congenital blindness

File:Coloboma.jpg

There are two categories in which the signs of congenital blindness can be classified. The first category pertains to consistently poor vision, such as not displaying preferential looking when presented with high-contrast visual stimuli. The second category encompasses severe ocular anomalies,{{cite journal |vauthors=Solebo AL, Teoh L, Rahi J |date=August 2017 |title=Epidemiology of blindness in children |journal=Archives of Disease in Childhood |volume=102 |issue=9 |pages=853–857 |doi=10.1136/archdischild-2016-310532 |pmid=28465303 |s2cid=22904590|url=https://discovery.ucl.ac.uk/id/eprint/10042835/ }} such as Anophthalmos (born with only one eye or lost both eyes), Microphthalmos (underdevelopment of one or both eyes), and Coloboma (a portion of tissue missing in the eye(s)).{{cite journal |vauthors=Basinski BW, Balikov DA, Aksu M, Li Q, Rao RC |date=February 2021 |title=Ubiquitous Chromatin Modifiers in Congenital Retinal Diseases: Implications for Disease Modeling and Regenerative Medicine |journal=Trends in Molecular Medicine |volume=27 |issue=4 |pages=365–378 |doi=10.1016/j.molmed.2021.01.001 |pmc=8034778 |pmid=33573910}}

File:NEI Animation- Retinopathy of Prematurity (ROP).gif

• Premature Birth
• Refractive error{{cite journal | vauthors = Gilbert C, Muhit M | title = Twenty years of childhood blindness: what have we learnt? | journal = Community Eye Health | volume = 21 | issue = 67 | pages = 46–47 | date = September 2008 | pmid = 19030129 | pmc = 2580065 }}
• Congenital cataract{{cite journal |vauthors=Taylan Şekeroğlu H, Utine GE |date=April 2021 |title=Congenital Cataract and Its Genetics: The Era of Next-Generation Sequencing |journal=Turkish Journal of Ophthalmology |volume=51 |issue=2 |pages=107–113 |doi=10.4274/tjo.galenos.2020.08377 |pmc=8109038 |pmid=33951899}}
• Retinopathy of prematurity{{cite journal |vauthors=Kim SJ, Port AD, Swan R, Campbell JP, Chan RV, Chiang MF |date=September 2018 |title=Retinopathy of prematurity: a review of risk factors and their clinical significance |journal=Survey of Ophthalmology |volume=63 |issue=5 |pages=618–637 |doi=10.1016/j.survophthal.2018.04.002 |pmc=6089661 |pmid=29679617}}{{cite journal | vauthors = Lim HW, Pershing S, Moshfeghi DM, Heo H, Haque ME, Lambert SR | title = Causes of Childhood Blindness in the United States using the IRIS® Registry (Intelligent Research in Sight) | journal = Ophthalmology | date = April 2023 | volume = 130 | issue = 9 | pages = 907–913 | pmid = 37037315 | doi = 10.1016/j.ophtha.2023.04.004 | pmc = 10524509 }}
• Infection
• Congenital toxoplasmosis{{cite journal | vauthors = Tomita T, Guevara RB, Shah LM, Afrifa AY, Weiss LM | title = Secreted Effectors Modulating Immune Responses to Toxoplasma gondii | journal = Life | volume = 11 | issue = 9 | pages = 988 | date = September 2021 | pmid = 34575137 | pmc = 8467511 | doi = 10.3390/life11090988 | doi-access = free | bibcode = 2021Life...11..988T }}
• Congenital cytomegalovirus infection{{cite journal | vauthors = Fowler KB, Boppana SB | title = Congenital cytomegalovirus infection | journal = Seminars in Perinatology | volume = 42 | issue = 3 | pages = 149–154 | date = April 2018 | pmid = 29503048 | doi = 10.1053/j.semperi.2018.02.002 }}

Gene alterations leading to retinal dystrophies or congenital malformations may cause congenital and childhood blindness. Examples of these include:

• Microphthalmia
• Anophthalmia
• Coloboma
• Leber's congenital amaurosis (LCA) is a collection of inherited, degenerative eye disorders that can reduce the strength of visual clarity or sharpness in infants and can cause childhood blindness.{{cite journal |vauthors=Wang X, Yu C, Tzekov RT, Zhu Y, Li W |date=February 2020 |title=The effect of human gene therapy for RPE65-associated Leber's congenital amaurosis on visual function: a systematic review and meta-analysis |journal=Orphanet Journal of Rare Diseases |volume=15 |issue=1 |pages=49 |doi=10.1186/s13023-020-1304-1 |pmc=7023818 |pmid=32059734 |doi-access=free }}{{cite journal | vauthors = Allikmets R | title = Leber congenital amaurosis: a genetic paradigm | journal = Ophthalmic Genetics | volume = 25 | issue = 2 | pages = 67–79 | date = June 2004 | pmid = 15370538 | doi = 10.1080/13816810490514261 | s2cid = 40629207 }} These eye disorders are mostly autosomal recessive diseases, and diagnoses of LCA are linked to multiple gene variants, including the Retinal pigment epithelium-specific 65 kDa (RPE65) gene. The RPE65 protein is essential in the process of vision, as it contributes to the regeneration process of the visual pigment rhodopsin.{{cite journal |vauthors=Wolf G |date=March 2005 |title=Function of the protein RPE65 in the visual cycle |journal=Nutrition Reviews |volume=63 |issue=3 |pages=97–100 |doi=10.1111/j.1753-4887.2005.tb00127.x |pmid=15825812|doi-access=free }} During the normal visual cycle, all-trans-retinyl palmitate, a stored form of vitamin A, binds and activates retinoid isomerohydrolase. This enzyme converts all-trans-retinyl palmitate into 11-cis-retinol, which is further oxidized into 11-cis-retinal. This compound binds with apo-rhodopsin to become rhodopsin, concluding the visual cycle. Biochemical studies suggest that the RPE65 protein binds with all-trans-retinyl palmitate and helps bring it to isomerohydrolase. RPE65-associated LCA is characterized by dysfunctional isomerization activity and early-onset blindness.{{cite journal | vauthors = Redmond TM, Poliakov E, Yu S, Tsai JY, Lu Z, Gentleman S | title = Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 38 | pages = 13658–13663 | date = September 2005 | pmid = 16150724 | pmc = 1224626 | doi = 10.1073/pnas.0504167102 | doi-access = free | bibcode = 2005PNAS..10213658R }}

File:Protein RPE65 PDB 3FSN.png

• Retinoblastoma is the most common intraocular malignancy present in children younger than 5 years old. The eye cancer can be passed down genetically as an autosomal dominant condition.{{cite journal | vauthors = Wong ES, Choy RW, Zhang Y, Chu WK, Chen LJ, Pang CP, Yam JC | title = Global retinoblastoma survival and globe preservation: a systematic review and meta-analysis of associations with socioeconomic and health-care factors | journal = The Lancet. Global Health | volume = 10 | issue = 3 | pages = e380–e389 | date = March 2022 | pmid = 35093202 | doi = 10.1016/s2214-109x(21)00555-6 | doi-access = free }}{{Cite web |year=2022 |title=Retinoblastoma | work = National Eye Institute | publisher = U.S. Department of Health and Human Services |url=https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/retinoblastoma |access-date=2023-07-30 }}

• Measles
• Ophtalmia neonatorum{{cite journal | vauthors = Kapoor VS, Evans JR, Vedula SS | title = Interventions for preventing ophthalmia neonatorum | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 9 | pages = CD001862 | date = September 2020 | pmid = 32959365 | pmc = 8524318 | doi = 10.1002/14651858.CD001862.pub4 | collaboration = Cochrane Eyes and Vision Group }}

As per the CDC recommendations, newborns should undergo an eye examination while they are still in the hospital nursery. It is equally important for caregivers to continue monitoring their eyes and vision system throughout their childhood and adolescence.{{cite journal | vauthors = Jullien S | title = Vision screening in newborns and early childhood | journal = BMC Pediatrics | volume = 21 | issue = Suppl 1 | pages = 306 | date = September 2021 | pmid = 34496780 | pmc = 8424784 | doi = 10.1186/s12887-021-02606-2 | doi-access = free }}

File:1606 Snellen Chart-02.jpg

The following methods are used to test infant's vision:

Pediatric nurses, medical officers and pediatricians trained in eye screening could detect small or large eyeballs, nystagmus, strabismus, “white pupils” and birth defects like coloboma and aniridia. People that are pregnant from families with a history of congenital blindness will be closely monitored and need to carry out genetic testing in order to identify whether there is a mutation or not.

Red reflex testing is done in neonates, infants, and children to assess eye and vision function.{{cite journal | vauthors = Taksande A, Jameel PZ, Taksande B, Meshram R | title = Red reflex test screening for neonates: A systematic review and meta analysis | language = en-US | journal = Indian Journal of Ophthalmology | volume = 69 | issue = 8 | pages = 1994–2003 | date = August 2021 | pmid = 34304165 | pmc = 8482932 | doi = 10.4103/ijo.IJO_3632_20 | doi-access = free }} Red reflex testing is a low-cost preventative examination that should be completed at birth before discharge. According to the American Academy of Ophthalmology, neonates found with eye abnormalities should be seen by a pediatric ophthalmologist immediately.{{cite journal | vauthors = Donahue SP, Nixon CN | title = Visual System Assessment in Infants, Children, and Young Adults by Pediatricians | journal = Pediatrics | volume = 137 | issue = 1 | pages = 28–30 | date = January 2016 | pmid = 29756730 | doi = 10.1542/peds.2015-3596 | collaboration = Section on Ophthalmology, American Academy of Pediatrics; Committee on Practice and Ambulatory Medicine, American Academy of Pediatrics; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus; American Association of Certified Orthoptists | doi-access = free }}

Of all the children in the world, about 19 million of them are estimated to be visually impaired or blind.{{cite journal | vauthors = Jauregui R, Cho GY, Takahashi VK, Takiuti JT, Bassuk AG, Mahajan VB, Tsang SH | title = Caring for Hereditary Childhood Retinal Blindness | journal = Asia-Pacific Journal of Ophthalmology | volume = 7 | issue = 3 | pages = 183–191 | date = May 2018 | pmid = 29536675 | doi = 10.22608/APO.201851 | doi-access = free }} There is evidence that the prevalence of visual impairment or blindness in children is much higher as many studies use data that are at risk bias and miss many children who fall under multiple categories of disadvantage (i.e. female, rural areas). Many of the cases occurring in low-income countries in the previous two decades were a result of low socioeconomic status and its association with disease and nutritional deficiencies, such as vitamin A deficiency.{{cite journal | vauthors = Ozturk T, Er D, Yaman A, Berk AT | title = Changing trends over the last decade in the aetiology of childhood blindness: a study from a tertiary referral centre | journal = The British Journal of Ophthalmology | volume = 100 | issue = 2 | pages = 166–171 | date = February 2016 | pmid = 26159454 | doi = 10.1136/bjophthalmol-2015-306737 }} However, recent studies have shown that most cases of visually impaired children are a result of causes such as cerebral visual impairment and optic nerve anomalies. This is due to a decrease in preventable or avoidable causes of blindness with the improvement and focus on maternal and neonatal healthcare worldwide.

There is limited knowledge on how childhood blindness affects long-term quality of life as there have not been many studies done to assess overall outcomes.{{cite journal | vauthors = Rahi JS | title = Childhood blindness: a UK epidemiological perspective | journal = Eye | volume = 21 | issue = 10 | pages = 1249–1253 | date = October 2007 | pmid = 17914426 | doi = 10.1038/sj.eye.6702837 | doi-access = free }} However, there is data that supports the functional burden of blindness for both individuals that later affect society, such as education and employment. Some potential questionnaires for gathering and assessing quality of life have been tested but not developed nor fully implemented in the healthcare system.{{cite journal | vauthors = Tadić V, Cooper A, Cumberland P, Lewando-Hundt G, Rahi JS | title = Development of the functional vision questionnaire for children and young people with visual impairment: the FVQ_CYP | journal = Ophthalmology | volume = 120 | issue = 12 | pages = 2725–2732 | date = December 2013 | pmid = 24120327 | doi = 10.1016/j.ophtha.2013.07.055 | url = http://gala.gre.ac.uk/id/eprint/22766/3/22766%20TADIC_Development_of_the_Functional_Vision_Questionnaire_2013.pdf }}{{cite journal | vauthors = Rahi JS, Tadić V, Keeley S, Lewando-Hundt G | title = Capturing children and young people's perspectives to identify the content for a novel vision-related quality of life instrument | journal = Ophthalmology | volume = 118 | issue = 5 | pages = 819–824 | date = May 2011 | pmid = 21126769 | doi = 10.1016/j.ophtha.2010.08.034 | url = http://gala.gre.ac.uk/id/eprint/23301/3/23301%20TADIC_Capturing_Children_and_Young_People%27s_Perspectives_2010.pdf }} Treatments currently available for those who are diagnosed are not readily accessible in developing countries due to financial and institutional limitations.{{cite journal | vauthors = Vinluan ML, Olveda RM, Olveda DU, Chy D, Ross AG | title = Access to essential paediatric eye surgery in the developing world: a case of congenital cataracts left untreated | journal = BMJ Case Reports | volume = 2015 | pages = bcr2014208197 | date = April 2015 | pmid = 25903202 | doi = 10.1136/bcr-2014-208197 | pmc = 4420824 }}

Leber congenital amaurosis (LCA) has been a major focus in the development of gene therapy for treatment of the disease, as it is the most severe form of congenital blindness and accounts for 5% of all inherited retinal diseases cases.{{cite journal | vauthors = Koenekoop RK | title = An overview of Leber congenital amaurosis: a model to understand human retinal development | journal = Survey of Ophthalmology | date = 2004 | volume = 49 | issue = 4 | pages = 379–398 | pmid = 15231395 | doi = 10.1016/j.survophthal.2004.04.003 }} Research on gene therapy is aimed at slowing retinal degeneration and improving visual function.{{cite journal | vauthors = Kumaran N, Moore AT, Weleber RG, Michaelides M | title = Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions | journal = The British Journal of Ophthalmology | volume = 101 | issue = 9 | pages = 1147–1154 | date = September 2017 | pmid = 28689169 | pmc = 5574398 | doi = 10.1136/bjophthalmol-2016-309975 }} Genetic testing is used to supplement clinical diagnosis and identify eligibility for future gene therapy use.{{cite journal | vauthors = Kondkar AA, Abu-Amero KK | title = Leber congenital amaurosis: Current genetic basis, scope for genetic testing and personalized medicine | journal = Experimental Eye Research | volume = 189 | pages = 107834 | date = December 2019 | pmid = 31639339 | doi = 10.1016/j.exer.2019.107834 }} LCA diagnosis occurs at birth or within the first few months of birth, with all cases following similar signs, but some genotypes present with a more severe form of the disease. There has since been a push for further research to investigate the role of gene therapy in the treatment of inherited retinal dystrophy.{{cite journal | vauthors = Tuohy GP, Megaw R | title = A Systematic Review and Meta-Analyses of Interventional Clinical Trial Studies for Gene Therapies for the Inherited Retinal Degenerations (IRDs) | journal = Biomolecules | volume = 11 | issue = 5 | pages = 760 | date = May 2021 | pmid = 34069580 | pmc = 8160708 | doi = 10.3390/biom11050760 | doi-access = free }} In 2017, the U.S. Food and Drug Administration approved Voretigene neparvovec (Luxturna), a gene therapy medication used for the treatment of retinal dystrophy.

Gene therapy treatment is done in the outpatient setting. Patients come to the hospital for the treatment, then return home. Patients do not need to be strictly monitored or stay in the hospital. The gene therapy treatment is in vivo which involves the use of a delivery vector to transmit the therapeutic gene into the targeted cells. People with congenital amaurosis will present with reduced or absent levels of retinal pigment epithelium 65 kDa protein (RPE65).{{cite journal | vauthors = Maguire AM, Bennett J, Aleman EM, Leroy BP, Aleman TS | title = Clinical Perspective: Treating RPE65-Associated Retinal Dystrophy | journal = Molecular Therapy | volume = 29 | issue = 2 | pages = 442–463 | date = February 2021 | pmid = 33278565 | pmc = 7854308 | doi = 10.1016/j.ymthe.2020.11.029 }} Luxturna works by delivering a normal copy of the RPE65 gene. The delivery vector uses a recombinant adeno-associated virus (AAV) carrying the RPE65 gene (AAV2-hRPE65v2).{{cite journal | vauthors = Bennett J, Ashtari M, Wellman J, Marshall KA, Cyckowski LL, Chung DC, McCague S, Pierce EA, Chen Y, Bennicelli JL, Zhu X, Ying GS, Sun J, Wright JF, Auricchio A, Simonelli F, Shindler KS, Mingozzi F, High KA, Maguire AM | display-authors = 6 | title = AAV2 gene therapy readministration in three adults with congenital blindness | journal = Science Translational Medicine | volume = 4 | issue = 120 | pages = 120ra15 | date = February 2012 | pmid = 22323828 | pmc = 4169122 | doi = 10.1126/scitranslmed.3002865 }} The procedure is a single injection of the AAV2-hRPE65v2 therapeutic gene into the unilateral subretinal of the eye. People must meet the following requirements to be eligible for Luxturna gene therapy: biallelic disease-causing RPE65 mutation, older than one year in age, no surgical contraindications, detectable photoreceptors and RPE, and measurable vision. Luxturna has now become the standard of care for the treatment of inherited retinal dystrophy. Due to the nature and rareness of inherited retinal disease, Luxturna was granted orphan drug designation by the FDA, which incentivizes pharmaceutical companies to continue innovating because tax credits are granted for qualified clinical trials.{{cite journal | vauthors = Papaioannou I, Owen JS, Yáñez-Muñoz RJ | title = Clinical applications of gene therapy for rare diseases: A review | journal = International Journal of Experimental Pathology | volume = 104 | issue = 4 | pages = 154–176 | date = August 2023 | pmid = 37177842 | pmc = 10349259 | doi = 10.1111/iep.12478 }}

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Category:Blindness