3. 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)
4. 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.
5. • 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.
6. 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)
7. • Blue cone monochromacy
As 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 blindness
Caused 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.
8. • Rod monochromacy
Total 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.
9. 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
10. 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.
11. 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
12. 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
13. 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
14. 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.
15. • 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
16. 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
17. 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
18.
19. 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.
20. 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.
21. 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
22. 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.
23. 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.
24. • Surgery
Surgeries 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.
25. 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.
27. 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
28. • 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.
29. 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.
30. 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.
31. 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
32. 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.
33. 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.
34. 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
36. • 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
37. 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).
38. • 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.
39. 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.
40. 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.
41. Signs and sypltoms
o Decreased vision at night or in low light
o Loss of side (peripheral) vision
o Loss of central vision (in advanced cases)
42.
43. 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
44. 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.
47. • 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.
48. 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.
49. 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.
50. 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.
51. 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
Fundus photograph of juvenile have only X-Chromosome).
retinoschisis demonstrating stellate • Sometimes, there is a possibility of
spokelike appearance with microcysts. this disorder even among girls (due
to the presence of two defective
genes).
52. 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.
53. 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.
54. Medical care
• No treatment is available to halt the natural
progression of schisis formation in patients
with X-linked juvenile retinoschisis (XJR).
55. 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
56. 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.
57. • 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.
58. • 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.
59. • 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.
60. • 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."
61. • "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."
63. 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.
64.
65. 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
66. • 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.
67. 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.
68. • 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.
69.
70. 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
71. 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 variants
2. Functional studies of variants / associated genes to
understand molecular etiologies
3. Improved treatment and outcome prediction through
accurate genetic characterization in advance of
intervention
73. • 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.
74. 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.
75. 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.
76. Genetics
It 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.
77. 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)
78. Embryonic stem cell trials for
macular degeneration: a
preliminary report
By
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
79. 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.
80. • 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.
81. • 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
82. 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.
83. 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.
84. 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.
85. • 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
86. 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)
87. DIAGNOSIS
• A complete eye examination by an
ophthalmologist will readily diagnose
congenital cataract.
88. 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
89. 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.
90. • 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.
91. APPROACHES AND CAUSATIVE
MUTATIONS
Two main approaches have been used to
identify 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.
92. 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.
93. • 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.
94. • 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.
95. • 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.
96. • 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.
97. • 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.
98. 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.
99. 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.
100. 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.
101. • 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.
102. 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
103. • 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.
104. 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.
105. • 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. SOX2
3. OTX2
4. PAX6
5. SIX6and STRA6
106. 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.
107. • 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.
108. • 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.
109. 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.
110. • 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.
111. • 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.
112. • STRA6 gene which is responsible for
transporting vitamin A into the cells.
113. OTHER FACTORS
1. 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.
114. • 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.
115. • 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.
116. DIAGNOSIS
1. 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.
117. • 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.
118. 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.
119. TREATMENT
1. 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.
120. • 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.
121. 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.
122. 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.
123. • 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.
124. 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.
125. 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.
126. 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 .
129. 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.
130.
131.
132. 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.
133. 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).
134. 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.
135. 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.
136. 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.
137. 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).
138. 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.
in a comitant strabismus the sameangle of misalignment of the eyes is maintained in all directions of gaze. Incomitant- due to weakness of the eye muscles
macular degeneration –loss vision due to damage to the retina
Visual phototransduction is a process by which light is converted into electrical signals in the rod cells, cone cells and photosensitive ganglion cells of the retina of the eye.
Stargardt disease has no impact on general health and longevity is normalNo cure
Those identified from family studies include the following.
