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Health Psychology and Behavioral... 2023Congenital aniridia is a rare genetic disorder of the eye characterized by visual impairment and progressive vision loss. While prior research has focused on ocular...
BACKGROUND
Congenital aniridia is a rare genetic disorder of the eye characterized by visual impairment and progressive vision loss. While prior research has focused on ocular manifestations in individuals with aniridia, there is a dearth of research on impacts on cognition and mental health. The aims of this study were to describe subjective symptoms of everyday executive functioning, fatigue and sleepiness in adults with aniridia and to compare self-reported health status with that of a normative reference group.
METHODS
Twenty-nine adults (aged 18-79 years) with congenital aniridia were included in this online survey, of whom 52% were females. Participants completed self-report measures of executive functioning (The Behavior Rating Inventory of Executive Function-Adult Version), sleepiness, fatigue, and health status (EQ-5D-5L).
RESULTS
Participants reported relatively few problems in everyday executive functioning, with only 14% experiencing impaired executive functioning. Scores on the five EQ-5D-5L domains (mobility, self-care, usual activities, pain, and anxiety/depression) did not differ from those of the normative reference group. The frequencies of excessive daytime sleepiness and severe fatigue were 17% and 38%, respectively. Ocular pain was experienced by 62% of participants.
CONCLUSIONS
The findings show that cognitive problems are related to and reflect self-reported health status and extent of fatigue. Moreover, those who suffered from ocular pain reported more difficulties with executive functioning, sleepiness and fatigue. These findings are important for understanding this disorder and supporting patients.
PubMed: 37811316
DOI: 10.1080/21642850.2023.2263534 -
Movement Disorders : Official Journal... Jan 2024The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP ) receptor type 1 (IP R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic...
BACKGROUND
The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP ) receptor type 1 (IP R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood.
OBJECTIVES
We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy.
METHODS
Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction.
RESULTS
We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression.
CONCLUSIONS
This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Cerebellar Ataxia; Mutation, Missense; Movement Disorders; Atrophy; Inositol 1,4,5-Trisphosphate Receptors; Carbonic Anhydrases; Intracellular Signaling Peptides and Proteins; Intellectual Disability; Spinocerebellar Degenerations; Aniridia
PubMed: 37964426
DOI: 10.1002/mds.29651 -
Graefe's Archive For Clinical and... Mar 2024Intraocular lenses (IOLs) require proper positioning in the eye to provide good imaging performance. This is especially important for premium IOLs. The purpose of this...
BACKGROUND
Intraocular lenses (IOLs) require proper positioning in the eye to provide good imaging performance. This is especially important for premium IOLs. The purpose of this study was to develop prediction models for estimating IOL decentration, tilt and the axial IOL equator position (IOLEQ) based on preoperative biometric and tomographic measures.
METHODS
Based on a dataset (N = 250) containing preoperative IOLMaster 700 and pre-/postoperative Casia2 measurements from a cataractous population, we implemented shallow feedforward neural networks and multilinear regression models to predict the IOL decentration, tilt and IOLEQ from the preoperative biometric and tomography measures. After identifying the relevant predictors using a stepwise linear regression approach and training of the models (150 training and 50 validation data points), the performance was evaluated using an N = 50 subset of test data.
RESULTS
In general, all models performed well. Prediction of IOL decentration shows the lowest performance, whereas prediction of IOL tilt and especially IOLEQ showed superior performance. According to the 95% confidence intervals, decentration/tilt/IOLEQ could be predicted within 0.3 mm/1.5°/0.3 mm. The neural network performed slightly better compared to the regression, but without significance for decentration and tilt.
CONCLUSION
Neural network or linear regression-based prediction models for IOL decentration, tilt and axial lens position could be used for modern IOL power calculation schemes dealing with 'real' IOL positions and for indications for premium lenses, for which misplacement is known to induce photic effects and image distortion.
Topics: Humans; Tomography, Optical Coherence; Lenses, Intraocular; Biometry; Eye, Artificial; Lens, Crystalline
PubMed: 37658183
DOI: 10.1007/s00417-023-06208-9 -
Genes Jul 2023The human fovea is a specialized pit structure in the central retina. Foveal hypoplasia is a condition where the foveal pit does not fully develop, and it is associated...
The human fovea is a specialized pit structure in the central retina. Foveal hypoplasia is a condition where the foveal pit does not fully develop, and it is associated with poor vision. Autosomal dominant isolated foveal hypoplasia (FVH1) is a rare condition of foveal hypoplasia (FH) that lacks any other ocular manifestations. FVH1 is associated with hypomorphic mutations in the gene that encodes a sequence-specific DNA-binding transcription factor for morphogenesis and evolution of the eye. We report our findings in 17 patients with mutations associated with FVH1 or FH with aniridia and corneal opacities. Patients with three mutations, p.V78E, p.V83F and p.R128H, in the C-terminal subdomain of the paired domain (CTS) consistently have severe FH. Luciferase assays for a single reporter containing a representative PAX6 binding site indicated that the transcriptional activities of these mutations were significantly reduced, comparable to that of the truncation mutation of p.G65Rfs*5. Patients with p.P20S in the N-terminal subdomain of the paired domain, and a patient with p.N365K in the proline-serine-threonine-rich domain (PSTD) had mild FH. A patient with p.Q255L in the homeodomain had severe FH. The P20S and Q255L mutants did not affect the transcriptional activity. Mutant N365K has a retained DNA-binding activity but a reduced transcriptional activity, due to a low PSTD transactivation. These findings demonstrated that mutations associated with FVH1 underlie a functional divergence between DNA-binding ability and transcriptional activity. We conclude that a wide range of mutations in the gene is not limited to the CST region and are responsible for FVH1.
Topics: Humans; DNA; Homeodomain Proteins; Mutation; Paired Box Transcription Factors; PAX6 Transcription Factor; Repressor Proteins
PubMed: 37510387
DOI: 10.3390/genes14071483 -
BMC Medical Genomics Aug 2023The genotype characteristics and their associated clinical phenotypes in patients with aniridia were analyzed to explore pathogenic variants using whole-exome sequencing.
BACKGROUND
The genotype characteristics and their associated clinical phenotypes in patients with aniridia were analyzed to explore pathogenic variants using whole-exome sequencing.
METHODS
One patient with aniridia was enrolled at the Beijing Tongren Hospital. Comprehensive ophthalmic and general examinations were performed on the patient. DNA was extracted from the patient, and whole-exome sequencing was performed to identify the causative variant. The pathogenicity of the variant was predicted using in silico analysis and evaluated according to American College of Medical Genetics and Genomics guidelines. Relationships between genetic variants and clinical features were analyzed.
RESULTS
In addition to the classical aniridia phenotype showing complete iris aplasia, foveal hypoplasia, and ectopic lentis, the patient also exhibited spontaneous reattachment rhegmatogenous retinal detachment (SRRRD). Whole-exome sequencing identified a novel heterozygous variant, exon8:c.640_646del:p.R214Pfs*28.
CONCLUSIONS
The present study broadens the range of genetic variants described in aniridia and presents an aniridia patient with SRRRD.
Topics: Humans; Aniridia; East Asian People; Genotype; Homeodomain Proteins; Mutation; PAX6 Transcription Factor; Pedigree; Retinal Detachment
PubMed: 37542296
DOI: 10.1186/s12920-023-01620-w -
Biomedicines Nov 2023This study assessed the efficacy and safety of Ahmed valve implantation in patients with aniridic glaucoma for three consecutive years.
BACKGROUND
This study assessed the efficacy and safety of Ahmed valve implantation in patients with aniridic glaucoma for three consecutive years.
METHODS
Six adult patients (seven eyes) with Ahmed valve (AV) implants for aniridic glaucoma were enrolled in the study. The primary outcome measures were intraocular pressure reduction, glaucoma medication use, success rates, and visual acuity after AV implantation. A 30% reduction in IOP from baseline without the need for re-intervention was considered an effective treatment. The cessation of antiglaucoma medications was defined as complete success. Intraoperative and postoperative complications were included as secondary outcome measures. Measurements were performed preoperatively, at the first week, and 1, 3, 6, 12, 18, 24, 30, and 36 months postoperatively.
RESULTS
A total of seven eyes (6 patients) were evaluated 36 months after AV implantation. The mean ± SD values of IOP preoperatively at 1 day, 1 week, and 1, 3, 6, 12, 18, 24, 30, and 36 months postoperatively were 30.4 ± 4.0 mmHg, 14.6 ± 4.6 mmHg, 16.1 ± 4.6 mmHg, 20.7 ± 7.0 mmHg, 14.5 ± 2.7 mmHg, 16.5 ± 5.9 mmHg, 16.2 ± 4.0 mmHg, 16.3 ± 4.3 mmHg, 17.2 ± 10.1 mmHg, 17.6 ± 6.9 mmHg, and 18.2 ± 5.5 mmHg, respectively. At the last follow up, the mean IOP was reduced by 40.2%. The qualified success rate was 85.7%. One patient (one eye) at the last follow-up visit did not require antiglaucoma medications, resulting in a complete success rate of 14.3%. Intra- and postoperative mild or moderate subconjunctival bleeding was observed in all the patients. No other major/minor intraoperative or postoperative complications were noted.
CONCLUSIONS
In long-term follow up, the AV implantation procedure is well-tolerated and relatively safe for reducing IOP in adult aniridia patients with glaucoma. These results should be validated through studies involving a larger patient cohort.
PubMed: 38001995
DOI: 10.3390/biomedicines11112996 -
Klinische Monatsblatter Fur... Mar 2024Congenital aniridia is a severe malformation of almost all eye segments. In addition, endocrinological, metabolic, and central nervous systems diseases may be present....
PURPOSE
Congenital aniridia is a severe malformation of almost all eye segments. In addition, endocrinological, metabolic, and central nervous systems diseases may be present. In order to develop better treatment options for this rare disease, an aniridia center must be established. The purpose of this work is to summarize ophthalmic findings of aniridia subjects examined at the Department of Ophthalmology, Saarland University Medical Center in Homburg.
METHODS
Our retrospective single-center study included patients who underwent a comprehensive ophthalmic examination through the head of the KiOLoN ("Kinderophthalmologie", Orthoptics, Low Vision and Neuroophthalmology) Unit of the department between June 2003 and January 2022. Data at the first examination time point have been included.
RESULTS
Of 286 subjects, 556 eyes of (20.1 ± 20.1 years; 45.5% males) were included. There was nystagmus in 518 (93.7%) eyes, and strabismus in 327 (58.8%) eyes. There were 436 (78.4%) eyes with age-appropriate axial length, 104 (18.7%) eyes with microphthalmos, and 13 (2.3%) eyes with buphthalmos. There was iris malformation with atypical coloboma in 34 eyes (6.1%), more than 6 clock hours of iris remnants in 61 eyes (10.9%), less than 6 clock hours of iris remnants in 96 eyes (17.2%), and complete aniridia in 320 (57.5%) eyes. The patients were graded according to the following aniridia-associated keratopathy (AAK) stages: Stage 0 (96 eyes [17.2%], no keratopathy), Stage 1 (178 eyes [32.0%]), Stage 2 (107 eyes [19.2%]), Stage 3 (67 eyes [12.0%]), Stage 4 (62 eyes [11.1%]), Stage 5 (45 eyes [8.0%]). There was secondary glaucoma in 307 (55.5%), macular hypoplasia in 395 (71.4%), and congenital optic nerve head pathology in 223 (40.3%) eyes. The iris malformation type was significantly positively correlated with AAK stage, lens properties, presence of glaucoma, congenital macular, and optic nerve head properties (p < 0.001 for all), while complete aniridia showed the most complications.
CONCLUSIONS
At the Homburg Aniridia Center, the most common ophthalmic signs in congenital aniridia were AAK, iris malformation, cataract, and macular hypoplasia. The iris malformation type may indicate future expression of AAK, cataract, and glaucoma development and it is correlated with a congenital optic nerve head and macular pathology. Our registry will support further detailed longitudinal analysis of ophthalmic and systemic diseases of aniridia subjects during long-term follow-up.
Topics: Male; Humans; Aged, 80 and over; Female; Cross-Sectional Studies; Retrospective Studies; Aniridia; Cataract; Corneal Diseases; Glaucoma; Vision Disorders
PubMed: 37647922
DOI: 10.1055/a-2065-8405 -
Gene Therapy Sep 2023Recently safety concerns have been raised in connection with high doses of recombinant adeno-associated viruses (rAAV). Therefore, we undertook a series of experiments...
Recently safety concerns have been raised in connection with high doses of recombinant adeno-associated viruses (rAAV). Therefore, we undertook a series of experiments to test viral capsid (rAAV9 and rAAV-PHP.B), dose, and route of administration (intrastromal, intravitreal, and intravenous) focused on aniridia, a congenital blindness that currently has no cure. The success of gene therapy for aniridia may depend on the presence of functional limbal stem cells (LSCs) in the damaged aniridic corneas and whether rAAV can transduce them. Both these concerns were unknown, and thus were also addressed by our studies. For the first time, we report ataxia and lethality after intravitreal or intrastromal rAAV-PHP.B virus injections. We demonstrated virus escape from the eye and transduction of non-ocular tissues by rAAV9 and rAAV-PHP.B capsids. We have also shown that intrastromal and intravitreal delivery of rAAV9 can transduce functional LSCs, as well as all four PAX6-expressing retinal cell types in aniridic eye, respectively. Overall, lack of adverse events and successful transduction of LSCs and retinal cells makes it clear that rAAV9 is the capsid of choice for future aniridia gene therapy. Our finding of rAAV lethality after intraocular injections will be impactful for other researchers developing rAAV-based gene therapies.
Topics: Mice; Animals; Herpesvirus 1, Cercopithecine; Limbal Stem Cells; Cornea; Aniridia; Genetic Therapy; Genetic Vectors; Dependovirus; Transduction, Genetic
PubMed: 37072572
DOI: 10.1038/s41434-023-00400-6 -
International Journal of Molecular... Nov 2023Three years ago, our patient, at that time a 16-month-old boy, was discovered to have bilateral kidney lesions with a giant tumor in the right kidney. Chemotherapy and...
Complex Chromosomal Rearrangement Involving Chromosomes 10 and 11, Accompanied by Two Adjacent 11p14.1p13 and 11p13p12 Deletions, Identified in a Patient with WAGR Syndrome.
Three years ago, our patient, at that time a 16-month-old boy, was discovered to have bilateral kidney lesions with a giant tumor in the right kidney. Chemotherapy and bilateral nephron-sparing surgery (NSS) for Wilms tumor with nephroblastomatosis was carried out. The patient also had eye affection, including glaucoma, eye enlargement, megalocornea, severe corneal swelling and opacity, complete aniridia, and nystagmus. The diagnosis of WAGR syndrome was suspected. De novo complex chromosomal rearrangement with balanced translocation t(10,11)(p15;p13) and a pericentric inversion inv(11)(p13q12), accompanied by two adjacent 11p14.1p13 and 11p13p12 deletions, were identified. Deletions are raised through the complex molecular mechanism of two subsequent rearrangements affecting chromosomes 11 and 10. WAGR syndrome diagnosis was clinically and molecularly confirmed, highlighting the necessity of comprehensive genetic testing in patients with congenital aniridia and/or WAGR syndrome.
Topics: Male; Humans; Infant; WAGR Syndrome; Chromosome Deletion; Aniridia; Wilms Tumor; Kidney Neoplasms; Chromosomes, Human, Pair 11; Chromosome Inversion
PubMed: 38069245
DOI: 10.3390/ijms242316923 -
PloS One 2023Intraocular lenses are typically calculated based on a pseudophakic eye model, and for toric lenses (tIOL) a good estimate of corneal astigmatism after cataract surgery...
BACKGROUND
Intraocular lenses are typically calculated based on a pseudophakic eye model, and for toric lenses (tIOL) a good estimate of corneal astigmatism after cataract surgery is required in addition to the equivalent corneal power. The purpose of this study was to investigate the differences between the preoperative IOLMaster (IOLM) and the preoperative and postoperative Casia2 (CASIA) tomographic measurements of corneal power in a cataractous population with tIOL implantation, and to predict total power (TP) from the IOLM and CASIA keratometric measurements.
METHODS
The analysis was based on a dataset of 88 eyes of 88 patients from 1 clinical centre before and after tIOL implantation. All IOLM and CASIA keratometric and total corneal power measurements were converted to power vector components, and the differences between preoperative IOLM or CASIA and postoperative CASIA measurements were assessed. Feedforward neural network and multivariate linear regression prediction algorithms were implemented to predict the postoperative total corneal power (as a reference for tIOL calculation) from the preoperative IOLM and CASIA keratometric measurements.
RESULTS
On average, the preoperative IOLM keratometric / total corneal power under- / overestimates the postoperative CASIA keratometric / real corneal power by 0.12 dpt / 0.21 dpt. The prediction of postoperative CASIA real power from preoperative IOLM or CASIA keratometry shows that postoperative total corneal power is systematically (0.18 dpt / 0.27 dpt) shifted towards astigmatism against the rule, which is not reflected by keratometry. The correlation of postoperative CASIA real power to the corresponding preoperative CASIA values is better than those as compared to the preoperative IOLM keratometry. However, there is a large variation from preoperative IOLM or CASIA keratometry to the postoperative CASIA real power of up to 1.1 dpt (95% confidence interval).
CONCLUSION
One of the challenges of tIOL calculation is the prediction of postoperative total corneal power from preoperative keratometry. Keratometric power restricted to a front surface measurement does not fully reflect the situation of corneal back surface astigmatism, which typically adds some extra against the rule astigmatism.
Topics: Humans; Astigmatism; Cornea; Lenses, Intraocular; Lenses; Corneal Diseases; Fabaceae; Cataract
PubMed: 37682881
DOI: 10.1371/journal.pone.0288316