Uneven Corneal Epithelial Redistribution After Femtosecond Laser-Assisted Lenticule Intrastromal Keratoplasty in Correcting Moderate-to-High Hyperopia.

PURPOSE: To evaluate the characteristic of corrective epithelial thickness after femtosecond laser-assisted lenticule intrastromal keratoplasty (LIKE) to correct moderate-to-high hyperopia. METHODS: The prospective case series study of the LIKE procedure was performed to correct moderate-to-high hyperopia. The epithelial thickness map was generated by anterior segment optical coherence tomography (AS-OCT) in the corneal central 9-mm zone. Keratometry and corneal higher order aberrations were analyzed by Pentacam (Oculus Optikgeräte GmbH) preoperatively and postoperatively. RESULTS: In the 26 eyes of 13 participants who underwent the LIKE procedure for moderate-to-high hyperopia, the attempted spherical equivalence (SEQ) was +6.50 ± 1.09 diopters (D). Compared to the preoperative epithelial thickness maps, the postoperative epithelial thickness had become significantly thinner in the central 5-mm zone; the difference was 6 to 7 µm. The paracentral epithelium performed nonuniform remodeling; the thinnest epithelial thickness was located in the inferotemporal section, which has the greatest difference from the superonasal; the difference between these two was approximately 3 µm. Through correlation analysis, it was found that the sections with thinner epithelium were significantly related to corneal curvature and corneal vertical coma. CONCLUSIONS: The LIKE procedure can be used to correct moderate-to-high hyperopia. This study further indicated the epithelial remodeling characteristic after the LIKE procedure: the central and paracentral corneal epithelial thickness becomes thinner, and the epithelial thickness distributes non-uniformly, which may be the important factor of the postoperative curvature asymmetric distribution and induction of corneal vertical coma. [J Refract Surg. 2024;40(5):e321-e327.].

Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes.

Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population and in children. The scope of this review is to familiarise clinicians and scientists with the current landscape of molecular genetics, clinical phenotype, retinal imaging and therapeutic prospects/completed trials in IRD. Herein we present in a comprehensive and concise manner: (i) macular dystrophies (Stargardt disease (ABCA4), X-linked retinoschisis (RS1), Best disease (BEST1), PRPH2-associated pattern dystrophy, Sorsby fundus dystrophy (TIMP3), and autosomal dominant drusen (EFEMP1)), (ii) cone and cone-rod dystrophies (GUCA1A, PRPH2, ABCA4, KCNV2 and RPGR), (iii) predominant rod or rod-cone dystrophies (retinitis pigmentosa, enhanced S-Cone syndrome (NR2E3), Bietti crystalline corneoretinal dystrophy (CYP4V2)), (iv) Leber congenital amaurosis/early-onset severe retinal dystrophy (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1), (v) cone dysfunction syndromes (achromatopsia (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2, ATF6), X-linked cone dysfunction with myopia and dichromacy (Bornholm Eye disease; OPN1LW/OPN1MW array), oligocone trichromacy, and blue-cone monochromatism (OPN1LW/OPN1MW array)). Whilst we use the aforementioned classical phenotypic groupings, a key feature of IRD is that it is characterised by tremendous heterogeneity and variable expressivity, with several of the above genes associated with a range of phenotypes.

Non-vasogenic cystoid maculopathy in autosomal recessive bestrophinopathy: novel insights from NIR-FAF and OCTA imaging.

BACKGROUND: Autosomal Recessive Bestrophinopathy (ARB) is an inherited retinal disease caused by biallelic mutations in the BEST1 gene. Herein, we report the multimodal imaging findings of ARB presenting with cystoid maculopathy and investigate the short-term response to combined systemic and topical carbonic anhydrase inhibitors (CAIs). MATERIAL AND METHODS: An observational, prospective, case series on two siblings affected by ARB is presented. Patients underwent genetic testing and optical coherence tomography (OCT), blue-light fundus autofluorescence (BL-FAF), near-infrared fundus autofluorescence (NIR-FAF), fluorescein angiography (FA), MultiColor imaging, and OCT angiography (OCTA). RESULTS: Two male siblings, aged 22 and 16, affected by ARB resulting from c.598C>T, p.(Arg200*) and c.728C>A, p.(Ala243Glu) BEST1 compound heterozygous variants, presented with bilateral multifocal yellowish pigment deposits scattered through the posterior pole that corresponded to hyperautofluorescent deposits on BL-FAF. Vice versa, NIR-FAF mainly disclosed wide hypoautofluorescent areas in the macula. A cystoid maculopathy and shallow subretinal fluid were evident on structural OCT, albeit without evidence of dye leakage or pooling on FA. OCTA demonstrated disruption of the choriocapillaris throughout the posterior pole and sparing of intraretinal capillary plexuses. Six months of combined therapy with oral acetazolamide and topical brinzolamide resulted in limited clinical benefit. CONCLUSIONS: We reported two siblings affected by ARB, presenting as non-vasogenic cystoid maculopathy. Prominent alteration of NIR-FAF signal and concomitant choriocapillaris rarefaction on OCTA were noted in the macula. The limited short-term response to combined systemic and topical CAIs might be explained by the impairment of the RPE-CC complex.

Nonsurgical Consecutive Exotropia Following Childhood Esotropia: A Multicentered Study.

PURPOSE: Nonsurgical consecutive exotropia (NCX) occurs when an esotropia (ET) spontaneously converts to exotropia (XT) without surgical intervention. Although NCX is considered to occur in early-onset accommodative ET with high hyperopia, consensus on causation is lacking. We report the clinical characteristics of NCX and assess the response to conservative management. DESIGN: Retrospective, multicenter, observational case series. METHODS: Patients aged 6 months and older with an initial diagnosis of ET who converted to XT without surgical intervention. Sensory strabismus was excluded. Age, visual acuity, cycloplegic refraction, glasses prescriptions, deviation, and binocular vision were collected. RESULTS: Forty-nine children were included with a mean age of 3.5 ± 1.6 years and 8.4 ± 3.6 years at the time of ET and NCX, respectively. Mean refractive error was +4.40 ± 2.13 diopters (D) and +4.05 ± 2.74 D at the time of ET and NCX, respectively. Accommodative ET occurred in 60% of cases, and only 35.7% were high hyperopes. All but 1 patient presented with XT at distance. In response to the XT, a mean decrease in hyperopic prescription of 1.55 ± 0.48 D was given (N = 17); only 1 case reverted to ET. Eventually, 43% underwent XT surgery, with similar rates between those who had refractive management and those who did not. CONCLUSIONS: NCX occurs in both accommodative and nonaccommodative ET; high hyperopia is present in only one-third of cases. On average, drift to XT occurs within 5 years. Refractive management has a modest result. No predictive risk factors were identified. Our findings challenge hyperopia-linked theories of causation. Nonrefractive explanations, such as the role of the vergence system, deserve further study.

Clinical and Genetic Characterization of RDH12-Retinal Dystrophy in a South American Cohort.

PURPOSE: To characterize the largest cohort of individuals with retinol dehydrogenase 12 (RDH12)-retinal dystrophy to date, and the first one from South America. DESIGN: Retrospective multicenter international study. SUBJECTS: Seventy-eight patients (66 families) with an inherited retinal dystrophy and biallelic variants in RDH12. METHODS: Review of clinical notes, ophthalmic images, and molecular diagnosis. MAIN OUTCOME MEASURES: Visual function, retinal imaging, and characteristics were evaluated and correlated. RESULTS: Thirty-seven individuals self-identified as Latino (51%) and 34 as White (47%). Sixty-nine individuals (88%) had Leber congenital amaurosis (LCA)/early-onset severe retinal dystrophy. Macular and midperipheral atrophy were seen in all patients from 3 years of age. A novel retinal finding was a hyperautofluorescent ring in 2 young children with LCA. Thirty-nine patients (50%) had subsequent visits, with mean follow-up of 6.8 ± 7.3 (range, 0-29) years. Eight variants (21%) were previously unreported, and the most frequent variant was c.295C>A, p.Leu99Ile, present in 52 alleles of 32 probands. Individuals with LCA homozygous for p.Leu99Ile (31%) had a later age of onset, a slower rate of best-corrected visual acuity decrease, the largest percentage of patients with mild visual impairment, and were predicted to reach legal blindness at an older age than the rest of the cohort. CONCLUSIONS: By describing the largest molecularly confirmed cohort to date, improved understanding of disease progression was possible. Our detailed characterization aims to support research and the development of novel therapies that may have the potential to reduce or prevent vision loss in individuals with RDH12-associated retinal dystrophy. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures.

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.

Drug metabolic activity as a selection factor for pluripotent stem cell-derived hepatic progenitor cells.

As a metabolic organ, the liver plays a variety of roles, including detoxification. It has been difficult to obtain stable supplies of hepatocytes for transplantation and for accurate hepatotoxicity determination in drug discovery research. Human pluripotent stem cells, capable of unlimited self-renewal, may be a promising source of hepatocytes. In order to develop a stable supply of embryonic stem cell (ESC)-derived hepatocytes, we have purified human ESC-derived hepatic progenitor cells with exposure to cytocidal puromycin by using their ability to metabolize drugs. Hepatic progenitor cells stably proliferated at least 220-fold over 120 days, maintaining hepatic progenitor cell-like properties. High drug-metabolizing hepatic progenitor cells can be matured into liver cells by suppressing hepatic proliferative signals. The method we developed enables the isolation and proliferation of functional hepatic progenitors from human ESCs, thereby providing a stable supply of high-quality cell resources at high efficiency. Cells produced by this method may facilitate cell therapy for hepatic diseases and reliable drug discovery research.

[Selective fundus screening for high-risk newborns: a realistic move in the Chinese mainland].

Owing to the popularization of fundus screening for high-risk prematurity promoted by the state, the prevention and treatment of retinopathy of prematurity (ROP) in China has achieved remarkable results in recent years. Accordingly, the applicable population scope for newborn fundus screening is under heated discussion. Is it better to screen for all neonates or selective high-risk newborns, who meet the national ROP guidelines, have a history of familial or/and hereditary eye diseases or a systemic disease related to the eye after birth, or show an abnormal eye appearance or suspicious eye diseases in the primary care examination? Despite the advantages of general screening in detecting and treating some malignant eye diseases in a timely manner, the conditions for carrying out general newborn screening are not mature, and there are certain risks in the fundus examination of children. This article points out that the rational use of existing scarce medical resources to carry out selective fundus screening for newborns with high risks of eye diseases is practical in clinical work.

Long-term anatomical and functional outcomes of surgical treatment of retinal complications in children and adolescents with Stickler syndrome between 2004 and 2021.

BACKGROUND: Stickler syndrome (STL) is an inherited progressive connective tissue collagen disorder. STL is the most common hereditary cause of retinal complications, retinal tears, and the development of retinal detachment (RD) in childhood. The aim of the study was to evaluate the long-term anatomical and functional results of surgical treatment of retinal complications in children and adolescents affected by STL. METHODS: A retrospective, single-center study was performed a cohort of children with STL who underwent retinal surgery between 2004 and 2021. RESULTS: The study group consisted of nine children; the mean age at the time of the retinal tear with/without retinal detachment was 7.2 (2-10) years, and the mean follow-up period was 9.6 (5-16) years. Pathogenic variants COL2A1 (5 children) and COL11A1 (3 children) were confirmed in our cohort. In total, we operated on 13 eyes, 11 eyes with complicated RD and two eyes with multiple retinal defects, but without RD. At the end of the follow-up period, an attached retina was achieved 77% (10 eyes) with or without silicone oil tamponade: cryopexy alone was successful in one eye (10%), scleral buckling (EB) in five eyes (50%), and vitrectomy with silicone oil tamponade combined with EB in four eyes (40%). The mean number of surgeries was 2.3 per eye. The resulting best corrected visual acuity ranged from 0.03 to 0.1 in one eye, from 0.16 to 0.4 in two eyes, and from 0.5 to 1.0 in 7 eyes. CONCLUSION: Repair of retinal tears with/without retinal detachment in patients with Stickler syndrome often requires multiple surgeries with combinations of cryopexy, scleral buckling, and/or vitrectomy with silicone oil tamponade. Treatment of the ocular complications arising from STL requires long-term comprehensive care.

Progressive degeneration of the retina in Loxl3 mutant mouse model of Stickler syndrome.

Stickler syndrome is a multisystem collagenopathy with affected individuals exhibiting a high rate of ocular complications. Lysyl oxidase-like 3 (LOXL3) is a human disease gene candidate with a critical role in catalyzing collagen crosslinking. A homozygous missense variant of LOXL3 was reported in Stickler syndrome with severe myopia. However, the underlying mechanisms of the LOXL3 missense mutation that causes Stickler syndrome are unknown. In this study, a mouse model of Stickler syndrome induced by LOXL3 mutation (c.2027G â€‹> â€‹A, p.Cys676Try) was obtained using CRISPR/Cas9 gene editing techniques. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, and cleft palate, and Loxl3 mutation also induced skeletal dysplasia and progressive visual degeneration. Furthermore, we observed the damage of the bruch's membrane (BrM) and an increase in the levels of glial fibrillary acidic protein (GFAP) and Rpe65 in the Loxl3 mutant mice. Thus, we provided the critical in vivo evidence that Loxl3 possibly has a pivotal role in maintaining the eye function.

Dual phenotype: co-occurring Leber congenital amaurosis and familial exudative vitreoretinopathy: a case report.

PURPOSE: To report the concurrent presentation and management of IQCB1-associated Leber Congenital Amaurosis and NDP-associated Familial Exudative Vitreoretinopathy (FEVR). MATERIALS AND METHODS: A 6-month-old Caucasian infant presented with poor visual response, high hypermetropia, and infantile-nystagmus with a provisional diagnosis of Leber Congenital Amaurosis based on clinical findings. Genetic counseling and testing were performed with a 285 gene retinal dystrophy panel (Blueprint Genetics). Clinical characteristics, presentation, ancillary testing results, and management are described. RESULTS: Two previously reported heterozygous pathogenic variants in ICQB1 were identified (c.1518_1519del (p.His506Glnfs*13) and c.1381C>T, p.Arg461*) segregating in trans. In addition, a variation of uncertain significance (VUS) was found in NDP (c.280C>T; p.His94Tyr). Fluorescein angiography was performed demonstrating peripheral avascularity and retinal telangiectasia without frank neovascularization. Peripheral ablative laser was applied to the avascular zone. CONCLUSIONS: The NDP VUS likely represents a pathogenic variant given the FEVR phenotype in addition to retinal degeneration, creating a rare dual phenotype. The combination of low oxygen demand from the IQCB1-associated retinal degeneration and NDP variant may have led to a more attenuated FEVR presentation with uncertain prognosis. A molecular diagnosis informed ocular and renal surveillance, as well as the recurrence risk for future offspring.

MFRP variant results in nanophthalmos, retinitis pigmentosa, variability in foveal avascular zone.

BACKGROUND: Membrane frizzled-related protein (MFRP) plays a critical role in ocular development. MFRP mutations are known to cause nanophthalmos and, in some cases, retinitis pigmentosa, foveoschisis, and/or optic nerve head (ONH) drusen. The broad clinical spectrum of MFRP mutations necessitates further investigation of specific genotype-phenotype relationships. MATERIALS AND METHODS: We reviewed ophthalmologic and genetic medical records of two affected siblings and one unaffected sibling. RESULTS: Genetic testing revealed variants MFRP c.855T>A, p.(Cys285*) and MFRP c.1235T>C, p.(Leu412Pro) in trans in the two affected siblings. In both cases, photopic and scotopic responses were markedly reduced on electroretinogram (ERG), with greater decrease in scotopic function. Optical coherence tomography for both siblings revealed non-cystoid thickening. Blunted foveal reflexes were also observed in both siblings. Notably, foveal avascular zone abnormalities were seen on fundus autofluorescence in only one affected sibling. CONCLUSIONS: MFRP-related ocular disease may be underrecognized due to its presentation with high hyperopia and possibly subtle retinal findings. Presence of variants MFRP c.855T>A, p.(Cys285*) and MFRP c.1235T>C, p.(Leu412Pro) in trans resulted in nanophthalmos and retinitis pigmentosa without associated foveoschisis or ONH drusen in our patients, consistent with the incomplete phenotype previously described in Neri et al. Abnormalities in the foveal avascular zone have been noted in other case studies and were inconsistently associated with the variants described here, representing a potential area for future investigation.

Ocular manifestations of systemic diseases in children.

Knowledge of ocular diseases and understanding of the complex interplay between eye and systemic health have increased over the years. This knowledge is particularly important when caring for our youngest and most vulnerable paediatric patients when ophthalmic manifestations may provide an insight to underlying systemic diseases and can act as the first indicator of an undiagnosed systemic condition. Further, the visual system can be vulnerable to manifestations of known systemic disease, with vigilant ophthalmic examination generally aiding early identification of ocular complications for collaborative multidisciplinary care to prevent avoidable vision loss. The potential ocular signs and complications of the following developmental, genetic or acquired childhood systemic disorders are presented: premature birth, trisomy 21, albinism, Marfan's syndrome, Stickler's syndrome, septo-optic dysplasia, aniridia, neurofibromatosis 1, Sturge-Weber syndrome, papilloedema, juvenile idiopathic arthritis and vitamin A deficiency. Rather than providing an exhaustive list of diseases, this review offers an overview of the more commonly encountered congenital or acquired childhood systemic conditions that have associated childhood ophthalmic disorders and presents referral and ongoing surveillance recommendations.

[A case of autologous corneal stromal lenticule transplantation and vision function training in the correction of hyperopia].

Hypermetropic anisometropia is often accompanied by visual fatigue, and the higher hyperopia is prone to form amblyopia. To avoid Wear glasses fatigue, the higher hyperopia is often under corrected and regulative spasm. Pseudomyopia may occur in the early stage after refractive surgery. In this case, autologous corneal stromal lenticule transplantation was used to correct hyperopia. After standard visual cognitive training, the Uncorrected Distance Visual Acuity was rapidly improved, and the binocular vision was normal.

[Anatomical and morphometric features of anterior eye segment structures in hyperopia and the risk of developing primary angle-closure glaucoma]. / Anatomo-morfometricheskie osobennosti struktur perednego segmenta glaza pri gipermetropii i risk razvitiya pervichnoi zakrytougol'noi glaukomy.

PURPOSE: To study features of anatomical and morphometric parameters of the structures of anterior eye segment in young patients with moderate and high hyperopia in order to identify the signs of an increased risk of developing primary angle-closure glaucoma (PACG) and its acute attack. MATERIAL AND METHODS: The study included 160 eyes (80 patients) with axial length (AL) of less than 23 mm. Patients with moderate or high hyperopia were divided into two groups according to their age ranges (the 1st - 27 patients (54 eyes) under 40 years old; the 2nd - 27 patients (54 eyes) of 41-50 years old, the comparison group - 26 patients (52 eyes) of 42-50 years old with the initial stage of PACG. AL of the eyes, anterior chamber (AC) depth in the central zone, lens thickness (LT) in the optical zone were measured using IOL Master 700 («Carl Zeiss Meditec AG¼, Germany). AC volume and peripheral AC depth were measured using rotating Scheimpflug camera Pentacam («Oculus¼, Germany). RESULTS: While the average values of AL in patients of the 1st and 2nd groups were comparable, a statistically significant decrease in AC depth and a significant increase in LT were revealed in the 2nd group. There was a statistically significant increase in LT, a decrease in peripheral AC depth and AC volume in the comparison group relative to the 2nd group. In the 1st group: in 2 eyes of one 38-year-old patient the maximum proximity of all 3 indices to the median values of the group of patients with PACG was found; in 4 eyes of two other patients (35 and 38 years old), a combination of small AC volume with increased LT or small AC volume with small AC on the periphery was noted. CONCLUSION: Significant differences in terms of LT, peripheral AC depth and AC volume were found between age-comparable (41-50 years old) healthy individuals with short eyes and patients with initial PACG. In 11% of the eyes of healthy patients with hyperopia aged 21 to 40 years, there was a combination of two or three of the studied morphometric signs, which may indicate the risk of developing PACG.

Hearing Loss in Stickler Syndrome: An Update.

Stickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory manifestations. Its main symptoms are high myopia, retinal detachment, joint hypermobility, early osteoarthritis, cleft palate, midfacial hypoplasia, micrognathia and hearing loss. Large phenotypical variability is apparent and partly explained by the underlying genetic heterogeneity, including collagen genes (COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3) and non-collagen genes (BMP4, LRP2, LOXL3). The most frequent type of Stickler syndrome (COL2A1) is characterized by a rather mild high-frequency sensorineural hearing loss in about half of the patients. COL11A1- and COL11A2-related Stickler syndrome results in more frequent hearing loss, being moderate and involving all frequencies. Hearing loss in the rarer types of Stickler syndrome depends on the gene expression in the cochlea, with moderate to severe downsloping hearing loss for Stickler syndrome caused by biallelic type IX collagen gene mutations and none or mild hearing loss for the non-collagen genes. Inherent to the orofacial manifestations, middle ear problems and temporary conductive hearing loss, especially at young age, are also prevalent. Consequently, hearing loss should be actively sought for and adequately treated in Stickler syndrome patients given its high prevalence and the concomitant visual impairment in most patients.