Long-Term Follow-Up of Pediatric Excimer Laser-Assisted Penetrating Keratoplasty for Congenital Stromal Corneal Dystrophy.

PURPOSE: The purpose of this study was to highlight characteristic clinical and microscopic findings and report the long-term follow-up of pediatric excimer laser-assisted penetrating keratoplasty (excimer-PKP) for congenital stromal corneal dystrophy (CSCD). METHODS: A 2-year-old Greek child presented with CSCD at our department. Clinical examination showed bilateral flake-like whitish corneal opacities affecting the entire corneal stroma up to the limbus. Genetic testing identified a mutation of the decorin gene (c.962delA). The variant was not present in the parents and represented a de novo mutation. The uncorrected visual acuity was 20/100 in both eyes. Excimer-PKP (8.0/8.1 mm) was performed on the right eye at the age of 2.5 years and on the left eye at the age of 3 years. Postoperatively, alternating occlusion treatment was performed. RESULTS: The light microscopic examination demonstrated a disorganized extracellular matrix of the corneal stroma characterized by a prominent irregular arrangement of stromal collagen lamellae with large interlamellar clefts containing ground substance, highlighted by periodic acid-Schiff- and Alcian blue-positive reaction detecting acid mucopolysaccharides. Electron microscopy showed disorganization and caliber variation of collagen lamellae and thin filaments within an electron-lucent ground substance. The postoperative course was unremarkable. Both grafts remained completely clear 14 years postoperatively. Corneal tomography showed moderate regular astigmatism with normal corneal thickness. The corrected distance visual acuity was 20/25 in both eyes. CONCLUSIONS: Excimer-PKP for CSCD might be associated with excellent long-term results and a good prognosis, particularly when the primary surgery is performed at a very young age. However, this requires close postoperative follow-up examinations by an experienced pediatric ophthalmologist to avoid severe amblyopia.

Protein profiling of conjunctival impression cytology samples of aniridia subjects.

PURPOSE: Congenital aniridia is a rare disease, which is in most cases related to PAX6 haploinsufficiency. Aniridia associated keratopathy (AAK) also belongs to ocular signs of congenital aniridia. In AAK, there is corneal epithelial thinning, corneal inflammation, vascularization and scarring. In advanced stage AAK, typically, conjunctival epithelial cells slowly replace the corneal epithelium. Based on previous results we hypothesize that alterations of the conjunctival cells in congenital aniridia may also support the corneal conjunctivalization process. The aim of this study was to identify deregulated proteins in conjunctival impression cytology samples of congenital aniridia subjects. METHODS: Conjunctival impression cytology samples of eight patients with congenital aniridia [age 34.5 ± 9.9 (17-51) years, 50% female] and eight healthy subjects [age 34.1 ± 11.9 (15-54) years, 50% female] were collected and analysed using mass spectrometry. Proteomic profiles were analysed in terms of molecular functions, biological processes, cellular components and pathway enrichment using the protein annotation of the evolutionary relationship (PANTHER) classification system. RESULTS: In total, 3323 proteins could be verified and there were 127 deregulated proteins (p < 0.01) in congenital aniridia. From the 127 deregulated proteins (DEPs), 82 altered biological processes, 63 deregulated cellular components, 27 significantly altered molecular functions and 31 enriched signalling pathways were identified. Pathological alteration of the biological processes and molecular functions of retinol binding and retinoic acid biosynthesis, as well as lipid metabolism and apoptosis related pathways could be demonstrated. CONCLUSIONS: Protein profile of conjunctival impression cytology samples of aniridia subjects identifies alterations of retinol binding, retinoic acid biosynthesis, lipid metabolism and apoptosis related pathways. Whether these changes are directly related to PAX6 haploinsufficiency, must be investigated in further studies. These new findings offer the possibility to identify potential new drug targets.

Visual Impairment and Low Vision Aids-A Comparison between Children and Adults.

(1) Background: This study aims to highlight differences in the etiology and fitting of low vision aids in visually impaired children and adolescents in comparison to adults. (2) Methods: A retrospective data collection from visually impaired patients presenting to obtain assistive devices from 1 January 2016 to 30 April 2020 was conducted. A total of 502 patients were included. Inclusion criteria were a minimum age of 4 years and the chart notation of a best-corrected distance visual acuity in the patient record prior to the fitting of magnifying visual aids. (3) Results: Of the 502 patients, 147 (29.3%) were children under the age of 18 years. The most common cause of visual impairment in children was albinism, and in adults, it was age-related macular degeneration (AMD). Children showed better distance visual acuity, with a median of 0.88 logMAR (Logarithm of the Minimum Angle of Resolution) compared to 1.0 in adults (p = 0.001). Near visual acuity was also significantly better, with a median of 0.54 logMAR in children compared to 0.9 in adults (p < 0.001). Near and distance visual acuity were significantly improved by fitting magnifying visual aids (p < 0.001). After fitting, near visual acuity averaged 0.3 logMAR, and distance visual acuity, 0.7. The most commonly prescribed aids were optical vision aids, which 68.5% of the patients received; 43.8% received electronic aids. In children, optical aids were more frequently prescribed, and in adults, electronic and acoustic aids (p < 0.001). (4) Conclusion: Visually impaired patients can regain the ability to read and improve distance vision by using individually adapted and tested magnifying vision aids, often with optical aids alone. Differences between children and adults could be discovered in the etiology and severity of visual impairment, as well as in the provision type of low vision aids.

The Effect of Glaucoma Treatment on Aniridia-Associated Keratopathy (AAK) - A Report from the Homburg Register for Congenital Aniridia.

BACKGROUND: Congenital aniridia is a severe malformation of almost all eye segments. Aniridia-associated keratopathy (AAK) and secondary glaucoma, which occur in more than 50% of affected individuals, are typically progressive and pose a high risk of blindness for patients with congenital aniridia. Our aim was to investigate the effect of glaucoma treatment on AAK in patients of the Homburg Aniridia Center. METHODS: Our retrospective monocentric study included patients who underwent a comprehensive ophthalmological examination at the Homburg Aniridia Center between June 2003 and January 2022. RESULTS: There were 556 eyes of 286 subjects (20.1 ± 20.1 years; 45.5% males) included. In 307 (55.2%) eyes of 163 subjects (27.5 ± 16.3 years; 43.1% males), glaucoma was present at the time of examination. The mean intraocular pressure in the glaucoma group was 19.0 mmHg (± 8.0), while in the non-glaucoma group, it was 14.1 mmHg (± 3.6) (p < 0.001). In the glaucoma group, 68 patients used antiglaucomatous topical monotherapy, 51 patients used 2 agents, 41 patients used 3 agents, 7 patients used quadruple therapy, and 140 did not use topical therapy (e.g., after pressure-lowering surgery, pain-free end-stage glaucoma, or incompliance). Patients were classified according to the following stages of AAK: Stage 0 (96 eyes [17.2%], no keratopathy), Stage 1 (178 eyes [32.0%]), Stage 2 (107 eyes [19.2%]), Stage 3 (67 eyes [12.0%]), Stage 4 (62 eyes [11.1%]), Stage 5 (45 eyes [8.0%]). The mean stage of AAK was 1.4 (1.2 - 1.5) in the group without eye drops, 1.9 (1.5 - 2.2) in the group with monotherapy, 1.8 (1.5 - 2.1) in the group with 2 drugs, 1.9 (1.5 - 2.2) in the group with 3 drugs, 3.4 (2.3 - 4.6) in the group with 4 drugs, and 3.3 (3.1 - 3.6) after antiglaucomatous surgery. The stage of AAK was significantly positively correlated with the number of pressure-lowering eye drops (p < 0.05) and prior pressure-lowering surgery (p < 0.05). Prostaglandin analogues were not correlated with a higher AAK stage compared to the other drug groups. CONCLUSIONS: At the Homburg Aniridia Center, patients using topical antiglaucomatous quadruple therapy or who had previously undergone antiglaucomatous surgery had by far the highest AAK stage. The different drug groups had no influence on the AAK stage.

Achromatopsia-Visual Cortex Stability and Plasticity in the Absence of Functional Cones.

Purpose: Achromatopsia is a rare inherited disorder rendering retinal cone photoreceptors nonfunctional. As a consequence, the sizable foveal representation in the visual cortex is congenitally deprived of visual input, which prompts a fundamental question: is the cortical representation of the central visual field in patients with achromatopsia remapped to take up processing of paracentral inputs? Such remapping might interfere with gene therapeutic treatments aimed at restoring cone function. Methods: We conducted a multicenter study to explore the nature and plasticity of vision in the absence of functional cones in a cohort of 17 individuals affected by autosomal recessive achromatopsia and confirmed biallelic disease-causing CNGA3 or CNGB3 mutations. Specifically, we tested the hypothesis of foveal remapping in human achromatopsia. For this purpose, we applied two independent functional magnetic resonance imaging (fMRI)-based mapping approaches, i.e. conventional phase-encoded eccentricity and population receptive field mapping, to separate data sets. Results: Both fMRI approaches produced the same result in the group comparison of achromatopsia versus healthy controls: sizable remapping of the representation of the central visual field in the primary visual cortex was not apparent. Conclusions: Remapping of the cortical representation of the central visual field is not a general feature in achromatopsia. It is concluded that plasticity of the human primary visual cortex is less pronounced than previously assumed. A pretherapeutic imaging workup is proposed to optimize interventions.

[Optic pit maculopathy: incidence and clinical course]. / Grubenpapillen-Makulopathie: Inzidenz und klinischer Verlauf.

PURPOSE: The aim of this case series was to investigate the clinical course of patients with optic pit maculopathy. METHODS: The medical records of all patients diagnosed with optic pit maculopathy in the past 10 years were reviewed. Optic pit maculopathy was diagnosed when localized intraretinal or/and subretinal fluid spread from the optic nerve to the macula. Outcome measures included changes in best corrected visual acuity (BCVA), central retinal thickness (RT) as well as nasal parafoveal and perifoveal RT. RESULTS: An optic disc pit was detected in 18 patients (9 female, 9 male, mean age: 33 ± 23 years). Retinal fluid accumulation was present in 6 (33.3%) of the patients (1 intraretinal, 1 subretinal, 4 intraretinal and subretinal). Pars plana vitrectomy with removal of peripapillary vitreous traction and peeling of the internal limiting membrane (ILM) was indicated in 5 patients and was performed in 4 patients. One patient underwent nanopulse laser treatment instead. The patients with optic pit maculopathy were 47 ± 16 years old. In this group of patients, mean BCVA (decimal) improved from 0.3 ± 0.2 before treatment to 0.5 ± 0.2 3 months after treatment (p = 0.03). Visual acuity improved in all patients with optic disc pit maculopathy after pars plana vitrectomy. The mean central RT decreased from 796 ± 214 before treatment to 324 ± 57 3 months after treatment (p = 0.005). The mean nasal parafoveal RT decreased from 683 ± 87 before treatment to 372 ± 41 (p = 0.0003) and the mean nasal perifoveal RT decreased from 547 ± 89 before treatment to 360 ± 48 (p = 0.007). A completely dry macula was achieved in 4 eyes after a mean follow-up of 3 months. At long-term follow-up (2.5 ± 1.2 years), no recurrence occurred in the vitrectomized eyes. CONCLUSION: This case series showed that more than one third of the patients had optic pit maculopathy presumably caused by disruption of the Kuhnt intermediate tissue. Interventional treatment was indicated in all cases, of which 4 were surgically treated and resulted in significant improvement of function and anatomical retinal structures.

A Cross-sectional Analysis of 556 Eyes Entering the Homburg Aniridia Centre.

PURPOSE: Congenital aniridia is a severe malformation of almost all eye segments. In addition, endocrinological, metabolic, and central nervous systems diseases may be present. In order to develop better treatment options for this rare disease, an aniridia center must be established. The purpose of this work is to summarize ophthalmic findings of aniridia subjects examined at the Department of Ophthalmology, Saarland University Medical Center in Homburg. METHODS: Our retrospective single-center study included patients who underwent a comprehensive ophthalmic examination through the head of the KiOLoN ("Kinderophthalmologie", Orthoptics, Low Vision and Neuroophthalmology) Unit of the department between June 2003 and January 2022. Data at the first examination time point have been included. RESULTS: Of 286 subjects, 556 eyes of (20.1 ± 20.1 years; 45.5% males) were included. There was nystagmus in 518 (93.7%) eyes, and strabismus in 327 (58.8%) eyes. There were 436 (78.4%) eyes with age-appropriate axial length, 104 (18.7%) eyes with microphthalmos, and 13 (2.3%) eyes with buphthalmos. There was iris malformation with atypical coloboma in 34 eyes (6.1%), more than 6 clock hours of iris remnants in 61 eyes (10.9%), less than 6 clock hours of iris remnants in 96 eyes (17.2%), and complete aniridia in 320 (57.5%) eyes. The patients were graded according to the following aniridia-associated keratopathy (AAK) stages: Stage 0 (96 eyes [17.2%], no keratopathy), Stage 1 (178 eyes [32.0%]), Stage 2 (107 eyes [19.2%]), Stage 3 (67 eyes [12.0%]), Stage 4 (62 eyes [11.1%]), Stage 5 (45 eyes [8.0%]). There was secondary glaucoma in 307 (55.5%), macular hypoplasia in 395 (71.4%), and congenital optic nerve head pathology in 223 (40.3%) eyes. The iris malformation type was significantly positively correlated with AAK stage, lens properties, presence of glaucoma, congenital macular, and optic nerve head properties (p < 0.001 for all), while complete aniridia showed the most complications. CONCLUSIONS: At the Homburg Aniridia Center, the most common ophthalmic signs in congenital aniridia were AAK, iris malformation, cataract, and macular hypoplasia. The iris malformation type may indicate future expression of AAK, cataract, and glaucoma development and it is correlated with a congenital optic nerve head and macular pathology. Our registry will support further detailed longitudinal analysis of ophthalmic and systemic diseases of aniridia subjects during long-term follow-up.

[Achromatopsia : Clinical aspects, diagnostics, genes, brain and quality of life]. / Achromatopsie : Klinik, Diagnostik, Gene, Gehirn und Lebensqualität.

Achromatopsia or rod monochromatism is a congenital autosomal recessive retinal dystrophy which leads to dysfunctional cones, with decreased visual acuity, extremely limited color vision, nystagmus and photophobia. Due to the initially normally appearing ocular morphology, the diagnosis is often delayed. With imaging procedures, e.g., fluorescence-autofluorescence (FAF) and optical coherence tomography (OCT), different morphological forms of achromatopsia can be discriminated that do not seem to have a differential effect on visual function. Crucial is the provision of specific edge filters. Mutations in six genes are known to cause achromatopsia. For the two most frequent genes, CNGA3 and CNGB3, gene addition therapies are currently being tested. Such future approaches should be applied before the manifestation of sensory-related amblyopia in the visual cortex. Accordingly, state of the art management of achromatopsia should provide a diagnosis in early childhood including genotyping.

Morphological and Functional Aspects and Quality of Life in Patients with Achromatopsia.

(1) Background: Achromatopsia is a rare disease of which the natural course and impact on life are still unknown to this date. We aimed to assess the morphological, functional characteristics, and quality of life in a large sample size of patients with achromatopsia. (2) A total of 94 achromats were included in this retrospective cohort study. Sixty-four were patients of the Department of Ophthalmology, Saarland University Medical Centre in Homburg/Saar, Germany, between 2008 and 2021. Thirty further participants with achromatopsia from the national support group were included using an online questionnaire, which is available under 'Supplementary data'. Statistical analysis was performed using SPSS Version 25; (3) The 94 patients (37 males (39.4%) and 57 females (60.6%)) showed a mean age of 24.23 ± 18.53 years. Visual acuity was stable (SD ± 0.22 logMAR at 1.0 logMAR) over a time of observation from 2008 to 2021. Edge filter glasses were the most used optical aids, while enlarged reading glasses were the most used low vision aids. (4) Conclusions: Our findings give an insight into describing the natural process and the quality of life of achromatopsia. The results demonstrate that achromatopsia is a predominantly stationary disease. The individual prescription of edge filters and low-vision aids is essential following a personalised fitting.

Early ocular surface and tear film status in congenital aniridia indicates a supportive treatment window.

AIM: To evaluate changes in the ocular surface and tear film with age and mutational status in congenital aniridia. METHODS: 45 participants with congenital aniridia (89 eyes) in a prospective, cross-sectional study. Whole-exome sequencing identified the causative mutation. Examinations included slit-lamp biomicroscopy, in vivo confocal microscopy, Ocular Surface Disease Index (OSDI) score, blink rate, Schirmer I test, Oxford Staining Score (OSS), tear film break-up time (TFBUT) and Ocular Protection Index (OPI). RESULTS: There were age-dependent increases in OSDI (ß=0.34, 95% CI 0.03 to 0.66; p=0.030), blink rate (ß=0.18, 95% CI 0.08 to 0.27; p<0.001) and OSS (ß=0.05, 95% CI 0.03 to 0.07; p<0.001) and age-dependent reductions in tear production (ß=-0.23, 95% CI -0.43 to 0.02; p=0.029) and TFBUT (ß=-0.10, 95% CI -0.17 to -0.04; p<0.001). Perturbed OSDI, OSS, blink rate, tear production and TFBUT were noted after the age of ten and OSDI, OSS, blink rate and TFBUT correlated with deficient corneal nerves and limbal stem cell function. OSDI, blink rate, Schirmer, OSS, TFBUT and OPI were not associated with type of PAX6 mutation, but OSDI, OSS and blink rate associated with grade of aniridia-associated keratopathy. CONCLUSIONS: Ocular surface damage and dry eye signs appear in congenital aniridia regardless of mutation, appearing after 10 years of age and progressing thereafter. An early treatment window may exist for therapies to protect the ocular surface homoeostasis and limbal function, to possibly delay keratopathy development and progression.

Topical NSAIDs and Oral Acetazolamide for Macular Edema after Uncomplicated Phacoemulsification: Outcome and Predictors of Non-Response.

PURPOSE: To investigate the effectiveness of nonsteroidal anti-inflammatory eye drops (NSAIDs) combined with oral acetazolamide for postoperative macular edema (PME) after uncomplicated phacoemulsification (PE) and identify predictors of non-response. METHODS: We analyzed data of uncomplicated PE and identified eyes with PME. First-line therapy included topical NSAIDs combined with oral acetazolamide. In the case of non-response, triamcinolone was administered subtenonally. Outcome measures included best-corrected visual acuity (BCVA) and central macular thickness (CMT). RESULTS: 94 eyes out of 9750 uncomplicated PE developed PME, of which 60 eyes were included. Follow-ups occurred 6.4 ± 1.8, 12.5 ± 3.7 and 18.6 ± 6.0 weeks after diagnosis. BCVA and CMT improved significantly in all follow-ups. In total, 40 eyes showed a response to first-line therapy at the first follow-up (G1). The remaining 20 eyes showed no response and required subtenon triamcinolone (G2), of which 11 eyes showed complete regression at the second follow-up and 4 eyes at third follow-up. A further 5 eyes showed no response and required intravitreal injection. Multivariate linear regression model showed that Diabetes mellitus (DM) and increased cumulative dissipated energy (CDE) are predictors of non-response. CONCLUSION: Topical NSAIDs with acetazolamide resulted in complete regression of PME in 67% of all cases. DM and increased CDE might be considered as predictors of non-response to this treatment.

[Optical rehabilitation and pediatric ophthalmological care following keratoplasty for childhood corneal opacities]. / Optische Rehabilitation und kinderophthalmologische Betreuung nach Keratoplastik bei kindlichen Hornhauttrübungen.

BACKGROUND: The younger the children are at the time of corneal transplantation, the worse the survival prognosis of the graft. PREOPERATIVE CONSIDERATIONS: Preoperative considerations are significant in terms of accurate parental education, ensuring adherence to treatment and choosing the appropriate surgical time frame (amblyopia versus graft failure, compliance of the patient). Parental education must include the reduced visual prognosis in young children, exceptions being later acquired corneal pathologies such as inflammatory corneal scars (herpes) and keratoconus. POSTOPERATIVE CARE: A distinction must be made between morphological care after transplantation and refractive correction as well as treatment of amblyopia. The younger the children, the less favorable the prognosis for the transplant and the more often multiple examinations with anesthesia are necessary in order to detect complications, such as infiltrates or suture loosening at an early stage. Especially unilateral congenital pathologies often do not lead to a sufficient improvement of amblyopia (refractory amblyopia, poor compliance). CONCLUSION: The prognosis after keratoplasty in childhood is already partly decided by the careful evaluation of indications (no surgery of a sclerocornea) and the detailed and realistic clarification for the parents (cooperation with long-term ocular and systemic treatment even if the child has poor compliance, frequent check-ups, reduced chances of amblyopia treatment). The younger the child is at the time of transplantation, the more frequent are graft failure and the development of complications. Later manifesting diseases in older children (herpetic corneal scars, keratoconus) have a better prognosis.

Decreased FABP5 and DSG1 protein expression following PAX6 knockdown of differentiated human limbal epithelial cells.

PAX6 haploinsufficiency related aniridia is characterized by disorder of limbal epithelial cells (LECs) and aniridia related keratopathy. In the limbal epithelial cells of aniridia patients, deregulated retinoic acid (RA) signaling components were identified. We aimed to visualize differentiation marker and RA signaling component expression in LECs, combining a differentiation triggering growth condition with a small interfering RNA (siRNA) based aniridia cell model (PAX6 knock down). Primary LECs were isolated from corneoscleral rims of healthy donors and cultured in serum free low Ca2+ medium (KSFM) and in KSFM supplemented with 0.9 mmol/L Ca2+. In addition, LECs were treated with siRNA against PAX6. DSG1, PAX6, KRT12, KRT 3, ADH7, RDH10, ALDH1A1, ALDH3A1, STRA6, CYP1B1, RBP1, CRABP2, FABP5, PPARG, VEGFA and ELOVL7 expression was determined using qPCR and western blot. DSG1, FABP5, ADH7, ALDH1A1, RBP1, CRABP2 and PAX6 mRNA and FABP5 protein expression increased (p ≤ 0.03), PPARG, CYP1B1 mRNA expression decreased (p ≤ 0.0003) and DSG1 protein expression was only visible after Ca2+ supplementation. After PAX6 knock down and Ca2+ supplementation, ADH7 and ALDH1A1 mRNA and DSG1 and FABP5 protein expression decreased (p ≤ 0.04), compared to Ca2+ supplementation alone. Using our cell model, with Ca2+ supplementation and PAX6 knockdown with siRNA treatment against PAX6, we provide evidence that haploinsufficiency of the master regulatory gene PAX6 contributes to differentiation defect in the corneal epithelium through alterations of RA signalling. Upon PAX6 knockdown, DSG1 differentiation marker and FABP5 RA signaling component mRNA expression decreases. A similar effect becomes apparent at protein level though differentiation triggering Ca2+ supplementation in the siRNA-based aniridia cell model. Expression data from this cell model and from our siRNA aniridia cell model strongly indicate that FABP5 expression is PAX6 dependent. These new findings may lead to a better understanding of differentiation processes in LECs and are able to explain the insufficient cell function in AAK.

Structural changes to primary visual cortex in the congenital absence of cone input in achromatopsia.

Autosomal recessive Achromatopsia (ACHM) is a rare inherited disorder associated with dysfunctional cone photoreceptors resulting in a congenital absence of cone input to visual cortex. This might lead to distinct changes in cortical architecture with a negative impact on the success of gene augmentation therapies. To investigate the status of the visual cortex in these patients, we performed a multi-centre study focusing on the cortical structure of regions that normally receive predominantly cone input. Using high-resolution T1-weighted MRI scans and surface-based morphometry, we compared cortical thickness, surface area and grey matter volume in foveal, parafoveal and paracentral representations of primary visual cortex in 15 individuals with ACHM and 42 normally sighted, healthy controls (HC). In ACHM, surface area was reduced in all tested representations, while thickening of the cortex was found highly localized to the most central representation. These results were comparable to more widespread changes in brain structure reported in congenitally blind individuals, suggesting similar developmental processes, i.e., irrespective of the underlying cause and extent of vision loss. The cortical differences we report here could limit the success of treatment of ACHM in adulthood. Interventions earlier in life when cortical structure is not different from normal would likely offer better visual outcomes for those with ACHM.

Structural Differences Across Multiple Visual Cortical Regions in the Absence of Cone Function in Congenital Achromatopsia.

Most individuals with congenital achromatopsia (ACHM) carry mutations that affect the retinal phototransduction pathway of cone photoreceptors, fundamental to both high acuity vision and colour perception. As the central fovea is occupied solely by cones, achromats have an absence of retinal input to the visual cortex and a small central area of blindness. Additionally, those with complete ACHM have no colour perception, and colour processing regions of the ventral cortex also lack typical chromatic signals from the cones. This study examined the cortical morphology (grey matter volume, cortical thickness, and cortical surface area) of multiple visual cortical regions in ACHM (n = 15) compared to normally sighted controls (n = 42) to determine the cortical changes that are associated with the retinal characteristics of ACHM. Surface-based morphometry was applied to T1-weighted MRI in atlas-defined early, ventral and dorsal visual regions of interest. Reduced grey matter volume in V1, V2, V3, and V4 was found in ACHM compared to controls, driven by a reduction in cortical surface area as there was no significant reduction in cortical thickness. Cortical surface area (but not thickness) was reduced in a wide range of areas (V1, V2, V3, TO1, V4, and LO1). Reduction in early visual areas with large foveal representations (V1, V2, and V3) suggests that the lack of foveal input to the visual cortex was a major driving factor in morphological changes in ACHM. However, the significant reduction in ventral area V4 coupled with the lack of difference in dorsal areas V3a and V3b suggest that deprivation of chromatic signals to visual cortex in ACHM may also contribute to changes in cortical morphology. This research shows that the congenital lack of cone input to the visual cortex can lead to widespread structural changes across multiple visual areas.

Similarities in DSG1 and KRT3 Downregulation through Retinoic Acid Treatment and PAX6 Knockdown Related Expression Profiles: Does PAX6 Affect RA Signaling in Limbal Epithelial Cells?

Congenital PAX6-aniridia is a rare panocular disease resulting from limbal stem cell deficiency. In PAX6-aniridia, the downregulation of the retinol-metabolizing enzymes ADH7 (All-trans-retinol dehydrogenase 7) and ALDH1A1/A3 (Retinal dehydrogenase 1, Aldehyde dehydrogenase family 1 member A3) have been described in limbal epithelial cells (LECs) and conjunctival epithelial cells. The aim of this study was to identify the role of retinol derivates in the differentiation of human LEC and its potential impact on aniridia-associated keratopathy development. Human LEC were isolated from healthy donor corneas and were cultured with retinol, retinoic acid, or pan-retinoic acid receptor antagonist (AGN 193109) acting on RARα, ß, γ (NR1B1, NR1B2 NR1B3) or were cultured with pan-retinoid X receptor antagonist (UVI 3003) acting on RXR α, ß, γ (retinoid X receptor, NR2B1, NR2B2, BR2B3). Using qPCR, differentiation marker and retinoid-/fatty acid metabolism-related mRNA expression was analysed. DSG1 (Desmoglein 1), KRT3 (Keratin 3), and SPINK7 (Serine Peptidase Inhibitor Kazal Type 7) mRNA expression was downregulated when retinoid derivates were used. AGN 193109 treatment led to the upregulation of ADH7, KRT3, and DSG1 mRNA expression and to the downregulation of KRT12 (Keratin 12) and KRT19 (Keratin 19) mRNA expression. Retinol and all-trans retinoic acid affect some transcripts of corneal LEC in a similar way to what has been observed in the LEC of PAX6-aniridia patients with the altered expression of differentiation markers. An elevated concentration of retinol derivatives in LEC or an altered response to retinoids may contribute to this pattern. These initial findings help to explain ocular surface epithelia differentiation disorders in PAX6-aniridia and should be investigated in patient cells or in cell models in the future in more detail.

A Novel Likely Pathogenic Variant in the BLOC1S5 Gene Associated with Hermansky-Pudlak Syndrome Type 11 and an Overview of Human BLOC-1 Deficiencies.

Hermansky-Pudlak syndrome (HPS) is a heterogeneous disorder combining oculocutaneous albinism (OCA) and a platelet function disorder of varying severity as its most prominent features. The genes associated with HPS encode for different BLOC- (biogenesis of lysosome-related organelles complex) complexes and for the AP-3 (adaptor protein-3) complex, respectively. These proteins are involved in maturation, trafficking, and the function of lysosome-related organelles (LROs) such as melanosomes and platelet δ-granules. Some patients with different types of HPS can develop additional complications and symptoms like pulmonary fibrosis, granulomatous colitis, and immunodeficiency. A new type of HPS has recently been identified associated with genetic alterations in the BLOC1S5 gene, which encodes the subunit Muted of the BLOC-1 complex. Our aim was to unravel the genetic defect in two siblings with a suspected HPS diagnosis (because of OCA and bleeding symptoms) using next generation sequencing (NGS). Platelet functional analysis revealed reduced platelet aggregation after stimulation with ADP and a severe secretion defect in platelet δ-granules. NGS identified a novel homozygous essential splice site variant in the BLOC1S5 gene present in both affected siblings who are descendants of a consanguine marriage. The patients exhibited no additional symptoms. Our study confirms that pathogenic variants of BLOC1S5 cause the recently described HPS type 11.

Dysfunction of the limbal epithelial stem cell niche in aniridia-associated keratopathy.

PURPOSE: Abnormalities in the limbal niche microenvironment have been suggested to be causally involved in aniridia-associated keratopathy (AAK), but histological analyses on the limbal structure and composition in AAK are lacking. Here, we investigated morphologic and molecular alterations of the limbal epithelial stem cell niche in human congenital aniridia. METHODS: The blind, buphthalmic and painful left eye of a 16-year old girl with congenital aniridia and juvenile glaucoma had to be enucleated because of uncontrolled intraocular pressure. The diagnosis of AAK was based on classical clinical features and partial limbal stem cell deficiency in the superior half. Genetic analysis identified a large heterozygous PAX6 gene deletion encompassing exons 11-15 as well as exon 9 of the neighboring ELP4 gene. Three limbal biopsies were taken from the superior, nasal and temporal regions to isolate and cultivate limbal epithelial progenitor cells and subject them to mRNA expression analyses. The globe was vertically bisected and processed for light and transmission electron microscopy and immunohistochemistry. RESULTS: Comparative analysis of the superior and inferior limbal zones showed a gradual degradation of palisade structures associated with the transition from a hyperplastic to an attenuated corneal epithelium, inflammatory cell infiltrations and basement membrane irregularities. The clinically unaffected inferior part revealed no distinct stem cell clusters in the preserved palisade region, but a uniform population of hyperproliferative, undifferentiated progenitor cells in the basal/suprabasal layers of limbal and corneal epithelia, which gave rise to maldifferentiated epithelial cells exhibiting a conjunctival/epidermal phenotype and nuclear-to-cytoplasmic translocation of Pax6. The structure of the limbal niche was fundamentally perturbed, showing marked alterations in extracellular matrix composition, dislocation of atypical melanocytes lacking melanosomes and melanin, aberrant Wnt/ß-catenin and retinoic acid signaling, and massive immune cell infiltration. CONCLUSIONS: Considering the limitations of a single Case study, the findings suggest that ocular surface alterations in AAK are caused by a primary dysfunction and gradual breakdown of the limbal stem cell niche through Pax6-related effects on both melanogenesis and epithelial differentiation.

[MDVI patients - Multiply disabled visually impaired : On the situation of the child, parents and ophthalmologist with MDVI children]. / MDVI-Patienten ­ "multiply disabled, visually impaired" : Zur Situation von Kind, Eltern und Augenarzt bei mehrfachbehinderten, sehgeschädigten Kindern.

Functional visual perception significantly contributes to the child's development and consists of much more than just visual acuity and the visual field. It includes cognitive interpretation of visual stimuli and runs along the temporal and parietal pathways of visual processing. Central visual impairment (CVI) usually affects otherwise healthy children with often good visual acuity, whereas the multiply disabled visually impaired (MDVI) have visual impairment and multiple disabilities. In MDVI patients an ocular and/or CVI can be present. The examination of MDVI patients poses a great challenge for the ophthalmologist and reflective visual test procedures should also be used. Particular attention should be paid to refraction and accommodation. The main ocular diagnosis in MDVI is optic atrophy and the general diagnoses are dominated by sequelae of premature birth, often in combination with spasticity and epilepsy. Early intervention is essential and is independent of the underlying diagnoses.