Broadening the ocular phenotypic spectrum of ultra-rare BRPF1 variants: report of two cases.

INTRODUCTION: BRPF1 gene on 3p26-p25 encodes a protein involved in epigenetic regulation, through interaction with histone H3 lysine acetyltransferases KAT6A and KAT6B of the MYST family. Heterozygous pathogenic variants in BRPF1 gene are associated with Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP), characterized by global developmental delay, intellectual disability, language delay, and dysmorphic facial features. The reported ocular involvement includes strabismus, amblyopia, and refraction errors. This report describes a novel ocular finding in patients affected by variants in the BRPF1 gene. METHODS: We performed exome sequencing and deep ocular phenotyping in two unrelated patients (P1, P2) with mild intellectual disability, ptosis, and typical facies. RESULTS: Interestingly, P1 had a Chiari Malformation type I and a subclinical optic neuropathy, which could not be explained by variations in other genes. Having detected a peculiar ocular phenotype in P1, we suggested optical coherence tomography (OCT) for P2; such an exam also detected bilateral subclinical optic neuropathy in this case. DISCUSSION: To date, only a few patients with BRPF1 variants have been described, and none were reported to have optic neuropathy. Since subclinical optic nerve alterations can go easily undetected, our experience highlights the importance of a more detailed ophthalmologic evaluation in patients with BRPF1 variant.

Efficacy of a Cationic Emulsion of Cyclosporine in Moderate Vernal Keratoconjunctivitis.

PURPOSE: The aim of this study was to demonstrate the efficacy of cyclosporine A 0.1% cationic emulsion (CsA CE) eye drops 4 times a day in pediatric patients affected by a moderate form of vernal keratoconjunctivitis (VKC). METHODS: This was a prospective study of pediatric patients, aged 5-16 years, with an active moderate form of VKC who were poor responders to topical antihistamines treatment and were treated 4 times a day with CsA CE. The clinical signs were graded for analysis as follows: hyperemia, tarsal papillae, and limbal papillae. RESULTS: Twenty-eight patients (22 males and 6 females) with a minimum follow-up period of 3 months were included in the analysis. Statistical analysis excluded tarsal papillae because of the very low baseline value. The clinical score of hyperemia and limbal papillae improved from the first evaluation and was maintained over the follow-up. No side effects were noted. CONCLUSION: CsA CE has been proposed as a treatment for severe forms of VKC. This study has shown that administration 4 times a day is also effective in the treatment of moderate forms of VKC in children.

The New Era of Therapeutic Strategies for the Treatment of Retinitis Pigmentosa: A Narrative Review of Pathomolecular Mechanisms for the Development of Cell-Based Therapies.

Retinitis pigmentosa, defined more properly as cone-rod dystrophy, is a paradigm of inherited diffuse retinal dystrophies, one of the rare diseases with the highest prevalence in the worldwide population and one of the main causes of low vision in the pediatric and elderly age groups. Advancements in and the understanding of molecular biology and gene-editing technologies have raised interest in laying the foundation for new therapeutic strategies for rare diseases. As a consequence, new possibilities for clinicians and patients are arising due to the feasibility of treating such a devastating disorder, reducing its complications. The scope of this review focuses on the pathomolecular mechanisms underlying RP better to understand the prospects of its treatment using innovative approaches.

Acute Rejection Following COVID-19 Vaccination in Penetrating Keratoplasty in a Young Male - A Case Report and Review of Literature.

PURPOSE: To report a case of a boy with acute keratoplasty rejection manifesting 12 days after receiving BNT162b2 messenger RNA (mRNA) vaccine for COVID-19. STUDY DESIGN: A case report. RESULTS: A 15-year-old boy with a history of penetrating keratoplasty due to acanthamoeba keratitis developed corneal decompensation 12 days after BNT162b2 messenger RNA vaccine for COVID-19 disease. One-week treatment with topical Dexamethasone 2% eye drops resulted in a complete resolution of corneal edema. CONCLUSIONS: This case suggests that BNT162b2 messenger RNA (mRNA) vaccine can be associated with acute keratoplasty rejection in children, which responds completely to topical steroids. Ophthalmologists should be aware of this risk of cornea decompensation after COVID-19 vaccine in children who received a cornea transplant.

Optic nerve involvement in CACNA1F-related disease: observations from a multicentric case series.

BACKGROUND: Congenital Stationary Night Blindness (CSNB) constitutes a group of non-progressive retinal disorders characterized by disturbances in scotopic vision and/or by a delay in adaptation to darkness, as well as by low visual acuity, myopia, nystagmus, and strabismus. Color vision and fundus appearance tend to be normal. To date, several CACNA1F gene variants have been linked to a CSNB phenotype but only few reports have focused on the optic nerve in this disease. MATERIALS AND METHODS: Twelve patients underwent standard ophthalmological and genetic evaluation including spectral domain optical coherence tomography (SD-OCT), full-field electroretinography (ffERG), kinetic perimetry, fundus photography, magnetic resonance imaging (MRI), and next-generation sequencing (NGS). Bilateral thinning of the peripapillary nerve fiber layer (pRNFL) and the ganglion cell complex (GCC) supported involvement of the optic nerves. MRI, when available, was assessed for gross intracranial optic pathway abnormalities. RESULTS: All patients were shown to carry pathogenic variants in the CACNA1F gene, and all showed signs of optic nerve involvement. All patients showed a certain degree of myopic refractive error. Low average pRNFL thickness was evident in all patients. In three of them, pRNFL thickness was evaluated longitudinally and was proven to be stable over time. MRI imaging was unremarkable in all cases. CONCLUSION: Our data support the hypothesis that CACNA1F could be related to early-onset or congenital optic nerve involvement without any signs of a progressive optic neuropathy. Even though additional data from larger cohorts and longer follow-up periods are needed to further support and confirm our findings, there is a clear significance to our findings in the preparation for future CACNA1F gene therapy trials.

Microperimetry assessment in foveal hypoplasia: functional results in a series of pediatric patients.

OBJECTIVE: To study the relationships of functional and morphologic retinal parameters in a series of pediatric patients with varying degrees of foveal hypoplasia (FH). DESIGN: Monocentric observational retrospective study. PARTICIPANTS: Among 21 pediatric patients, 16 met inclusion criteria, having FH confirmed with spectral-domain optical coherence tomography (SD-OCT) scan METHODS: Data were analyzed retrospectively. Patients able to undergo macular microperimetry (MP) and SD-OCT examinations were included in the analysis. MP and SD-OCT outcomes were compared with FH grading and best-corrected visual acuity (BCVA) using Pearson's correlation. RESULTS: Thirty-one eyes from 16 patients (mean age 12.4 years) with different degrees of FH were analyzed. Two patients had grade 1, 7 had grade 2, 5 had grade 3, and 2 had grade 4 FH. Clinical nystagmus was present in 8 patients. The correlation between BCVA and SD-OCT data (-0.31) was lower than that found between BCVA and nystagmus (0.64), that for fixation index P1 (-0.60), as well as that for macular sensitivity (-0.63). CONCLUSIONS: Although limited by the small sample, our study confirms the feasibility of automated MP evaluation in pediatric patients with FH. The added value of this work is the provision of data on relationships between anatomic and functional macular measurements acquired with SD-OCT, MP, and BCVA in eyes with various degrees of FH. Larger prospective studies are necessary to confirm these results.

Optical Coherence Tomography Significance in Managing Early Onset of Optic Pathway Gliomas in Children Younger than 5 Years of Age-A Retrospective Study.

We aimed to investigate the significance of optical coherence tomography (SD-OCT) in managing pediatric optic pathway gliomas (OPGs) in children younger than 5 years of age. A retrospective monocentric study was conducted. SD-OCT scans were obtained using the handheld iVue system to assess peripapillary retinal nerve fibre layer (pRNFL) thickness at three time points: baseline (OCT1), end of treatment (OCT2), and at last follow-up (OCT3). We compared the median value of pRNFL (and interquartile range-IQR) at different follow-up times and in different sub-groups (stable disease-SD, partial response-PR, and progression disease-PD). Thirteen children younger than 5 years of age were included. The Median follow-up time was 3.9 years (IQR 1.2). Six patients showed a pRNFL change of more than 10% during follow-up. Seven patients showed PD during follow-up. Median pRNFL at baseline was 81.5 µm (IQR 31.5); median pRNFL at the end of treatment was 73 µm (IQR 33); median pRNFL at last follow-up was 72 µm (IQR 38.5). The mean pRNFL at baseline was significantly lower than the mean normative values. Only subjects with PD showed pRNFL change close to statistical significance. This study confirms the role of SD-OCT in managing OPGs for therapeutic decisions and strategy planning of visual rehabilitation.

Expanding the Spectrum of Oculocutaneous Albinism: Does Isolated Foveal Hypoplasia Really Exist?

Oculocutaneous albinism is an autosomal recessive disorder characterized by the presence of typical ocular features, such as foveal hypoplasia, iris translucency, hypopigmented fundus oculi and reduced pigmentation of skin and hair. Albino patients can show significant clinical variability; some individuals can present with only mild depigmentation and subtle ocular changes. Here, we provide a retrospective review of the standardized clinical charts of patients firstly addressed for evaluation of foveal hypoplasia and slightly subnormal visual acuity, whose diagnosis of albinism was achieved only after extensive phenotypic and genotypic characterization. Our report corroborates the pathogenicity of the two common TYR polymorphisms p.(Arg402Gln) and p.(Ser192Tyr) when both are located in trans with a pathogenic TYR variant and aims to expand the phenotypic spectrum of albinism in order to increase the detection rate of the albino phenotype. Our data also suggest that isolated foveal hypoplasia should be considered a clinical sign instead of a definitive diagnosis of an isolated clinical entity, and we recommend deep phenotypic and molecular characterization in such patients to achieve a proper diagnosis.

Treatment of Inherited Retinal Dystrophies with Somatic Cell Therapy Medicinal Product: A Review.

Inherited retinal dystrophies and retinal degenerations related to more common diseases (i.e., age-related macular dystrophy) are a major issue and one of the main causes of low vision in pediatric and elderly age groups. Advancement and understanding in molecular biology and the possibilities raised by gene-editing techniques opened a new era for clinicians and patients due to feasible possibilities of treating disabling diseases and the reduction in their complications burden. The scope of this review is to focus on the state-of-the-art in somatic cell therapy medicinal products as the basis of new insights and possibilities to use this approach to treat rare eye diseases.

Long-Term Safety and Efficacy of Tacrolimus 0.1% in Severe Pediatric Vernal Keratoconjunctivitis.

PURPOSE: The aim of this study was to evaluate the safety and efficacy of tacrolimus 0.1% eye drops in a large population of pediatric patients affected by a severe form of vernal keratoconjunctivitis (VKC) who responded poorly to cyclosporine eye drops. METHODS: This is a retrospective study based on standardized clinical charts and data collection of consecutive patients affected by severe VKC who responded poorly to cyclosporine eye drops topical treatment but treated with tacrolimus 0.1% eye drops with a follow-up of 18 months. Four clinical signs were graded for analysis: hyperemia, tarsal papillae, giant papillae, and limbal papillae. The blood tests for kidney and liver function and the tacrolimus level were studied. Visits were scheduled at baseline and at 3, 6, 12, and 18 months. Patients received tacrolimus 0.1% eye drops in both eyes 2 times daily. RESULTS: Four hundred thirty-one patients were included. Three hundred twenty-five patients were affected by a seasonal form, whereas the remaining 106 by a perennial form. Statistical analysis on each single score showed a positive relevance (P < 0.001) from baseline to all other visits. No local or systemic complications were recorded. CONCLUSIONS: Tacrolimus has been proposed as a treatment for severe forms of VKC. This study has confirmed the safety and efficacy of tacrolimus 0.1% eye drops in a large pediatric population of patients affected by a severe form of VKC who responded poorly to cyclosporine eye drops.

The efficacy of biofeedback visual rehabilitation therapy in patients with infantile nystagmus syndrome: A retrospective study.

OBJECTIVE: To report fixation stability changes in patients with different forms of infantile nystagmus syndrome (INS), who have undergone a visual rehabilitation through biofeedback fixation training (BFT) with microperimetry (MP). DESIGN: Retrospective study. METHODS: Patients 6 to 12 years-old with INS who performed BFT with MP. Initially 10 once-weekly followed by eight twice-weekly sessions of BFT during a minimum of 6 months period were performed. Visual acuity (VA) and MP fixation stability indices were analyzed, including displacement from fixation point (P1, P2) and percentage of retinal loci used during fixation attempt (BCEA 63% and 95%). Statistical analysis was conducted at baseline (BL), 10 weeks (W10) and 6 months (M6). RESULTS: Twelve patients (mean age 8.9 years.) with INS completed the whole training session. All patients showed significant improvement in the mean BCEA fixation area (deg2): For BCEA@95% BL was 78.0, 46.1 at W10, and 27.4 at M6 (p-value = 0.004). For BCEA@63% BL was 27.3, 15.4 in W10, and 9.17 at M6 (p = 0.01). The ANOVA test for the FS indices of P1 and P2, as well as for BCVA showed no significant difference when compared at the same intervals. CONCLUSION: Fixation stability (FS) indices of BCEAs (63% and 95%) improved at W10 and M6, while P1 and P2 showed significant improvement at W10 but not at M6, probably because BCEA involves a much larger area than P1 and P2. VA did not show significant improvement at any time point.

Ultrathin Descemet stripping automated endothelial keratoplasty versus Descemet membrane endothelial keratoplasty: a fellow-eye comparison.

BACKGROUND: To compare the visual outcome and patients' satisfaction after ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK) and Descemet membrane endothelial keratoplasty (DMEK) performed on fellow eyes of the same patients. METHODS: In this retrospective study, the records of 18 pseudophakic patients affected by Fuchs endothelial dystrophy who underwent DMEK in one eye and UT-DSAEK in the fellow eye were reviewed. Best corrected visual acuity (BCVA), corneal pachymetry, keratometry, corneal aberrations, photopic and mesopic contrast sensitivity, and endothelial cell counts measured 12 months after surgery in either eye were analyzed and compared. The results of a satisfaction questionnaire were also reviewed. RESULTS: Twelve months after surgery, BCVA was not significantly different in UT-DSAEK and DMEK eyes (0.10 ± 0.04 and 0.07 ± 0.07 logMAR, respectively); at both 4- and 6 mm optical zones total and posterior corneal higher order aberrations (HOAs), posterior astigmatism and total coma were significantly lower after DMEK; BCVA in both groups was significantly correlated mainly with anterior corneal aberrations; contrast sensitivity was higher after DMEK especially in mesopic conditions and at medium spatial frequencies; the endothelial cell density was similar, although slightly higher in the UT-DSAEK group (p = 0.10). The satisfaction questionnaire showed that although patients were highly satisfied from both procedures, more than half of them preferred DMEK and reported a more comfortable and quicker postoperative recovery. CONCLUSIONS: DMEK and UT-DSAEK showed no evidence of difference in terms of postoperative BCVA, although DMEK had a better performance in terms of contrast sensitivity, posterior corneal aberrations and overall patient satisfaction.

Novel mutations in MFRP and PRSS56 are associated with posterior microphthalmos.

Background: Biallelic pathogenic variants in MFRP and PRSS56 genes can be responsible for nanophthalmos (NO) or posterior microphthalmos (PM). This study describes detailed clinical and molecular findings in a series of five patients affected by PM from four unrelated families.Materials and Methods: All patients underwent a complete ophthalmological and genetic evaluation. For proper and deep phenotyping a multimodal instrumental approach was used for all cases: B-scan ultrasound, spectral domain optical coherence tomography (SD-OCT), fundus retinal imaging and anterior segment data were obtained. Molecular analysis of PRSS56 and MFRP genes was performed with Next-Generation Sequencing (NGS) methodology and segregation analysis on parents and one affected sibling was performed with Sanger sequencing.Results: A very high hyperopia of +14.00D or more was the main refractive error and macular abnormalities were identified in all patients. Axial length ranged from 15.3 mm to 17.86 mm (mean 16.58 mm) and age at first presentation ranged from 6 to 36 months (mean 18 months). Anterior chamber depth was within normal values, according to age, while total axial length was severely reduced in all patients. All our patients met the diagnostic criteria for PM. Three patients, including a pair of siblings, carried compound heterozygous mutations in the PRSS56 gene; in the other two patients, one homozygous or two compound heterozygous mutations in the MFRP gene were detected.Conclusion: Our study describes four novel mutations in the PRSS56 gene and one in the MFRP gene in patients with non-syndromic posterior microphthalmos. Proper genotype-phenotype correlation and early diagnosis could lead to good functional results.

IN VIVO OBSERVATION OF RETINAL VASCULAR DEPOSITS USING ADAPTIVE OPTICS IMAGING IN FABRY DISEASE.

PURPOSE: To report a novel finding in patients with Fabry disease, that is, the observation by adaptive optics ophthalmoscopy of intracellular lipidic deposits in retinal vessels. METHODS: Observational two-center case series. Eighteen patients with genetically proven Fabry disease underwent flood-illumination adaptive optics ophthalmoscopy imaging (rtx1; Imagine Eyes, Orsay, France) of retinal vessels. RESULTS: Fourteen patients (78% of all patients; 7 of the 10 women and 7 of the 8 men) showed paravascular punctuate or linear opacities in both eyes. In the least-affected patients, these were seen only in the wall of precapillary arterioles as discrete spots of 5 µm to 10 µm large, whereas in those more severely affected, capillaries and first-order vessels were also involved with diffuse opacification of the wall. These deposits sometime showed a striated pattern, suggesting colocalization with vascular smooth muscle cells. CONCLUSION: Adaptive optics ophthalmoscopy of retinal vessels may be of interest for patients with Fabry disease, providing noninvasive, gradable evaluation of microvascular involvement.