Genetic Ophthalmic Disorders

Normal Structure of the Eye

Color Blindness

• Color blindness is a color vision deficiency that makes it difficult to impossible to perceive differences between some colors.

(The inability to identify colors in a normal way)

Pathophysiology

• Colorblindness mainly affects males because the genes for red and green cones are on the X chromosome

• Males have only one copy of this chromosome.

• Females, on the other hand, have a second X chromosome that serves as a backup if something goes wrong with the first.

• The male children of a carrier parent (mother) have a 50% probability of being color blind. These odds don't change even if the father is color vision defective.

Types • Red-green color blindness

This combines four different types of color blindness. Protanomaly and protanopia are caused by defective

or even missing L-cones (long-wavelengths). Deuteranomaly or deuteranopia are in opposite

defective or missing M-cones (medium-wavelengths)

• Blue cone monochromacyAs this type of monochromacy is caused by a complete absence of L- and M-cones, blue cone monochromacy is encoded at the same place as red-green color blindness on the X chromosome.

• Blue-yellow color blindnessCaused by defective or missing S-cones (short-wavelength). These photopigments are encoded in genes which reside on chromosome 7, an autosomal chromosome. This is why blue-yellow color blindness occures at the same rate on both sexes.

• Rod monochromacyTotal loss of color vision and is also known as complete achromatopsia.

• In this case the retina does not have any cone cells at all.

• It is known to be an autosomal recessive disease and can be provoked by different circumstances.

• Recent studies show that it can be encoded on chromosome 2 as well as on chromosome 8.

• Earlier studies assigned chromosome 14 to rod monochromacy but this could not be reconstructed.

Cause• Color vision deficiency or color blindness is caused when the cone

cells are unable to distinguish among the different light wavelengths and therefore misfire, causing the brain to misinterpret certain colors.

• Mutations in the following genes results in defects in color vision : CNGA3, CNGB3, GNAT2, OPN1LW, OPN1MW, and OPN1SW.

More specifically:• OPN1LW mutations impact cells that are designed to pick up the

red end of the light spectrum• OPN1MW mutations impact cells that detect the midrange colors

of the light spectrum, such as yellow and green.• OPN1SW mutations impact cells that detect the lower range of

the light spectrum, such as indigo and violet

Signs and Symptoms Symptoms vary from person to person, but may

include:• Trouble seeing colors and the brightness of colors

in the usual way• Inability to tell the difference between shades of

the same or similar colors

Often, the symptoms may be so mild that some people do not know they are color blind. A parent may notice signs of color blindness when a child is learning his or her colors.

Rapid, side-to-side eye movements (nystagmus) and other symptoms may occur in severe cases.

Diagnosis The Ishihara test• This comprises of a picture made of many dots

with an image/s that the normal eye can detect or the color blind can detect

Treatment • There is no cure for colorblindness • Some patients are given light filtering lenses

to help them distinguish colors.• Gene therapy is now being tested and has

been successful in treating two adult monkeys that were colorblind from birth

• The aim is to target the gene expression using normal cells

Glaucoma

Dictionary.com defines glaucoma as abnormally high fluid pressure in the eye, most

commonly caused either by blockage of the channel through which aqueous humor drains or by pressure of the iris against the lens

Pathophysiology

• The major risk factor for glaucoma is the increase of intraocular pressure (also known as ocular hypertension)

• Intraocular pressure is a function of production of liquid aqueous humor by the ciliary processes of the eye, and its drainage through the trabecular meshwork.

• Aqueous humor flows from the ciliary processes into the posterior chamber, bounded posteriorly by the lens and the zonules of Zinn, and anteriorly by the iris.

• It then flows through the pupil of the iris into the anterior chamber, bounded posteriorly by the iris and anteriorly by the cornea.

• From here the trabecular meshwork drains aqueous humor via Schlemm's canal into scleral plexuses and general blood circulation

Types of Glaucoma

There are several types of glaucoma, but there are two main two types:

• Open-Angle Glaucoma “Open-angle” means that the angle where the iris meets the cornea is as wide and open as it should be. Open-angle glaucoma is also called primary or chronic glaucoma. It is the most common type of glaucoma

• This type is caused by the slow clogging of the drainage canals, resulting in increased eye pressure and has a wide and open angle between the iris and cornea

• Develops slowly and is a lifelong condition

Angle- Closure Glaucoma

• It is also called acute glaucoma or narrow-angle glaucoma and is a less common form of glaucoma.

• Unlike open-angle glaucoma, angle-closure glaucoma is a result of the angle between the iris and cornea closing.

• Caused by blocked drainage canals, resulting in a sudden rise in intraocular pressure

• Has a closed or narrow angle between the iris and cornea • Develops very quickly • Has symptoms and damage that are usually very

noticeable and thus demands immediate medical attention

Gene Affected

• Myocilin was the first gene known to cause glaucoma and was discovered in 1995.

• This gene on chromosome 1 makes a protein that is secreted in the trabecular meshwork (drainage angle) of the eye. It is most likely that mutant Myocilin protein causes glaucoma by damaging the trabecular meshwork, thereby impairing outflow of aqueous fluid from the eye.

Cause • Several groups have shown that some

individuals carry two mutations; one each in Myocilin and CYP1B1(causes congenital glaucoma)

• Congenital glaucoma is caused by 2 mutations in CYP1B1.

• The glaucoma associated with Myocilin AND CYP1B1 is more aggressive, with an earlier onset than Myocilin alone.

Signs and symptoms

Primary open-angle glaucoma signs and symptoms include: • Gradual loss of peripheral vision, usually in both eyes• Tunnel vision in the advanced stages

Acute angle-closure glaucoma signs and symptoms include: • Severe eye pain• Nausea and vomiting (accompanying the severe eye pain)• Sudden onset of visual disturbance, often in low light• Blurred vision• Halos around lights• Reddening of the eye

Diagnosis There are many ways to diagnose glaucoma:• Measuring intraocular pressure Tonometry is a simple, painless procedure that measures the intraocular pressure, after numbing

the eyes with drops. It is usually the initial screening test for glaucoma.

• Test for optic nerve damage To check the fibers of the optic nerve, the doctor uses instruments to look directly through the

pupil to the back of your eye. This can reveal slight changes that may indicate the beginnings of glaucoma.

• Measuring cornea thickness (pachymetry) The eyes are numbed for this test, which determines the thickness of each cornea, an important

factor in diagnosing glaucoma. If the corneas are thick, the eye-pressure reading may read higher than normal even though the patient may not have glaucoma. Similarly, people with thin corneas can have normal pressure readings and still have glaucoma.

• Other tests To distinguish between open-angle glaucoma and angle-closure glaucoma, your eye doctor may

use a technique called gonioscopy in which a special lens is placed on your eye to inspect the drainage angle. Another test, tonography, can measure how quickly fluid drains from your eye.

Treatment The aim of treatment for glaucoma is to reduce intraocular pressure. Listed below

are some of the treatment available: Prostaglandin-like compounds. These eyedrops increase the outflow of

aqueous humor. E.g. latanoprost (Xalatan) and bimatoprost (Lumigan) Beta blockers. These reduce the production of aqueous humor. E.g. timolol

(Betimol, Timoptic), betaxolol (Betoptic) and metipranolol (Optipranolol)

Alpha-agonists. These reduce the production of aqueous humor and increase drainage. E.g. apraclonidine (Iopidine) and brimonidine (Alphagan)

Carbonic anhydrase inhibitors. These also reduce the production of aqueous humor. E.g. dorzolamide (Trusopt) and brinzolamide (Azopt)

Miotic or cholinergic agents. These also increase the outflow of aqueous humor. E.g. pilocarpine (Isopto Carpine) and carbachol (Isopto Carbachol)

Epinephrine compounds. These compounds, such as dipivefrin (Propine), also increase the outflow of aqueous humor.

• SurgerySurgeries used to treat glaucoma include: • Laser surgery. In the last couple of decades, a procedure called

trabeculoplasty has had an increased role in treating open-angle glaucoma. After giving an anesthetic eyedrop, the doctor uses a high-energy laser beam to open clogged drainage canals and help aqueous humor drain more easily from the eye.

• Filtering surgery. If eyedrops and laser surgery aren't effective in controlling your eye pressure, you may need an operation called a filtering procedure, usually in the form of a trabeculectomy

• Drainage implants. Another type of operation, called drainage implant surgery, may be an option for people with secondary glaucoma or for children with glaucoma. The eye surgeon inserts a small silicone tube into the eye to help drain aqueous humor.

Gene Therapy

• In recent studies, researchers found that both viral and nonviral vector gene delivery systems have been used to target specific tissues involved in the pathogenesis of glaucoma.

• These tissues include the trabecular meshwork, ciliary body, ciliary epithelium, Müller cells, and retinal ganglion cells.

• Recent studies in large animal models have demonstrated effective long-term gene expression in the trabecular meshwork following intracameral delivery of adeno-associated viral vectors and lentiviral vectors with limited effect on surrounding ocular tissues.

• Other promising studies have focused on vector-mediated expression of neurotrophic factors and have demonstrated a neuroprotective effect following intravitreal delivery of vectors in glaucomatous animal models.

Nystagmus

Nystagmus can be defined as involuntary, rapid movements of the eye. Movemements can be either:

• Side to side (horizontal nystagmus)• Up and down (vertical nystagmus)• Rotary (rotary or torsional nystagmus)

Nystagmus is also known as dancing eyes

• When affected by nystagmus, either one or both of the eyes can move in a circular motion, up and down, or from side to side

• Dysfunction in the inner ear or the part of the brain that controls eye movements can cause nystagmus to develop, which has a variety of causes.

• Nystagmus occurs often in infants.

Types Congenital nystagmus is present at birth. With this condition, the eyes

move together as they oscillate (swing like a pendulum). Most other types of infantile nystagmus are also classified as forms of strabismus, which means the eyes don't necessarily work together at all times.

Manifest nystagmus is present at all times Latent nystagmus occurs when one eye is covered. Manifest-latent nystagmus is continually present, but worsens when

one eye is covered. Acquired nystagmus can be caused by a disease (multiple sclerosis,

brain tumor, diabetic neuropathy), an accident (head injury), or a neurological problem (side effect of a medication).

Hyperventilation, a flashing light in front of one eye, nicotine and even vibrations have been known to cause nystagmus in rare cases. Some acquired nystagmuses can be treated with medications or surgeries.

Cause Mutations in the FRMD7 gene cause X-linked

infantile nystagmus. The FRMD7 gene provides instructions for making

a protein whose exact function is unknown. This protein is found mostly in areas of the brain

that control eye movement and in the light-sensitive tissue at the back of the eye (retina).

Research suggests that FRMD7 gene mutations cause nystagmus by disrupting the development of certain nerve cells in the brain and retina.

Signs and sypmtoms

To and fro movements of the eyes are observed by other people and the patient himself is unaware about the eye movements as the objects being viewed do not seem to move.

If nystagmus is developed during childhood, the child has tends to nod his head depending upon the type and direction of nystagmus. In cases of acquired adult nystagmus, the environment appears to oscillate horizontally, vertically or torsionally.

Blurred and unstable vision is a frequent complaint For a better vision, abnormal head posturing, may be resorted

to by patients suffering from nystagmus

Diagnosis o One way to observe nystagmus is by spinning

an individual around for about 30 seconds, stopping, and then having them try to stare at an object. If nystagmus is present, the eyes will first move slowly in one direction, then move rapidly in the opposite direction.

Other tests that may be used to diagnose nystagmus are:

• Eye-movement recordings — to verify the type of nystagmus and determine the details of the movements;

• Ear exam;• Neurologic exam;• Computerized tomography (CT) — X-rays of the

brain;• Magnetic resonance imaging (MRI) — magnetic

and radio waves used to make images of the brain.

Treatment • Since the discovery of the gene (FRMD7) that

causes nystagmus, the drugs memantine and gabapentin were used to reduce acquired nystagmus.

• They also help people with congenital (also known as infantile or early onset) nystagmus.

• Wearing of contact lenses have been known to help improve vision even more since the lenses move along with the eye movements

• A clinical trial of using gene therapy has restored the vision of three young adults in 2008

Retinitis Pigmentosa

• Retinitis pigmentosa (RP) refers to a group of inherited disorders that slowly lead to blindness due to abnormalities of the photoreceptors (primarily the rods) in the retina

• It is commonly known as night blindness

Pathophysiology • The retina lines the interior surface of the back of the eye and is

made up of several layers• One layer contains two types of photoreceptor cells referred to

as the rods and cones.• The cones are responsible for sharp, central vision and color

vision and are primarily located in a small area of the retina called the fovea.

• The area surrounding the fovea contains the rods, which are necessary for peripheral vision and night vision (scotopic vision). The number of rods increases in the periphery.

• The rod and cone photoreceptors convert light into electrical impulses and send the message to the brain via the optic nerve.

• Another layer of the retina is called the retinal pigmented epithelium (RPE).

• In RP, the photoreceptors (primarily the rods) begin to deteriorate and lose their ability to function.

• Because the rods are primarily affected, it becomes harder to see in dim light, thus causing a loss of night vision.

• As the condition worsens, peripheral vision disappears, which results in tunnel vision. The ability to see color is eventually lost.

• In the late stages of the disease, there is only a small area of central vision remaining. Ultimately, this too is lost.

Cause

This disorder has many modes of inheritance and is caused by over 100 mutations

In the non-sex-linked, or autosomal, form, it can either be a dominant or recessive trait.

In the sex-linked form, called x-linked recessive, it is a recessive trait.

This x-linked form is more severe than the autosomal forms.

Researchers found a mutation in a gene called MAK (male germ cell associated kinase).

This gene had not previously been associated with eye disease in humans.

However, examining tissue from donated eyes showed that MAK protein was located in the parts of the retina that are affected by the disease.

Signs and sypltoms

o Decreased vision at night or in low lighto Loss of side (peripheral) visiono Loss of central vision (in advanced cases)

diagnosis• Tests to evaluate the retina:• Color vision• Examination of the retina by ophthalmoscopy after the

pupils have been dilated• Fluorescein angiography• Intraocular pressure• Measurement of the electrical activity in the retina

(electroretinogram)• Pupil reflex response• Refraction test• Retinal photography • Side vision test (visual field test)• Slit lamp examination• Visual acuity

Treatment

• Researchers generated induced pluripotent stem cells (iPSCs) from the patient's own skin cells and coaxed these immature cells to develop into retinal tissue.

• Analyzing this tissue showed that the gene mutation caused the loss of the MAK protein in the retina.

• Currently, synthetic treatment nor surgery has been developed to treat this condition

RETINOSCHISIS

• Retinoschisis is a disease of the nerve tissue in the eye. It affects the retinal cells in the macula (the central fixation point of vision at the back of the eye). Retinoschisis is technically a form of macular degeneration.

• Retinoschisis is a genetic eye disease that affects the vision of men who inherit the disease from their mothers.

• This condition frequently starts during childhood and is officially called Juvenile X-linked Retinoschisis.

TYPES

• There are two forms of this disorder. The most common is an acquired form that affects both men and women. It usually occurs in middle age or beyond, although it can occur earlier, and it is sometimes known as senile retinoschisis.

• The other form is present at birth (congenital) and affects mostly boys and young men. It is known as juvenile, X-linked retinoschisis.

Symptoms

• Decreased vision• Loss of peripheral vision• The symptoms described above may not

necessarily mean that you have retinoschisis. However, if you experience one or more of these symptoms, contact your eye doctor for a complete exam.

Diagnosis

• The electroretinogram (ERG) is an important test used in assessing the function of the nerve tissue (retina) in the back of the eye.

• The eye is stimulated with light after either dark or light adaptation.

• Contact lenses, embedded with an electrode, are worn by the patient.

• The reaction of the eye is recorded and evaluated. • This test expresses photoreceptor activity and the

overall response of the external layer of the retina, and is a very important tool in diagnosis.

Juvenile Retinoschisis • A genetic disorder of the X-

Chromosome can lead to juvenile retinoschisis.

• It is caused due to a defective gene(RS1). This gene produces an amino acid that can affect the photoreceptors (light sensitive pigments) in the eye.

• Juvenile Retinoschisis can bring physical changes in the retina (sometimes, the retina may be split into two) which can impair vision permanently.

• This means that this disorder can be primarily among boys (since boys have only X-Chromosome).

• Sometimes, there is a possibility of this disorder even among girls (due to the presence of two defective genes).

Fundus photograph of juvenile retinoschisis demonstrating stellate spokelike appearance with microcysts.

Causes

• The gene responsible for X-linked juvenile retinoschisis, XLRS1, is located on band Xp22. XLRS1 encodes a 224 amino acid protein retinoschisin that is expressed in photoreceptor and bipolar cells.

• Retinoschisin is a secreted protein that is involved in cellular adhesion and cell-cell interactions within the inner nuclear layer as well as synaptic connection between photoreceptors and bipolar cells.

Pathophysiology

• Using positional cloning, Sauer and associates identified XLRS1, the gene responsible for X-linked juvenile retinoschisis.

• Defective or absent retinoschisin may reduce adhesion of the retinal layers, resulting in the creation of schisis cavities.

Medical care

• No treatment is available to halt the natural progression of schisis formation in patients with X-linked juvenile retinoschisis (XJR).

Drugs to treat retinoschisis

• The use of topical dorzolamide and oral acetazolamide in reducing cystic spaces and foveal thickness with a concomitant increase in visual acuity has been reported.

• Both are diuretics• MOA: both decrease aqueous secretion due to lack

of bicarbonate or inhibit carbonic anhydrase.• Acetazolamide is also useful in treating seizures

Gene Therapy

• Currently, gene therapy research on an Rs1h-deficient mouse model of human retinoschisis has shown restoration of expression of retinoschisin protein in photoreceptors and normal ERG configuration. Gene therapy may be a viable therapeutic option in the future.

• University of Florida scientists used a healthy human gene to prevent blindness in mice with a form of an incurable eye disease that strikes boys.

• Writing in the August issue of Molecular Therapy, scientists from the UF Genetics Institute describe how they successfully used gene therapy in mice to treat retinoschisis, a rare genetic disorder that is passed from mothers, who retain their sight, to their sons.

• In a healthy eye, retinal cells secrete a protein called retinoschisin, or RS1, which acts like glue to connect the layers of the retina. Without it, the layers separate and tiny cysts form, devastating the vision and often leading to blindness in about 1 of every 5,000 boys.

• UF researchers injected a healthy version of the human RS1 gene to the sub-retinal space of the right eyes of 15-day-old male mice, which, like boys with the disease, don't have the healthy gene to maintain the retina. In terms of disease development, the condition in the mice was roughly equivalent to retinoschisis in a 10-year-old boy.

• Six months later, researchers looked at the interior of the eyes with a laser ophthalmoscope and found cyst formation was clearly evident in the untreated eyes, but the treated eyes appeared healthy.

• The eye's photoreceptor cells - the rods and cones that help the brain process light and color - were spared from the disease and the connections between the layers of the retinas were intact.

• In addition, the protein appears capable of moving within the retina to its target sites and the beneficial changes appear to be long lasting, researchers said. Especially encouraging were signs the treatment may be able to repair retinal damage.

• We've been very successful in curing a disease in mice that has a direct copy in humans," said Hauswirth. "It may take two to five years before we try this in human patients because of the need for safety studies, but we feel based on success so far, we will be able to provide formal evidence for safety that will allow us to get treatment into the clinic."

• "We now have proof of principle that gene therapy can basically prevent retinoschisis," said Stephen Rose, Ph.D., chief research officer for the Maryland-based Foundation Fighting Blindness.

"Furthermore, this therapy apparently demonstrates that even if disease has begun, there is a healing that takes place. That raises hope for suffering patients that we may be able to offer something that can improve the quality of their lives."

Strabismus

Strabismus also known as heterotropia, is a condition in which the eyes are not properly aligned with each other.

It typically involves a lack of coordination between the extraocular muscles, which prevents bringing the gaze of each eye to the same point in space and preventing proper binocular vision, which may adversely affect depth perception.

Common among children.

Pathophysiology

• Strabismus is caused by a lack of coordination between the muscles in the eyes. This can happen due to:

• Problems, imbalances, or injuries of the muscles that move the eyes

• Uncorrected refractive errors (ie, the need for glasses) • Nervous system disorders that affect vision, such as:

– Problems or injury of the nerves that control the eye muscles – Tumor in or near the eye or brain – Stroke or bleeding in the brain – Increased pressure in the brain – Myasthenia Gravis

• Strabismus can be caused when the cranial nerves III (oculomotor), IV (trochlear) or VI (abducens) have a lesion. A strabismus caused by a lesion in either of these nerves results in the lack of innervation to eye muscles and results in a change of eye position.

• Brain Damage• Injury to eye muscles• Hormone problems, such as:

– Diabetes – Thyroid disease

• Vision loss in one eye (one blind eye will often turn in or out)

• In some cases it may be genetic.

Genetics

• Genetics suggest that these disorders can result from errors in the development of ocular motor neurons and, in particular, in the appropriate guidance and/or targeting of axons to extraocular muscles.

• Althought much research is not done, one study show that the disorder result from mutations in genes necessary for the normal development and connectivity of brainstem ocular moto neurons, including PHOX2A, SALL4, KIF21A, ROBO3, and HOXA1, and it is now refered to as “congenital cranial dysinnervation disorders,” or CCDD.

Treatment

• If strabismus is minor and detected early, can often be corrected with use of an eyepatch on the dominant eye and/or vision therapy, the use of eyepatches is unlikely to change the angle of strabismus

• Advanced strabismus is usually treated with a combination of eyeglasses or prisms, vision therapy, and surgery, depending on the underlying reason for the misalignment. Surgery does not change the vision; it attempts to align the eyes by shortening, lengthening, or changing the position of one or more of the extraocular eye muscles

• Strabismus due to genetics- No available therapy

Long-term goals to advance the field:

• Long-term goals to advance the field:Incomitant: 1. Functional studies of molecular etiologies with eventual translation to treatment

• Comitant: 1. Linkage, GWAS meta-analysis, replication, identification of causal variants2. Functional studies of variants / associated genes to understand molecular etiologies3. Improved treatment and outcome prediction through accurate genetic characterization in advance of intervention

Stargardt disease

• Stargardt disease, or fundus flavimaculatus, is an inherited juvenile macular degeneration that causes progressive vision loss usually to the point of legal blindness. It is caused by a mutation of a gene.

• The progression usually starts between the ages of six and twelve years old and plateaus shortly after rapid reduction in visual acuity.

Pathopsyiology

It is caused by mutations in a gene called ABCA4 also known as Atp binding cassette transporter in the visual phototransduction cycle.

Researchers do not yet understand why a change in the ABCA4 gene causes Stargardt disease, but it is thought that this gene abnormality leads to an accumulation of a material called lipofuscin that may be toxic to the retinal pigment epithelium, the cells needed to sustain vision.

Symptoms

Symptoms appear befor the age of 20 and usually include:• wavy vision• blind spots• Blurriness• impaired color vision• difficulty adapting to dim lighting• Yellow spots on the retina• The centre of the retina, called the macula, has a shiny

appearance called a beaten bronze appearence.

GeneticsIt can be associated with several different genes:

• STGD1: The most common form of Stargardt disease is the recessive form caused by mutations in the ABCA4 gene. It can also be associated with CNGB3.

• STGD3: There is also a rare dominant form of Stargardt disease caused by mutations in the ELOVL4 gene.

• STGD4: Associated with PROM1.

• The classification "STGD2" is no longer used.

Stem Cell Research

• Stem cell research claims the ability to generate healthy RPE cells from human embryonic stem cells. The idea is to replace the genetically diseased RPE cells with healthy replacements. In theory, the healthy RPE cells should prevent loss of the photoreceptors, thereby preserving vision.

• The layer of cells just beneath the retina ,is called the retinal pigment epithelium (RPE)

Embryonic stem cell trials for macular degeneration: a

preliminary reportBy

Steven D Schwartz, Jean-Pierre Hubschman, Gad Heilwell, Valentina Franco-Cardenas, Carolyn K

Pan, Rosaleen M Ostrick, Edmund Mickunas, Roger Gay, Irina Klimanskaya, Robert Lanza

Published OnlineJanuary 23, 2012

Findings

• Controlled hESC( human embryonic stem • cells ) differentiation resulted in greater than 99% pure

RPE. The cells displayed typical RPE behaviour and integrated into the host RPE layer forming mature quiescent monolayers after transplantation in animals.

• The stage of differentiation substantially affected attachment and survival of the cells in vitro after clinical formulation. Lightly pigmented cells attached and spread in a substantially greater proportion (>90%) than more darkly pigmented cells after culture.

• After surgery, structural evidence confirmed cells had attached and continued to persist during our study. We did not identify signs of hyperproliferation, abnormal growth, or immune mediated transplant rejection in either patient during the first 4 months.

• Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision.

• Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of the patient with Stargardt’s macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration

Interpretation

• The hESC-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. The future therapeutic goal will be to treat patients earlier in the disease processes, potentially increasing the likelihood of photoreceptor and central visual rescue.

CONGENITAL CATARACT

• A congenital cataract is a clouding of the lens of the eye that is present at birth.

• The lens of the eye is normally clear. • It focuses light that comes into the eye onto

the retina.

PATHOPHYSIOLOGY

• The lens forms during the invagination of surface ectoderm overlying the optic vesicle. The embryonic nucleus develops by the sixth week of gestation. Surrounding the embryonic nucleus is the fetal nucleus.

• At birth, the embryonic and fetal nuclei make up most of the lens. Postnatally, cortical lens fibers are laid down from the conversion of anterior lens epithelium into cortical lens fibers.

• The Y sutures are an important landmark because they identify the extent of the fetal nucleus. Lens material peripheral to the Y sutures is lens cortex, whereas lens material within and including the Y sutures is nuclear. At the slit lamp, the anterior Y suture is oriented upright, and the posterior Y suture is inverted.

• Any insult (eg, infectious, traumatic, metabolic) to the nuclear or lenticular fibers may result in an opacity (cataract) of the clear lenticular media. The location and pattern of this opacification may be used to determine the timing of the insult as well as the etiology.

• Cataracts clouding the eye's natural lens usually are associated with aging processes. But congenital cataracts occur in newborn babies for many reasons that can include inherited tendencies, infection, metabolic problems, diabetes, trauma, inflammation or drug reactions

SIGNS AND SYMPTOMS

• Cloudiness of the lens that looks like a white spot in an otherwise normally dark pupil -- often obvious at birth without special viewing equipment

• Failure of an infant to show visual awareness of the world around him or her (if cataracts present in both eyes)

• Nystagmus (unusual rapid eye movements)

DIAGNOSIS

• A complete eye examination by an ophthalmologist will readily diagnose congenital cataract.

TREATMENT

• In some cases, congenital cataracts are mild and do not affect vision, and these cases require no treatment.

• Moderate to severe cataracts that affect vision will require cataract removal surgery, followed by placement of an artificial intraocular lens (IOL). Patching to force the child to use the weaker eye may be required to prevent amblyopia

CONGENITAL CATARACT AND INHERITANCE

• Congenital cataract, although uncommon, accounts for about 10% of childhood blindness. The cataract is usually seen as an isolated abnormality but may occur in association with other ocular developmental or systemic abnormalities.

• About 50% of bilateral cases have a genetic basis.

• Congenital cataract is both clinically and genetically heterogeneous; isolated congenital cataract is usually inherited as an autosomal dominant trait although autosomal recessive and X linked inheritance are seen less commonly.

• Most progress has been made in identifying the genes causing autosomal dominant congenital cataract.

APPROACHES AND CAUSATIVE MUTATIONS

Two main approaches have been used toidentify the causative mutations.1. In large families linkage analysis has been used

to identify the chromosomal locus followed by screening of positional candidate genes; most genes have been identified using this strategy.

2. A second approach has been to screen DNA from large panels of patients with inherited cataract for mutation in the many candidate genes available.

FINGINGS• The α, β, and γ-crystallins are stable water

soluble proteins which are highly expressed in the lens; they account for about 90% of total lens protein, have a key role in lens transparency, and thus represent excellent candidate genes for inherited cataract.

• α-Crystallin is made up of two polypeptides αA and αB encoded by the CRYAA gene on chromosome 21q22.3 and CRYAB gene on 11q22–q22.3, respectively.

• In addition to its structural role α-crystallin also functions as a molecular chaperone within the lens and other tissues.

• Mutations in both CRYAA and CRYAB have been identified in families with ADCC and in one family with a missense mutation in CRYAB affected individuals had both cataract and an associated desmin related myopathy presumably caused by impaired chaperone function of the mutant protein.

• A nonsense mutation in CRYAA has also recently been reported in a consanguineous family with autosomal recessive cataract.

• The γ-crystallin gene cluster on chromosome 2q33–35 encompasses genes γA to D but only γC (CRYGC) and γD(CRYGD) are highly expressed in the human lens.

• Missense mutations in both genes have been identified in families with ADCC exhibiting a range of different phenotypes.

• Two different missense mutations within CRYGD (R36S and R58H) are associated with a crystalline-like cataract and functional studies suggest that this may be due to reduced solubility and increased likelihood of crystallisation of the mutant protein.

• The β-crystallin family encompasses four acidic (A) and three basic (B) forms encoded by genes on chromosomes 2, 17, and 22.

• Four mutations have been reported in the β-crystallin genes.

• Two different splice site mutations have been reported in the CRYBA1 gene on chromosome 17q11.2 associated with nuclear and pulverulent phenotypes and a CRYBB1 nonsense mutation has been reported in a family with pulverulent cataract.

• A missense mutation in CRYBB2 (Q155X) has been identified in three unrelated families with ADCC; interestingly, the phenotype in each family is very different despite the identical mutation indicating that other modifier genes are likely to influence the cataract phenotype.

• Such modifier gene influences have recently been identified in a recessive murine cataract and it is likely that similar gene-gene interactions will be identified in human cataract.

• At least 15 different mutations in the crystallin genes have now been implicated in human cataract associated with a diverse range of phenotypes.

• It is still unclear what proportion of inherited cataract is associated with crystallin gene mutations as few studies have involved systematic screening of all crystallin genes in a large patient population.

GENE THERAPY?

• The identification of the genetic mutations underlying congenital cataract and subsequent functional studies will improve our understanding of normal lens development and the mechanisms of cataractogenesis.

• This information, although important, is unlikely to lead to any major clinical advance in the prevention of or management of congenital cataract as the cataracts in this young age group are usually present from birth.

What is Anophthalmia?• Anophthalmia, also known as anophthalmos is

the congenital absence of one or both eyes. • It is a medical term that describes the lack of eye

of occular tissue and globe from the eye.• Anophthalmia and microphthalmia are often used

interchangeably. • Microphthalmia is a disorder in which one or

both eyes are abnormally small, while anophthalmia is the absence of one or both eyes.

Pathophysiology

• Anophthalmia occurs when the neuroectoderm of the primary optic vesicle fails to develop properly from the anterior neural plate of the neural tube during embryological development.

• The more commonly seen microphthalmia can result from a problem in development of the globe at any stage of growth of the optic vesicle.

• Proper growth of the orbital region is dependent on the presence of an eye, which stimulates growth of the orbit and proper formation of the lids and the ocular fornices.

• Commonly, a child born with anophthalmia has a small orbit with narrow palpebral fissure and shrunken fornices.

SIGNS AND SYMPTOMS

• Small orbital rim and the entry • Reduced size of the orbit bone or the eye

socket• The eye muscles are usually lacking. • Tear glands and ducts may be missing. • Optic foramen is small and/or maldeveloped

• The shortening of the eyelids in all directions • The contraction of the orbicularis muscle.• Eyeball is completely absent in primary

anophthalmia. • Eyeball is very small and malformed in

microphthalmia. • Due to anopthalmia a small bony orbit called

hemifacial hypoplasia is formed which does not allow a prosthesis to be fit.

LINKING CAUSE AND THE DISEASE• The development of the eye is highly complex

and it is determined by sequential and coordinated expression of eye development genes within the developing tissues.

• Although some individuals with anophthalmia or microphthalmia have relatives with other eye malformations, the frequent lack of clear Mendelian inheritance in these conditions has made identifying the genes for eye development very challenging.

• However, using a variety of techniques, some genes involved in anophthalmia or microphthalmia have now been identified.

• These include genes principally involved in ocular development, such as

1. CHX10 2. SOX23. OTX24. PAX65. SIX6and STRA6

Sox2 GENE• The most genetic based cause for

anophthalmia is caused by the Sox2 gene.• Sox2 anophthalmia syndrome is caused by a

mutation in the Sox2 gene that does not allow it to produce the Sox2 protein that regulates the activity of other genes by binding to certain regions of DNA.

• Without this Sox2 protein, the activity of genes that is impotant for the development of the eye is disrupted.

• Sox2 anophthalmia syndrome is an autosomal dominant inheritance, but the majority of patients who suffer from Sox2 anophthalmia are the first in their family history to have this mutation.

• In certain cases, one parent will possess the mutated gene only in their egg or sperm cell and the offspring will inherit it through that. This is called germline mosaicism.

• There are at least 33 mutations in the Sox2 gene that have been known to cause anophthalmia.

• Some of these gene mutations will cause the Sox2 protein not to be formed, while other mutations will yield a non-functional version of this protein.

OTHER INFLUENCIAL GENES• Other important genes causes anophthalmia

include OTX2, CHX10 and RAX.• Each of these genes are an important in retinal

expression. Mutations in these genes can cause a failure of retinal differentiation.

• OTX2 is dominantly inherited and varies in severity. It has also been linked with microphthalmia.

• BMP4 is also linked in anophthalmia is also a cause of myopia, microphthalmia and is dominantly inherited. BMP4 interacts with Sonic Hedgehog pathway and can cause anophthalmia.

• CHX10 is involve in development of the eye. Many of which are involved in the development of substructures within the eye.

• Genes that are involved in eye and brain development including SOX2, OTX2, and PAX6.

• Several syndromic genes are involved in developing other organs in addition to the eye, including CHD7, the gene for CHARGE syndrome and PTCH, the gene for Gorlin syndrome.

• There is a complex interplay between the different eye development gene pathways, which allows their expression to be finely regulated and begins to explain why there is such an overlap of the phenotypes associated with mutations of each gene.

• STRA6 gene which is responsible for transporting vitamin A into the cells.

OTHER FACTORS1. Environmental Influence

• Many environmental conditions have also been known to cause anophthalmia. The strongest support for environmental causes has been studies where children have had gestational-acquired infections.

• These infections are typically viral. A few known viruses that can cause anophthalmia are toxiplasmosis, rubella, and certain strands of the flu virus.

• Other known environmental conditions that have lead to anophthalmia are maternal vitamin A deficiency, exposure to X-rays during gestation, solvent misuse, and exposure to thalidomide.

2. Chromosome 14

• An interstitial deletion of chromosome 14 has been known to occasionally be the source of anophthalmia. The deletion of this region of chromosome has also been associated with patients having a small tongue, and high arched palate, developmental and growth retardation, undescended testes with a micropenis, and hypothyroidism.

• The region that has been deleted is region q22.1-q22.3. This confirms that region 22 on chromosome 14 influences the development of the eye.

DIAGNOSIS1. Prenatal Diagnosis• Ultrasounds can be used to diagnose

anophthalmia during gestation. Due to the resolution of the ultrasound, however, it is hard to diagnose it until the second trimester. The earliest to detect anophthalmia this way is approximately 20 weeks.

• 3D and 4D ultrasounds have proven to be more accurate at viewing the fetus's eyes during pregnancy and are another alternative to the standard ultrasound.

• Amniocentesis, it is possible to diagnose prenatally with amniocentesis, but it may not show a correct negative result.

• Amniocentesis can only diagnose anophthalmia when there is a chromosomal abnormality. Chromosomal abnormalities are only a minority of cases of anophthalmia.

2. Postnatal Diagnosis• MRIs and CTs can be used to scan the brain

and orbits. Clinicians use this to assess the internal structures of the globe, the optic nerve and extraocular muscles, and brain anatomy.

• Examination, physicians, specifically opthamologists, can examine the child and give a correct diagnosis. Some will do molecular genetics tests to see if the cause is linked with gene mutations.

TREATMENT1. Prosthetic eye• Currently, there is not a treatment option for

regaining vision by developing a new eye. • However, cosmetic options so the absence of

the eye is not as noticeable. • Typically, the child will need to go to

prosthetic specialist to have conformers fitted into the eye. Conformers are made of clear plastic and are fitted into the socket to promote socket growth and expansion.

• As the child's face grows and develops, the conformer will need to be changed. Expander may also be needed in anophthalmia to expand the socket that is present.

• The conformer is changed every few weeks the first two years of life. After that, a painted prosthetic eye can be fitted for the child's socket.

1. Cosmetic Surgery• If the proper actions are not taken to expand

the orbit, many physical deformities can appear.

• It is important that if these deformities do appear, that surgery is not done until at least the first two years of life. Many people get eye surgery, such as upper eyelid ptosis surgery and lower eyelid tightening. These surgeries can restore the function of the surrounding structures like the eyelid in order to create the best appearance possible.

ANOPHTHALMIA AND GENE THERAPY

1. Scientists at University College Dublin, Ireland, have identified a genetic alteration which causes a child to be born with anophthalmia.

• According to the findings published in the current issue (December 2011) of Human Mutation, a child’s eyes will not develop fully in the womb if the child has alterations in both copies of its STRA6 gene which is responsible for transporting vitamin A into the cells.

• This new discovery means that scientists can now develop a genetic test for couples who may be carrying the altered gene and planning to have children.

• If identified, the couples can receive advice and counselling about the implications of carrying the gene alteration for their present and future children.

What is Microphthalmia?• Microphthalmia is an eye abnormality that

arises before birth. In this condition one or both eyeballs are abnormally small. In some affected individuals the eyeball may appear to be completely missing however, even in these cases some remaining eye tissue is generally present.

• Microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all.

Etiology • Microphthalmia in newborns is sometimes associated with

fetal alcohol syndrome or infections during pregnancy

particularly herpes simplex virus, rubella and cytomegalovirus

(CMV) but the evidence is inconclusive.

• Genetic causes of microphthalmia include chromosomal

abnormalities (trisomy 13 (Patau syndrome), Triploid

Syndrome and Wolf-Hirschhorn Syndrome) or monogenetic

Mendelian disorders.

• The latter maybe autosomal dominant, autosomal recessive or

X linked. Genes that have been implicated in microphthamia

include many transcription and regulatory factors.

Prevalence

• Between 3.2% and 11.2% of blind children have microphthalmia.

• A national study of all live births in Scotland over a 16-year period showed a prevalence of 19 per 100,000 .

Changes in genes that are associated with Microphthalmia.

Pathophysiology • Anophthalmia and Microphthalmia may result from growth arrest of

the optic vesicles.• Anophthalmia occurs with faulty neuroectodermal development in

the primary optic vesicle from the anterior neural plate. • Microphthalmos can result from disruption of any stage of optic

vesicle growth. Microphthalmia is sometimes associated with an orbital cyst.

• The development of the orbital bones, eyelids and fornices depends largely on the presence of volume within the orbit(a growing globe in the normal state) .

• The cyst associated with microphthalmos may stimulate adequate growth.

• In addition to visual system impairment, disfigurement of the midface, orbit and eyelid may occur without treatment. Also the patient may be unable to wear a prosthetic eye.

Pathophysiology Cont’ue• Orbital hypoplasia is most commonly related to

congenital Microphthalmos.• A clear inheritance pattern has not been established,

most cases are sporadic or idiopathic in nature.• However, prepartum maternal infections and

exposures to toxins have been implicated.• Microphthalmia may also occur as part of more

extensive craniofacial malformations. • Orbital hypoplasia is sometimes a result of

enucleation early in life for trauma or retinoblastoma.

Signs/symptoms• The signs and symptoms of Microphthalmia with linear skin

defects syndrome vary widely, even among affected individuals within the same family.

• In addition to the characteristic eye problems and skin markings this condition can cause abnormalities in the brain, heart and genitourinary system.

• A hole in the muscle that separates the abdomen from the chest cavity (the diaphragm) which is called a diaphragmatic hernia may occur in people with this disorder.

• Affected individuals may also have short stature and fingernails and toenails that do not grow normally (nail dystrophy).

Diagnosis/testing • The diagnosis of Microphthalmia is based on clinical

examination and imaging studies including: • A-scan ultrasonography to measure total axial length; • B-scan ultrasonography to evaluate the internal

structures of the globe. • CT scan or MRI of the brain and orbits to evaluate the

size and internal structures of the globe, the optic nerve and extraocular muscles.

• Evaluation for other malformations, assessment of hearing, chromosome analysis, family history and parental eye examinations may help establish the underlying cause.

Diagnosis Cont’ue• Molecular genetic testing for mutations in

genes associated with Micropthalmia is clinically available for SIX3, HESX1, BCOR, SHH, PAX6, RAX, CHD7 (CHARGE syndrome), IKBKG (incontinentia pigmenti), NDP (Norrie disease), SOX2(SOX2-related eye disorders), POMT1 (Walker-Warburg syndrome), and SIX6.

• Molecular genetic testing for isolated (nonsyndromic) Micropthalmia is available on a research basis only.

Treatment

• Large cysts causing microphthalmia should be aspirated or removed surgically. There is no known cure for anophthalmia or microphthalmia.

• For anophthalmia a prosthetic eye can be fitted which may involve surgery.

• Treatment for microphthalmia depends on the complexity of eye involvement.

Gene Therapy.

Retinal stem cells isolated from the ciliary epithelium of the adult ciliary body proliferate and form neurospheres in culture.

Immuno-labeled with the progenitor cell marker, nestin (green).

Molecular patterning across the dorso-ventral axis of the embryonic eye. Tbx5 gene expression (blue) is restricted to retinal progenitor cells in the dorsal peripheral region of the developing optic cup.

Transplanted photoreceptor precursor cells integrate and develop into mature photoreceptor cells (green) that form functional connections with the host retina (blue) and improve visual function .

Transplanted cone photoreceptor (yellow) within the outer nuclear layer (magenta) of a recipient retina.

References • http://vision.about.com/od/eyediseasesandconditions/g/Color_Blindness.htm• http://www.genomenewsnetwork.org/articles/2004/05/28/optics.php• http://www.brighthub.com/science/genetics/articles/28771.aspx• http://journals.lww.com/co-ophthalmology/Abstract/2011/03000/

Gene_therapy_for_glaucoma.2.aspx• en.wikipedia.org/wiki/Strabismus • http://www.nature.com/pr/journal/v59/n3/abs/pr200667a.html• http://www.nei.nih.gov/strategicplanning/genetics1.asp• http://www.thirdage.com/hc/c/strabismus• http://en.wikipedia.org/wiki/Stargardt_disease• http://www.mdsupport.org/library/stargardt2.html• http://www.lifenews.com/2012/01/24/first-report-on-embryonic-stem-cells-in-

patients-results-tbd/• http://www.livestrong.com/article/257857-what-are-the-causes-of-nystagmus/• http://www.geteyesmart.org/eyesmart/diseases/nystagmus-diagnosis.cfm• http://www.sciencedaily.com/releases/2008/04/080427194726.htm