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Genes Sep 2021Monogenic syndromic disorders frequently feature ocular manifestations, one of which is glaucoma. In many cases, glaucoma in children may go undetected, especially in... (Review)
Review
Monogenic syndromic disorders frequently feature ocular manifestations, one of which is glaucoma. In many cases, glaucoma in children may go undetected, especially in those that have other severe systemic conditions that affect other parts of the eye and the body. Similarly, glaucoma may be the first presenting sign of a systemic syndrome. Awareness of syndromes associated with glaucoma is thus critical both for medical geneticists and ophthalmologists. In this review, we highlight six categories of disorders that feature glaucoma and other ocular or systemic manifestations: anterior segment dysgenesis syndromes, aniridia, metabolic disorders, collagen/vascular disorders, immunogenetic disorders, and nanophthalmos. The genetics, ocular and systemic features, and current and future treatment strategies are discussed. Findings from rare diseases also uncover important genes and pathways that may be involved in more common forms of glaucoma, and potential novel therapeutic strategies to target these pathways.
Topics: Aniridia; Collagen Diseases; Eye Abnormalities; Eye Diseases, Hereditary; Glaucoma; Glaucoma, Angle-Closure; Humans; Hyperopia; Immune System Diseases; Metabolic Diseases; Microphthalmos; Syndrome; Vascular Diseases
PubMed: 34573386
DOI: 10.3390/genes12091403 -
BMC Biology Feb 2023Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the...
BACKGROUND
Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome.
RESULTS
Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation.
CONCLUSIONS
Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.
Topics: Humans; Mice; Animals; Eye Abnormalities; Anophthalmos; Microphthalmos; Coloboma; Mice, Knockout; Embryonic Development; Phenotype; Eye; Mammals
PubMed: 36737727
DOI: 10.1186/s12915-022-01475-0 -
Clinical & Experimental Optometry Sep 2020Posterior microphthalmos (PM) is a rare developmental disorder characterised by high hyperopia, short axial length, presence of retinal papillomacular fold and... (Comparative Study)
Comparative Study
BACKGROUND
Posterior microphthalmos (PM) is a rare developmental disorder characterised by high hyperopia, short axial length, presence of retinal papillomacular fold and relatively normal anterior segment findings. The study objective is to describe the retinal structural and vascular changes in eyes with PM with spectral domain optical coherence tomography, optical coherence tomography angiography and multicolour imaging.
METHODS
In this retrospective, comparative case series, 10 eyes of five patients with PM as cases and 10 eyes of five age- and sex-matched controls were included. Structural changes, namely inner and outer retinal layer thicknesses, were measured using optical coherence tomography. Multicolour imaging findings were noted. Perifoveal vascular changes with qualitative and quantitative assessments were analysed using optical coherence tomography angiography.
RESULTS
The foveal dip was absent in all 10 eyes (100 per cent) with PM. There was an elevated retinal papillomacular fold in six eyes (60 per cent) and intraretinal cystoid spaces in two eyes (20 per cent) with PM. The inner retinal layers were thicker in PM. On multicolour imaging, foveal avascular zone and retinal wrinkles were identified in eyes with retinal papillomacular fold in blue and green reflectance images. Perifoveal vascular changes in optical coherence tomography angiography included foveal area size reduction in superficial and deep vascular networks. The foveal capillary vessel densities were higher in PM compared to the controls in both superficial (46.3 ± 3.7 per cent; p = 0.000) and deep (54.7 ± 3.5 per cent; p = 0.000) capillary plexuses. Flow areas in superficial (p = 0.693) and deep (p = 0.088) capillary plexuses were not statistically relevant.
CONCLUSION
The study suggests that in PM, retinal foreshortening occurs in one meridian leading to secondary changes such as loss of foveal dip, posterior bowing of the outer layers of the eye, thickening of the inner retina and ultimately, retinal papillomacular fold formation. The findings of the study need further validation in a larger series of patients with PM.
Topics: Adolescent; Adult; Biometry; Female; Fluorescein Angiography; Follow-Up Studies; Fovea Centralis; Fundus Oculi; Humans; Male; Microphthalmos; Retinal Vessels; Retrospective Studies; Tomography, Optical Coherence; Visual Acuity; Young Adult
PubMed: 31489720
DOI: 10.1111/cxo.12966 -
Nucleic Acids Research Aug 2023Many genetic syndromes are linked to mutations in genes encoding factors that guide chromatin organization. Among them, several distinct rare genetic diseases are linked...
Many genetic syndromes are linked to mutations in genes encoding factors that guide chromatin organization. Among them, several distinct rare genetic diseases are linked to mutations in SMCHD1 that encodes the structural maintenance of chromosomes flexible hinge domain containing 1 chromatin-associated factor. In humans, its function as well as the impact of its mutations remains poorly defined. To fill this gap, we determined the episignature associated with heterozygous SMCHD1 variants in primary cells and cell lineages derived from induced pluripotent stem cells for Bosma arhinia and microphthalmia syndrome (BAMS) and type 2 facioscapulohumeral dystrophy (FSHD2). In human tissues, SMCHD1 regulates the distribution of methylated CpGs, H3K27 trimethylation and CTCF at repressed chromatin but also at euchromatin. Based on the exploration of tissues affected either in FSHD or in BAMS, i.e. skeletal muscle fibers and neural crest stem cells, respectively, our results emphasize multiple functions for SMCHD1, in chromatin compaction, chromatin insulation and gene regulation with variable targets or phenotypical outcomes. We concluded that in rare genetic diseases, SMCHD1 variants impact gene expression in two ways: (i) by changing the chromatin context at a number of euchromatin loci or (ii) by directly regulating some loci encoding master transcription factors required for cell fate determination and tissue differentiation.
Topics: Humans; Muscular Dystrophy, Facioscapulohumeral; Neural Crest; Microphthalmos; Euchromatin; Chromosomal Proteins, Non-Histone; Muscle, Skeletal; Phenotype; Chromatin
PubMed: 37334829
DOI: 10.1093/nar/gkad523 -
Indian Journal of Ophthalmology Jul 1993
Topics: Aphakia; Female; Hallermann's Syndrome; Humans; Microphthalmos; Middle Aged; Nystagmus, Pathologic; Radiography; Skull; Vision Disorders
PubMed: 8262609
DOI: No ID Found -
Indian Journal of Ophthalmology Jul 2022To compare the clinical and biometric characteristics of children presenting with nanophthalmos (NO group) with that of age-matched controls (CO group).
PURPOSE
To compare the clinical and biometric characteristics of children presenting with nanophthalmos (NO group) with that of age-matched controls (CO group).
METHODS
Electronic medical records of 40 children (<18 years of age) with diagnosis of nanophthalmos (NO), presented to a tertiary center in Tamil Nadu between January 2010 and December 2019, were reviewed and compared with 30 age-matched controls (CO) presenting for routine eye examination between October 2019 and December 2019. Clinical parameters compared were best-corrected visual acuity (BCVA), axial length (AxL), keratometry (K), anterior chamber depth (ACD), lens thickness (LT), retinochoroidal scleral thickness (RCS), corneal diameter, central corneal thickness (CCT), intraocular pressure (IOP), lens axial length factor (LAF), and lens thickness/anterior chamber depth ratio (LT/ACD).
RESULTS
Mean age of the NO group was 8.95 ± 4.0 years. Mean spherical equivalent (SE) in NO group was 10.87 ± 3.1 D and was inversely correlated to AxL (r = -0.46, P value = 0.003). All biometric parameters (AxL, ACD, LT, RCS, LAF, and LT/ACD), except CCT were significantly different between NO and CO groups. NO group children had 52.5% visual impairment with BCVA ≤ 6/24 and 17.5% had esotropia. Common ocular associations in NO group were amblyopia (64.3%), primary angle-closure glaucoma (PACG) (17.8%), pigmentary retinopathy (14.3%), and retinal detachment (3.6%). Angle-closure disease was seen in 50% of NO group and 30% underwent laser peripheral iridotomy (LPI). There was a significant difference in SE, ACD, and LAF among NO children with AxL <17 mm or >17 mm. Multivariable regression analysis revealed a significant correlation of SE and ACD with AxL.
CONCLUSION
Nanophthalmos in children often present as amblyopia with visual impairment and strabismus. NO group with AxL <17 mm, had angle-closure disease as a common association with significantly lower ACD, higher SE, and LAF. All morphometric characteristics, except CCT, were significantly different between NO and CO groups. Close monitoring with serial biometry in NO group is needed for the timely diagnosis and prompt intervention to avoid visual impairment, due to glaucoma.
Topics: Amblyopia; Biometry; Child; Child, Preschool; Humans; India; Microphthalmos; Sclera; Vision, Low
PubMed: 35791127
DOI: 10.4103/ijo.IJO_2880_21 -
Trends in Immunology Feb 2020Microphthalmia/TFE (MiT) transcription factors (TFs), such as transcription factor EB (TFEB) and transcription factor E3 (TFE3), are emerging as key regulators of innate... (Review)
Review
Microphthalmia/TFE (MiT) transcription factors (TFs), such as transcription factor EB (TFEB) and transcription factor E3 (TFE3), are emerging as key regulators of innate immunity and inflammation. Rapid progress in the field requires a focused update on the latest advances. Recent studies show that TFEB and TFE3 function in innate immune cells to regulate antibacterial and antiviral responses downstream of phagocytosis, interferon (IFN)-γ, lipopolysaccharide (LPS), and adenosine receptors. Moreover, overexpression of TFEB or TFE3 can drive inflammation in vivo, such as in atherosclerosis, while in other scenarios they can perform anti-inflammatory functions. MiT factors may constitute potential therapeutic targets for a broad range of diseases; however, to harness their therapeutic potential, sophisticated ways to manipulate MiT factor activity safely and effectively must be developed.
Topics: Humans; Immunity, Innate; Inflammation; Microphthalmos; Transcription Factors
PubMed: 31959514
DOI: 10.1016/j.it.2019.12.003 -
Indian Journal of Ophthalmology Dec 2022Congenital hereditary endothelial dystrophy affects the Descemet membrane and endothelium, resulting in corneal decompensation. Penetrating keratoplasty (PKP) has been... (Review)
Review
Congenital hereditary endothelial dystrophy affects the Descemet membrane and endothelium, resulting in corneal decompensation. Penetrating keratoplasty (PKP) has been the gold-standard surgical management until recently; however, at present, endothelial keratoplasty (DSEK/DSAEK/n-DSEK: Descemet-stripping or non-Descemet stripping endothelial keratoplasty and DMEK/n-DMEK: Descemet membrane endothelial keratoplasty) is being preferred due to lesser intraoperative and postoperative complications, early visual recovery, and comparable visual outcomes. Endothelial keratoplasty (EK) can be challenging, especially in pediatric eyes with CHED due to smaller eyeballs, shallow anterior chambers, phakic status, and poor intraoperative visibility due to thick and hazy corneas. A total of 198 articles matched our search strategy. After screening for duplication and going through the titles and abstracts, 12 relevant original articles, one case series, and six case reports were included in this review. Various surgical modifications have to be adopted in comparison to adult eyes to overcome the aforementioned difficulties. Regardless, studies have shown favorable visual outcomes with better graft survival and fewer complications in eyes that underwent EK compared to PKP. Hence, timely surgical intervention and strict amblyopia management can result in better final visual outcomes. The purpose of this review is to summarize various intraoperative difficulties and the surgical modifications required, different surgical techniques, visual and graft-related outcomes, and various complications of EK in CHED eyes.
Topics: Adult; Humans; Child; Corneal Dystrophies, Hereditary; Corneal Transplantation; Keratoplasty, Penetrating; Eye; Microphthalmos
PubMed: 36453297
DOI: 10.4103/ijo.IJO_1313_22 -
Acta Ophthalmologica Jun 2021To (i) describe a series of patients with isolated or syndromic nanophthalmos with the underlying genetic causes, including novel pathogenic variants and their...
PURPOSE
To (i) describe a series of patients with isolated or syndromic nanophthalmos with the underlying genetic causes, including novel pathogenic variants and their functional characterization and (ii) to study the association of retinal dystrophy in patients with MFRP variants, based on a detailed literature review of genotype-phenotype correlations.
METHODS
Patients with nanophthalmos and available family members received a comprehensive ophthalmological examination. Genetic analysis was based on whole-exome sequencing and variant calling in core genes including MFRP, BEST1, TMEM98, PRSS56, CRB1, GJA1, C1QTNF5, MYRF and FAM111A. A minigene assay was performed for functional characterization of a splice site variant.
RESULTS
Seven patients, aged between three and 65 years, from five unrelated families were included. Novel pathogenic variants in MFRP (c.497C>T, c.899-3C>A, c.1180G>A), and PRSS56 (c.1202C>A), and a recurrent de novo variant in FAM111A (c.1706G>A) in a patient with Kenny-Caffey syndrome type 2, were identified. In addition, we report co-inheritance of MFRP-related nanophthalmos and ADAR-related Aicardi-Goutières syndrome.
CONCLUSION
Nanophthalmos is a genetically heterogeneous condition, and the severity of ocular manifestations appears not to correlate with variants in a specific gene. However, retinal dystrophy is only observed in patients harbouring pathogenic MFRP variants. Furthermore, heterozygous carriers of MFRP and PRSS56 should be screened for the presence of high hyperopia. Identifying nanophthalmos as an isolated condition or as part of a syndrome has implications for counselling and can accelerate the interdisciplinary care of patients.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; DNA; DNA Mutational Analysis; Female; Genetic Association Studies; Genetic Testing; Humans; Male; Membrane Proteins; Microphthalmos; Middle Aged; Mutation; Pedigree; Phenotype; Young Adult
PubMed: 32996714
DOI: 10.1111/aos.14615 -
Ophthalmic Genetics Jun 2021: To describe a family with presumed gonadosomatic mosaicism diagnosed upon ophthalmic examination of the proband's mother.: The family underwent comprehensive...
: To describe a family with presumed gonadosomatic mosaicism diagnosed upon ophthalmic examination of the proband's mother.: The family underwent comprehensive ophthalmic and physical examination. Variant detection was performed using trio exome analysis on peripheral leukocyte DNA from blood and saliva samples. Variant segregation analysis was performed using a custom panel NGS sequencing. An identified variant in the gene was confirmed in the proband by Sanger sequencing.: We report an individual with bilateral microphthalmia, developmental delay, hearing loss, and dysmorphic features. Her mother was found to have asymptomatic uveal coloboma affecting her anterior segment. Her father, aunt, and sisters were unaffected. Trio exome sequence analysis showed an apparent heterozygous deletion in the proband, NM_003106.3:c.70_89del, NP_003097.1:p.(Asn24Argfs*65), classified as pathogenic. Testing of the other family members' peripheral blood and saliva was negative for this variant. The iris transillumination abnormalities in the proband's mother supports a gonadosomatic mosaicism scenario.: The results from this family underscore the importance of performing detailed evaluations of the parents of apparently sporadically affected individuals with heritable ophthalmic disorders. The identification of mildly affected individuals could substantially alter recurrence risks.
Topics: Adult; Craniofacial Abnormalities; Developmental Disabilities; Female; Hearing Loss; High-Throughput Nucleotide Sequencing; Humans; Infant, Newborn; Male; Microphthalmos; Mosaicism; Pedigree; SOXB1 Transcription Factors; Sex Chromosome Disorders; Exome Sequencing
PubMed: 33719903
DOI: 10.1080/13816810.2021.1888127