Aniridia

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Aniridia information for patients

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Overview
The condition
Treatment
Current research in aniridia
Practical advice
Further information and support
Other resources

Overview


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This image demonstrates the difference between a patient with aniridia and a normal healthy individual. On the left is an eye without an iris while on the right of the image shows an eye with a fully formed iris, giving the eye a hazel colour.
An eye affected by aniridia where the iris is absent (A) and an eye with a fully developed iris (B)

Aniridia is a rare condition affecting 1 in 40,000 to 100,000[1] people. It is caused by genetic changes to the PAX6 gene, resulting in the characteristic appearance of an under-developed or absent iris. Apart from the iris, other structures of the eye could be affected as well, namely the cornea, the trabecular meshwork, lens, fovea, optic disc and overall size of the eye.

Consequently, patients experience a variety of symptoms such as glare, severe light sensitivity, poor vision and nystagmus. It typically affects both eyes and is present at birth, although it may be noticed later in infancy. Aniridia can either be inherited from a parent in an autosomal dominant inheritance pattern, or develop spontaneously in an individual (when they were developing in the womb during pregnancy) without prior family history, known as sporadic aniridia. The condition varies in severity among patients, even within the same family but individuals usually show little variability between the two eyes.

Aniridia is typically an isolated eye condition. However, in one-third[2] of cases it is associated with a condition that affects other parts of the body as well. This condition is known as the Wilms tumor, aniridia, genitourinary anomalies and mental retardation (WAGR) syndrome due to mutations involving both PAX6 and WT1 genes. Affected individuals of WAGR syndrome are at increased risk of developing Wilms tumour, a type of childhood kidney cancer.[3]


The condition


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Symptoms

  • Glare or light sensitivity
A normal iris can control the amount of light entering into the eye by changing the size of the pupil, reducing glare and sensitivity to light in bright conditions. Patients with aniridia are not able to do this as the iris tissue is not formed properly. As a result, patients experience severe light sensitivity which sometimes causes headaches.
  • Poor vision from a young age
  • Incomplete development of the fovea
This is usually known medically as foveal hypoplasia. The fovea is responsible for central and colour vision and is usually identified by a “central dip” on a specialised scan called optical coherence tomography (OCT). This “central dip” is absent in fovea hypoplasia. This is a common finding in patients with aniridia.
OCT scans of a normal fovea which shows a central dip and one with foveal hypoplasia, which does not have a central dip.
Comparison between the OCT scans of a normal fovea and foveal hypoplasia
This is medically known as optic nerve hypoplasia. The optic nerve is a structure at the back of the eye that relays electrical signals to the brain to generate images. With an under-developed optic nerve, the visual processing part of our brain is not able to receive information from our retina, leading to visual impairment.
Both disorders tend to manifest as nystagmus at around 6 weeks of age. The quick, involuntary movement of the eye from nystagmus further affects vision due to difficulty in focusing.
  • Progressive visual deterioration
The PAX6 mutation associated with aniridia disrupts the function of the stem cells in the cornea.[4][5] As a result, the stem cells are not able to regenerate and replace old or damaged cells, leading to dryness and difficulty recovering from minor injuries to the eye. Eventually, the cornea becomes scarred and opaque (not clear) from the migration of non-transparent conjunctival tissue and its blood vessels.
The severity of visual symptoms experienced vary among patients, even for individuals within the same family.
  • Other systemic issues[2]
  • Affected sense of smell
  • Hearing difficulties
  • Behavioural problems
  • Sleep disorders
  • Obesity
  • Type 1 diabetes (rarely)


Cause

In aniridia that is only localised to the eyes (isolated aniridia), 99%[2] of cases are caused by mutations in the PAX6 gene. The gene provides instructions for the development of multiple vital organs during early pregnancy including the eyes and the brain.[1] The ELP4 gene has been implicated in very rare cases.[2]


How is it diagnosed?

Aniridia is usually discovered at birth or during infancy. Diagnosis is based on clinical examination. Genetic testing is performed to exclude WAGR syndrome and to look for genetic changes in the PAX6 or ELP4 genes.


How is it inherited?

Two-thirds[2] of isolated aniridia cases are inherited from a parent through this pattern. This means that the child of an affected individual has a 50% chance on inheriting the condition. This risk applies to every newborn of the affected person.
  • Sporadic
This occurs in one-third of isolated aniridia cases. Due to the variability of the condition, parents of an individual with presumed sporadic aniridia should undergo genetic testing to confirm this is indeed the case. Individuals with sporadic aniridia may pass on to their children in an autosomal dominant pattern.

If you or your child is affected by aniridia, it is advisable to see a genetic counsellor to obtain more information and advice on inheritance and family planning options.


Related links


Treatment


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Is there any treatment?

There is currently no treatment for aniridia but researches are exploring various approaches, one of which has entered clinical trial. In the meantime, here are some ways to help alleviate symptoms and treating eye conditions associated with aniridia:

  • Visual development in children
    • Regular eye examinations to correct short (myopia) or long-sightedness (hyperopia) with glasses
    • Patching therapy to avoid development of a “lazy eye”
  • Glare or light sensitivity
    • Wearing hats when out in bright daylight
    • Wearing tinted or photochromic glasses
    • Wearing tinted, coloured or artificial pupil contact lenses (might not be suitable for every patient due to aniridia-related keratopathy)
    • Placing sunlight diffusers at back windows of a car
  • Cataract
    • Cataract surgery can be undertaken if severely impacting vision
    • Surgery can be more complicated due to aniridia
    • Vision improvement might be limited due to other associated eye conditions
  • Glaucoma
    • Regular check-up with a glaucoma specialist to ensure eye pressure is well controlled and therefore preserve sight
    • Eye drops are usually first line of treatment
    • Surgery may be considered if not responding to eye drops
  • Aniridia-related keratopathy
    • Frequent use of eye drops to keep corneal surface moist
    • Corneal transplant surgery may be considered if scarring affects the centre of the cornea, causing severe impact to vision. A careful and thorough discussion with your ophthalmologist is required to see if it is beneficial.


Children newly diagnosed with aniridia are often assumed to potentially have WAGR syndrome until proven otherwise by genetic testing. As it can also be associated with hearing difficulties, behavioural issues, sleep disorders, obesity and sometimes type 1 diabetes, they will be referred to a geneticist and a paediatrician for further assessment and monitoring.


How can I be referred for further expert care?

You can ask your GP or ophthalmologist to refer you to the Moorfields Genetic Eye Disease service. It is advisable that you are referred to a specialised genetic eye service for a more comprehensive management of your condition such as genetic testing, genetic counselling and advice on the latest clinical trials.


Current research in aniridia


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Nonsense suppression therapy

Nonsense suppression therapy is a new drug-based treatment targeting conditions caused by nonsense mutations. A nonsense mutation introduces an abnormal “stop” signal into a gene that halts protein production prematurely, resulting in a protein which is too short and not functional. A drug called ataluren (TranslarnaTM) modifies the affected cell to “ignore” these abnormal “stop” signals and produce normal full-length functional protein.

Up to 40%[6] of patients with aniridia are due to nonsense mutations. Animal studies have shown that ataluren eye drops is able to reverse the developmental defects associated with aniridia when given at a specific time frame after birth.[7][8]

Due to the positive findings from these studies, a clinical trial called Study of Ataluren in Participants With Nonsense Mutation Aniridia (STAR) is now underway to assess the safety and effectiveness of oral ataluren in patients with aniridia due to nonsense mutations.


Related links


Limbal stem cell transplant

  • Limbal stem cells
In a normal healthy cornea, the cells on the superficial layer called the epithelium are maintained by a group of stem cells located in the limbus. These cells reside in a highly specialised structure called the limbal niche. It provides an environment for the stem cells to survive and function optimally. During normal shedding of the epithelium or when injured (such as a scratch in the eye), the stem cells multiply to replace the shed or damaged cells. They also keep the cornea transparent by preventing migration of the non-transparent conjunctival tissue.
This image demonstrates the location of the limbus. It appears as the junction between the coloured part of the eye and the white of the eye.
Location of the limbus in relation to the cornea and conjunctiva


  • Role of PAX6 mutation in aniridia-related keratopathy (ARK)
In aniridia patients, mutation in the PAX6 gene disrupts the limbal niche and subsequently affects the function of the stem cells.[4]This leads to ARK and when it is severely impacting vision, limbal stem cell transplant surgery may be required.
  • Types of transplant
  • Allografts
Allografts are tissues harvested from either a living-related relative or a cadaver. As anirdia usually affects both eyes, conventional transplant surgeries for ARK require stem cells to be harvested from these sources before embedding it on a patient’s eye.[9]The long-term outcomes of these surgeries are variable.[10][11] In addition, patients with allografts require long-term medications to suppress the body’s immune system so that the transplanted cells are not rejected.
  • Cultivated oral mucosal epithelial transplantation (COMET)
To avoid using such potent medications, COMET was developed where cells lining the patient’s own oral cavity are harvested and cultured in the laboratory to transform into corneal epithelium. The transformed cells are subsequently transplanted onto the patient’s eye. The visual outcome of this technique was not optimal as the transplanted epithelium was thicker and less transparent compared to normal corneal epithelium.[12]
Scientists believe that the variable results seen with conventional limbal stem cell transplant surgeries are partly due to their failure to restore the highly specialised limbal niche. Therefore, RAFT, a bioengineered mould made from a type of natural human protein called collagen typically found in skin was developed to mimic the limbal niche.[13]A clinical trial for ARK patients, funded by the Medical Research Council (MRC) is due to start in 2020.


Artificial iris prosthesis

These are devices that are surgically inserted into the eye to alleviate glare and to improve cosmetic appearance. The three main types of prosthesis are the CustomFlex Artificial Iris (HumanOptics AG), the Morcher Iris diaphragm (Morcher® GmbH) and the 311 Aniridia Lens II (Ophtec). The CustomFlex Artificial Iris was recently approved for clinical use in the USA.

Although these devices might improve quality of life, we do not advocate them due to the potential sight threatening complications that might arise. One of the most common complications is the development or progression of glaucoma.[14] Other significant complications include development or worsening of ARK, prolonged inflammation in the eye which might lead to glaucoma, retinal detachment, severe eye infections and repeated surgeries if the device is out of position.[14]


Finding out current clinical research/trials for aniridia

www.ClinicalTrials.gov is a useful resource on international clinical studies provided by the US National Library of Medicine. Not all listed studies are trials; some are natural history studies identifying the genetic basis and outcomes of disease. ClinicalTrials.gov can be searched by the name of the disease, name of disease-causing gene if known or by drug or device name, by names of investigators, or by country, or combinations of these terms.

The database includes trials completed, underway and some yet to start. Some trials are unsuccessful and are never published.

A word of warning is necessary. The presence of a study on ClinicalTrials.gov does not mean that the study has been evaluated by an ethics committee or given approval. Several women went blind after an unproven intervention, listed as a “stem cell trial” on ClinicalTrials.gov. If you are interested in a particular trial, it is important that you seek advice from your doctor on whether they think it is reputable and ethically approved.


Practical advice


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Living with aniridia

Patients are still able to lead a fairly independent life through maximising their available vision and having access to social support. Here is some advice:

  • Noticing your child’s preferred head position when looking at objects can guide you to where you should hold toys or position yourself as this is often the position your child finds to have the best vision or least glare
  • Contacting the local council’s social services department for access to rehabilitation services and assist with practical home adaptations
  • Getting in touch with the local education authority for access to qualified teachers for children with visual impairment (QTVI)
  • Registering as sight impaired (SI) or severely sight impaired (SSI) if eligible for access to social support and financial concessions
  • Getting in touch with national or local charities for advice and peer support


Related links


Further information and support


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Other resources


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References

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  1. 1.0 1.1 Hingorani M, Hanson I, Van Heyningen V. Aniridia. European Journal of Human Genetics. 2012;20(10):1011.
  2. 2.0 2.1 2.2 2.3 2.4 Moosajee M, Hingorani M, Moore AT. PAX6-Related Aniridia. In: GeneReviews®[Internet]. University of Washington, Seattle; 2018.
  3. Breslow NE, Norris R, Norkool PA, et al. Characteristics and outcomes of children with the Wilms tumor-Aniridia syndrome: a report from the National Wilms Tumor Study Group. J Clin Oncol. 2003;21(24):4579-4585.
  4. 4.0 4.1 Shortt AJ, Secker GA, Munro PM, Khaw PT, Tuft SJ, Daniels JT. Characterization of the limbal epithelial stem cell niche: novel imaging techniques permit in vivo observation and targeted biopsy of limbal epithelial stem cells. Stem Cells. 2007;25(6):1402-1409.
  5. Ramaesh K, Ramaesh T, Dutton GN, Dhillon B. Evolving concepts on the pathogenic mechanisms of aniridia related keratopathy. Int J Biochem Cell Biol. 2005;37(3):547-557
  6. Lee H, Khan R, O'Keefe M. Aniridia: current pathology and management. Acta Ophthalmol. 2008;86(7):708-715.
  7. Gregory-Evans CY, Wang X, Wasan KM, Zhao J, Metcalfe AL, Gregory-Evans K. Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects. J Clin Invest. 2014;124(1):111-116.
  8. Wang X, Gregory-Evans K, Wasan KM, Sivak O, Shan X, Gregory-Evans CY. Efficacy of Postnatal In Vivo Nonsense Suppression Therapy in a Pax6 Mouse Model of Aniridia. Mol Ther Nucleic Acids. 2017;7:417-428.
  9. Fernandez-Buenaga R, Aiello F, Zaher SS, Grixti A, Ahmad S. Twenty years of limbal epithelial therapy: an update on managing limbal stem cell deficiency. BMJ Open Ophthalmol. 2018;3(1):e000164.
  10. Baylis O, Figueiredo F, Henein C, Lako M, Ahmad S. 13 years of cultured limbal epithelial cell therapy: a review of the outcomes. J Cell Biochem. 2011;112(4):993-1002.
  11. Shortt AJ, Secker GA, Notara MD, et al. Transplantation of ex vivo cultured limbal epithelial stem cells: a review of techniques and clinical results. Surv Ophthalmol. 2007;52(5):483-502.
  12. Yazdanpanah G, Haq Z, Kang K, Jabbehdari S, Rosenblatt ML, Djalilian AR. Strategies for reconstructing the limbal stem cell niche. Ocul Surf. 2019;17(2):230-240.
  13. Levis HJ, Kureshi AK, Massie I, Morgan L, Vernon AJ, Daniels JT. Tissue Engineering the Cornea: The Evolution of RAFT. J Funct Biomater. 2015;6(1):50-65
  14. 14.0 14.1 Srinivasan S, Ting DS, Snyder ME, Prasad S, Koch HR. Prosthetic iris devices. Can J Ophthalmol. 2014;49(1):6-17

Aniridia information for doctors

Quick links


Overview
Associated syndromes
Clinical phenotype
Genetics
Key investigations
Diagnosis
Differential diagnoses
Management
Current research
Further information for patients

Overview


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It shows an eye without an iris, which is the coloured part of the eye. This is typical of aniridia.
Iris hypoplasia with some lens opacity

Aniridia (OMIM #106210) is a pan-ocular bilateral congenital eye anomaly characterised by complete or partial iris hypoplasia, foveal and/or optic nerve hypoplasia and early-onset nystagmus. There are frequently associated ocular abnormalities, often of later onset, which include cataract, glaucoma, aniridia-related keratopathy (ARK), and retinal involvement including exudative vascular retinopathy or chorioretinal degeneration. Microphthalmia and ocular coloboma (iris, chorioretinal and/or optic disc) can also be found in association with aniridia. Symptoms depend on the structures affected but patients typically have reduced vision and photophobia. The prevalence of aniridia is between 1 in 40,000–100,000[1] with no known racial or gender predilection. Isolated aniridia is mainly caused by mutations involving the PAX6 gene. It is either inherited in an autosomal dominant inheritance pattern (2/3 of cases) or it can arise sporadically (1/3 of cases).[2]


Associated syndromes


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1. Wilms tumor, aniridia, genitourinary anomalies and mental retardation (WAGR) syndrome (OMIM #194072)


Clinical phenotype


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Inter- and intra-familial phenotypic variability exists (in terms of severity), although affected individuals usually show little variability between the two eyes. Affected individuals characteristically show iris hypoplasia, nystagmus, impaired visual acuity, and foveal hypoplasia.[2] Milder forms of aniridia with subtle changes to the iris architecture, good vision, and normal foveal structure do occur. Other abnormalities include ARK, glaucoma, cataract, lens subluxation, strabismus, optic nerve coloboma and hypoplasia, and occasionally microphthalmia.[2]

The reduction in visual acuity is primarily caused by foveal hypoplasia, but cataracts, glaucoma, and corneal opacification are responsible for progressive visual failure. Most children with aniridia present at birth with an obvious iris or pupillary abnormality or in infancy with nystagmus (usually apparent by six weeks of age).[2] Congenital glaucoma rarely occurs in aniridia.[3] In such cases, a large corneal diameter and corneal oedema may be the presenting findings.

Aniridia can be associated with central auditory processing deficits, behavioural problems, sleep disorders, obesity and rarely glucose intolerance due to the role of PAX6 in development of other organs.[2][4][5][6]


Genetics


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Genes involved: PAX6 (OMIM 607108), ELP4 (OMIM 606985), WT1 (OMIM 194072)

The PAX6 gene is located on chromosome 11p13 and codes for a highly conserved transcription regulator that is involved in the early development of the eye, brain, olfactory bulb, neural tube, pancreas and gut in the embryo.[1] 99%[2] of isolated aniridia are due to mutations in the PAX6 gene. The remainder are either unsolved or have been identified to have a variant in the ultra-conserved PAX6 cis-regulatory element (SIMO) that resides downstream from PAX6 in intron 9 of the ELP4 gene.[2]

WAGR syndrome is associated with contiguous gene deletions involving both PAX6 and the adjacent WT1 gene. The WT1 gene encodes for a protein involved in the development of kidneys and gonads before birth. Postnatally, the WT1 protein regulates renal cell division, differentiation and apoptosis. Deletion of the WT1 gene leads to unregulated cell cycle and thus increases the risk Wilms tumour formation.[7]


Key investigations


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Ocular

1) Optical coherence tomography (OCT)

OCT can be used to detect fovea hypoplasia and support a clinical diagnosis especially where iris defects may be subtle. Anterior segment OCT is able to help delineate anterior segment structures even in the presence of corneal opacity.[8]


2) High-frequency ultrasound biomicroscopy (UBM)

This is usually performed in infants (under general anaesthesia) presenting with corneal opacity or corneal oedema associated with congenital glaucoma. It is able to assess for iris hypoplasia and/or absence.


3) Ultrasound B-scan

This should be performed routinely to assess axial length (AL) due to the association with microphthalmia. Microphthalmia is defiend as AL < 19mm in infants at 1 year of age or <21mm in adults.


4) Electrophysiology

To assess level of vision and exclude other causes of nystagmus such as ocular or oculocutaneous albinism.


Systemic

Children should be referred to a paediatrician for investigation of systemic features which include:

  • Serial 3 monthly renal ultrasound for children under the age of 8 whilst awaiting genetic results
  • Audiology
  • MRI brain imaging
  • Endocrine assessment (if indicated)
  • Sleep assessment (if indicated)


Diagnosis


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New patients should be under joint care with a paediatrician and have genetic testing done urgently either by a clinical geneticist or an ophthalmologist specialising in genetic eye disease. Patients should be tested for WT1 and PAX6 deletions with chromosomal microarray in the first instance to exclude WAGR syndrome. If this is negative, PAX6 is then screened using sequence analysis to identify a causative mutation. Consider testing for pathogenic variants in the SIMO region of ELP4 if no PAX6 variants are identified. For unsolved cases, whole genome sequencing is undertaken to identify novel mutations in genes or non-coding regulatory elements


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Differential diagnoses


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Cases of aniridia-like phenotype secondary to variants in the FOXC1 gene have been reported.[9][10] Both cases presented with congenital glaucoma which is rare in aniridia.

Conditions Genes involved Mode of inheritance Distinguishing features
Axenfeld-Reiger syndrome FOXC1, PITX2, PITX3 AD
  • Posterior embroyotoxon
  • Congenital glaucoma common
  • Nystagmus and foveal hypoplasia absent
Iris coloboma >90 genes AD, AR, XL, de novo sporadic
  • VA rarely affected unless chorioretinal coloboma present as well
Oculocutaneous (OCA) or ocular (OA) albinism TYR, OCA2, TYRP1, MATP, SLC24A5, C10ORF11 AR, XL
  • Iris structurally intact; iris transillumination present
  • Hypopigmented fundus
  • Skin and hair hypopigmentation (OCA)
  • Cross-lateralisation on VEP testing
Gillespie syndrome ITPR1[11][12] AD, AR
  • Typical iris phenotype
  1. Aplasia of constrictor pupillae (congenital mydriasis)
  2. Pupillary border of iris has scalloped edges with strands extending onto anterior lenticular surface
  • Non-progressive cerebellar hypoplasia, ataxia, congenital hypotonia, intellectual disability
Multisystemic smooth muscle dysfunction syndrome ACTA2[13] AD
  • Iris phenotype similar to Gillespie syndrome
  • Congenital smooth muscle dysfunction throughout body
  1. Cardiac disorders
  2. Cerebrovascular disease
  3. Aortic anomalies
  4. Intestinal hyperperistalsis
  5. Hypotonic bladder
  • Cardiac disorders usual presenting feature in childhood along with congenital mydriasis
  1. Patent ductus arteriosus
  2. Aortopulmonary septal defect


Management


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Patient management

There is currently no treatment for aniridia. Management is mainly supportive and treating associated ocular and systemic manifestations.

Ocular

  • Observe visual development, treat amblyopia if present
  • Regular refraction
  • Advise tinted/photochromic lenses. Contact lens might not be suitable due to ARK
  • Regular monitoring by glaucoma specialists
  • Cataract surgery if indicated
  • Referral to corneal specialists if evidence of limbal stem cell deficiency
  • Referral to low vision services
  • Direct patients to supporting organisations
  • Consider registration if criteria met


Systemic
Children diagnosed with WAGR syndrome require serial 3 monthly renal ultrasound monitoring by paediatricians until the age of 8 due to the increased risk of developing Wilms tumour (90% of patients develop by age 4 and 98% develop by 7 years old).[14] They will need to be managed by the appropriate multidisciplinary team due to other systemic issues. For children that did not receive genetic testing or refused to, they need to be monitored similarly as children with confirmed WT1 deletion until the age of 8. If WT1 deletion is negative, regular renal ultrasound monitoring is not required.[2]


Family management and counselling

  • Proband with positive family history
It will be inherited in an autosomal dominant pattern.[2]
  • Proband with negative family history (sporadic aniridia)
Careful examination of both parents is required due to phenotypic variability among family members. Genetic testing of both parents is recommended to confirm a sporadic case.

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.


Emotional and social support

Eye Care Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients in clinic. They provide emotional and practical support to help patients deal with their diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.


Referral to a specialist service

You can refer patients to the Moorfields Genetic Eye Disease service. Patients will have access to genetic testing, genetic counselling and advice on the latest clinical trials


Related links


Current research


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Nonsense suppression therapy

Nonsense suppression therapy is a new drug-based genetic treatment that can override the effect of nonsense mutations within the coding region of a gene. It promotes “read-through” of premature termination codons (PTC) during translation to continue protein production.

Nonsense mutations account for up to 40%[15] of the disease-causing mutations in aniridia. Ataluren (or TranslarnaTM) eye drops has been shown to reverse ocular defects associated with aniridia in mouse models when given at a specific time frame after birth.[16][17] These proof-of-concept studies led to the development of a phase 2 randomized, double-masked, placebo-controlled study of oral ataluren in patients with aniridia caused by nonsense mutations (NCT 02647359) which is currently underway.


Related links


Limbal stem cell transplant

  • Role of limbal stem cells
Limbal stem cells reside in a specialised microenvironment called the limbal niche. It is characterised by extracellular matrix, signalling molecules and various supporting cells (fibroblasts, melanocytes and vascular cells).[18] The stem cells are dependent on the limbal niche to function optimally and maintain corneal epithelium homeostasis.
  • Role of PAX6 mutation in ARK
PAX6 mutation causes dysfunction of the limbal stem cells, its associated niche and the limbal barrier.[18][19] Consequently, this affects corneal epithelial healing, corneal epithelial integrity and conjuntivalisation of the cornea. Patients with ARK may require surgery if the central corneal opacity is severely impacting vision.
This image demonstrates a patient affected by aniridia-related keratopathy. The usually transparent cornea is now covered with blood vessels from the conjunctiva, causing it to be opaque.
Aniridia-related keratopathy (ARK)
  • Types of transplant tissue
  • Allografts
Penetrating keratoplasty alone usually results in graft failure as limbal stem cell deficiency is not addressed.[1] As a result, limbal stem cell allografts (due to bilateral nature of aniridia), either in the form of cultured stem cell sheet or direct tissue transplant are indicated.[20] However, these therapies have variable long term results[21][22] and lifelong systemic immunosuppression might be required to prevent rejection.
  • Cultivated oral mucosal epithelial transplantation (COMET)
To avoid systemic immunosuppression use, COMET has been used instead to achieve ocular surface stability. However, the associated visual outcomes are sub-optimal as the transplanted epithelium does not convert to a corneal phenotype, producing a thicker and more opaque epithelium.[23] The long term outcome of this technique is not available yet.
The variable outcomes associated with the above treatment strategies is in part due to the failure of restoring the dysfunctional limbal niche.[23] In addition, the amniotic membranes used as limbal stem cell scaffolds are biologically variable and carries a small risk of infectious disease transmission.[24] Due to these challenges, RAFT was developed as an alternative extracellular matrix scaffold. It is a type 1 collagen hydrogel based substrate cast moulded to mimic the limbal niche architecture.
Proper alignment of the niche was demonstrated with the detection of corneal epithelium on the surface, limbal stem cell markers in the basal layer and limbal fibroblasts in the stroma.[24] While amniotic membranes rely on suitable donors, RAFT plates can be manufactured consistently with low risk of infection. Its success in pre-clinical studies led to the planning of a phase 1/2 clinical trial for ARK which is due to start in 2020.


Artificial iris prosthesis

These devices aim to improve visual acuity, alleviate photophobia and improve cosmetic appearance. Although studies have demonstrated functional and anatomic improvement in patients (mainly traumatic aniridia), we do not advocate implanting these devices in congenital aniridia patients due to the following reasons[25]:

  • Variable visual outcome—associated ocular co-morbidities might limit visual improvement
  • Development/progression of glaucoma and ARK
  • Prolonged anterior uveitis
  • Hypotony
  • Retinal/choroidal detachment, vitreous haemorrhage, cystoid macular oedema development
  • Endophthalmitis
  • Implant malposition—Surgical repositioning of implant is rare but can lead to aniridic fibrosis syndrome


The three main types of prosthesis are the CustomFlex Artificial Iris (HumanOptics AG), the Morcher Iris diaphragm (Morcher® GmbH) and the 311 Aniridia Lens II (Ophtec). The CustomFlex Artifical Iris recently received FDA approval in 2018.[26]

They are categorised into three groups, iris-lens diaphragm (Morcher and Ophtec), endocapsular tension ring-based (Morcher) and customised artificial iris (HumanOptics). These devices are inserted into aphakic or pseudophakic eyes, either as a separate procedure or combined with cataract surgery. They are mainly inserted either into the capsule or in the sulcus with transcleral fixation sutures.


Finding out current clinical research/trials for choroideremia

This can be found on www.ClinicalTrials.gov.

It is important to note that the presence of a study on ClinicalTrials.gov does not mean that the study has been evaluated by an ethics committee or given approval. Several women went blind after an unproven intervention, listed as a “stem cell trial” on ClinicalTrials.gov.


Further information for patients


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References

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  1. 1.0 1.1 1.2 Hingorani M, Hanson I, Van Heyningen V. Aniridia. European Journal of Human Genetics. 2012;20(10):1011.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Moosajee M, Hingorani M, Moore AT. PAX6-Related Aniridia. In: GeneReviews®[Internet]. University of Washington, Seattle; 2018.
  3. Gramer E, Reiter C, Gramer G. Glaucoma and frequency of ocular and general diseases in 30 patients with aniridia: a clinical study. Eur J Ophthalmol. 2012;22(1):104-110.
  4. Bamiou DE, Free SL, Sisodiya SM, et al. Auditory inter-hemispheric transfer deficits, hearing difficulties, and brain magnetic resonance imaging abnormalities in children with congenital aniridia due to PAX6 mutations. Arch Pediatr Adolesc Med. 2007;161(5):463-469
  5. Yasuda T, Kajimoto Y, Fujitani Y, et al. PAX6 mutation as a genetic factor common to aniridia and glucose intolerance. Diabetes. 2002;51(1):224-230.
  6. Lim HT, Kim DH, Kim H. PAX6 aniridia syndrome: clinics, genetics, and therapeutics. Curr Opin Ophthalmol. 2017;28(5):436-447.
  7. US National Library of Medicine. WT1 gene. https://ghr.nlm.nih.gov/gene/WT1. Published 2019. Updated September 2018. Accessed 30/10/19.
  8. Majander AS, Lindahl PM, Vasara LK, Krootila K. Anterior segment optical coherence tomography in congenital corneal opacities. Ophthalmology. 2012;119(12):2450-2457
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Commonly known as "wobbly eyes". It is a condition where the eyes make constant and repetitive involuntary movements which could affect vision. The eyes can move from side to side, up and down, in a circular fashion or a combination of these.

An unhealthy or dysfunctional cornea

A doctor who specialises in the diagnosis and management of genetic disorders

Visual clarity

A thread-like structure in our cells that contains all our genetic characteristics

Commonly known as "wobbly eyes". It is a condition where the eyes make constant and repetitive involuntary movements which could affect vision. The eyes can move from side to side, up and down, in a circular fashion or a combination of these.