Ophthalmic Genetics最新文献

Background: GLI-Similar 3 (GLIS3) gene plays a critical role in the regulation of several biological processes and is implicated in the development of various diseases. However, documentation regarding congenital glaucoma and other ophthalmic features in patients with GLIS3 variants is lacking. We aimed to expand the ophthalmological features related to GLIS3 deletion.

Methods: We present a case report of two Saudi Arabian siblings with congenital glaucoma, congenital diabetes mellitus, and congenital hypothyroidism. Full ophthalmological examination, medical evaluation, and genetic testing of all family members were conducted.

Results: In both patients, ophthalmic assessments revealed congenital glaucoma, high hyperopia, and short axial length of the globe. Genetic testing confirmed the presence of a large homozygous deletion, including the non-coding exon 1 and the entire coding exon 2 of the GLIS3 gene. Endocrine abnormalities included neonatal diabetes, congenital hypothyroidism, along with characteristic facial features that shows a long philtrum and thin and tight upper lip. Genetic testing of other siblings showed a heterozygous deletion of the GLIS3 gene. Although their ophthalmic examinations were unremarkable, all carriers presented with juvenile hypothyroidism.

Conclusion: Congenital glaucoma is commonly associated with myopia. We report an association between congenital glaucoma and high hyperopia related to GLIS3 partial deletion, which to our knowledge, has not been previously reported. We recommend that pediatric patients with neonatal diabetes and hypothyroidism to be evaluated for congenital glaucoma. Additionally, we suggest screening carriers for hypothyroidism.

Background: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare autosomal dominant neurodevelopmental disorder that typically presents in early childhood. It is characterized by intellectual disability, developmental delay, and visual impairment, with optic atrophy being the most prominent ophthalmologic feature. The nuclear receptor subfamily 2, group F, member 1 (NR2F1) gene is currently the only known causative gene associated with BBSOAS. To date, no cases of BBSOAS have been reported in the Japanese population.

Cases presentation: We reported a 13-year-old Japanese male suspected of having BBSOAS, who presented with decreased visual acuity due to bilateral optic atrophy, as well as intellectual disability and developmental delay. Microarray-based comparative genomic hybridization (array-CGH), followed by whole-genome sequencing (WGS), identified a novel de novo 1.48-Mb heterozygous microdeletion involving NR2F1.

Conclusions: This is the first reported case of BBSOAS in a Japanese patient. These findings highlight the utility of array-CGH and WGS as powerful tools for detecting NR2F1-related microdeletions. BBSOAS should be considered in the differential diagnosis of patients presenting with developmental delay, intellectual disability, and visual impairment, even in the absence of a family history.

Introduction: Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder characterized by the rapid loss of vision due to the degeneration of retinal ganglion cells. Current therapeutic options are limited. However, idebenone, a synthetic analog of coenzyme Q10, has shown promising neuroprotective properties. This systematic review and meta-analysis aim to evaluate the efficacy of idebenone in improving visual acuity in patients with LHON.

Methods: We performed a systematic review on PubMed, Cochrane, and Embase databases on 7 July 2024, for randomized and non-randomized studies analyzing the effect of idebenone on visual acuity in patients with LHON. Analyses were conducted using random-effects models. The main outcome of interest was visual acuity measured by the Logarithm of the Minimum Angle of Resolution (LogMAR). All statistical analyses were performed in R software version 4.3.2, using the "meta" and "metafor" packages. We registered the study on PROSPERO under protocol number CRD42024617308.

Results: Five studies (3 clinical trials and 2 retrospective cohorts) with 375 patients were included. The overall mean LogMAR difference was -0.32 (95% CI: -0.50 to -0.15), with a favorable effect of idebenone as compared to treatment without idebenone. This indicates a meaningful improvement in visual acuity with idebenone therapy, with changes translating to approximately 1.5-5 lines of better visual performance on the LogMAR scale.

Conclusion: This systematic review and meta-analysis found a substantial clinical improvement in visual acuity with idebenone therapy among patients with LHON.

Background: Phosphoribosyl pyrophosphate synthetase 1 (PRPS1) deficiency is a rare neurometabolic disorder with wide spectrum of presentation. It can present in early childhood with global developmental delay, retinal dystrophy, and hearing loss, or can present as isolated neuropathy or hearing loss in adulthood. Here we describe a patient with vision impairment, fatigue, and unilateral hearing loss caused by a somatic mosaic pathogenic variant in PRPS1 gene which encodes PRPS1. Supplementation with S-adenosylmethionine (SAMe) and Nicotinamide Riboside (NR) resulted in improvement in symptoms.

Method and results: This retrospective clinical-laboratory observational study has a reference patient who was found to have right-sided hearing loss and vision impairment in right eye in early childhood. Later on, he developed epilepsy. He had deterioration in cognitive function in adolescence. At the age of 26 years, he developed progressive vision impairment due to bilateral, asymmetric retinal degeneration. In addition, he had severe generalized fatigue. Molecular diagnostic workup showed a mosaic pathogenic variant c.383A > T, p. Asp128Val in PRPS1. Subsequently, SAMe at 800mg twice a day and NR at 800 mg daily doses were started leading to significant improvement in fatigue and stabilization of vision.

Conclusion: PRPS1 deficiency is an inherited disease of nucleotide biosynthesis. The age of onset of symptoms as well as severity of symptoms are variable. Supplementations with nucleotide precursors may stabilize the clinical course.

Introduction: Pathogenic variants in TUBB4B, which encodes the β-tubulin 4B isotype of microtubule subunits, have been associated with Leber congenital amaurosis with early-onset deafness (LCAEOD), an autosomal dominant condition characterized by early and severe loss of photoreceptor and cochlear cells. The majority of reported cases feature early disease onset and are caused by missense mutations in the R390/R391 hotspot.

Methods: Multimodal evaluation included ultra-widefield pseudocolor and autofluorescence fundus photography, spectral-domain optical coherence tomography, full-field electroretinography, Goldmann kinetic perimetry, audiography, and genetic testing with next-generation sequencing.

Results: We report seven individuals from three unrelated families affected by cone-rod dystrophy and sensorineural hearing loss associated with a novel variant in TUBB4B (c.784C > T, p.R262W). Cone-rod dystrophy associated with this variant generally features a later age of onset compared to the Leber congenital amaurosis caused by variants in the canonical hotspot.

Discussion: This report expands the mutation spectrum and phenotypic range of TUBB4B-associated retinopathies beyond the R390/R391 hotspot and may offer insight into the pathogenesis of this rare tubulinopathy.

Disorders of bone formation or resorption affecting the cranium can lead to ophthalmic complications. We describe a family with Worth endosteal hyperostosis (WEH), an autosomal dominant condition characterized by mandibular overgrowth and cortical thickening of long bones. Although traditionally considered benign, we report significant neuro-ophthalmic complications in this kindred.This retrospective case series examines a two-generation family of three siblings and their mother, all with clinical features of WEH and a confirmed lipoprotein-related protein 5 (LRP5) gene mutation. A literature review is also included.The proband was diagnosed with WEH after an incidental finding of dense bones on a chest x-ray at age 16, with no neurological complications. However, her three affected children developed papilledema due to elevated intracranial pressure, requiring calvarial expansion. Computed tomography imaging revealed calvarial thickening and late-onset sagittal synostosis in two individuals. In two cases, intracranial hypertension was detected only after routine ophthalmic monitoring revealed papilledema. All had successful outcomes with resolution of papilledema following surgery.Here, we show that WEH can be associated with serious and late onset neuro-ophthalmic manifestations and secondary sagittal synostosis. We recommend regular ophthalmic review to facilitate early detection of potential complications, as part of the multidisciplinary care.

Background: Trisomy 8 mosaicism (T8M) also known as Warkany syndrome 2 is a rare chromosomal disorder characterized by a highly variable phenotypic presentation. Ranging from mild congenital anomalies to life and sight threatening associations. Currently, the most common ophthalmic manifestations are strabismus, hypertelorism, and corneal opacities. Other visually debilitating features include microphthalmia, retinal dystrophy, and optic disc coloboma.

Case presentation: We present a case of a 9-year-old male who was referred to our ophthalmology service as a case of strabismus and bilateral ptosis with syndromic facial features of a protruded jaw, low set ears, and wide nasal bridge, and was later confirmed with cytogenetic analysis of T8M. To the best of our knowledge, this is the first reported case of T8M in our region, and the first to present euryblepharon as an associated ophthalmic manifestation, in addition to providing an updated review of the most commonly and newly documented manifestations of T8M.

Conclusion: The phenotypic variation of T8M is diverse and often unpredictable, ranging from mild ocular findings to visually debilitating manifestations. Comprehensive awareness of its ophthalmic features can aid ophthalmologists in early recognition and appropriate genetic evaluation and counseling.

Introduction: We report the case of a 42-year-old Venezuelan woman with childhood-onset autosomal recessive retinitis pigmentosa type 90 (RP90), presenting an unusual and distinctive clinical phenotype characterized by macular pseudocoloboma, very early-onset acquired color vision disorder progressing to severe functional dyschromatopsia, and early-onset severe posterior subcapsular cataracts. Her affected brother exhibited a similar phenotype, while her parents and the other two siblings remained unaffected.

Methods and results: Massive parallel sequencing identified two novel IDH3A variants: c.127G>T (chr15:78449926 G>T; no dbSNP entry) and c.419T>C (chr15:78454052T>C; no dbSNP entry), in compound heterozygosity and confirmed to be in trans location. Both missense variants, absent from population databases, were predicted to be deleterious by multiple in silico tools and are located in critical domains involved in enzymatic complex stability, catalytic activity and subunit interactions.

Conclusions: This case reinforces the association between IDH3A mutations and RP90, corroborates key phenotypic features described in limited published reports-the presence of macular pseudocoloboma-and expands the mutational spectrum of the gene. Moreover, it highlights the role of mitochondrial metabolism in photoreceptor degeneration and proposes a link between them. Our findings underscore the need for functional studies to elucidate the pathogenic mechanisms underlying IDH3A-related retinopathies.

Introduction: To evaluate the changes in central corneal thickness and curvature parameters in pediatric patients with Triple A syndrome and alacrima.

Methods: This retrospective study included 52 eyes of 26 patients with Triple A syndrome. All patients had alacrima. Pentacam was used to analyze the keratometry in the flat (K1) and steep meridian (K2) and maximum keratometry (Kmax), mean keratometry (Kmean) readings, central corneal thickness at the vertex (CCT) and at the thinnest point (CCT-TP) were recorded. Patients were divided into three groups based on their age (Group 1: 3-6 years, group 2: 7-12 years, group 3: 13-18 years). Values were compared between pediatric patients with Triple A and normal controls.

Results: The K1 values of all patients were significantly higher than those observed in healthy data (p < 0.001). 15 Group 1 had significantly lower K2 and higher CCT values (p = 0.008, p = 0.015). In group 2, K1 and Kmax were significantly higher, while CCT and CCT-TP were lower (p = 0.016, p < 0.001, p < 0.001, p < 0.001, respectively). In group 3, K1 and CCT and CCT-TP were significantly higher than the normal data (p = 0.019, p < 0.001, p < 0.001, respectively).

Discussion: Since dry eye syndrome may cause corneal changes, in AAAS patients, corneal topographic variations may occur due to alacrima. Thus, these patients should be evaluated during follow-up visits.

Introduction: Loeys-Dietz syndrome (LDS) is a rare autosomal dominant connective tissue disorder most commonly due to pathogenic variants in the transforming growth factor beta receptor genes TGFBR1 and TGFBR2. There have been reports of a few sporadic cases of LDS patients exhibiting a vitreoretinopathy phenotype due to pathogenic variants in the TGFBR2 gene.

Case presentation: We report a 13-year-old female with LDS who harbored a de novo pathogenic missense variant (c.1582C>T, p.Arg528Cys) in TGFBR2. She presented with reduced visual acuity in the right eye due to a vitreous hemorrhage. Fluorescein angiography identified neovascularization in the right eye with peripheral avascular retina in both eyes. These phenotypic features were similar to those seen in familial exudative vitreoretinopathy (FEVR). Intravitreal anti-VEGF treatment in the right eye led to visual improvement, followed by laser photocoagulation of the peripheral retina of both eyes to mitigate future complications.

Discussion: This is the second reported case of a missense variant at the amino acid residue 528 (Arg528) of TGFBR2 that results in a FEVR-like phenotype in a LDS patient. In silico protein prediction and machine learning analyses of the affected region of the TGFBR2 protein suggest this missense variant disrupts the protein kinase domain. We hypothesize this change influences the Wnt/beta-catenin pathway, leading to abnormal retinal vasculogenesis.

Conclusions: This case highlights the importance of a genotype to phenotype relationship in LDS and suggests that certain variants in TGFBR2 may predispose to vitreoretinopathy. Recognition of this is important as timely anti-VEGF and laser intervention can limit visual threatening complications.