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Clinical and Experimental Ophthalmology 2010; 38: 211 doi: 10.1111/j.1442-9071.2010.02363.

Anatomy and physiology of the human eye:
effects of mucopolysaccharidoses disease on
structure and function a review


Colin E Willoughby MD, PhD,1 Diego Ponzin MD,2 Stefano Ferrari PhD,2 Aires Lobo MD,3
Klara Landau MD, PhD4 and Yadollah Omidi PhD5

Centre for Vision Science and Royal Victoria Hospital, Belfast Queens University, Belfast, UK, 2The Veneto Eye Bank Foundation,
Venice, Italy; 3Moorelds at Bedford, Moorelds Eye Hospital NHS Foundation Trust, Bedford, UK; 4Department of Ophthalmology,
University Hospital Zurich, Zurich, Switzerland; and 5Research Centre for Pharmaceutical Nanotechnology, Tabriz University of Medical
Sciences, Tabriz, Iran

The current paper provides an overview of current
knowledge on the structure and function of the eye. It
describes in depth the different parts of the eye that are
involved in the ocular manifestations seen in the
mucopolysaccharidoses (MPS). The MPS are a group of
rare inheritable lysosomal storage disorders characterized by the accumulation of glycosaminoglycans
(GAGs) in cells and tissues all over the body, leading to
widespread tissue and organ dysfunction. GAGs also
tend to accumulate in several tissues of the eye,
leading to various ocular manifestations affecting both
the anterior (cornea, conjunctiva) and the posterior
parts (retina, sclera, optic nerve) of the eye.
Key words: anatomy, eye disease, mucopolysaccharidosis, physiology, review.

The mucopolysaccharidoses (MPS) are a group of
inheritable lysosomal storage disorders, characterized by the progressive accumulation of incompletely degraded glycosaminoglycans (GAGs) in
tissues and organs due to a deficiency in one of
the enzymes involved in GAG catabolism (Table 1).
All MPS types have a progressive course and involve
multiple organs. They share several common clinical
features, but with variable degrees of severity.
Typical features of the MPS include coarse facial fea-

tures, affected hearing and vision, cardiorespiratory problems, reduced joint mobility, organomegaly
and skeletal deformities (dysostosis multiplex,
dwarfism) (Fig. 1).1 Patients with MPS IH (Hurler
syndrome), MPS III (Sanfilippo syndrome) and the
severe form of MPS II (Hunter syndrome) typically
show mental retardation. Patients with MPS IV
(Morquio syndrome) show bony lesions specific
for that disorder (dwarfism with short trunk and
neck). There is a wide spectrum of phenotypes and
progression rates within any one MPS type.
Characteristic ocular features in patients with
MPS include corneal clouding, glaucoma, retinopathy, optic disc swelling and optic atrophy.25 Ocular
problems in patients with MPS are among the
first symptoms to arise and can ultimately result in
visual impairment or blindness.4,5 This review of the
anatomy and physiology of the normal eye and overview of changes in structure and function seen in
MPS disease was presented at the International
Symposium MPS and the eye: What do we know
and how can we treat, which was held on 79
October 2009 in Venice, and provided the introduction necessary to focus on diagnosis and treatment of
eye disease in this patient group.


The eye is one of the most complex organs of the
human body. In the human eye, three layers can be

Correspondence: Dr. Diego Ponzin, The Veneto Eye Bank Foundation, c/o Padiglione G Rama, Via Paccagnella, 11, 30174 Zelarino, Venice, Italy. Email:
Received 10 May 2010; accepted 16 June 2010.
2010 The Authors
Journal compilation 2010 Royal Australian and New Zealand College of Ophthalmologists

Anatomy and physiology of the eye

Table 1. The mucopolysaccharidoses (MPS)

MPS type


Figure 1. Typical features of the

mucopolysaccharidoses (MPS). (a)
Claw hand of a patient with MPS
IH/S (Hurler/Scheie). (b) Umbilical
hernia in a child with MPS VI
(Maroteaux-Lamy). (c) Coarse facial
features in a child with MPS VI.


Enzyme deciency

Hurler, Scheie, Hurler/Scheie

Sanlippo A
Sanlippo B
Sanlippo C
Sanlippo D
Morquio A
Morquio B

Heparan N-sulfatase
Acetyl CoA:a-glucosamine N-acetyltransferase




distinguished (Fig. 2). The outer region consists of

the cornea and the sclera. The cornea refracts and
transmits the light to the lens and the retina and
protects the eye against infection and structural
damage to the deeper parts. The sclera forms a connective tissue coat that protects the eye from internal
and external forces and maintains its shape. The
cornea and the sclera are connected at the limbus.
The visible part of the sclera is covered by a transparent mucous membrane, the conjunctiva. The
middle layer of the eye is composed of the iris,
the ciliary body and the choroid. The iris controls
the size of the pupil, and thus the amount of light
reaching the retina; the ciliary body controls the
power and shape of the lens and is the site of
aqueous production; and the choroid is a vascular
layer that provides oxygen and nutrients to the outer
retinal layers. The inner layer of the eye is the retina,
a complex, layered structure of neurons that capture
and process light. The three transparent structures

surrounded by the ocular layers are called the

aqueous, the vitreous and the lens.



The cornea is the most anterior part of the eye,

in front of the iris and pupil. It is the most densely
innervated tissue of the body, and most corneal
nerves are sensory nerves, derived from the ophthalmic branch of the trigeminal nerve.7 The cornea
of an adult human eye has an average horizontal
diameter of about 11.5 mm and a vertical diameter of
10.5 mm, and a curvature that remains rather constant throughout life.8 The optic zone (pre-pupillary
cornea), which provides most of the corneas refractive function, has a diameter of 4 mm and is located
in the centre of the cornea, anterior to the pupil,
in photopic conditions. The cornea is avascular and
the branches of the anterior ciliary arteries stop at
the limbus where they form arcades that supply

2010 The Authors

Journal compilation 2010 Royal Australian and New Zealand College of Ophthalmologists

Willoughby et al.
Figure 2. Schematic illustration
of the structure of the eye and the
ocular barriers. The primary physiologic blockage against instilled
drugs is the tear lm. Cornea is
the main route for drug transport
to the anterior chamber (I). The
retinal pigment epithelium and the
retinal capillary endothelium are
the main barriers for systemically
administered drugs (II). Intravitreal
injection is an invasive strategy
to reach the vitreous (III). The
administered drugs can be carried
away from the anterior chamber
either by venous blood ow after
diffusing across the iris surface
(1) or by the aqueous outow
(2). Drugs can be removed away
from the vitreous through diffusion into the anterior chamber
(3) or by the bloodretinal barrier
(4). Adapted from Barar J et al.6

Basement membrane

Figure 3. Schematic presentation of the different layers of the

cornea. Reproduced from Daniels
JT et al.,11 with permission of John
Wiley and Sons.

Bowmans layer


Descemets membrane


the peripheral cornea.9 Therefore, the peripheral and central cornea are very distinct in terms of
physiology and pathology.
Five layers can be distinguished in the human
cornea: the epithelium, Bowmans membrane, the
lamellar stroma, Desemets membrane and the
endothelium (Fig. 3).10 The surface of the corneal
epithelium is covered by the tear film, which protects
the corneal surface from chemical, toxic or foreign
body damage and from microbial invasion and
smoothes out micro-irregularities of the surface of the
epithelium.10 It consists of an outer lipid layer and an
inner water-mucous layer. The mucous layer interacts
with the epithelial cells, allowing the tear film to
spread with each eyelid blink.
The corneal epithelium is composed of two to
three layers of superficial cells, two to three layers of
wing cells and one layer of basal cells.10 The surface

of the superficial epithelial cells is irregular due to

the presence of microplicae (ridge-like folds of the
plasmalemma) that interact with the overlying tear
film. The cells of the corneal epithelium are renewed
every 710 days from a pluripotent stem cell population, which resides in the palisades of Vogt at the
corneoscleral limbus. The stem cells differentiate
into transient amplifying cells when they migrate to
the central cornea.11,12 Recent research has also identified oligopotent stem cells in the corneal epithelium of mice and pigs, suggesting that the limbus
is not the only niche for corneal stem cells.13 The
corneal epithelium is extremely impermeable and
stable due to the presence of cell junctions.10 It is also
anchored very strongly to the basal lamina. The latter
is secreted by the basal cells and mainly consists of
type IV collagen and laminin. Because innervations
are essential for the physiology of the epithelium,

2010 The Authors

Journal compilation 2010 Royal Australian and New Zealand College of Ophthalmologists

Anatomy and physiology of the eye

practically all epithelial cells are in contact with
nerve cells.
The corneal lamellar stroma (500-mm-thick)
provides structural integrity to the cornea. Stromal
keratocytes secrete collagen and proteoglycans,
which are ultimately fundamental for the transparency of the cornea and hydration. The stroma is separated from the epithelium by the Bowmans layer, an
acellular zone of 1015 mm beneath the basal lamina.
The bulk of the stromal extracellular matrix consists
of collagen fibrils arranged in 200250 parallel lamellae that run from limbus to limbus.14 The network of
collagen fibrils is responsible for the mechanical
strength of the cornea and its regular organization is
essential for corneal transparency. In the pre-pupillar
cornea, the fibrils are packed more compact than in
the peripheral cornea, probably contributing to the
mechanical strength and dioptric stability in the
cornea.15 The stromal collagen fibrils are surrounded
by proteoglycans consisting of keratan sufate or chondroitin sulfate/dermatan sulfate side chains. These
proteoglycans have an important structural function
and help regulate hydration. Keratocytes are the
predominant cell type in the stroma and play a role
in maintaining its organization. These stellar-shaped
cells contact to each other by long cytoplasmatic
extensions (morphologic and functional syncytium)
and also interact with the corneal epithelium.
The corneal endothelium consists of a single layer
of five- to seven-sided cuboidal cells with little or no
self-renewing potential. The endothelial cell density
at birth in a normal cornea is 35007000 cells/mm2.
They secrete the Descemets membrane that separates
the endothelium from the stroma. This elastic membrane thickens with age and is composed of an anterior layer with a banded appearance and a posterior
layer with an amorphous texture.16 The endothelium
possesses intracellular and membrane-bound ion
transport systems that establish an osmotic gradient
from a relatively hypo-osmotic stroma to a hypertonic
aqueous. The osmotic gradient produces a net fluid
flux from the stroma to the aqueous that produces a
constant percentage of water in the stroma (78%
H2O), which is essential for the clarity and transparency of the cornea.10 This process is called deturgescence. Corneal oedema may develop if deturgescence
is disturbed for some reason.
Incident light on the cornea can be transmitted,
absorbed or scattered. In a normal transparent
cornea, visible light is not absorbed and scattering is
negligible. Only irregularities with dimensions
similar to the wavelength of visible light (400
700 nm) will affect the retinal image. An increase of
corneal scattering can arise in case of corneal
oedema, the relaxation of collagen fibrils, haze
(extracellular matrix production by keratocytes) or
irregularities due to surgery.17



The retina is the tissue that lines the inner surface of

the eye, surrounding the vitreous cavity. During
embryogenesis, the vertebral retina develops from the
optic cup. The latter is formed by invagination of the
optic vesicle, which is an outgrowth of the embryonic
forebrain. The inner wall of the optic cup (surrounding the vitreous cavity) ultimately becomes the neural
retina; the outer wall (surrounded by the choroid
and sclera) becomes the retinal pigment epithelium
(RPE).18,19 The retina is protected and held in the
appropriate position by the surrounding sclera and
The neural retina consists of six major classes of
neurons: photoreceptors, bipolar cells, horizontal
cells, amacrine cells and ganglion cells, which capture and process light signals, and the Mllerian
glia, which act as the organizational backbone of the
neural retina. The cells of the neural retina are
arranged in several parallel layers (Fig. 4).1820 The
nuclei of the photoreceptor cells lie in the outer
nuclear layer, their outer segments lie proximal from
the nuclei, close to the RPE. The nuclei of the Mllerian glia, the bipolar cells, the amacrine and the
horizontal cells are located in the inner nuclear layer
of the retina. The inner nuclear layer has plexiform
layers at both sides. In the outer plexiform layer, the
photoreceptors connect with bipolar and horizontal
cells, whereas in the inner plexiform layer, bipolar
and amacrine cells synapse with ganglion cells. The
nuclei of the ganglion cells lie in the ganglion layer,
their axons in the nerve fibre layer. Processes of the
Mllerian glia extend throughout the retina. The
apical processes form the outer limiting membrane
by making junctional complexes with one another
and with photoreceptors. The apposed end-feet of
the vitreal processes form the inner limiting
membrane. Lateral processes of the Mllerian glia
contact with blood vessels and neurons and form
synapses with dendrites within the plexiform layers
and axons in the nerve fiber layer.18
The eyes of most vertebrates contain two types of
photoreceptors: rods and cones. In humans, rods are
approximately 20 times more abundant than cones.18
The photoreceptors are responsible for phototransduction, the conversion of light into an electrical
signal. For this purpose, the membranes of the outer
segment discs of the photoreceptors contain pigments. Cones, which are responsible for colour
vision, have pigments with absorption peaks in the
blue, green or yellow parts of the spectrum. Pigments
of the rods have an absorption peak in the blue-green
part of the spectrum. Rods are active with low light
levels, and are not involved in colour vision.
The density of rods and cones varies between different regions of the retina. In humans, about 50% of

2010 The Authors

Journal compilation 2010 Royal Australian and New Zealand College of Ophthalmologists

Willoughby et al.

Vitreous chamber

Internal limiting

Ganglion cell

Amacrine cell
Horizontal cell


Inner nuclear

Middle limiting

External limiting

fiber (glia)






Figure 4. The cells and layers of the retina. GCL, ganglion cell layer; ILM, inner limiting membrane; INL, inner nuclear layer; IPL, inner
plexiform layer; NFL, nerve bre layer; OLM, outer limiting membrane; ONL, outer nuclear layer; OPL, outer plexiform layer; (R)PE, (retinal)
pigment epithelium; R&CL, rods and cones layer. Reproduced from Yanoff & Duker Ophthalmology,19 with permission from Elsevier.

Optic disc




Figure 5. The fundus of the eye showing the macula, the fovea
and the optic disc.

the cones are located in the central 30% of the visual

field, roughly corresponding with the macula. The
macula lutea refers to an area in the retina between the
temporal vascular arcades containing xanthophylls
pigment (Figs 2,5).19 Histologically, the macula has
several layers of ganglion cells, whereas in the surrounding peripheral retina the ganglion cell layer is
only one-cell thick. The excavation near the centre of
the macula is called the fovea (Fig. 5). This area of the
retina is responsible for sharp central vision and

contains the largest concentration of cones in the

eye.19 Visual acuity is highest in the foveola, the thin,
avascular bottom of the fovea, which contains only
densely packed cone cells. Due to the high density of
cone cells in the foveola, the cone synaptic terminals
and the ganglion cells to which they connect are
pushed away from its centre, resulting in elongations
between the nuclei and synaptic terminals of the cone
cells, called Henles fibres.18 At the level of the internal nuclear layer, the foveola is surrounded by a
circular system of capillaries, the vascular arcades. No
photoreceptor cells are present at the optic disc or
optic nerve head where the axons from the ganglion
cells exit the eye to form the optic nerve (Fig. 5).
The RPE is a monolayer of cuboidal epithelial
cells intercalated between the photoreceptors and
the choriocapillaris, a layer of capillaries adjacent to
the innermost layer of the choroid. The RPE incorporates about 3.5 million epithelial cells arranged in
a hexagonal pattern, with a density that is relatively
uniform throughout the retina. At the apical side, the
cells of the RPE form long microvilli that reach up
between the outer segments of rod photoreceptors.19
Numerous pigment (melanin and lipofuscin) granules are present in the apical cytoplasm of RPE cells.
Important functions of the RPE include the maintenance of photoreceptor function (phagocytosis of

2010 The Authors

Journal compilation 2010 Royal Australian and New Zealand College of Ophthalmologists

Anatomy and physiology of the eye

photoreceptor wastes, regeneration and synthesis of
pigments), retinal adhesion, storage and metabolism
of vitamin A, the production of growth factors necessary for nearby tissues and wound healing after
injury or surgery.19,2124 In addition, the RPE plays an
important role in the bloodretinal barrier (BRB)
function, which will be discussed later.
The retina receives its blood supply from two circulatory systems: the retinal and the choroidal blood
vessels.18,19 The retinal circulation supplies the inner
retina, except for the avascular foveal zone. The outer
avascular retinal layers receive their nutrients by diffusion from the choroid vessels. The choriocapillaris
is fenestrated, which allows leakage of molecules to
the RPE. Specialized transport systems in the RPE
control the transportation of fluid and nutrients to
the photoreceptors.
Retinal function depends on several factors,
including the region of the retina being illuminated,
the wavelength and intensity of the light stimulus
and the state of light adaptation.



Light that enters the eye via its anterior components

travels through the different layers of transparent
neurons of the retina where it is captured by the
photoreceptors at the back of the retina. As visual
images are inverted as they pass through the lens, the
right half of the image is projected on the nasal retina
of the right eye (and the temporal retina of the left
eye), whereas the left half of the image is projected
on the temporal retina of the right eye (and the nasal
retina of the left eye).
The neurons of the neural retina translate the
visual information into nerve impulses, which travel
through the optic nerve to the brain. The photoreceptors, the bipolar cells and the ganglion cells form a
direct pathway to the brain (Fig. 4). The horizontal
and amacrine cells form lateral pathways that modify
and control the signal that passes through the direct
pathway.19 The axons of the ganglion cells first travel
towards the nerve fibre layer at the vitreal surface
and then towards the optic disc, where they make a
sharp turn to the optic nerve. The optic nerve extends
from the eye to the optic chiasm. The next synapses
lie deep in the brain, in the lateral geniculate nuclei
(LGN).18 Both LGN receive information from both
eyes, but only from one half of the visual field. This
is due to a hemidecussation of both optic nerves in
the optic chiasm, before they reach the LGN. Neurons
from the LGN send their axons to the ipsilateral
primary visual cortex. The left primary visual cortex
receives information from the right visual field, and
vice versa.
A lesion in one or both optic nerves will result in
visual loss in one or both eyes, respectively. This will

be apparent in the optic disc, which may become
swollen or develop pallor (optic atrophy). Increased
intracranial pressure results in the swelling of
both optic discs (papilloedema) that may cause optic
atrophy when untreated. The hallmarks of chiasmal
lesions are defects that affect the temporal visual field
in each eye. A lesion behind the optic chiasm is
characterized by homonymous visual field defects
occurring in both eyes (e.g. the temporal field in one
eye and the nasal field in the other eye).



The transport of fluids and solutes in the eye is controlled by several membranes and barriers. These
barriers can hamper the delivery of topical ocular
drugs (i.e. eye drops) and systemically (i.e. orally or
intravenously) administered drugs.
Topical ocular drugs, mostly given as eyedrops, are
the most frequently used dosage forms for treating
ocular diseases. The first barrier to cross for these
drugs is the tear film, which rapidly removes instilled
compounds from the eye, resulting in low bioavailability. Other membranous barriers are located in the
cornea, the conjunctiva, the irisciliary body and the
retina.25,26 Depending on the physiochemical characteristics of the compounds, delivery of drugs can occur
through the corneal route and/or the conjunctival/
scleral route (Fig. 2). The corneal route is the main route
for delivery of drugs to the anterior chamber. Permeation of hydrophilic drugs and macromolecules
through the corneal epithelium is limited by the presence of tight junctions between adjacent outer superficial epithelial cells.10 The abundant presence of
hydrated collagen in the stroma may hamper the
diffusion of highly lipophilic agents. The endothelium is more permeable and allows the passage of
hydrophilic drugs and macromolecules between the
aqueous and the stroma due to the presence of leaky
tight junctions called desmosomes or macula adherens. The passage of topical ocular drugs through the
corneal route depends on their lipophylicity, molecular weight, charge and degree of ionization. Particularly small lypophilic drugs can easily permeate
through the cornea. After crossing the cornea, the
drug diffuses into the aqueous and to the anterior
The non-corneal or conjunctival/scleral route is
usually less efficient for drug delivery, but may be
used for the delivery of hydrophilic and larger molecules, which cannot easily diffuse through the
corneal epithelium.25 Unlike the cornea, the conjunctiva has a rich vasculature and a large amount of the
administered drug crossing it is removed by the systemic circulation. The remaining drug penetrates
through the sclera, which is more permeable than the
cornea, but less permeable than the conjunctiva. The

2010 The Authors

Journal compilation 2010 Royal Australian and New Zealand College of Ophthalmologists

Willoughby et al.

Figure 6. The retinal cellular architecture. The schematic structure of the retinal pigmented epithelial (RPE) cells and the retinal capillary
endothelial (RCE) cells represent the outer and inner retinal barriers, respectively. RPE and RCE are the main organization of the transport
limiting layers. The outer layer of the RPE displays tight barriers due to the presence of tight junctions (zona occludens). The inner RCE
cells possessing tight junctions are non-fenestrated compared with choroidal capillary endothelial cells that are fenestrated. Adapted
from Barar J et al.6

passage of drugs from the anterior to the posterior

segments of the eye is not very efficient due to the
aqueous turnover. Therefore, ocular surface administered drugs usually do not reach the posterior
segments of the eye (retina, vitreous, choroid) in
sufficient therapeutic concentrations.
Intravenous and intravitreal administrations
appear to be the main strategies for treating posterior
segment infections/diseases. However, intravenous
administration has limited success primarily due to
the exclusion of the eye from the systemic circulation.

Of the ocular barriers, the BRB selectively controls

traverse of substances and pharmaceuticals after systemic and periocular administration to the retina
(Fig. 2). Despite some similarity, the BRB differs from
the bloodbrain barrier (BBB) by the functional presence of its outer barrier that is formed by the RPE. The
inner barrier is formed by the endothelial cells of
retinal vessels (Fig. 6).18,25,26 Both barriers display
restricted tight junctions, by which the permeation/
transfer of hydrophilic substances and macromolecules can selectively be regulated in inward and

2010 The Authors

Journal compilation 2010 Royal Australian and New Zealand College of Ophthalmologists

Anatomy and physiology of the eye

outward directions, that is, blood to vitreous and vice
versa.26 Transcellular passive permeation is the main
route for the inward/outward traverse of small molecules across the BRB, whereas the paracellular permeability of RPE is quite low. Besides, there exists an
inverse correlation between the molecular weight
and permeability. For example, in isolated bovine
RPE choroids, the inward permeability differs
between dextrans with various molecular weights
(i.e. 2.36, 0.46 and 0.27 10-7 cm/s for 4, 40 and
80 kDa macromolecules).27 The following equation
represents overall flux of drug across the BRB:
J = C P S = C CL, with J (mg/min), C (mg), P (cm/s)
and S (cm2) representing the overall flux of the drug,
the concentration gradient of the drug, the permeability in the barrier and the surface area of the barrier. CL
represents the drug clearance into the tissue.27
Various pharmaceuticals appear to be substrates/
inhibitors of carrier- or receptor-mediated transporters, which might open the door to a more advanced
intraocular delivery and targeting. Although the
current knowledge on ocular drug transporters
within the BRB is far from complete, the functional
expressions of many transporters have been reported,
including efflux and influx transport machineries
such as organic anion transporter, organic cation
transporter and organic anion-transporting polypeptide. The expression of clathrin and caveolin-1 in
retinal vascular endothelial cells highlights the
importance of the endocytic pathway for circulation of
hormones, peptides and proteins.28,29
Intravitreal injection may be associated with
patient non-compliance and endophthalmitis, cataract, astigmatism and retinal detachment. To avoid
such complications, a variety of innovative drug delivery systems [e.g. Vitrasert (Bausch & Lomb Inc.,
Rochester, NY, USA) for 6 months constant release of
ganciclovir from the pars plana area of the vitreous;
Retisert(Bausch & Lomb Inc., Rochester, NY, USA)
for 2.5 years constant release of fluocinolone acetonide] have been exploited. More recently, a branched
PEGylated anti-vascular endothelial growth factor
(VEGF) aptamer [pegaptanib sodium marketed as
Macugen (OSI pharmaceuticals Inc., Long Island,
NY, USA] was approved by the Food and Drug
Administration for the treatment of neovascular agerelated macular degeneration (AMD). Ranibizumab
Lucentis (developed and marketed by Genentech
Inc., South San Francisco, CA, USA and Novartis
International AG, Basel, Switzerland) is a recombinant humanized monoclonal antibody fragment that
targets VEGF-A and reduces neovascularization
and leakage in wet AMD. Unlike RhuMAb VEGF
[bevacizumab, Avastin (developed and marketed
by Genentech Inc., South San Francisco, CA, USA
and Roche Applied Science, Basel, Switzerland)
148 kDa], ranibizumab (48 kDa) is able to penetrate

the retina and enter the subretinal space after
intravitreal injection because of the notable size
Enzyme replacement therapy (ERT), that is,
replacement of a defective or absent enzyme by a
recombinant variant, has raised high expectations for
the treatment of some devastating ocular diseases
such as ocular manifestations of MPS I and VI.
For example, Naglazyme (BioMarin Pharmaceutical
Inc., Novato, CA, USA) (galsulfase marketed by
BioMarin) is a variant form of the polymorphic
human enzyme, N-acetylgalactosamine-4-sulfatase.
The intravenously administered galsulfase can be
taken up into lysosomes and increase the catabolism
of GAGs.30,31 Such lysosomal uptake is most likely
mediated by the binding of mannose-6-phosphateterminated oligosaccharide chains of galsulfase to
specific mannose-6-phosphate receptors.30 The effectiveness of ERT on the central nervous system and
ocular manifestations of MPS needs further investigations, as its traverse through the BBB and BRB is
not fully understood.
There is growing interest in ocular gene therapy
for treating inherited retinal degenerations, such
as Lebers congenital amaurosis due to defects in
the gene encoding the enzyme RPE65.32,33 Futuristic
genomedicines for ocular diseases are deemed to
become more effective therapeutics by exploiting
molecular Trojan delivery systems for safe shuttling
(e.g. antisense, ribozyme and short-interfering RNA
[siRNA]) and targeting the desired biomarkers.34,35
There is particularly much excitement about the
potential of the siRNA.
Encapsulated cell technology (ECT) and cell
therapy also appear to have treatment potentials
for ocular diseases. ECT implants consist of
living cells encapsulated within a semipermeable
polymer membrane and supportive matrices, which
are genetically engineered to produce a specific
therapeutic substance to target a specific disease or
condition. Once implanted, it allows the outward
passage of the therapeutic product.36 This may be a
novel treatment strategy for some life-threatening
diseases (e.g. MPS), for which an in situ source for
ERT could be developed.




Membrane-bound vacuoles containing GAG deposits have been found in almost all ocular tissues in
MPS patients, where they can alter the cellular shape
and tissue ultrastructure.5,37 Therefore, both the
anterior and posterior segments of the eye can be
affected. Characteristic ocular features in patients
with MPS include corneal clouding, glaucoma, retinopathy, optic disc swelling and optic atrophy.25
Corneal clouding develops as a result of the

2010 The Authors

Journal compilation 2010 Royal Australian and New Zealand College of Ophthalmologists


Willoughby et al.

intracellular and extracellular deposition of GAG in

the cornea, which can affect keratocyte size and
disrupt the regular network of collagen fibrils in the
stroma.5,37,38 Narrowing of the angle secondary to
GAG accumulation within the cornea can result in
raised intraocular pressure and subsequent chronic
or acute angle closure glaucoma.39 GAG deposition in the trabeculocytes and subsequent outflow
obstruction can lead to open-angle glaucoma.5
Retinopathy results from GAG deposition in the RPE
and the inter-photoreceptor matrix, leading to retinal
degeneration and photoreceptor loss.4 Optic disc
swelling and secondary optic atrophy can have
several causes. Optic disc swelling can arise due to
chronic elevation of intracranial pressure (papilloedema), impingement of the optic nerve due to
thickening of the sclera or as a result of GAG deposition within ganglion cells.3,4,40
Ocular problems in patients with MPS can ultimately result in visual impairment or blindness.4,5
As many patients with MPS first present with ocular
features, it is important that ophthalmologists are
aware of the typical clinical features of MPS and can
recognize them as being of metabolic origin, so that
they can refer the patients to paediatricians for
further diagnosis. The severity of the ocular findings
differs between MPS types.41

The anatomy and function of the eye is extremely
complex and pathological events can lead to a wide
range of ocular disease manifestations that may
occur. MPS patients may present with a variety of
ocular diseases in both the anterior and posterior
components of the eye, resulting from GAG accumulation in various tissues. The treatment of these
ocular features warrants the investigation of methods
to circumvent various ocular barriers that hamper
drug delivery.

The authors are grateful to Ismar Healthcare NV for
their writing assistance, which was funded by BioMarin Europe Ltd. The content of the manuscript is
based on presentations and discussions during a scientific meeting entitled MPS and The Eye, which
took place from 7 to 9 October 2009 in Venice, Italy.
This meeting was supported by an educational grant
from BioMarin Europe Ltd, London, UK. BioMarin
had no role in the content presented and discussed at
the meeting. All authors participated in the development and writing of the manuscript and are fully
responsible for its content.

1. Neufeld EF, Muenzer J. The mucopolysaccharidoses.
In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The
Metabolic and Molecular Bases of Inherited Disease, 8th edn.
Chapter 136. New York: McGraw-Hill Medical Publishing Division, 2001; 342152.
2. Biswas J, Nandi K, Sridharan S, Ranjan P. Ocular
manifestation of storage diseases. Curr Opin Ophthalmol
2008; 19: 50711.
3. Collins MLZ, Traboulsi EI, Maumenee IH. Optic
nerve head swelling and optic atrophy in the systemic mucopolysaccharidoses. Ophthalmology 1990; 97:
4. Ashworth JL, Biswas S, Wraith E, Lloyd IC. The ocular
features of the mucopolysaccharidoses. Eye 2006; 20:
5. Ashworth JL, Biswas S, Wraith E, Lloyd IC. Mucopolysaccharidoses and the eye. Surv Ophthalmol 2006;
51: 117.
6. Barar J, Asadi M, Mortazavi-Tabatabaei SA, Omidi Y.
Ocular drug delivery; impact of in vitro cell culture
models. J Ophthalmic Vis Res 2009; 4: 23852.
7. Mller LJ, Marfurt CF, Kruse F, Tervo TMT. Corneal
nerves: structure, contents and function. Exp Eye Res
2003; 76: 52142.
8. Rfer F, Schrder A, Erb C. White-to-white corneal
diameter: normal values in healthy humans obtained
with the Orbscan II topography system. Cornea 2005;
24: 25961.
9. Van Buskirk EM. The anatomy of the limbus. Eye
(Lond) 1989; 3 (Pt 2): 1018.
10. Farjo AA, McDermott ML, Soong HK. Corneal
anatomy, physiology, and wound healing. In: Yanoff
M, Duker JS, eds. Ophthalmology, 3rd edn. Edinburgh,
Mosby Elsevier: Elsevier Inc., 2009; 2038.
11. Daniels JT, Dart JKG, Tuft SJ, Khaw PT. Corneal stem
cells in review. Wound Repair Regen 2001; 9: 48394.
12. Dua HS, Shanmuganathan VA, Powell-Richards AO,
Tighe PJ, Joseph A. Limbal epithelial crypts: a novel
anatomical structure and a putative limbal stem cell
niche. Br J Ophthalmol 2005; 89: 52932.
13. Majo F, Rochat A, Nicolas M, Jaoude GA, Barrandon
Y. Oligopotent stem cells are distributed throughout
the mammalian ocular surface. Nature 2008; 456:
14. Maurice DM. The transparency of the corneal stroma.
Vision Res 1970; 10: 1078.
15. Boote C, Dennis S, Newton RH, Puri H, Meek KM.
Collagen fibrils appear more closely packed in the
prepupillary cornea: optical and biomechanical
implications. Invest Ophthalmol Vis Sci 2003; 44: 29418.
16. Johnson DH, Bourne WM, Campbell RJ. The ultrastructure of Descemets membrane. I. Changes with
age in normal corneas. Arch Ophthalmol 1982; 100:
17. Gallagher B, Maurice D. Striations of light scattering
in the corneal stroma. J Ultrastruct Res 1977; 61: 100
18. Miller NR, Newman NJ, eds. Embryology, anatomy,
and physiology of the afferent visual pathway. In:

2010 The Authors

Journal compilation 2010 Royal Australian and New Zealand College of Ophthalmologists

Anatomy and physiology of the eye











Miller NR, Newman NJ, eds. Walsh & Hoyts Clinical

Neuro-Ophthalmology, Vol. 1, 6th edn. Philadelphia, PA:
Lippincott Williams & Wilkins, 2005; 382.
Schubert HD. Structure and function of the neural retina.
Marmor MF. Retinal pigment epithelium. Roh S, Weiter
JJ. Retinal and choroidal circulation. In: Yanoff M, Duker
JS, eds. Ophthalmology, 3rd edn. Edinburgh, Mosby
Elsevier: Elsevier Inc., 2009; 51121.
Masland RH. The functional architecture of the retina.
Sci Am 1986; 255: 10211.
Young RW. The renewal of rod and cone outer segments in the rhesus monkey. J Cell Biol 1971; 49: 303
Foulds WS. Do we need a retinal pigment epithelium
(or choroid) for the maintenance of retinal apposition?
Br J Ophthalmol 1985; 69: 2379.
Grierson I, Hiscott P, Hogg P, Robey H, Mazure A,
Larkin G. Development, repair and regeneration of the
retinal pigment epithelium. Eye 1994; 8 (Pt 2): 255
Reh TA, Levine EM. Multipotential stem cells and
progenitors in the vertebrate retina. J Neurobiol 1998;
36: 20620.
Urtti A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug Deliv Rev 2006; 58:
Barar J, Javadzadeh AR, Omidi Y. Ocular novel drug
delivery: impacts of membranes and barriers. Expert
Opin Drug Deliv 2008; 5: 56781.
Mannermaa E, Vellonen KS, Urtti A. Drug transport in
corneal epithelium and blood-retina barrier: emerging
role of transporters in ocular pharmacokinetics. Adv
Drug Deliv Rev 2006; 58: 113663.
Klaassen I, Hughes JM, Vogels IM, Schalkwijk CG,
Van Noorden CJ, Schlingemann RO. Altered expression of genes related to blood-retina barrier disruption
in streptozotocin-induced diabetes. Exp Eye Res 2009;
89: 415.
Stitt AW, Anderson HR, Gardiner TA, Bailie JR,
Archer DB. Receptor-mediated endocytosis and intracellular trafficking of insulin and low-density lipoprotein by retinal vascular endothelial cells. Invest
Ophthalmol Vis Sci 1994; 35: 338492.

30. Valayannopoulos V, Nicely H, Harmatz P, Turbeville S.
Mucopolysaccharidosis VI. Orphanet J Rare Dis 2010;
5: 5.
31. Pastores GM. Laronidase (Aldurazyme): enzyme
replacement therapy for mucopolysaccharidosis type I.
Expert Opin Biol Ther 2008; 8: 10039.
32. Le MG, Stieger K, Smith AJ et al. Restoration of vision
in RPE65-deficient Briard dogs using an AAV serotype
4 vector that specifically targets the retinal pigmented
epithelium. Gene Ther 2007; 14: 292303.
33. Bainbridge JWB, Smith AJ, Barker SS et al. Effect of
gene therapy on visual function in Lebers congenital
amaurosis. N Engl J Med 2008; 358: 22319.
34. Janoria KG, Gunda S, Boddu SH, Mitra AK. Novel
approaches to retinal drug delivery. Expert Opin Drug
Deliv 2007; 4: 37188.
35. Maguire AM, Bennett J. Gene therapy for retinal
disease. In: Jaffe GJ, Ashton P, Pearson PA, eds.
Intraocular Drug Delivery. New York: Taylor & Francis
Group, LLC, 2006; 15773.
36. Tao W, Wen R, Laties A, Aguirre GD. Cell-Based
Delivery systems: development of encapsulated cell
technology for ophthalmic applications. In: Jaffe GJ,
Ashton P, Pearson PA, eds. Intraocular Drug Delivery.
New York: Taylor & Francis Group, LLC, 2006; 111
37. Kenyon KR. Ocular manifestations and pathology of
systemic mucopolysaccharidoses. Birth Defects Orig Artic
Ser 1976; 12: 13353.
38. Alroy J, Haskins M, Birk DE. Altered corneal stromal
matrix organization is associated with mucopolysaccharidosis I, III and VI. Exp Eye Res 1999; 68: 523
39. Cantor LB, Disseler JA, Wilson FM II. Glaucoma in the
Maroteaux-Lamy syndrome. Am J Ophthalmol 1989;
108: 42630.
40. Schumacher RG, Brzezinska R, Schulze-Frenking G,
Pitz S. Sonographic ocular findings in patients with
mucopolysaccharidoses I, II and VI. Pediatr Radiol 2008;
38: 54350.
41. Ashworth JL, Kruse FE, Bachmann B et al. Ocular
manifestations in the mucopolyscaccharidoses. Clin
Experiment Ophthalmol 2010; 38(S1): 1222.

2010 The Authors

Journal compilation 2010 Royal Australian and New Zealand College of Ophthalmologists