Review

Authors: Melanie Hingorani, Isabel Hanson, Veronica van Heyningen...

Aniridia is a rare congenital disorder in which there is a variable degree of hypoplasia or the absence of iris tissue associated with multiple other ocular changes, some present from birth and some arising progressively over time. Most cases are associated with dominantly inherited mutations or deletions of the PAX6 gene. This article will review the clinical manifestations, the molecular basis including genotype-phenotype correlations, diagnostic approaches and management of aniridia.

Topics: Aniridia; Eye Proteins; Genotype; Homeodomain Proteins; Humans; Intellectual Disability; Mutation; PAX6 Transcription Factor; Paired Box Transcription Factors; Phenotype; Repressor Proteins; Syndrome; Urogenital Abnormalities; WT1 Proteins; Wilms Tumor

PubMed: 22692063
DOI: 10.1038/ejhg.2012.100

Review

Authors: Dorsa Abdolkarimi, Dulce Lima Cunha, Manuela Lahne...

Aniridia is a pan-ocular genetic developmental eye disorder characterized by complete or partial iris and foveal hypoplasia, for which there is no treatment currently. Progressive sight loss can arise from cataracts, glaucoma, and aniridia-related keratopathy, which can be managed conservatively or through surgical intervention. The vast majority of patients harbor heterozygous mutations involving the PAX6 gene, which is considered the master transcription factor of early eye development. Over the past decades, several disease models have been investigated to gain a better understanding of the molecular pathophysiology, including several mouse and zebrafish strains and, more recently, human-induced pluripotent stem cells (hiPSCs) derived from aniridia patients. The latter provides a more faithful cellular system to study early human eye development. This review outlines the main aniridia-related animal and cellular models used to study aniridia and highlights the key discoveries that are bringing us closer to a therapy for patients.

Topics: Humans; Animals; Mice; Zebrafish; Aniridia; Iris; Cataract; Glaucoma; PAX6 Transcription Factor

PubMed: 36453299
DOI: 10.4103/ijo.IJO_316_22

Review

Authors: Alejandra Daruich, Melinda Duncan, Matthieu P Robert...

Congenital PAX6-aniridia, initially characterized by the absence of the iris, has progressively been shown to be associated with other developmental ocular abnormalities and systemic features making congenital aniridia a complex syndromic disorder rather than a simple isolated disease of the iris. Moreover, foveal hypoplasia is now recognized as a more frequent feature than complete iris hypoplasia and a major visual prognosis determinant, reversing the classical clinical picture of this disease. Conversely, iris malformation is also a feature of various anterior segment dysgenesis disorders caused by PAX6-related developmental genes, adding a level of genetic complexity for accurate molecular diagnosis of aniridia. Therefore, the clinical recognition and differential genetic diagnosis of PAX6-related aniridia has been revealed to be much more challenging than initially thought, and still remains under-investigated. Here, we update specific clinical features of aniridia, with emphasis on their genotype correlations, as well as provide new knowledge regarding the PAX6 gene and its mutational spectrum, and highlight the beneficial utility of clinically implementing targeted Next-Generation Sequencing combined with Whole-Genome Sequencing to increase the genetic diagnostic yield of aniridia. We also present new molecular mechanisms underlying aniridia and aniridia-like phenotypes. Finally, we discuss the appropriate medical and surgical management of aniridic eyes, as well as innovative therapeutic options. Altogether, these combined clinical-genetic approaches will help to accelerate time to diagnosis, provide better determination of the disease prognosis and management, and confirm eligibility for future clinical trials or genetic-specific therapies.

Topics: Humans; PAX6 Transcription Factor; Aniridia; Eye Abnormalities; Mutation; Phenotype; Eye Proteins

PubMed: 36280537
DOI: 10.1016/j.preteyeres.2022.101133

Authors: Sho Ichioka, Akiko Ishida, Kazunobu Sugihara...

BACKGROUND

Total aniridia after ocular trauma without disruption of the intraocular lens (IOL) has been reported in patients with a history of small-incisional cataract surgery. We report one case each of total and partial aniridia after accidental falls experienced by two elderly Japanese women.

CASE PRESENTATIONS

Case 1. A 76-year-old woman with a history of small-incisional cataract surgery more than 10 years previously fell onto concrete and had a contusion that affected the left side of her face. At the initial visit, the best-corrected visual acuity (BCVA) was hand motions and the intraocular pressure (IOP) was 38 mmHg in her left eye (OS). A blood clot was present in the well-formed anterior chamber and expulsed iris tissue was seen beneath the conjunctiva. Exploratory surgery showed no scleral laceration other than the previous sclerocorneal tunnel. After hyphema removal, total aniridia and an intact in-the-bag fixed IOL were seen. By 4 months, the BCVA was 1.2 and the IOP was 13 mmHg OS.

CASE 2

An 88-year-old woman with a history of small-incisional cataract surgery more than 10 years previously had a fall that resulted in right-sided zygomatic and maxillary bone fractures. The BCVA was light perception and the IOP was 29 mmHg in her right eye (OD). Exploratory surgery showed no scleral laceration and the previous sclerocorneal tunnel was found; iris strand prolapsing from the sclerocorneal tunnel was seen. After hyphema removal, partial iris loss and an intact lens position were seen. By 1 week postoperatively, the BCVA was 0.05 OD and the IOP was 12 mmHg OD.

CONCLUSIONS

It has been postulated that previously created small-incision tunnels can function as release valves during blunt trauma by preventing further global rupture and limiting IOL prolapse or retinal injury. Our cases suggested this can happen even long periods after cataract surgery. The case with partial aniridia demonstrated the process of the expulsive aniridia, and its findings do not contradict the postulated mechanisms.

Topics: Aged; Aged, 80 and over; Aniridia; Cataract; Cornea; Corneal Diseases; Eye Injuries; Female; Humans; Hyphema; Iris; Iris Diseases; Lacerations; Lenses, Intraocular

PubMed: 36183072
DOI: 10.1186/s12886-022-02615-4

Authors: Jussi Pekka Tolonen, Ricardo Parolin Schnekenberg, Simon McGowan...

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

Authors: Yoshinosuke Shimamura, Takayuki Okamoto, Koki Abe...

Topics: Humans; WAGR Syndrome

PubMed: 33390234
DOI: 10.1016/j.kint.2020.05.017

Review

Authors: Ruchi Shah, Cynthia Amador, Kati Tormanen...

There is a number of systemic diseases affecting the cornea. These include endocrine disorders (diabetes, Graves' disease, Addison's disease, hyperparathyroidism), infections with viruses (SARS-CoV-2, herpes simplex, varicella zoster, HTLV-1, Epstein-Barr virus) and bacteria (tuberculosis, syphilis and Pseudomonas aeruginosa), autoimmune and inflammatory diseases (rheumatoid arthritis, Sjögren's syndrome, lupus erythematosus, gout, atopic and vernal keratoconjunctivitis, multiple sclerosis, granulomatosis with polyangiitis, sarcoidosis, Cogan's syndrome, immunobullous diseases), corneal deposit disorders (Wilson's disease, cystinosis, Fabry disease, Meretoja's syndrome, mucopolysaccharidosis, hyperlipoproteinemia), and genetic disorders (aniridia, Ehlers-Danlos syndromes, Marfan syndrome). Corneal manifestations often provide an insight to underlying systemic diseases and can act as the first indicator of an undiagnosed systemic condition. Routine eye exams can bring attention to potentially life-threatening illnesses. In this review, we provide a fairly detailed overview of the pathologic changes in the cornea described in various systemic diseases and also discuss underlying molecular mechanisms, as well as current and emerging treatments.

Topics: Autoimmune Diseases; COVID-19; Comorbidity; Cornea; Humans; SARS-CoV-2

PubMed: 33485845
DOI: 10.1016/j.exer.2021.108455

Review

Authors: L Latta, F C Figueiredo, R Ashery-Padan...

Aniridia, a rare congenital disease, is often characterized by a progressive, pronounced limbal insufficiency and ocular surface pathology termed aniridia-associated keratopathy (AAK). Due to the characteristics of AAK and its bilateral nature, clinical management is challenging and complicated by the multiple coexisting ocular and systemic morbidities in aniridia. Although it is primarily assumed that AAK originates from a congenital limbal stem cell deficiency, in recent years AAK and its pathogenesis has been questioned in the light of new evidence and a refined understanding of ocular development and the biology of limbal stem cells (LSCs) and their niche. Here, by consolidating and comparing the latest clinical and preclinical evidence, we discuss key unanswered questions regarding ocular developmental aspects crucial to AAK. We also highlight hypotheses on the potential role of LSCs and the ocular surface microenvironment in AAK. The insights thus gained lead to a greater appreciation for the role of developmental and cellular processes in the emergence of AAK. They also highlight areas for future research to enable a deeper understanding of aniridia, and thereby the potential to develop new treatments for this rare but blinding ocular surface disease.

Topics: Aniridia; Cornea; Corneal Diseases; Humans; Scleral Diseases; Stem Cells

PubMed: 34520870
DOI: 10.1016/j.jtos.2021.09.001