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Experimental Eye Research Feb 2021Congenital aniridia is caused by heterozygous mutations in the PAX6 gene. In this disease, congenital iris and foveal hypoplasia is associated with juvenile onset... (Comparative Study)
Comparative Study
Congenital aniridia is caused by heterozygous mutations in the PAX6 gene. In this disease, congenital iris and foveal hypoplasia is associated with juvenile onset cataract, glaucoma, and corneal keratopathy. In rodents, Pax6 mutations result in a congenital reduction in ocular size that is not typically described in human aniridia. Here, the ocular morphometry of aniridia patients is compared with the lens phenotype of Pax6 mice to reveal whether there are species differences in Pax6 regulation of lens development and homeostasis. Ultrasound biometry (UBM) revealed that eleven percent of aniridia patients exhibited mild microphthalmia while the anterior chamber depth of aniridic eyes was significantly reduced from 6 months of age onward. Although aniridic lens thickness was normal from birth, it was significantly decreased in aniridic lenses older than 30. Notably, 86% of aniridic lenses exhibited cataractous changes in this cohort. In addition, a significant proportion of aniridia patients develop lens subluxation as they age associated with reduced lens diameter as measured by anterior segment optical coherence tomography (AS-OCT). Analysis of young adult Pax6 mouse lenses by micro-computed tomography (microCT), bright field and dark field imaging revealed that they are reduced in size but did not exhibit overt cataracts at this age. Overall, this study reveals that congenital microphthalmia as assessed by axial length, or microphakia, as assessed by lens thickness, are not typical in human aniridia, although these are primary manifestations of Pax6 mutations in mice, suggesting that PAX6 regulates some aspects of lens development differently between these species.
Topics: Adolescent; Adult; Aged; Animals; Aniridia; Anterior Chamber; Axial Length, Eye; Cataract; Child; Child, Preschool; Disease Models, Animal; Female; Humans; Infant; Lens, Crystalline; Male; Mice; Mice, Mutant Strains; Microphthalmos; Microscopy, Acoustic; Middle Aged; PAX6 Transcription Factor; Phenotype; Slit Lamp Microscopy; Tomography, Optical Coherence; Young Adult
PubMed: 33248069
DOI: 10.1016/j.exer.2020.108371 -
Acta Ophthalmologica Aug 2015To quantify diadenosine polyphosphate levels in tears of congenital aniridia patients to estimate the ocular surface changes associated with congenital aniridia compared...
PURPOSE
To quantify diadenosine polyphosphate levels in tears of congenital aniridia patients to estimate the ocular surface changes associated with congenital aniridia compared to normal individuals.
METHODS
Fifteen patients diagnosed with congenital aniridia and a control group of forty volunteers were studied. Tears were collected to quantify the levels of diadenosine polyphosphates Ap4 A and Ap5 A by high-performance liquid chromatography (H.P.L.C). Break-up time (BUT), corneal staining, McMonnies questionnaire and the Schirmer I test were applied to both groups.
RESULTS
Dinucleotides in congenital aniridia patients were higher than in control subjects. For the congenital aniridia group, under 15 years old, the values were 0.77 ± 0.01 μm and 0.17 ± 0.02 μm for Ap4 A and Ap5 A, respectively. The group aged from 15 to 40 years old provided concentrations of 4.37 ± 0.97 μm and 0.46 ± 0.05 μm for Ap4 A and Ap5 A, the group over 40 gave concentrations of 11.17 ± 5.53 μm and 0.68 ± 0.17 μm for Ap4 A and Ap5 A. Dinucleotide concentrations increased with age, being statistically significant different among the three age groups (p < 0.05). Congenital aniridia patients showed a normal tear secretion and no dry eye McMonnies scores, except for the group over 40 years old. BUT values decreased and corneal staining increased with age and correlated with the levels of diadenosine polyphosphates (p < 0.05).
CONCLUSIONS
The levels of dinucleotides in tears increase in aniridia patients compared with healthy subjects, and they seem to be related with the progression of corneal disorders in aniridia patients, both of which increase with ageing.
Topics: Adolescent; Adult; Aging; Aniridia; Child; Chromatography, High Pressure Liquid; Dinucleoside Phosphates; Female; Humans; Male; Middle Aged; Surveys and Questionnaires; Tears; Young Adult
PubMed: 25545014
DOI: 10.1111/aos.12626 -
Experimental Eye Research May 2022Aniridia is a panocular condition characterized by impaired eye development and vision, which is mainly due to the haploinsufficiency of the paired-box-6 (PAX6) gene....
Aniridia is a panocular condition characterized by impaired eye development and vision, which is mainly due to the haploinsufficiency of the paired-box-6 (PAX6) gene. Like what is seen in aniridia patients, Pax6-deficient mice Pax6 exhibit a varied degree of ocular damage and impaired vision. Our previous studies showed that these phenotypes were partially rescued by PD0325901, a mitogen-activated protein kinase kinase (MEK or MAP2K) inhibitor. In this study, we assessed the long-term efficacy of PD0325901 treatment in retinal health and visual behavior. At about one year after the postnatal treatment with PD0325901, Pax6 mice showed robust improvements in retina size and visual acuity, and the elevated intraocular pressure (IOP) was also alleviated, compared to age-matched mice treated with vehicles only. Moreover, the Pax6 eyes showed disorganized retinal ganglion cell (RGC) axon bundles and retinal layers, which we termed as hotspots. We found that the PD treatment reduced the number and size of hotspots in the Pax6 retinas. Taken together, our results suggest that PD0325901 may serve as an efficacious intervention in protecting retina and visual function in aniridia-afflicted subjects.
Topics: Animals; Aniridia; Disease Models, Animal; Eye Proteins; Haploinsufficiency; Homeodomain Proteins; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; PAX6 Transcription Factor; Paired Box Transcription Factors; Repressor Proteins; Retina
PubMed: 35245513
DOI: 10.1016/j.exer.2022.109012 -
BMC Genetics May 2005The PAX6 protein is a highly conserved transcriptional regulator that is important for normal ocular and neural development. In humans, heterozygous mutations of the...
BACKGROUND
The PAX6 protein is a highly conserved transcriptional regulator that is important for normal ocular and neural development. In humans, heterozygous mutations of the PAX6 gene cause aniridia (absence of the iris) and related developmental eye diseases. PAX6 mutations are archived in the Human PAX6 Allelic Variant Database, which currently contains 309 records, 286 of which are mutations in patients with eye malformations.
RESULTS
We examined the records in the Human PAX6 Allelic Variant Database and documented the frequency of different mutation types, the phenotypes associated with different mutation types, the contribution of CpG transitions to the PAX6 mutation spectrum, and the distribution of chain-terminating mutations in the open reading frame. Mutations that introduce a premature termination codon into the open reading frame are predominantly associated with aniridia; in contrast, non-aniridia phenotypes are typically associated with missense mutations. Four CpG dinucleotides in exons 8, 9, 10 and 11 are major mutation hotspots, and transitions at these CpG's account for over half of all nonsense mutations in the database. Truncating mutations are distributed throughout the PAX6 coding region, except for the last half of exon 12 and the coding part of exon 13, where they are completely absent. The absence of truncating mutations in the 3' part of the coding region is statistically significant and is consistent with the idea that nonsense-mediated decay acts on PAX6 mutant alleles.
CONCLUSION
The PAX6 Allelic Variant Database is a valuable resource for studying genotype-phenotype correlations. The consistent association of truncating mutations with the aniridia phenotype, and the distribution of truncating mutations in the PAX6 open reading frame, suggests that nonsense-mediated decay acts on PAX6 mutant alleles.
Topics: Alleles; Aniridia; Codon, Nonsense; Databases, Nucleic Acid; Eye Abnormalities; Eye Proteins; Genotype; Homeodomain Proteins; Humans; Mutation; Open Reading Frames; PAX6 Transcription Factor; Paired Box Transcription Factors; Phenotype; Repressor Proteins
PubMed: 15918896
DOI: 10.1186/1471-2156-6-27 -
Case Reports in Obstetrics and... 2015Wilm's tumour, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome is a rare genetic disorder with an estimated prevalence of 1 in 500,000 to 1...
Wilm's tumour, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome is a rare genetic disorder with an estimated prevalence of 1 in 500,000 to 1 million. It is a contiguous gene syndrome due to deletion at chromosome 11p13 in a region containing WT1 and PAX6 genes. Children with WAGR syndrome mostly present in the newborn/infancy period with sporadic aniridia. The genotypic defects in WAGR syndrome have been well established. However, antenatal ultrasonographic presentation of this syndrome has never been reported. Prenatal diagnosis of this condition is possible in some cases with careful ultrasound examination of classical and nonclassical manifestations of this syndrome. The key point for this rare diagnosis was the decision to perform chromosomal microarray analysis after antenatal diagnosis of absent corpus callosum and absent cavum septum pellucidum, as this finding mandates search for potentially associated genetic disorders. We report a case of WAGR syndrome diagnosed prenatally at 29-week gestation. The diagnosis of the anomaly was based on two- and three-dimensional ultrasound as well as fetal MRI scan and microarray analysis. The ultrasonographic findings included borderline ventriculomegaly, absent corpus callosum, and absent cavum septum pellucidum. Cytogenetic results from the amniotic fluid confirmed WAGR syndrome. Parental karyotype was normal, with no evidence of copy number change, deletion, or rearrangement of this region of chromosome 11.
PubMed: 26605098
DOI: 10.1155/2015/928585 -
Annals of Medicine and Surgery (2012) Feb 2022Gillespie syndrome (GS) is a rare genetic disorder that combines ocular and cerebral defects.It was first described in 1965, by Frederick D. Gillespie. He reported a...
INTRODUCTION
Gillespie syndrome (GS) is a rare genetic disorder that combines ocular and cerebral defects.It was first described in 1965, by Frederick D. Gillespie. He reported a triad of congenital aniridia, cerebellar ataxia and mental retardation in a 22-year-old woman and her 19-year-old brother. Its etiology is still unknown.To date, less than 30 patients have been reported in the literature.
OBSERVATION
We report the case of a 2 years old child, born of a consanguineous marriage. At the age of 8 months, the parents consulted for a delay in psychomotor acquisition for which the MRI performed showed a vermian hypoplasia. It was only at the age of 2 years, following a contusive trauma of the left eye that a partial aniridia was objectified on both eyes associated with a lens coloboma on the left eye. In view of these clinico-radiological data, the diagnosis of Gillespie syndrome was retained.
DISCUSSION
Gillespie syndrome is a genetic disease. It combines ocular and neurological abnormalities. It was first described in 1965 by Gillespie. The ocular manifestations of Gillespie syndrome mainly concern the iris. Aniridia is always present with, in most cases, a scalloped appearance of the pupillary margin. It can be accompanied with additional ocular findings such as foveal, optic nerve hypoplasia, retinal hypopigmentation, and/or pigmentary macular changes leading to reduced visual acuity.In addition to ocular abnormalities, the Gillespie syndrome. (GS) includes neurological deficiencies, particularly axial hypotonia, lack of coordination, dysarthria and static and kinetic ataxia.
CONCLUSION
The diagnosis of Gillespie Syndrome should be evoked in any hypotonic child presenting with bilateral but partial aniridia. Prognosis depends on the proper management and anticipation of ocular and mental symptoms and disabilities.
PubMed: 35070290
DOI: 10.1016/j.amsu.2022.103244 -
Molecular Genetics & Genomic Medicine Apr 2020Congenital aniridia involves total or partial hypoplasia of the iris and is due to a deficiency in PAX6 gene expression. WAGR syndrome is comprised of Wilms tumor,...
BACKGROUND
Congenital aniridia involves total or partial hypoplasia of the iris and is due to a deficiency in PAX6 gene expression. WAGR syndrome is comprised of Wilms tumor, aniridia, genitourinary abnormalities, and intellectual disability. Numerous genitourinary pathologies may be associated with WAGR syndrome, necessitating an evaluation of the genitourinary anatomy. The WT1 is vital for the development of kidneys, ovaries in females, and testes in males. WT1 gene mutations result in a WT1 protein with a decreased ability to bind to DNA, leading to uncontrolled growth, and cell division in the kidney which permits the development of Wilms tumor. A congenital ureteral valve is an exceedingly rare cause of obstructive uropathy.
RESULTS
A renal and bladder ultrasound demonstrated a renal cyst. A voiding cystourethrogram revealed grade 3 vesicoureteral reflux, and a MAG3 renal scan showed ureteropelvic junction obstruction and hydronephrosis. A ureteral stent was inserted at 3 months of age after which the renal cyst resolved. The patient was urinary tract infection-free at 27 months of age. Genetic testing confirmed a heterozygous alteration in PAX6 (c.495delG, p.Thr166Leufs*41) and no abnormalities of WT1, excluding WAGR syndrome.
CONCLUSION
The genitourinary risks potentially associated with aniridia necessitate prompt genetic analysis to evaluate for WAGR syndrome.
Topics: Aniridia; Child, Preschool; Diagnosis, Differential; Female; Genetic Testing; Humans; Kidney; Mutation; PAX6 Transcription Factor; Syndrome; Urethra; Urethral Obstruction
PubMed: 32056389
DOI: 10.1002/mgg3.1183 -
Brain Research Apr 2020PAX6 encodes a highly conserved transcription factor necessary for normal development of the eyes and central nervous system. Heterozygous loss-of-function mutations in...
PAX6 encodes a highly conserved transcription factor necessary for normal development of the eyes and central nervous system. Heterozygous loss-of-function mutations in PAX6 cause the disorder aniridia in humans and the Small eye trait in mice. Aniridia is a congenital and progressive disorder known for ocular phenotypes; however, recently, consequences of PAX6 haploinsufficiency in the brains of aniridia patients have been identified. These findings span structural and functional abnormalities, including deficits in cognitive and sensory processing. Furthermore, some of these abnormalities are accelerated as aniridia patients age. Although some functional abnormalities may be explained by structural changes, variability of results remain, and the effects of PAX6 heterozygous loss-of-function mutations on neuroanatomy, particularly with regard to aging, have yet to be resolved. Our study used high-resolution magnetic resonance imaging (MRI) and histology to investigate structural consequences of such mutations in the adult brain of our aniridia mouse model, Small eye Neuherberg allele (Pax6), at two adult age groups. Using both MRI and histology enables a direct comparison with human studies, while providing higher resolution for detection of more subtle changes. We show volumetric changes in major brain regions of the the Pax6 mouse compared to wild-type including genotype- and age-related olfactory bulb differences, age-related cerebellum differences, and genotype-related eye differences. We also show alterations in thickness of major interhemispheric commissures, particularly those anteriorly located within the brain including the optic chiasm, corpus callosum, and anterior commissure. Together, these genotype and age related changes to brain volumes and structures suggest a global decrease in adult brain structural plasticity in our Pax6 mice.
Topics: Age Factors; Aging; Animals; Aniridia; Brain; Disease Models, Animal; Magnetic Resonance Imaging; Mice; Mice, Knockout; Mutation; Neuronal Plasticity; PAX6 Transcription Factor
PubMed: 32014531
DOI: 10.1016/j.brainres.2020.146698 -
A neophyte gonioscopist's animative and videographic atlas with focal points for effective practice.Indian Journal of Ophthalmology Feb 2022Though various gonioscopy teaching platforms are available, they predominantly comprise of real time scenarios and videos. For a beginner, we suggest providing...
BACKGROUND
Though various gonioscopy teaching platforms are available, they predominantly comprise of real time scenarios and videos. For a beginner, we suggest providing animations of the real time scenario for cognitive training; and then putting them in real time scenarios for a better concept application and practice.
PURPOSE
This video highlights the basic tips and tricks needed to perform gonioscopy with metaphorical conceptual learning matching the 2D and 3D animations with real time scenarios.
SYNOPSIS
Simple and practical scenarios with technical details on how to perform gonioscopy and various challenges are shown. All the animations and videos are created by us, tailored to a neophyte. The following concepts are covered: normal angle (animation versus real-time), dynamicity of the gonioscopic dates of person, methods of gonioscopy - direct and Indirect, precautions and slit lamp adjustment, bubble trouble, patient examination, iris process versus peripheral anterior synechiae (animation versus real-time), patient examination (angle viewing order) for different lens, how to remove gonioscopy lens from the eye, static versus dynamic gonioscopy, situations where gonioscopy is contraindicated, grading of the angle (with animations), clinical scenarios (pseudoexfoliation, pigment dispersion, angle recession and aniridia), and surgical scenarios (patent ostium and blocked ostium).
HIGHLIGHTS
Multiple animations and real-time videos with focal points for effective practice are the highlights of this video.
VIDEO LINK
https://youtu.be/fFmPmqgdjyM.
Topics: Anterior Chamber; Glaucoma, Angle-Closure; Glaucoma, Open-Angle; Gonioscopy; Humans; Intraocular Pressure; Iris; Iris Diseases; Slit Lamp
PubMed: 35086290
DOI: 10.4103/ijo.IJO_151_22 -
Saudi Journal of Ophthalmology :... 2021Congenital aniridia is a rare ocular disorder characterized by iris malformation. We present a 3-year-old boy with bilateral anterior-segment dysgenesis, congenital...
Congenital aniridia is a rare ocular disorder characterized by iris malformation. We present a 3-year-old boy with bilateral anterior-segment dysgenesis, congenital aniridia, congenital aphakia, secondary glaucoma, limbal stem cell deficiency, and band keratopathy. As the intraocular pressure was uncontrolled with antiglaucoma medications, the patient underwent multiple bilateral traditional cyclophotocoagulation (CPC), in addition to micropulse CPC. To the best of our knowledge, aniridia association with congenital aphakia and congenital glaucoma has been very rarely reported.
PubMed: 35814998
DOI: 10.4103/1319-4534.347313