Congenital blindness

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Human eye anatomy Schematic diagram of the human eye.png
Human eye anatomy

Congenital blindness refers to blindness present at birth. [1] Congenital blindness is sometimes used interchangeably with "Childhood Blindness." However, current literature has various definitions of both terms. Childhood blindness encompasses multiple diseases and conditions present in ages up to 16 years old, which can result in permanent blindness or severe visual impairment over time. [2] Congenital blindness is a hereditary disease and can be treated by gene therapy. Visual loss in children or infants can occur either at the prenatal stage (during the time of conception or intrauterine period) or postnatal stage (immediately after birth). [3] There are multiple possible causes of congenital blindness. In general, 60% of congenital blindness cases are contributed from prenatal stage and 40% are contributed from inherited disease. [4] However, most of the congenital blindness cases show that it can be avoidable or preventable with early treatment. [5]

Contents

Signs and symptoms

Coloboma in the right eye of a 10-month-old child Coloboma.jpg
Coloboma in the right eye of a 10-month-old child

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. [6] The second category encompasses severe ocular anomalies, [6] 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)). [7]

Causes

Prenatal

Retinopathy of prematurity NEI Animation- Retinopathy of Prematurity (ROP).gif
Retinopathy of prematurity

Mutations

Gene alterations leading to retinal dystrophies or congenital malformations may cause congenital and childhood blindness. [7] Examples of these include:

  • Microphthalmia [7]
  • Anophthalmia [7]
  • Coloboma [7]
  • 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. [14] [15] 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. [14] [16] The RPE65 protein is essential in the process of vision, as it contributes to the regeneration process of the visual pigment rhodopsin. [17] During the normal visual cycle, all-trans-retinyl palmitate, a stored form of vitamin A, binds and activates retinoid isomerohydrolase. [17] This enzyme converts all-trans-retinyl palmitate into 11-cis-retinol, which is further oxidized into 11-cis-retinal. [17] This compound binds with apo-rhodopsin to become rhodopsin, concluding the visual cycle. [17] Biochemical studies suggest that the RPE65 protein binds with all-trans-retinyl palmitate and helps bring it to isomerohydrolase. [17] [16] RPE65-associated LCA is characterized by dysfunctional isomerization activity and early-onset blindness. [17] [16]
RPE65 Protein RPE65 PDB 3FSN.png
RPE65
  • 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. [18] [19]

Postnatal

Screening

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. [21]

Screening test: Snellen Chart 1606 Snellen Chart-02.jpg
Screening test: Snellen Chart

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

Type of visual impairmentScreening tests
Visual acuity (Being able to tell and recognize the sharp and well-defined visual information when there is a noticeable contrast between light and dark areas) [22]
  • HOTV eye test
  • Picture identification tests
  • Tumbling E
  • Snellen
Strabismus (Squint; [23] eyes are not looking in the same direction)
  • Hirschberg test (corneal light reflex test)
  • Cover-uncover test (cross cover test)
  • Bruckner test (red reflex test)
Anisometropia (Two eyes have varying refractive power) [24]
  • Stereo Smile
  • Random Dot E
  • TNO
Refractive errors
  • Photorefraction
  • Autorefractive screening

Diagnosis

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. [2] 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. [26] Red reflex testing is a low-cost preventative examination that should be completed at birth before discharge. [26] According to the American Academy of Ophthalmology, neonates found with eye abnormalities should be seen by a pediatric ophthalmologist immediately. [27]

Epidemiology

Of all the children in the world, about 19 million of them are estimated to be visually impaired or blind. [28] 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). [6] 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. [29] 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. [29] This is due to a decrease in preventable or avoidable causes of blindness with the improvement and focus on maternal and neonatal healthcare worldwide. [6]

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. [30] However, there is data that supports the functional burden of blindness for both individuals that later affect society, such as education and employment. [6] Some potential questionnaires for gathering and assessing quality of life have been tested but not developed nor fully implemented in the healthcare system. [31] [32] Treatments currently available for those who are diagnosed are not readily accessible in developing countries due to financial and institutional limitations. [33]

Research

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. [34] [35] Research on gene therapy is aimed at slowing retinal degeneration and improving visual function. [36] Genetic testing is used to supplement clinical diagnosis and identify eligibility for future gene therapy use. [35] 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. [36] There has since been a push for further research to investigate the role of gene therapy in the treatment of inherited retinal dystrophy. [37] In 2017, the U.S. Food and Drug Administration approved Voretigene neparvovec (Luxturna), a gene therapy medication used for the treatment of retinal dystrophy. [35]

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). [38] Luxturna works by delivering a normal copy of the RPE65 gene. [38] The delivery vector uses a recombinant adeno-associated virus (AAV) carrying the RPE65 gene (AAV2-hRPE65v2). [39] The procedure is a single injection of the AAV2-hRPE65v2 therapeutic gene into the unilateral subretinal of the eye. [39] 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. [38] Luxturna has now become the standard of care for the treatment of inherited retinal dystrophy. [38] 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. [40]

Related Research Articles

<span class="mw-page-title-main">Retina</span> Part of the eye

The retina is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then processes that image within the retina and sends nerve impulses along the optic nerve to the visual cortex to create visual perception. The retina serves a function which is in many ways analogous to that of the film or image sensor in a camera.

<span class="mw-page-title-main">Retinitis pigmentosa</span> Gradual retinal degeneration leading to progressive sight loss

Retinitis pigmentosa (RP) is a genetic disorder of the eyes that causes loss of vision. Symptoms include trouble seeing at night and decreasing peripheral vision. As peripheral vision worsens, people may experience "tunnel vision". Complete blindness is uncommon. Onset of symptoms is generally gradual and often begins in childhood.

The National Eye Institute (NEI) is part of the U.S. National Institutes of Health (NIH), an agency of the U.S. Department of Health and Human Services. The mission of NEI is "to eliminate vision loss and improve quality of life through vision research." NEI consists of two major branches for research: an extramural branch that funds studies outside NIH and an intramural branch that funds research on the NIH campus in Bethesda, Maryland. Most of the NEI budget funds extramural research.

Amaurosis is vision loss or weakness that occurs without an apparent lesion affecting the eye. It may result from either a medical condition or excess acceleration, as in flight. The term is the same as the Latin gutta serena, which means, in Latin, clear drop. Gutta serena is a condition of partial or complete blindness with a transparent, clear pupil. This term contrasts with suffusio nigra which means, in Latin, dark suffusion, indicating partial or complete blindness with a dark pupil, e.g., a cataract. Milton, already totally blind for twelve years by the time he published Paradise Lost, refers to these terms in Book 3, lines 25–26.

<span class="mw-page-title-main">Visual impairment</span> Decreased ability to see

Visual or vision impairment is the partial or total inability of visual perception. In the absence of treatment such as corrective eyewear, assistive devices, and medical treatment – visual impairment may cause the individual difficulties with normal daily tasks including reading and walking. The terms low vision and blindness are often used for levels of impairment which are difficult or impossible to correct and significantly impact daily life. In addition to the various permanent conditions, fleeting temporary vision impairment, amaurosis fugax, may occur, and may indicate serious medical problems.

Leber congenital amaurosis (LCA) is a rare inherited eye disease that appears at birth or in the first few months of life.

<span class="mw-page-title-main">Choroideremia</span> Medical condition

Choroideremia is a rare, X-linked recessive form of hereditary retinal degeneration that affects roughly 1 in 50,000 males. The disease causes a gradual loss of vision, starting with childhood night blindness, followed by peripheral vision loss and progressing to loss of central vision later in life. Progression continues throughout the individual's life, but both the rate of change and the degree of visual loss are variable among those affected, even within the same family.

Stargardt disease is the most common inherited single-gene retinal disease. In terms of the first description of the disease, it follows an autosomal recessive inheritance pattern, which has been later linked to bi-allelic ABCA4 gene variants (STGD1). However, there are Stargardt-like diseases with mimicking phenotypes that are referred to as STGD3 and STGD4, and have a autosomal dominant inheritance due to defects with ELOVL4 or PROM1 genes, respectively. It is characterized by macular degeneration that begins in childhood, adolescence or adulthood, resulting in progressive loss of vision.

The visual cycle is a process in the retina that replenishes the molecule retinal for its use in vision. Retinal is the chromophore of most visual opsins, meaning it captures the photons to begin the phototransduction cascade. When the photon is absorbed, the 11-cis retinal photoisomerizes into all-trans retinal as it is ejected from the opsin protein. Each molecule of retinal must travel from the photoreceptor cell to the RPE and back in order to be refreshed and combined with another opsin. This closed enzymatic pathway of 11-cis retinal is sometimes called Wald's visual cycle after George Wald (1906–1997), who received the Nobel Prize in 1967 for his work towards its discovery.

<span class="mw-page-title-main">RPE65</span> Protein-coding gene in humans

Retinal pigment epithelium-specific 65 kDa protein is a retinoid isomerohydrolase enzyme of the vertebrate visual cycle. RPE65 is expressed in the retinal pigment epithelium and is responsible for the conversion of all-trans-retinyl esters to 11-cis-retinol during phototransduction. 11-cis-retinol is then used in visual pigment regeneration in photoreceptor cells. RPE65 belongs to the carotenoid oxygenase family of enzymes.

<span class="mw-page-title-main">AIPL1</span> Protein-coding gene in the species Homo sapiens

Aryl-hydrocarbon-interacting protein-like 1 is a protein that in humans is encoded by the AIPL1 gene.

<span class="mw-page-title-main">RDH12</span> Protein-coding gene in humans

Retinol dehydrogenase 12 is an enzyme that in humans is encoded by the RDH12 gene.

Gene therapy using lentiviral vectors was being explored in early stage trials as of 2009.

<span class="mw-page-title-main">The Llura Liggett Gund Award</span> Medical award

The Llura Liggett Gund Award honors researchers for career achievements that have significantly advanced the research and development of preventions, treatments and cures for eye disease.

Gene therapy for color blindness is an experimental gene therapy of the human retina aiming to grant typical trichromatic color vision to individuals with congenital color blindness by introducing typical alleles for opsin genes. Animal testing for gene therapy began in 2007 with a 2009 breakthrough in squirrel monkeys suggesting an imminent gene therapy in humans. While the research into gene therapy for red-green colorblindness has lagged since then, successful human trials are ongoing for achromatopsia. Congenital color vision deficiency affects upwards of 200 million people in the world, which represents a large demand for this gene therapy.

Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness.

<span class="mw-page-title-main">Childhood blindness</span> Medical condition

Childhood blindness is an important contribution to the national prevalence of the disability of blindness. Blindness in children can be defined as a visual acuity of <3/60 in the eye with better vision of a child under 16 years of age. This generally means that the child cannot see an object 10 feet away, that another child could see if it was 200 feet away.

<span class="mw-page-title-main">Robert MacLaren</span> British ophthalmologist

Robert E. MacLaren FMedSci FRCOphth FRCS FACS VR is a British ophthalmologist who has led pioneering work in the treatment of blindness caused by diseases of the retina. He is Professor of Ophthalmology at the University of Oxford and Honorary Professor of Ophthalmology at the UCL Institute of Ophthalmology. He is a Consultant Ophthalmologist at the Oxford Eye Hospital. He is also an Honorary Consultant Vitreo-retinal Surgeon at the Moorfields Eye Hospital. MacLaren is an NIHR Senior Investigator, or lead researcher, for the speciality of Ophthalmology. In addition, he is a member of the research committee of Euretina: the European Society of Retina specialists, Fellow of Merton College, in Oxford and a Fellow of the Higher Education Academy.

Voretigene neparvovec, sold under the brand name Luxturna, is a gene therapy medication for the treatment of Leber congenital amaurosis.

Jean Bennett is the F. M. Kirby Professor of Ophthalmology in the Perelman School of Medicine at the University of Pennsylvania. Her research focuses on gene therapy for retinal diseases. Her laboratory developed the first FDA approved gene therapy for use in humans, which treats a rare form of blindness. She was elected a member of the National Academy of Sciences in 2022.

References

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  29. 1 2 Ozturk T, Er D, Yaman A, Berk AT (February 2016). "Changing trends over the last decade in the aetiology of childhood blindness: a study from a tertiary referral centre". The British Journal of Ophthalmology. 100 (2): 166–171. doi:10.1136/bjophthalmol-2015-306737. PMID   26159454.
  30. ↑ Rahi JS (October 2007). "Childhood blindness: a UK epidemiological perspective". Eye. 21 (10): 1249–1253. doi: 10.1038/sj.eye.6702837 . PMID   17914426.
  31. ↑ Tadić V, Cooper A, Cumberland P, Lewando-Hundt G, Rahi JS (December 2013). "Development of the functional vision questionnaire for children and young people with visual impairment: the FVQ_CYP". Ophthalmology. 120 (12): 2725–2732. doi:10.1016/j.ophtha.2013.07.055. PMID   24120327.
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  34. ↑ Koenekoop RK (2004). "An overview of Leber congenital amaurosis: a model to understand human retinal development". Survey of Ophthalmology. 49 (4): 379–398. doi:10.1016/j.survophthal.2004.04.003. PMID   15231395.
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  37. ↑ Tuohy GP, Megaw R (May 2021). "A Systematic Review and Meta-Analyses of Interventional Clinical Trial Studies for Gene Therapies for the Inherited Retinal Degenerations (IRDs)". Biomolecules. 11 (5): 760. doi: 10.3390/biom11050760 . PMC   8160708 . PMID   34069580.
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