Ocular Developmental Anomalies Research Articles

Serous Maculopathy Due to Aspecific Choroidopathy (SMACH).

Serous Maculopathy Due to Aspecific Choroidopathy (SMACH).

Serous business: Delineating the broad spectrum of diseases with subretinal fluid in the macula.

A wide range of ocular diseases can present with serous subretinal fluid in the macula and therefore clinically mimic central serous chorioretinopathy (CSC). In this manuscript, we categorise the diseases and conditions that are part of the differential diagnosis into 12 main pathogenic subgroups: neovascular diseases, vitelliform lesions, inflammatory diseases, ocular tumours, haematological malignancies, paraneoplastic syndromes, genetic diseases, ocular developmental anomalies, medication-related conditions and toxicity-related diseases, rhegmatogenous retinal detachment and tractional retinal detachment, retinal vascular diseases, and miscellaneous diseases. In addition, we describe 2 new clinical pictures associated with macular subretinal fluid accumulation, namely serous maculopathy with absence of retinal pigment epithelium (SMARPE) and serous maculopathy due to aspecific choroidopathy (SMACH). Differentiating between these various diseases and CSC can be challenging, and obtaining the correct diagnosis can have immediate therapeutic and prognostic consequences. Here, we describe the key differential diagnostic features of each disease within this clinical spectrum, including representative case examples. Moreover, we discuss the pathogenesis of each disease in order to facilitate the differentiation from typical CSC.

Activation of cryptic donor splice sites by non-coding and coding PAX6 variants contributes to congenital aniridia

BackgroundThe paired-domain transcription factor paired box gene 6 (PAX6) causes a wide spectrum of ocular developmental anomalies, including congenital aniridia, Peters anomaly and microphthalmia. Here, we aimed to functionally assess...

Genetic architecture of retinoic-acid signaling-associated ocular developmental defects.

Ocular developmental anomalies are among the most common causes of severe visual impairment in newborns (combined incidence 1-2:10,000). They comprise a wide range of inborn errors of eye development with a spectrum of overlapping phenotypes and they are frequently associated with extraocular malformations, neuropsychomotor developmental delay and/or intellectual disabilities. Many studies from model organisms have demonstrated the role of retinoic acid (RA) during organogenesis, including eye development, and have revealed the wide spectrum of malformations that can arise from defective RA signaling. However, genes coding for homeobox proteins and morphogenetic factors were implicated in anomalies of ocular development long before genes coding for RA-signaling proteins. The purpose of this review is to discuss current knowledge about the highly complex genetic architecture of RA-signaling-associated ocular developmental anomalies in humans. Despite less than a dozen genes identified thus far, all steps of RA-signaling, from vitamin A transport to target cells to transcriptional activation of RA targets, have been implicated. Furthermore, the majority of these genetic disorders are associated with both dominant and recessive inheritance patterns and a wide spectrum of ocular malformations, which can dominate the phenotype or represent one of many features. Although some genotype-phenotype correlations are described, in many cases, the variability of clinical expression cannot be accounted for by the genotype alone. This observation and the large number of unsolved cases suggest that the relationship between RA signaling and eye development deserves further investigation.

High-throughput genetic analysis in a cohort of patients with Ocular Developmental Anomalies

High-throughput genetic analysis in a cohort of patients with Ocular Developmental Anomalies

The RaDiCo AC‐OEIL : a French rare disease cohort dedicated to ocular developmental anomalies in children

PurposeOcular development may be disrupted at various stages, leading to a wide range of congenital ocular dysgenesis. Incidence of such defects is estimated to 1‐2 in 10.000. They may be isolated or associated with extra‐ocular malformations. In addition, psychomotor delay may be present, secondary to the sensory involvement or linked to a cerebral developmental anomaly leading to intellectual disability. Visual outcome, frequency of extra‐ocular features and psychomotor delay are still poorly known. Given the rarity of these malformations, available data concern very heterogeneous groups of patients, which make their utility limited in clinical practice. It is thus difficult to anticipate visual and neurologic outcomes when a congenital ocular developmental anomaly is diagnosed.MethodsRaDiCo‐AC‐ŒIL is an observational study launched in May 2017 sponsored by Inserm, relying on the French Rare Diseases healthcare networks SENSGENE and ANDDI‐Rare for patients’ enrolment, and supported by patients ‘associations. Patients will have a maximum of three clinical examinations (at time of diagnosis, at 5‐7‐year‐old, and at 9‐11‐year‐old) during which visual, neuro‐developmental and quality‐of‐life data will be collected in addition to the usual clinical data, using REDCap EDC system. It will extend to other EU countries once regulatory requirements will be fulfilled.ResultsAbout 800 patients are expected to be enrolled during a recruitment period of 10 years. ConclusionsRaDiCo‐AC‐ŒIL will improve i) our knowledge on the natural history of ocular developmental defects in children ii) the identification of prognostic factors for ocular and neurodevelopmental outcome iii) genetics counselling and iv) the design of optimised management protocols. This project will also pave the way to clinical and basic research in a homogeneous cohort.

Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network

Ocular developmental anomalies (ODA) such as anophthalmia/microphthalmia (AM) or anterior segment dysgenesis (ASD) have an estimated combined prevalence of 3.7 in 10,000 births. Mutations in SOX2 are the most frequent contributors to severe ODA, yet account for a minority of the genetic drivers. To identify novel ODA loci, we conducted targeted high-throughput sequencing of 407 candidate genes in an initial cohort of 22 sporadic ODA patients. Patched 1 (PTCH1), an inhibitor of sonic hedgehog (SHH) signaling, harbored an enrichment of rare heterozygous variants in comparison to either controls, or to the other candidate genes (four missense and one frameshift); targeted resequencing of PTCH1 in a second cohort of 48 ODA patients identified two additional rare nonsynonymous changes. Using multiple transient models and a CRISPR/Cas9-generated mutant, we show physiologically relevant phenotypes altering SHH signaling and eye development upon abrogation of ptch1 in zebrafish for which in vivo complementation assays using these models showed that all six patient missense mutations affect SHH signaling. Finally, through transcriptomic and ChIP analyses, we show that SOX2 binds to an intronic domain of the PTCH1 locus to regulate PTCH1 expression, findings that were validated both in vitro and in vivo. Together, these results demonstrate that PTCH1 mutations contribute to as much as 10% of ODA, identify the SHH signaling pathway as a novel effector of SOX2 activity during human ocular development, and indicate that ODA is likely the result of overactive SHH signaling in humans harboring mutations in either PTCH1 or SOX2.

Chromosomal microarray analysis in ocular developmental anomalies

Ocular developmental anomalies (ODAs) are structural defects of the eye with vari-ous severities, caused by the disruption of the complex process of ocular morpho-genesis. Although the reported prevalence at birth varies greatly, congenital eye mal-formations are rare; they are estimated to occur in four to six per 10,000 neonates in European registries

Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies

In 65 patients, who had unexplained ocular developmental anomalies (ODAs) with at least one other birth defect and/or intellectual disability, we performed oligonucleotide comparative genome hybridisation-based microarray analysis (array-CGH; 105A or 180K, Agilent Technologies). In four patients, array-CGH identified clinically relevant deletions encompassing a gene known to be involved in ocular development (FOXC1 or OTX2). In four other patients, we found three pathogenic deletions not classically associated with abnormal ocular morphogenesis, namely, del(17)(p13.3p13.3), del(10)(p14p15.3), and del(16)(p11.2p11.2). We also detected copy number variations of uncertain pathogenicity in two other patients. Rearranged segments ranged in size from 0.04 to 5.68 Mb. These results show that array-CGH provides a high diagnostic yield (15%) in patients with syndromal ODAs and can identify previously unknown chromosomal regions associated with these conditions. In addition to their importance for diagnosis and genetic counselling, these data may help identify genes involved in ocular development.

Novel SOX2 partner-factor domain mutation in a four-generation family

Anophthalmia (no eye), microphthalmia (small eye) and associated ocular developmental anomalies cause significant visual handicap. In most cases the underlying genetic cause is unknown, but mutations in some genes, such as SOX2, cause ocular developmental defects, particularly anophthalmia, in a subset of patients. Here, we describe a four-generation family with a p.Asp123Gly mutation in the highly conserved partner-factor interaction region of the SOX2 protein, which is important for cell-specific actions of SOX2. The proband in this family has bilateral anophthalmia and several other family members have milder ocular phenotypes, including typical optic fissure coloboma. Expression studies indicate that Sox2 is expressed in the eye at the site of closure of the optic fissure during development. The SOX2 mutation in this family implicates the partner-factor interaction region of SOX2 in contributing to the specificity of SOX2 action in optic fissure closure. Our findings indicate that investigation of SOX2 in a broad range of eye anomaly patients aids in the determination of particular functions of SOX2 in development.

The albino chick as a model for studying ocular developmental anomalies, including refractive errors, associated with albinism

Albinism is associated with a variety of ocular anomalies including refractive errors. The purpose of this study was to investigate the ocular development of an albino chick line. The ocular development of both albino and normally pigmented chicks was monitored using retinoscopy to measure refractive errors and high frequency A-scan ultrasonography to measure axial ocular dimensions. Functional tests included an optokinetic nystagmus paradigm to assess visual acuity, and flash ERGs to assess retinal function. The underlying genetic abnormality was characterized using a gene microarray, PCR and a tyrosinase assay. The ultrastructure of the retinal pigment epithelium (RPE) was examined using transmission electron microscopy. PCR confirmed that the genetic abnormality in this line is a deletion in exon 1 of the tyrosinase gene. Tyrosinase gene expression in isolated RPE cells was minimally detectable, and there was minimal enzyme activity in albino feather bulbs. The albino chicks had pink eyes and their eyes transilluminated, reflecting the lack of melanin in all ocular tissues. All three main components, anterior chamber, crystalline lens and vitreous chamber, showed axial expansion over time in both normal and albino animals, but the anterior chambers of albino chicks were consistently shallower than those of normal chicks, while in contrast, their vitreous chambers were longer. Albino chicks remained relatively myopic, with higher astigmatism than the normally pigmented chicks, even though both groups underwent developmental emmetropization. Albino chicks had reduced visual acuity yet the ERG a- and b-wave components had larger amplitudes and shorter than normal implicit times. Developmental emmetropization occurs in the albino chick but is impaired, likely because of functional abnormalities in the RPE and/or retina as well as optical factors. In very young chicks the underlying genetic mutation may also contribute to refractive error and eye shape abnormalities.

Roles of Maf family proteins in lens development.

Lens provides a good model for studying developmental cues relevant to cellular and molecular interactions. Basic region/leucine zipper (bZIP) transcription factors have been found to play key roles during eye formation in various species, including human, mouse, rat, Xenopus, zebrafish, chick, and quail. Different ocular developmental anomalies associated with MAF mutation in human implicate its active role during eye development. Several members of the maf gene family with this bZIP motif participate directly in lens morphogenesis. One vital Maf protein, L-Maf, is expressed in developing lens cells of chick embryos. Its homolog recently has been detected in lens placode of Xenopus embryos and regulates expression of lens fiber-specific genes in this species. Ectopic expression of L-Maf can induce lens-specific genes in cultured retina cells and embryonic ectoderm. The dominant-negative form of L-Maf causes the suppression of crystallin expression and subsequently inhibits lens formation, indicating that L-Maf plays a central role in chick lens development.

Morning glory syndrome: a histopathological study.

The clinical and histopathological findings in a case of morning glory syndrome are described. Axial optic nerve retrodisplacement into a peripapillary scleral ectasia (staphyloma), absence of fibrous lamina cribrosa, and optic nerve atrophy were associated with various other, non-inherent ocular developmental anomalies. The uninterrupted lining of the inner wall of the staphyloma by one-layered, normal retinal pigment epithelium proves that the syndrome is not due to a neuroectodermal closure defect.