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Inosine monophosphate dehydrogenase (IMPDH) is a key regulatory enzyme in the de novo synthesis of the purine base guanine. Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) are causative for RP10 autosomal dominant retinitis pigmentosa (adRP). This study reports a novel variant in a family with IMPDH1-associated retinopathy. We also performed a comprehensive review of all reported IMPDH1 disease causing variants with their associated phenotype. Multimodal imaging and functional studies documented the phenotype including best-corrected visual acuity (BCVA), fundus photograph, fundus autofluorescence (FAF), full field electroretinogram (ffERG), optical coherence tomography (OCT) and visual field (VF) data were collected. A literature search was performed in the PubMed and LOVD repositories. We report 3 cases from a 2-generation family with a novel heterozygous likely pathogenic variant p. (Lys314Gln) (exon 10). The ophthalmic phenotype showed diffuse outer retinal atrophy with mild pigmentary changes with sparse pigmentary changes. FAF showed early macular involvement with macular hyperautofluorescence (hyperAF) surrounded by hypoAF. Foveal ellipsoid zone island can be found in the youngest patient but not in the older ones. The literature review identified a further 56 heterozygous, 1 compound heterozygous, and 2 homozygous variant. The heterozygous group included 43 missense, 3 in-frame, 1 nonsense, 2 frameshift, 1 synonymous, and 6 intronic variants. Exon 10 was noted as a hotspot harboring 18 variants. We report a novel IMPDH1 variant. IMPDH1-associated retinopathy presents most frequently in the first decade of life with early macular involvement. [ABSTRACT FROM AUTHOR]

Although eye abnormalities are reported in fetal alcohol spectrum disorders (FASD), no systematic review based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines has been undertaken. Our aim was to document the range and prevalence of eye abnormalities reported in children with prenatal alcohol exposure (PAE) and/or FASD. Searches of electronic databases and manual searches. Eligible articles were observational studies in children with PAE and/or FASD; peer reviewed journal articles in the English language; and studies reporting quantitative or frequency data on functional/structural eye abnormalities. Pooled prevalence, odds ratio, and mean differences were calculated. Of the 1,068 retrieved articles 36 were eligible, including articles on children with diagnosed fetal alcohol syndrome/FASD (N = 31); PAE (N = 3); and FASD or PAE without FASD (N = 2). Structural and functional eye abnormalities were identified, the most prevalent being short palpebral fissure length (66.1%), visual impairment (55.5%), epicanthus (53.5%), subnormal stereoacuity (53.0%), abnormal retinal tortuosity (50.5%), impaired fixation ability (33.3%), telecanthus (31.7%), optic nerve hypoplasia (30.2%), and small optic discs (27.0%). Compared to non-exposed controls, strabismus, subnormal vision, ptosis, short palpebral fissure length, microphthalmos, smaller optic disc area, and retinal vessel tortuosity were more prevalent in children with FASD. Examination of eyes and vision should be considered in children with PAE and suspected or diagnosed FASD to enable early identification and optimal management. This first comprehensive, systematic literature review demonstrates the variety and frequency of eye abnormalities reported in PAE/FASD. [ABSTRACT FROM AUTHOR]

Keywords: Neurofibromatosis; glaucoma; hemifacial enlargement; ectropion uveae; buphthalmos; Lisch nodules EN Neurofibromatosis glaucoma hemifacial enlargement ectropion uveae buphthalmos Lisch nodules 709 712 4 09/29/22 20221001 NES 221001 Introduction Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder primarily affecting the skin, eyes and peripheral nervous system ([1]). Neurofibromatosis, glaucoma, hemifacial enlargement, ectropion uveae, buphthalmos, Lisch nodules Wang et al. ([9]) discussed 3 cases with CEU-associated glaucoma who underwent glaucoma drainage device implantation and reported plate encapsulation causing early failure leading to subsequent glaucoma surgery with cryoablation or trabeculectomy with MMC. Intraoperative findings of the right eye, seen in Figures 2 and 3, included ectropion uveae, buphthalmos and Lisch nodules with no obvious neurofibromas in the angle on gonioscopy. [Extracted from the article]

Mer tyrosine kinase-retinitis pigmentosa (MERTK-RP) causes a primary defect in the retinal pigment epithelium, which subsequently affects rod and cone photoreceptors. The study aims to identify the most appropriate MERTK-RP biomarkers to measure disease progression for deciding the optimum therapeutic trial intervention time. Patients' data from baseline (BL) and last follow-up (LFU) were reviewed. Best corrected visual acuity (BCVA), spectral domain-optical coherence tomography (SD-OCT), ultra-widefield fundus autofluorescence (UWF-FAF) patterns, kinetic perimetry (KP), and electroretinography (ERG) parameters were analyzed. Five patients were included with the mean age of 17.7 ± 14.4 years old (6.7–42.3) at BL and mean BCVA follow-up of 8.4 ± 5.1 years. Mean BCVA at BL and LFU were 0.84 ± 0.86 LogMAR and 1.14 ± 0.86 LogMAR, respectively. The BCVA decline rate was 0.05 ± 0.03 LogMAR units/year. Ellipzoid zones (EZ) were measurable in eight eyes with mean BL length of 1293.75 ± 421.07 µm and reduction of 140.95 ± 69.28 µm/year and mean BL CMT of 174.2 ± 37.52 µm with the rate of 11.2 ± 12.77 µm declining/year. Full-field ERG (ffERG) and pattern ERG (pERG) were barely recordable. UWF-FAF showed central macular hyper-autofluorescence (hyperAF). KP (III4e and V4e) was normal in two eyes, restricted nasally in four eyes, superior wedge defect in two eyes and undetectable in two eyes. The four restricted nasally KPs became worse, while the others stayed almost unchanged. This cohort showed early visual loss, moderately rapid EZ reduction and macular hyperAF. EZ, CMT, and BCVA were consistently reduced. Relative rapid decline in these biomarkers reflecting visual function suggests an early and narrow timespan for intervention. [ABSTRACT FROM AUTHOR]

Background: Leber congenital amaurosis (LCA) is a severe form of retinal dystrophy with marked underlying genetic heterogeneity. Until recently, allele-specific assays and Sanger sequencing of targeted segments were the only available approaches for attempted genetic diagnosis in this condition. A broader next-generation sequencing (NGS) strategy, such as whole exome sequencing, provides an improved molecular genetic diagnostic capacity for patients with these conditions. Materials and Methods: In a child with LCA, an allele-specific assay analyzing 135 known LCA-causing variations, followed by targeted segment sequencing of 61 regions in 14 causative genes was performed. Subsequently, exome sequencing was undertaken in the proband, unaffected consanguineous parents and two unaffected siblings. Bioinformatic analysis used two independent pipelines, BWA-GATK and SOAP, followed by Annovar and SnpEff to annotate the variants. Results: No disease-causing variants were found using the allele-specific or targeted segment Sanger sequencing assays. Analysis of variants in the exome sequence data revealed a novel homozygous nonsense mutation (c.1081C > T, p.Arg361*) inTULP1, a gene with roles in photoreceptor function where mutations were previously shown to cause LCA and retinitis pigmentosa. The identified homozygous variant was the top candidate using both bioinformatic pipelines. Conclusions: This study highlights the value of the broad sequencing strategy of exome sequencing for disease gene identification in LCA, over other existing methods. NGS is particularly beneficial in LCA where there are a large number of causative disease genes, few distinguishing clinical features for precise candidate disease gene selection, and few mutation hotspots in any of the known disease genes. [ABSTRACT FROM AUTHOR]

A 6-month-old boy presented with a congenital eye movement disorder consistent with congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Mutational analysis confirmed the most common mutation in the CFEOM1 gene KIF21A. In addition to the typical findings in CFEOM1, distinctive conjunctival changes and small bilateral optic disc colobomata were also noted. It is suggested that optic disc colobomata represent a new association of CFEOM1. [ABSTRACT FROM AUTHOR]

PAX6 is a key regulator of eye development and there are many well recognized ophthalmic sequelae of mutations at this locus. The 14 exon PAX6 gene is well conserved across species and phyla. Coding region mutations manifest in a variety of phenotypes. Predicted premature protein truncations are generally associated with classical aniridia. Missense mutations are often found in cases with variant phenotypes such as ectopia pupillae; isolated foveal hypoplasia; nystagmus and hyaloid vessel proliferation. The locus has also been implicated, through a genome-wide sib-pair scan, to be important in the normal variation of myopia. We investigated the association between identified PAX6 mutations and refractive error in Australian patients from four pedigrees. Two of eight subjects with a 1410delC PAX6 mutation had a mean spherical equivalence < -9D, whilst a mean spherical equivalence ≤ -5D was recorded in two from four subjects with an Arg240Stop PAX6 mutation and one of two subjects with a Glu93Stop mutation. One individual identified with a Pro346Ala PAX6 mutation had a mean spherical equivalence of +2.8 D. Thus, our observations generally support other incidental findings, that PAX6 mutation, particularly predicted haploinsufficiency, may be associated with extreme refractive error, although the mechanism by which this occurs is not clear. [ABSTRACT FROM AUTHOR]