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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 These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice.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 -
Human Genetics Sep 2019Eye formation is the result of coordinated induction and differentiation processes during embryogenesis. Disruption of any one of these events has the potential to cause... (Review)
Review
Eye formation is the result of coordinated induction and differentiation processes during embryogenesis. Disruption of any one of these events has the potential to cause ocular growth and structural defects, such as anophthalmia and microphthalmia (A/M). A/M can be isolated or occur with systemic anomalies, when they may form part of a recognizable syndrome. Their etiology includes genetic and environmental factors; several hundred genes involved in ocular development have been identified in humans or animal models. In humans, around 30 genes have been repeatedly implicated in A/M families, although many other genes have been described in single cases or families, and some genetic syndromes include eye anomalies occasionally as part of a wider phenotype. As a result of this broad genetic heterogeneity, with one or two notable exceptions, each gene explains only a small percentage of cases. Given the overlapping phenotypes, these genes can be most efficiently tested on panels or by whole exome/genome sequencing for the purposes of molecular diagnosis. However, despite whole exome/genome testing more than half of patients currently remain without a molecular diagnosis. The proportion of undiagnosed cases is even higher in those individuals with unilateral or milder phenotypes. Furthermore, even when a strong gene candidate is available for a patient, issues of incomplete penetrance and germinal mosaicism make diagnosis and genetic counseling challenging. In this review, we present the main genes implicated in non-syndromic human A/M phenotypes and, for practical purposes, classify them according to the most frequent or predominant phenotype each is associated with. Our intention is that this will allow clinicians to rank and prioritize their molecular analyses and interpretations according to the phenotypes of their patients.
Topics: Animals; Anophthalmos; Exome; Eye; Eye Abnormalities; Humans; Microphthalmos; Phenotype; Syndrome
PubMed: 30762128
DOI: 10.1007/s00439-019-01977-y -
The British Journal of Ophthalmology Sep 2023To evaluate treatment with custom, three-dimensional (3D) printed conformers for socket expansion in congenital microphthalmia and anophthalmia (MICA).
BACKGROUND/AIMS
To evaluate treatment with custom, three-dimensional (3D) printed conformers for socket expansion in congenital microphthalmia and anophthalmia (MICA).
METHODS
Retrospective analysis of prospective cohort from 2016 to 2020. All children received custom-made 3D-printed conformers increasing in size. We measured height, width, thickness, surface and volume of first and consecutive conformers, as well as horizontal palpebral fissure length (HPF) at start and follow-up visits. We analysed these parameters for severely (<45%) and moderately (>45%-75%) affected children, based on affected axial length on ultrasonography.
RESULTS
We included 18 cases (9 severe, 9 moderate) with a total of 174 conformers (88 severe, 86 moderate) and a mean follow-up of 2.8 years (range 1.3-4.8). The mean relative HPF increased from 77% to 93% with 16/17 cases reaching >80%, and 12/17 cases >90% symmetry. Horizontal and vertical conformer dimensions increased up to 10 months of treatment, with a steeper slope for the severe group (10.5% vs 5.5% for height and 9.0% vs 6.1% for width gain per treatment month, for severe and moderate MICA, respectively). After 10 months of treatment conformer height and width increased only slightly. No serious complications were observed.
CONCLUSION
3D-design and printing of solid conformers results in highly acceptable horizontal eyelid symmetry in the treatment of congenital MICA. The mean increase in conformer height and width in the first 10 months should be about 170% for moderate and about 200% for severe MICA. The presented conformer size formulas can aid ophthalmologists and ocularists to plan conformer treatment.
Topics: Child; Humans; Anophthalmos; Retrospective Studies; Microphthalmos; Workflow; Prospective Studies; Computer-Aided Design; Printing, Three-Dimensional
PubMed: 35477668
DOI: 10.1136/bjophthalmol-2021-320882 -
Arquivos Brasileiros de Oftalmologia 2022To assess the anterior and posterior segments of full-term neonates over a 1.5-year period.
PURPOSE
To assess the anterior and posterior segments of full-term neonates over a 1.5-year period.
METHODS
The findings of full-term neonates who underwent ophthalmological examinations between June 2019 and December 2020 were analyzed, and the results were retrospectively recorded.
RESULTS
The study comprised 2972 neonates with a mean birth week of 38.7 ± 1.2 weeks and a mean birth weight of 3235 ± 464 g. The neonates were examined on an average of 49.3 ± 18.9 postnatal days. Of the examined neonates, 185 (6.2%) showed abnormal ophthalmological findings, the most prevalent of which were retinal hemorrhage in 2.3% (n=68) and white changes in the peripheral retina in 1.9% (n=55) of the neonates. Cases of optic disc pathologies (n=20), choroidal nevus (n=10), iris-choroidal coloboma (n=5), subconjunctival hemorrhage (n=6), non-specific retinal pigmentary change (n=4), congenital cataract (n=3), posterior synechia (n=3), iris nevus (n=3), corneal opacity (n=1), choroidal coloboma (n=1), iris coloboma (n=1), buphthalmos (n=1), anophthalmos (n=1), microphthalmia (n=1), lid hemangioma (n=1), and vitreous hemorrhage (n=1) collectively accounted for approximately 2% of all neonates. Pathologies that could potentially impair vision, which were detected by ophthalmological examination, accounted for 1.2% of all neonates (n=37).
CONCLUSION
The most prevalent finding of the ophthalmological examinations of neonates in the present study was retinal hemorrhage. Ophthalmological examinations of neonates can help in identifying diseases that may affect their vision and are curable or may lead to amblyopia in the long term.
Topics: Humans; Infant, Newborn; Coloboma; Retinal Hemorrhage; Retrospective Studies; Eye Abnormalities; Nevus
PubMed: 35857993
DOI: 10.5935/0004-2749.2021-0536 -
Ophthalmic Genetics Apr 2022To report ocular outcome, somatic co-morbidities, genetics, and quality of life in children born with anophthalmia (A) or microphthalmia (M). (Review)
Review
PURPOSE
To report ocular outcome, somatic co-morbidities, genetics, and quality of life in children born with anophthalmia (A) or microphthalmia (M).
METHODS
Thirty-five children (19 boys) with A/M underwent ophthalmological examinations and a review of medical records. Parents of 12/22 cases completed the Pediatric Quality of Life Inventory (PedsQL).
RESULTS
Age at examination ranged from 7 months to 18 years (median 2.3 years). Ten cases were totally blind or had light perception. Isolated A/M occurred in 16/35 cases, while somatic, psychomotor, neuroradiological and/or genetic pathology occurred in 19/35 cases both in the bilateral (7/9) and in the unilateral group (12/26). Among 26 unilateral cases, 4/16 with one normal eye had associated problems compared to 9/10 if the contralateral eye was pathological ( < .01). There was an increased risk for heart defects in children with psychomotor delay ( = .04). Pathogenic genetic abnormalities were identified in 10/24 cases. Neuroimaging demonstrated pathology in 14/20 cases with corpus callosum dysgenesis (6/20) being the most common. The median total PedsQL score of parent reports for ages 2-12 was 52.4 (range 22.6-100).
CONCLUSIONS
Somatic, psychomotor and/or neuroradiological pathologies were more common in bila-teral than unilateral cases, but the difference was not significant. There was decreased risk in unilateral cases with one normal eye. Genetic defects occurred in both unilateral and bilateral cases. Health-related quality of life was reduced.
Topics: Anophthalmos; Child; Child, Preschool; Female; Humans; Infant; Male; Microphthalmos; Morbidity; Quality of Life
PubMed: 35105264
DOI: 10.1080/13816810.2021.1989600 -
Seminars in Ophthalmology May 2023Blindness with no light perception is clinically irreversible. This cross-sectional hospital-based study analyzed patients presenting with no light perception in at...
Blindness with no light perception is clinically irreversible. This cross-sectional hospital-based study analyzed patients presenting with no light perception in at least one eye. Between 2010 and 2022, 60,668 (1.85%) such patients were identified, of which 3,476 (5.73%) had bilateral and 57,192 (94.27%) had unilateral blindness. The major causes were glaucoma (21.8%), trauma (17.7%), phthisis bulbi (13.1%), retinal diseases (10.6%), anophthalmos (7.8%), and optic atrophy (4.9%). The majority of the affected individuals were adults (89.9%) and male (64%), and affected individuals were more likely to be from the lower socio-economic strata (3.14%) and from a rural location (1.99%). Despite recent therapeutic advances in ophthalmology, many patients with blindness cannot be restored to sight. Although preventive measures can mitigate sight loss to some extent, regenerative therapies, retinal and ciliary body transplantation, and whole eyeball transplantation need to be developed as sight restorative procedures to help those who currently have no hope of regaining vision.
Topics: Adult; Humans; Male; Cross-Sectional Studies; Blindness; Glaucoma; Retinal Diseases; Retina; Vision, Low; Prevalence
PubMed: 36967577
DOI: 10.1080/08820538.2023.2194980 -
Human Genetics Sep 2019As new genes for A/M are identified in the genomic era, the number of syndromes associated with A/M has greatly expanded. In this review, we provide a brief synopsis of... (Review)
Review
As new genes for A/M are identified in the genomic era, the number of syndromes associated with A/M has greatly expanded. In this review, we provide a brief synopsis of the clinical presentation and molecular genetic etiology of previously characterized pathways involved in A/M, including the Sex-determining region Y-box 2 (SOX2), Orthodenticle Homeobox 2 (OTX2) and Paired box protein-6 (PAX6) genes, and the Stimulated by retinoic acid gene 6 homolog (STRA6), Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3), and RA Receptor Beta (RARβ) genes that are involved in retinoic acid synthesis. Less common genetic causes of A/M, including genes involved in BMP signaling [Bone Morphogenetic Protein 4 (BMP4), Bone Morphogenetic Protein 7 (BMP7) and SPARC-related modular calcium-binding protein 1 (SMOC1)], genes involved in the mitochondrial respiratory chain complex [Holocytochrome c-type synthase (HCCS), Cytochrome C Oxidase Subunit 7B (COX7B), and NADH:Ubiquinone Oxidoreductase subunit B11 (NDUFB11)], the BCL-6 corepressor gene (BCOR), Yes-Associated Protein 1 (YAP1) and Transcription Factor AP-2 Alpha (TFAP2α), are more briefly discussed. We also review several recently described genes and pathways associated with A/M, including Smoothened (SMO) that is involved in Sonic hedgehog (SHH) signaling, Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) and Solute carrier family 25 member 24 (SLC25A24), emphasizing phenotype-genotype correlations and shared pathways where relevant.
Topics: Animals; Anophthalmos; Genetic Association Studies; Genotype; Humans; Microphthalmos; Phenotype; Syndrome
PubMed: 30374660
DOI: 10.1007/s00439-018-1949-1 -
Ophthalmic Plastic and Reconstructive... 2020To perform a comprehensive review of dermis fat graft (DFG) in socket reconstruction and illustrate the technical nuances and outcomes using a retrospective case review. (Review)
Review
PURPOSE
To perform a comprehensive review of dermis fat graft (DFG) in socket reconstruction and illustrate the technical nuances and outcomes using a retrospective case review.
METHODS
A literature search of 143 texts was reviewed. A retrospective case series of 34 patients following primary or secondary DFG after enucleation at a single institution (2009-2019) was performed. Clinical outcomes were statistically analyzed. Variables investigated included age, sex, race, surgical indication, muscle reattachment, complications, motility, eyelid position, prosthesis fit, and need for additional surgery.
RESULTS
The history of DFG, use in socket reconstruction, primary and secondary indications, and surgical techniques are described. Thirty-two adults and 2 pediatric cases of DFG were reviewed; 18.75% indications were primary and 81.25% were secondary. Good eyelid position was observed in 83.3% of patients with primary DFG versus 37.5% with secondary DFG (p = 0.07). Postoperative complications occurred in 58.8% of patients, were typically mild, and resolved with minimal or no intervention. No statistically significant differences were found between occurrence of any particular complication in primary versus secondary DFG placement (p = 0.36) or between primary and secondary DFG placement and the need for additional surgery (p = 1.0). Among the 67.7% patients who had implant exposure or extrusion as an indication for DFG, 39.1% required additional surgery within 2 years. Advanced age was not associated with higher complication rates (p = 0.12).
CONCLUSIONS
DFG is an excellent option for socket reconstruction, particularly in cases involving pediatric patients, complicated orbits, history of multiple previous surgeries, and inflamed, contracted, or scarred sockets.
Topics: Adult; Anophthalmos; Child; Dermis; Eye Enucleation; Eye, Artificial; Humans; Orbit; Orbital Implants; Retrospective Studies
PubMed: 32134765
DOI: 10.1097/IOP.0000000000001610 -
European Journal of Medical Genetics Feb 2024Infants with anophthalmia and microphthalmia (an/microphthalmia) have often other associated congenital anomalies. The reported frequency and the types of these...
Infants with anophthalmia and microphthalmia (an/microphthalmia) have often other associated congenital anomalies. The reported frequency and the types of these associated anomalies vary between different studies. The purpose of this investigation was to assess the frequency and the types of associated anomalies among cases with an/microphthalmia in a geographically well defined population of northeastern France of 387,067 consecutive pregnancies from 1979 to 2007. Of the 98 infants with an/microphthalmia born during this period (prevalence at birth of 2.53 per 10,000), 88.8 % had associated anomalies. Cases with associated anomalies were divided into recognizable conditions (25 (25.5%) cases with chromosomal and 17 (17.3%) cases with non chromosomal conditions), and non recognizable conditions (45-45.9%- cases with multiple congenital anomalies -MCA). Trisomy 13 and trisomy 18 were the most frequent chromosomal abnormalities. Amniotic bands sequence, oculo-auriculo-vertebral spectrum, CHARGE syndrome and VACTERL association were most often present in recognizable non chromosomal conditions. Anomalies in the musculoskeletal, cardiovascular and central nervous systems were the most common other anomalies in cases with MCA and non recognizable conditions. However, given the limitation of the limited numbers of cases there should be urging caution in interpreting these results. In conclusion the frequency of associated anomalies in infants with anophthalmia and microphthalmia emphasizes the need for a thorough investigation of these cases. Routine screening for other anomalies especially musculoskeletal, cardiac and central nervous systems anomalies may need to be considered in infants with anophthalmia and microphthalmia, and referral of these cases for genetic counselling seems warranty.
Topics: Infant; Infant, Newborn; Pregnancy; Female; Humans; Anophthalmos; Microphthalmos; Heart Defects, Congenital; Limb Deformities, Congenital; CHARGE Syndrome; Prevalence
PubMed: 38110175
DOI: 10.1016/j.ejmg.2023.104892 -
Annals of Human Genetics Jan 2020Biallelic mutations in the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 cause autosomal recessive primary microcephaly type 3 (MCPH3)....
Biallelic mutations in the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 cause autosomal recessive primary microcephaly type 3 (MCPH3). MCPH is characterized by intellectual disability and microcephaly at birth, classically without further organ involvement. Only recently, congenital cataracts were reported in four patients of one pedigree with MCPH3. Given the lack of a further pedigree with this phenotype, it remained unclear whether this was a true causal relationship. Here we support the link between CDK5RAP2 and eye development by showing that most Cdk5rap2 mutant mice (an/an) exhibit eye malformations ranging from reduced size of one or both eyes (microphthalmia) to total absence of both eyes (anophthalmia). We also detected increased apoptosis in the an/an retinal progenitor cells associated with more mitotic cells. This indicates an important role of Cdk5rap2 in physiologic eye development.
Topics: Animals; Anophthalmos; Cell Cycle Proteins; Eye; Gene Expression Regulation, Developmental; Mice; Mice, Inbred C57BL; Microcephaly; Microphthalmos; Mutation
PubMed: 31355417
DOI: 10.1111/ahg.12343