and pleiotropy (p > 0.05) confirmed there was no pleiotropy and heterogeneity in our IVW analysis. The association of TNF-α, MIP1a, MIG and IL-16 with RP from sensitivity analyses using these two sets of restricted IVs remained stable.

Conclusion: Our study provides evidence of potential causal relationships between several circulating cytokine levels and RP. Elevated levels of TNF-α, MIP1a, and MIG are associated with a higher risk of RP, while elevated levels of IL-16 are associated with a lower risk of RP. These cytokines may be novel biomarkers and therapeutic targets for RP.

Purpose: To report the occurrence of unilateral, neonatal-onset congenital glaucoma in a child with Rubinstein-Taybi Syndrome (RTS).

Case report: A 15-day-old male with features of RTS was presented with an enlarged corneal diameter, corneal haze, and peripheral corneal vascularization of the left eye. Ultrasound biomicroscopy of his left eye revealed iris atrophy, iridocorneal adhesions, and iris adhesions to a partially absorbed cataractous lens. Genetic evaluation of the child and the parents revealed a novel de novo heterozygous pathogenic variant in exon 5 of the CREBBP gene (NM_004380.3:c.1390C>T). A diode laser cyclophotocoagulation was performed to control the IOP in the left eye.

Conclusion: Unilateral neonatal-onset congenital glaucoma due to iridocorneal adhesions can be a rare presentation of Rubinstein-Taybi Syndrome.

Background: Neurofibromatosis type-2-related schwannomatosis (NF2-SWN, formerly neurofibromatosis type 2) is a rare genetic disorder marked by the development of multiple nervous system tumors.

Case presentation: We report a 21-month-old female patient who presented for left eye deviation. Upon examination, intermittent exotropia and a fundus mass were detected. Wide field fundus examination revealed the presence of a combined hamartoma involving the optic nerve and retina. This finding was supported by MRI highlighting the lesion's characteristics. The patient's father and other relatives on the paternal side displayed symptoms of NF2-SWN, evident through the presence of acoustic neuroma, although they did not exhibit any ocular symptoms. DNA analysis revealed a novel loss-of-function mutation in exon 15 of the NF2 gene (NM_000268.3: c.1627_1628del, p.Lys543Aspfs *21) in both the patient and her father at a heterozygous state. By the age of three, her vision worsened, and optical coherence tomography showed vitreomacular traction and intraretinal fluid surrounding the lesion.

Conclusion: This case underscores the need to consider NF2- SWN in peripapillary hamartoma diagnoses and highlights the importance of genetic testing for early detection and management.

Background: The clinical approach to inherited eye diseases has evolved due to advances in genetic testing methods and treatment opportunities. However, no data are available on the current practices of ophthalmologists in countries, such as Turkey, with higher rates of consanguinity and inherited eye diseases. The aim of this study was to evaluate the current practices, knowledge, and needs of ophthalmologists in Turkey regarding inherited eye diseases.

Methods: A 29-item self-administered survey with a branching algorithm was developed through Google Forms. The survey link was sent to 2983 ophthalmologists in Turkey. The survey assessed respondents' occupational characteristics, current practices, knowledge about available diagnostic and therapeutic options, and opinions on improving continuing education and healthcare services.

Results: Responses from 414 ophthalmologists (20.8%) were analyzed. The responses suggested that ophthalmologists mainly collaborate with medical geneticists in respect of inherited eye diseases. The majority of ophthalmologists reported a lack of knowledge about genetic diagnostic tests, and approximately 90% of the ophthalmologists thought training after residency was inadequate for inherited eye diseases.

Conclusion: This is the most extensive survey exploring ophthalmologists' practice patterns and needs in a setting without specialists or specialized centers in ophthalmic genetics. The results emphasize the need for continued education on updated approaches to inherited eye diseases.

Background: Biallelic pathogenic variants in CDH23 can cause Usher syndrome type I (USH1), typically characterized by sensorineural hearing loss, variable vestibular areflexia, and a progressive form of rod-cone dystrophy. While missense variants in CDH23 can cause DFNB12 deafness, other variants can affect the cadherin 23 function, more severely causing Usher syndrome type I D. The main purpose of our study is to describe the genotypes and phenotypes of patients with mild retinitis pigmentosa (RP), including sector RP with two pathogenic variants in CDH23.

Materials and methods: Clinical examination included medical history, comprehensive ophthalmologic examination, and multimodal retinal imaging, and in case 1 and 2, full-field electroretinography (ERG). Genetic analysis was performed in all cases, and segregation testing of proband relatives was performed in case 1 and 3.

Results: Three unrelated cases presented with variable clinical phenotype for USH1 and were found to have two pathogenic variants in CDH23, with missense variant, c.5237 G > A: p.Arg1746Gln being common to all. All probands had mild to profound hearing loss. Case 1 and 3 had mild RP with mid peripheral and posterior pole sparing, while case 2 had sector RP. ERG results were consistent with the marked loss of retinal function in both eyes at the level of photoreceptor in case 1 and case 2, with normal peak time in the former.

Conclusion: Patients harbouring c.5237 G > A: p.Arg1746Gln variants in CDH23 can present with a mild phenotype including sector RP. This can aid in better genetic counselling and in prognostication.

Purpose: To explore patterns of disease expression in Alagille syndrome (ALGS).

Methods: Patients underwent ophthalmic examination, optical coherence tomography (OCT) imaging, fundus intravenous fluorescein angiography (IVFA), perimetry and full-field electroretinograms (ffERGs). An adult ALGS patient had multimodal imaging and specialized perimetry.

Results: The proband (P1) had a heterozygous pathogenic variant in JAG1; (p.Gln410Ter) and was incidentally diagnosed at age 7 with a superficial retinal hemorrhage, vascular tortuosity, and midperipheral pigmentary changes. The hemorrhage recurred 15 months later. Her monozygotic twin sister (P2) had a retinal hemorrhage at the same location at age 11. Visual acuities for both patients were 20/30 in each eye. IVFA was normal. OCT showed thinning of the outer nuclear in the peripapillary retina. A ffERG showed normal cone-mediated responses in P1 (rod-mediated ERGs not documented), normal ffERGs in P2. Coagulation and liver function were normal. An unrelated 42-year-old woman with a de-novo pathogenic variant (p. Gly386Arg) in JAG1 showed a similar pigmentary retinopathy and hepatic vascular anomalies; rod and cone function was normal across large expanses of structurally normal retina that sharply transitioned to a blind atrophic peripheral retina.

Conclusion: Nearly identical recurrent intraretinal hemorrhages in monozygotic twins with ALGS suggest a shared subclinical microvascular abnormality. We hypothesize that the presence of large areas of functionally and structurally intact retina surrounded by severe chorioretinal degeneration, is against a predominant involvement of JAG1 in the function of the neurosensory retina, and that instead, primary abnormalities of chorioretinal vascular development and/or homeostasis may drive the peculiar phenotypes.