Aniridia and Axenfeld-Rieger Syndrome: Clinical presentations, molecular genetics and current/emerging therapies

Chrystal, Paul; Walter, Michael A.

doi:10.1016/j.exer.2019.107815

Cited by 23 publications

(25 citation statements)

References 91 publications

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“…FOXC1-associated ARS is commonly reported without other systemic abnormalities (Zeynep et al,2009;Strungaru et al,2007). However, there are still patients with FOXC1 mutations demonstrating symptoms of systemic dysplasia, including congenital heart defects (CHDs), such as tetralogy of Fallot (Vande et al,2018), sensorineural hearing loss (Souzeau et al,2017) and brain abnormalities (Chrystal et al,2019). The proband in the pedigree involved in our study presented with double eyeball enlargement at birth, was diagnosed with glaucoma, and underwent ventricular septal defect repair in our hospital when he was 3 years old, as well as sublingual cystectomy when he was 5.…”

Section: Discussionmentioning

confidence: 99%

A novel variant of the FOXC1 gene causes Axenfeld-Rieger syndrome with congenital glaucoma in a Chinese boy

Tang

Zhou

et al. 2020

Preprint

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Axenfeld-Rieger syndrome is an autosomal dominant genetic disease characterized by binocular anterior segment development defects and systemic dysplasia. In our study, a Chinese Axenfeld-Rieger syndrome pedigree was analyzed. After obtaining consent from the subjects, ophthalmic examinations were performed, and blood samples were collected. Then, the causative gene was identified by targeted next-generation sequencing, and candidate mutations were verified by Sanger sequencing. Pathogenicity analysis and conservative analysis were performed on the mutant gene to evaluate its pathogenicity, and SWISS-MODEL was used to construct the three-dimensional structure of the FOXC1 region to predict the effect of mutations on the structure of the FOXC1 protein. Optimistically, a novel heterozygous, deleterious variant of the FOXC1 gene, c.246C>A(p.S82R), was successfully identified in this Axenfeld-Rieger syndrome pedigree, which cosegregated with the clinical phenotype. This variant resulted in the mutation of amino acid 82 from serine to arginine. The evolution of serine(s) in different species was highly conserved. This mutation led to a change in the three-dimensional structure of the protein, which was pathogenic. The discovery of these new mutation sites further expands its mutation spectrum. Our understanding of Axenfeld-Rieger syndrome will facilitate the development of methods for the diagnosis, prevention and genetic counseling of this disease.

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Section: Discussionmentioning

confidence: 99%

A novel variant of the FOXC1 gene causes Axenfeld-Rieger syndrome with congenital glaucoma in a Chinese boy

Tang

Zhou

et al. 2020

Preprint

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“…Patients with ARS present with ocular features that can include iris hypoplasia, misplaced pupils, full thickness tears in the iris (polycoria), adhesions between the iris and the cornea, and a displaced Schwalbe line. Patients may also present with nonocular malformations of the teeth, jaw and umbilicus, as well as cerebellar, hearing and heart defects (Chrystal & Walter, 2019). More than 50% of ARS patients present with glaucoma that is often recalcitrant to normally prescribed glaucoma medications (Strungaru, Dinu, & Walter, 2007).…”

Section: Identification Of the Genetic Basis Of Axenfeld-rieger Synmentioning

confidence: 99%

Ocular genetics in the genomics age

Walter

Rezaie

Hufnagel

et al. 2020

American J of Med Genetics Pt C

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Current genetic screening methods for inherited eye diseases are concentrated on the coding exons of known disease genes (gene panels, clinical exome). These tests have a variable and often limited diagnostic rate depending on the clinical presentation, size of the gene panel and our understanding of the inheritance of the disorder (with examples described in this issue). There are numerous possible explanations for the missing heritability of these cases including undetected variants within the relevant gene (intronic, up/down-stream and structural variants), variants harbored in genes outside the targeted panel, intergenic variants, variants undetectable by the applied technology, complex/non-Mendelian inheritance, and nongenetic phenocopies. In this article we further explore and review methods to investigate these sources of missing heritability.

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“…Congenital aniridia may be part of a syndrome as in WAGR contiguous gene syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) or in the rare Gillespie syndrome (cerebellar ataxia and mental retardation) [1][2][3]. A minority of different gene mutations may also be observed in congenital aniridia due to other gene anomalies [1,4]. The visual prognosis of aniridia is severe, with congenital low vision due to foveal hypoplasia and occasionally optic nerve hypoplasia.…”

Section: Introductionmentioning

confidence: 99%

“…The visual prognosis of aniridia is severe, with congenital low vision due to foveal hypoplasia and occasionally optic nerve hypoplasia. The severe evolution results from keratopathy associated with corneal opacification, glaucoma, and cataract [1][2][3][4][5][6]. In the corneal limbus, the loss of the stem cell niche in Vogt's palisades progresses and causes corneal opacity called aniridia-related keratopathy (ARK), which can finally lead to blindness [7].…”

Section: Introductionmentioning

confidence: 99%

Formulation and Stability of Ataluren Eye Drop Oily Solution for Aniridia

et al. 2020

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Congenital aniridia is a rare and severe panocular disease characterized by a complete or partial iris defect clinically detectable at birth. The most common form of aniridia occurring in around 90% of cases is caused by PAX6 haploinsufficiency. The phenotype includes ptosis, nystagmus, corneal limbal insufficiency, glaucoma, cataract, optic nerve, and foveal hypoplasia. Ataluren eye drops aim to restore ocular surface PAX6 haploinsufficiency in aniridia-related keratopathy (ARK). However, there are currently no available forms of the ophthalmic solution. The objective of this study was to assess the physicochemical and microbiological stability of ataluren 1% eye drop in preservative-free low-density polyethylene (LDPE) bottle with an innovative insert that maintains sterility after opening. Because ataluren is a strongly lipophilic compound, the formulation is complex and involves a strategy based on co-solvents in an aqueous phase or an oily formulation capable of totally dissolving the active ingredient. The visual aspect, ataluren quantification by a stability-indicating chromatographic method, and microbiological sterility were analyzed. The oily formulation in castor oil and DMSO (10%) better protects ataluren hydrolysis and oxidative degradation and permits its complete solubilization. Throughout the 60 days period, the oily solution in the LDPE bottle remained clear without any precipitation or color modification, and no drug loss and no microbial development were detected. The demonstrated physical and microbiological stability of ataluren 1% eye drop formulation at 22–25 °C might facilitate clinical research in aniridia.

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Aniridia and Axenfeld-Rieger Syndrome: Clinical presentations, molecular genetics and current/emerging therapies

Cited by 23 publications

References 91 publications

A novel variant of the FOXC1 gene causes Axenfeld-Rieger syndrome with congenital glaucoma in a Chinese boy

A novel variant of the FOXC1 gene causes Axenfeld-Rieger syndrome with congenital glaucoma in a Chinese boy

Ocular genetics in the genomics age

Formulation and Stability of Ataluren Eye Drop Oily Solution for Aniridia

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