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X-linked juvenile retinoschisis (×LRS) is an X-linked vitreoretinal degenerative disease that consists of variable phenotypes ranging from severe early-onset defects to subtle abnormalities diagnosed in elderly patients. XLRS is caused by a loss of function of the protein Retinoschisin (RS1), which is essential to preserve retinal integrity and function of photoreceptor-bipolar synapse. The literature data so far mostly agree on the absence of a clear genotype-phenotype correlation in XLRS. We reviewed clinical and molecular characteristics of a cohort of Italian pediatric XLRS patients to assess the presence of a correlation between genotype and phenotype severity. We retrospectively examined clinical and genetic features of a cohort of 27 XLRS patients. In this study we included patients with a diagnosis of XLRS confirmed by fundus photography, spectral domain optical coherence tomography, and molecular analysis and with an onset of less than 10 years of age. We sorted RS1 variants according to their effect of RS1 structure and function in three separate groups. According to previous studies, we did not observe a conclusive genotype-phenotype correlation in our cohort; nevertheless, we noticed that patients harboring RS1 variants leading to RS1-secreted mutants show a more homogeneous phenotype, with an overall good visual acuity, compared to the other two groups. Our data support the hypothesis that secretion profile of RS1 could influence the severity of the phenotype. More extensive and functional studies are needed to acquire notions in view of the opportunity of gene replacement therapy for XLRS patients. [ABSTRACT FROM AUTHOR]

Introduction: Phosphoribosyl pyrophosphate synthetase 1 ( PRPS1 ) is an X-linked gene critical for nucleotide metabolism. Pathogenic PRPS1 variants cause three overlapping phenotypes: Arts syndrome (severe neurological disease), Charcot-Marie-Tooth type 5 [CMTX5] (peripheral neuropathy), and non-syndromic sensorineural hearing loss (SNHL). Each may be associated with retinal dystrophy. Multicenter phenotypic studies are limited., Methods: A multicenter retrospective clinical case series of 15 patients from 12 pedigrees with PRPS1 -associated retinal degeneration is presented., Results: Of 15 patients, 11 (73.3%) were female. Mean age of ocular disease onset was 8.5 years (range, 0.5-35 years). Many were diagnosed with Leber congenital amaurosis prior to genetic testing ( n = 5). Five patients had clinical diagnoses of CMTX5 and Arts syndrome, two had isolated ocular disease, and one was asymptomatic. Mean initial VA (LogMAR) was 0.74, 0.74, 0.83, and 0.85 for isolated ocular disease, CMTX5, Arts, and SNHL, respectively. Ten patients were hyperopic and eight had asymmetric VA. Macular atrophy ( n = 13), optic atrophy ( n = 13), bone spicules ( n = 10), and parafoveal outer retinal atrophy (n = 12) were common findings. Electroretinogram showed delayed and attenuated photopic and scotopic responses ( n = 10). Median follow-up of 2.9 years (range, 1.5-11.6 years) in six patients showed retinal disease progression in two patients., Discussion: PRPS1 -associated retinal degeneration predominantly manifests as a bilateral asymmetric cone and rod dystrophy, commonly associated with hyperopia and optic atrophy.

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.

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.

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.