Retinitis Pigmentosa Case

OPTOMETRY
I INVITED REVIEW
Retinitis pigmentosa:
understanding the clinical presentation,
mechanisms and treatment options
Clin Ex$ Optom 2004; 87: 2: 65-80
Michael Kalloniatis' PhD
Erica L Fletcher' PhD
* Department of Optometry and Vision
Science, University of Auckland,
New Zealand
Department ofAnatomy and Cell Biology,
The University of Melbourne, Australia
Submitted: 19January 2004
Revised: 9 February 2004
Accepted for publication: 9 February 2004
Retinitis pigmentosa (RP) is a leading cause of human blindness due to degeneration

of retinal photoreceptor cells. Causes of retinal degeneration include defects in the
visual pigment, defects in the proteins important for photoreceptor function or in
enzymes involved in initiating visual transduction. Despite the diversity of genetic mutations identified in inherited forms of retinal dystrophy, there is a common end result of
photoreceptor death and functional blindness. In this review, pertinent anatomical and
physiological pathways involved in RP and the underlying genetic mutations are outlined, including a discussion on the inheritance patterns revealed by advances in
molecular biological techniques. Characteristics of progression rates of visual field loss
and current management options will provide useful clinical guidelines for the management of patients with RP.
Key words: cGMP, degeneration, gene mutations, retina, retinal transplants, retinitis pigmentosa, visual field, vitamin A
RETINAL STRUCTURE/FUNCTION
AS IT RELATES TO IDENTIFIED
GENE MUTATIONS IN RETINITIS
PIGMENTOM
Retinitis pigmentosa (RP) reflects a heterogenous group of inherited ocular diseases
representing the most recurrent retinal
dystrophies, with a worldwide prevalence of
1:3000 to 1:5000.' Inherited forms of retinal degeneration are largely focused on
gene mutations within photoreceptors or
W E cells leading to devastatingloss ofvisual
function, often progressing to functional
blindness. The chief gene mutations leading to the RP phenotype24relate to defects
in the activation/de-activation of the visual
pigment or pathways involved in the visual
phototransduction cascade. To better manage patients with RP, it is important to review
the basic structure of the retina and the key

in the retina, with the major retinal glial
pathways involved in the visual response
cell being the Miiller cell" (Figure 1).
affected in the disease process.
Mtller cells are intimately involved in a
T h e visual process begins with light
range of activities essential for normal retiabsorption in the photoreceptor outer segnal functions that include neurotransmitment with subsequent encoding occurring
ter a n d metabolite metabolism, a n d
through interactions between the five
chromophore recycling. The retinal pigother major classes of retinal n e ~ l r o n s . ~ . ~ment epithelial (RPE) cells are considered
Photoreceptor cells (rods and cones), bipart of the retina and are involved in a
polar cells and ganglion cells form the
multitude of functions essential for neu'through' pathway, while horizontal cells,
ral retinal function. These include the
amacrine cells and interplexiform cells
transport and storage of vitamin A derivaform the 'lateral' or 'modulatory' pathways
tives (retinoids), recycling of the visual pig(Figure 1). The complex interplay bem e n t , o u t e r photoreceptor segment
tween the different retinal neurons leads
phagocytosis and anti-oxidant functions.'J3
to the encoding of spatial, temporal and
chromatic information that is subseActivation and deactivation of the
visual pigment
quently relayed by ganglion cells to the
central visual pathway~.~.'-'I
In addition to
The visual pigment within the photorecep
neural cells, several glial cells are localised
tor outer segment is composed of an inClinical and Experimental Optometry 87.2 March 2004
65
Retinitis pigmentosa Kulloniutis and Fletcher
ing of Mata and colleagues14 that all trans

retinol to 11-cis retinol conversion can
occur in Miiller cells, explains the reason
why M U e r cells have long been known to
contain retinoid binding protein^.'^.'^ With
t h e 11-cis retinol available to c o n e
photoreceptors, pigment regeneration
can occur after cones convert 1 1 4 s retinol
to 1l-cis retinal: a reaction known to occur
in isolated cone photoreceptors but not
in rod photo receptor^.'^
Phototransduction cascade
Figure 1. Schematic of the mammalian retina showing the different retinal layers and the rod
and cone circuitry. The cone pathway involves a unique set of cone bipolar cells that synapse
onto ganglion cells. The signal in both the rod and cone pathway is modified by horizontal
cells in the OPL and amacrine cells in the IPL. The rod pathway has one type of bipolar cell
that synapses with a unique amacrine cell (MI amacrine cell), which subsequently passes the
information to the cone pathway via conventional synapses or via gap junctions (gi) with
cone bipolar cells. These latter cells synapse onto ganglion cells and hence, ganglion cells
carry both the rod and cone signals. Miiller cells span the entire retina. The blood supply in
most mammalian retinas involves the outer blood supply from the choriocapillaris and the
inner blood supply through the central retinal artery. The inner blood supply has capillary
beds in both the inner and outer plexiform layers (for simplicity they are not shown in this
diagram). The locations of the outer and inner retinal blood vessels imply that the mid-retina
has poor vascular coverage.
Abbreviations: ORBV = outer retinal blood vessels, RL = receptor layer, OPL = outer plexiform
layer, INL = inner nuclear layer, IPL = inner plexiform layer, GCL = ganglion cell layer, NFL
= nerve fibre layer, IRBV = inner retinal blood vessels, HC = horizontal cell, BC = bipolar
cell, AC = amacrine cell, HCCB = horizontal cell cell body, HC-AT = horizontal cell axon
terminal, GC = ganglion cell
trinsic membrane protein (opsin) and a

chromophore (vitamin-A derivative).
Light activation leads to a conformational
change in the chromophore (1l-cis to alltrans conformational change), that initiates a series of protein changes within the
opsin closing the ion channels in the outer
segment (Figure 2). The activated form
of the visual pigment (Rh*for rhodopsin) ,
must be deactivated to ensure that subsequent light can be detected. The rhodopsin deactivation process begins by
multiple phosphorylations catalysed by

rhodopsin kinase, followed by the binding
of a protein (arrestin) that terminates the
activation properties of rhodopsin.
Regeneration of the
photopigment
Subsequent to the phosphorylation and
arrestin binding, the chromophore (alltrans retinal) detaches from the opsin and
begins its regeneration via the RPE or
Miiller cells'4 (Figures 3 and 4). The findClinical and Experimental Optometry 87.2 March 2004
66
Activation of the visual pigment (Rh* in

rod photoreceptors or the long- middleor short-wavelength photopigment for
cone photoreceptors), allows for the binding of a series of membrane-associated
proteins involved in the visual transduction cascade. The first protein to bind,
transducin, is in the Gfamily of proteins,
which are often associated with processes
linked with signal amplification. The binding and activation of transducin subsequently leads to activation of phosphodiesterase (PDE): the enzyme hydrolysing 3'
5' cyclic guanyl monophosphate (cGMP),
the intermediary compound controlling
cation ion entry in the photoreceptor
outer segment. The hydrolysis of cGMP
leads to closure of cation channels with a
subsequent photoreceptor hyperpolarisation to a light
The production of cGMP is dependent on the enzyme
guanylate cyclase, the activity of which is
modulated by a calcium-sensitive enzyme,
guanylate cyclase activation protein
(GCAP: also referred to as recoverin).
Guanylate cyclase maintains a steady state
level of cGMP with the activity of this enzyme markedly increasing secondary to
GCAP activation (subsequent to calcium
concentration changes in the photorecep
tor outer segment2u-22
(Figure 4).
Rhodopsin gene mutations cause the
majority of RP, although gene mutations
in different catalytic units of PDE,
peripherin and the cyclic nucleotide gated
channel proteins are also known to cause
RP.Gene mutations alter proteins such as
transducin, rhodopsin kinase, arrestin,
and proteins forming the voltage gated
calcium channel. A few rhodopsin gene
mutations cause congenital stationary
Retinitis pigmentosa Kalloniatis and Fletcher
night blindness; g e n e mutations in

guanylate cyclase may cause cone dystrophy o r a form of Lebers congenital amaurosis; whereas a well-defined gene mutation in the RPE (RPE65) causes another
form of Lebers congenital amaurosis; the
gene encoding the alpha subunit of the
cone cGMP gated channel is mutated in
rod monochromacy. Other gene mutations may cause syndromes associated with
RP that include Laurence-Moon/BardetBiedl and Ushers syndrome as well as
other RP-like conditions involving metabolic defects such as Refsums disease.
Recent reviews on the molecular biology
of RP a n d other inherited retinal
dystrophies are provided by several articless.2328 and Daiger and co-worker? maintain an up-to-date website at the address
http://www.sph.uth.tmc.edu/Retnet/,
which outlines genes causing inherited retinal dystrophies. In addition, clinical trial
information can he obtained from the
National Institutes of Health (USA) address
http://clinicaltrials.gov/ct/gui.
RP INHERITANCE PAITERNS AND

CLINICAL CHARACTERISTICS
RP inheritance patterns
The advent of molecular techniques has
lead to the identification of a number of
genes that are thought to he causally
linked to the onset of RP. This suggests
that there is a number of possible genetic
origins, all of which result in the same
degenerative process. As a general rule,
retinal conditions that demonstrate a
bilateral involvement, loss of peripheral
vision, predominantly rod dysfunction
(elevated rod threshold shown by electophysiological methods o r psychophysically) and progression of photoreceptor
dysfunction are classified as RP. Clinical presentation may he varied hut include
symptoms of night blindness (nyctalopia)
with elevated dark adaptation thresholds
(predominantly rod hut also cone thresholds), abnormal electroretinographic
a- and h-wave, difficulty with mobility secondary to visual field constriction, acquired blue-yellow (tritan) colour vision
defect, abnormal retinal pigmentation,
Figure 2. Simplifiedphotoreceptor outer segment under dark and light adaptation. The nonspecific cationic channel is maintained in the open state by cGMP, allowing sodium, calcium
and magnesium (not shown) ions to enter the outer segment. Light leads to activation of
rhodopsin (R), tranducin (T) and phosphodiesterase (the different subunits are shown with
the alpha and beta identified), causing hydrolysis of cCMP to GMP,closing the cationic
channels and driving the photoreceptor away for the equilibrium potential of these ions
(hyperpolarising the photoreceptor).
including mid-peripheral hone spicules,

arterial narrowing; optic nerve pallor, predisposition to myopia, posterior subcapsular cataract and vitreous changes.30-3z
Visual disturbances occur when visual acuity is relatively unaffected and careful
choice of colour vision tests may reveal the
acquired tritan colour vision defect early
M o st of the
in the disease pro~ess.~~~
ocular signs noted earlier are evident in
more advanced stages of the condition.
Massof and associate^^^ reported on the
existence of two general categories of RP
patients d e p e n d e n t on t h e relative
involvement of rod a n d cone photoreceptors. Patients with Type 1 RP display
an early diffuse and preferential loss of rod
sensitivity (hence early nyctalopia) and
later progression and regionalised loss of
visual field. Patients with Type 2 RP have a
regionalised and progressive combined
loss of rod and cone sensitivity with late
difficulty with night vision, typically in
adulthood. The inheritance patterns in RP
are classified into autosomal dominant,
X-linked, simplex a n d multiple^.'^^^^^^
Heckenlively, Boughman and Friedmansfi
Clinical and Experimental Optometry 87.2 March 2004
67
averaged data from five studies (n = 2,406)

and showed that RP could he classified as
autosomal recessive in about 31 per cent
of cases, autosomal dominant in approximately 16 per cent, X-linked in around
nine per cent and simplex/multiplex in
approximately 44 per cent. Calculations
from the Danish RP register showed that
the prevalence and distribwion were not
significantly different from those published from around the world, with autosoma1 recessive (18.8 per cent), autosomal
dominant (8.4per cent), X-linked (14.4 per
cent), simplex (43 per cent), multiplex
(11.2 per cent), with 4.2 per cent being
unclassified. The prevalence rate for all
forms of RP in Denmark was 1:3,333 to
4,000 for females and 1:2,500 to 2,857 for
males. It is likely that the prevalence of the
various forms of RP within the Australian
and New Zealand populations are similar.
Autosomal dominant classification is
primarily based on an established parentto-child transmission. Autosomal recessive
classification is based on established inheritance within different family groups
consistent with Mendelian characteristics.
Figure 3. A schematic of the rhodopsin activation, deactivation and the recycling of the visual
pigment. The recycling of the chromophore for cone photoreceptors involving retinoid
transport and recycling through Miiller cells (Mataand colleaguees") is not shown.Rhodopsin
is an integral membrane protein with an amino terminal (N-) and a carboxyl terminal (C),
where the binding of tranducin occurs. Activated rhodopsin (RW)is deactivated via the action
of rhodopsin kinase (Rh-kinase) causing multiple phosphorylations (P(n))and the binding
of arrestin leads to separation of the chromophore from the opsin. The chromophore, in the
form of all-trans retinal is converted to all-trans-retinol before leaving the retina to be
converted to 1l-cis-retinol and 114s-retinal, before reentering the photoreceptor outer
segment to bind to the opsin. The retinoids in the RPE also arrive via the complex containing
retinoid binding protein (RBP),thransthyretin (Tr) and all-trans retinol (AT-retinol). Retinoids
can also be stored in the form of retinyl esters. The scheme of the RPE and rod photoreceptor
has the cyclic nucleotide channels identified by cG and the voltage gated calcium channels in
the axon terminal by vCa.
Other abbreviations: RPE = retinal pigment epithelium, 0s = outer segment, IS = inner
segment, N = nucleus, AT = axon terminal
X-linked is also based on established family inheritance based on Mendelian characteristics. Simplex reflects isolated cases
with one affected member and multiplex
where at least two family members are
affected. Often, simplex and multiplex
cases were thought to reflect autosomal
recessive inheritance patterns, however,
when simplex and multiplex cases are
taken together, there are too many simplex cases compared with predictions by
Mendelian genetic^.^^^^^^'^^* FishmanSg
reported 60 per cent with a known Mendelian inheritance pattern, whereas in a

recent Danish study,' 40 per cent of the
patients were characterised by a known
inheritance pattern. Considering that it is
estimated that one in 50 carries a gene for
the recessive form of RP,40a key consideration in this classification is the exclusion of consanguinity. Consanguinity
would significantly increase the odds of
carrying the same mutated gene.'
A new evolving concept in the inheritClinical and Experimental Optometry 87.2 March 2004
68
ance of many conditions, including some

forms of RP or syndromes associated with
RP (Usher type 1; RDS/ROMl; BardetBiedl), is referred to as ~ l i g o g e n i cPoly.~~
genic traits are disorders that occur
through poorly understood interactions
between many genes and the environment. Such an environmental interaction
could explain the higher correlation between perinatal stress and some simplex
forms of RF' reported by Stone and coll e a g u e ~ . ~T*h, e~ ~authors suggest the
existence of a non-hereditary explanation
for photoreceptor death (such as perinatal stress), for some simplex RP. This
suggestion awaits further experimental evidence and the exclusion of polygenic and
oligogenic inheritance. Oligogenic traits
are primarily genetic in nature but require
synergistic action of mutant alleles at a
small number of loci to exhibit the phen ~ t y p e . ~For
' example, if heterozygous
mutations in either the RDS gene or the
ROMl gene were present, individuals were
asymptomatic, whereas if gene mutations
were evident in both the RDS and ROMl
gene, patients would exhibit the RP phenotype despite the fact that the mutations
were in two distinct genes.49In addition,
it may be possible to modify the expression of an autosomal dominant gene by
the effect of a mutation in a second or
third gene.41
In the classical analysis of inheritance
patterns in RP, when considering the high
number of simplex and multiplex cases,
variously the typical RP phenotype does
not follow classical Mendelian inheritance
patterns, the expressivity or penetrance is
altered,',35or other non-genetic mechanisms are in p l a ~ e . ~For
~ *example,
~'
we
now know that human subjects with specific gene mutations such as that affecting
a photoreceptor structural protein
peripherin (peripherin/RDS gene mutation), display marked variations in the age
of onset and progression of the disease and
exhibit oligogenic inheritance patterns,
offering one explanation for the high
prevalence of simplex and multiplex cases
in RP.23*43*44
Wang and associates45outlined
the following clinical implications of gene
mutations. Different gene mutations of the
same gene result in different clinical pres-
entations, (for example, different mutations in the rhodopsin gene give rise to
different clinical presentations: allelic heterogeneity); mutations in different genes
lead to the same disease phenotype, (for
example, mutations in peripherin/RDS
and rhodopsin gene both lead to typical
RP: non-allelic heterogeneity); mutations
in different genes at different loci lead to
the same phenotype (for example, in Usher's syndrome: locus heterogeneity); the
expression is different for the same genetic defect (expressivity) ; the defective
gene is not expressing leading to variations in visual function (penetrance).45
The evolution of our understanding of
polygenic and ohgogenic disorders and
further work on potential environmental
factors will allow us to better understand
the high number of simplex/multiplex
cases of RP.
The examination of family members is
essential to assist in the identification of
the hereditary nature of the condition. In
particular, patients with possible X-linked
recessive RP require careful assessment of
the mother. Dr Mary Lyon proposed that
in every somatic cell of a female, only one
X-chromosome is functioning, that is, one
X-chromosome in every cell is randomly
inactivated during development. The
Lyon hypothesis predicts that every female
carrier of X-linked RP will have two cell
populations: one with normal activity and
one with mutant a~tivity.~"~'
Thus, in Xlinked RP, female carriers should display
signs and symptoms of RP; a common finding, although there is considerable varia b i l i t ~ . ~Female
" . ~ ~ carriers may display a
tapetal reflex, irregular pigmentation in
the posterior pole, WE atrophy and pigment stippling and may express a phenotype typical of more advanced RP.4R-50
Visual function in Rp
Traditionally it has been thought that the
progression of visual dysfunction is slowest in those with autosomal dominant RP,
followed by recessive (including simplex/
multiplex) RP and the fastest are those
that are X-linked.35The advent of molecular biological techniques to classify RP patients has provided useful insights to complement studies supporting this clinical
Figure 4. Schematic of the key pathways controlling cGMP concentration. Activated rhodopsin
(Rh*)activates transducin (T*),
which binds the two gamma inhibitory subunits of
phospodiesterase to activate the enzyme (PDE*)
and hydrolyse cGMP. Steady state production
of cGMP from guanyl tri-phosphate (GTP) is maintained by guanylate cyclase, the activity of
which is controlled by the calcium-sensitive guanylate cyclase activation protein (GCAP).
view5' and those that found no significant

difference in progression between the different genetic subgroups.52In a major
study of 172 typical RP patients followed
from 2.5 to 10 years, Massof and coll e a g u e ~ "reported
~
some key features of
visual field changes measured with
Goldmann perimetry. Two key parameters
will be reviewed here: the time constant
(tc), reflecting the time taken to lose one
half of the remaining visual field, and the
critical age (Ac: extrapolated age of onset). These parameters reflect photopic
visual fields that represent cone loss secondary to rod loss or concurrent rod and
cone loss. It follows that such measurements overestimate the age of onset of scotopic visual field loss by an unknown
amount because we d o not know when rod
photoreceptor degeneration begins in
classical RP.
When using bright small targets
[Goldmann II/4e (0.22 degrees)], the
time constant was found to be tc = 7.4 f
4.7 years (ISD range of 2.7 to 12.1 years);
whereas the use of a bright larger target
[Goldmann V/4e (1.72 degrees)] resulted
69
in a time constant = 8.4 f 4.9 years ( E D

range of 3.5 to 13.3years) ..y5 There was no
significant difference in the time constant
for visual field progression across the different genetic subtypes, providing support
for the proposition that, on average, visual
field progression is consistent for RP
subtypes that are broadly classified. The
time constants and ranges noted above
provide useful guidelines for the likely progression of patients with RP.The second
parameter investigated by Massof and colleaguess5 was the critical age value (that
is, age of onset ofvisual field loss). For the
Goldmann II/4e target, Ac was 22 f 13.8
years ( E D range 8.2 to 35.8 years) and
for the Goldmann V/4e target, 28 f 13.9
years (1SD range of 14.1 to 41.9 years).35
Massof and c011eagues~~
report close to
significant difference ( p = 0.07) for differences in type 1 versus type 2 RF', implying
that the age of onset demonstrates some
variability. T h e study of Haim' has a
younger mean age of onset (six to18 years
of age) but includes atypical RP cases. The
data of Massof and colleaguess5 more
accurately reflect the patient pool of RP
patients likely to be encountered in optometric practice.

Berson and associates53followed 94
patients over three years and found visual
field loss (approximately five per cent of
field per year), which is half that predicted
by Massof and colleague^.^^ The key finding was that a minimum of two years was
required to follow visual fields. Visual acuity and dark adaptation ( 1 1 degrees central) remained unchanged over three years
and 77 per cent showed significant reduction in the electroretinogram (16 per cent
amplitude loss per year). There was no significant difference in loss of electroretinogram amplitude across genetic subtypes,
supporting the view that broadly classified
RP cases follow a similar time course in
changes of visual function.
With the advent of molecular biological genotyping, several studies have
focused on visual function measurements
in patients with specific gene mutations
s~~
causing RP. Berson and c o - ~ o r k e rstudied 17 cases with an autosomal dominant
form of RP (P23H:proline to histidine substitution at position 23 of the rhodopsin
molecule) and found that median onset
of night blindness was at 13 to 14 years. As
a group, these patients displayed better
visual acuity and larger ERG amplitudes
compared with 131 subjects with other
autosomal dominant rhodopsin gene mutations. However, there was considerable
heterogeneity within families. At 37 years,
visual fields ranged from greater than120
degrees to less than 21 degrees and Berson
and co-~orkers'~
proposed that some patients may have functional vision up to 70
years of age. In another form of rhodopsin
autosomal dominant gene mutation
(P347L:proline to leucine amino acid sub
stitution at location 347), Berson and cow o r k e r ~reported
~~
considerable he terogeneity within families with onset of night
blindness often at early childhood (n = 8
cases). This group of patients with the
P347L gene mutation displayed smaller
ERG amplitudes and visual fields compared with 140 unrelated subjects with
autosomal dominant rhodopsin gene mutations. Mobility was impaired between 12
and 27 years of age.55Although the
number of subjects in these original stud-
ies was small, the characteristic of gene

mutations involving the C-terminus (for
example, P347L) of rhodopsin being more
severe than that involving the N-terminus
(for example, P23H) has held up in a subsequent study encompassing a spectrum
of rhodopsin gene mutations at these two
terminals.56The G and N-terminus are illustrated in Figure 3. The same amino acid
switch (proline to alanine) at two different locations (P23A versus P347A), resulted in a greater loss in all visual functions measured for the Gterminus located
gene mutation (P347A).56Gene mutations
at loci encoding the C-terminal may impact function, for example, by slowing the
deactivation of activated rhodopsin,
whereas gene mutations at loci encoding
the N-terminal impact on the delivery of
rhodopsin to the outer segment (see below for further comments). The use of
genetic phenotyping invariably will lead to
a better understanding of the RP phenotype including visual function progression
characteristics.
The following two case studies illustrate
the usefulness of appreciating the inheritance pattern and the use of appropriate
visual function testing in routine clinical
practice.
years earlier with a 2/1000 white target

were reported to be five degrees (R and L) .
There was no detectable visual field in the
mid-to-far periphery and automated visual
fields were conducted to obtain the extent
of the remaining visual fields (Figure 5h).
The visual fields were largely confined to
the central five degrees, although some
more peripheral locations were detected.
The visual fields have remained stable over
a three-year follow up.
Although this is an example of advanced
RP,it illustrates several points. This patient
displayed the characteristics of Type 2 RP
with what appears to be regionalised and
progressive combined loss of rod and cone
sensitivity with late difficulty with night
vision in adulthood. The age of presentation secondary to functional mobility difficulties was within the critical age prediction from the results of Massof and
colleague^.^^ The fact that a male cousin
was affected with a similar condition indicates that autosomal recessive may be a
mode of inheritance, although the possibility of oligogenic inheritance should also
be con~idered.~'
O n further questioning,
it was ascertained that the parents of both
affected members were related and therefore consanguinity of the parents may be
a factor in the inheritance pattern.
CASE I
A 44year-old female with typical RP was
diagnosed at age 29 years after seeking an
ophthalmic examination because of 'tripping over her children's toys'. Nyctalopia
was not a problem at the time of diagnosis. A first cousin (male) was also affected
but there was no other family history reported (her parents and the parents of her
affected cousin had normal vision). Her
siblings were examined and were unaffected (Figure 5a). Visual acuity with spectacle correction was RE 6/18, LE 6/21 but
corneal topography indicated a keratoconus-like appearance and the patient was
referred for a hard contact lens assessment
and fitting. Visual acuity of 6/ 15 (R and L)
was achieved with her new hard contact
lenses and the patient gained a marked
improvement in confidence in mobility
and a perceptual improvement in contrast
levels. Bjerrum visual fields conducted two
70
CASE 2
A 54year-old male with typical RP had
been diagnosed at age 44 years. Nyctalopia was first noticed about 10 years before
diagnosis. There was no history of consanguinity and the patient had no siblings.
The mother may have had abnormal vision
(but was deceased), with one sister and
one brother being normal. The patient
complained of nyctalopia but avoided going out at night. There was a detectable
30 Hz flicker ERG signal indicating cone
function and mobility was excellent under
photopic conditions. A previous report
had noted that after automated perimetry,
'the patient has only 10 to 15 degrees of
central vision'. The patient was referred
for evaluation of dark adaptation and reassessment of visual fields using Goldmann
perimetry. Visual acuities were 6/6 R and L
a n d dark adaptation thresholds were
Patient#l
Cousin
Figure 5. Pedigree showing the affected members in two families (a). Automated visual field
results of Patient 1 showing severe restriction to within the central five degrees (b).
elevated approximately 0.8 log units for

the cone component with no detectable
rod function (that is, the rod dark adaptation thresholds were elevated by about
four log units and the dark adaptation
curve was monophasic). Goldmann W/4e
(Figure 6 has the right eye results) showed
an annular loss located only around the
region of maximal rod density. Visual fields
were normal under photopic conditions
outside this range for both eyes.
This patient also fits into the Type 2 RP
with a critical age still within one standard
deviation of the upper limit predictions5
of 42 years. With the mother potentially
affected, the possible modes of inheritance include X-linked or autosomal dominant. Because the patient has no siblings
and did not intend to procreate, genetic
counselling was not required. The extent
of the visual field should be evident from
observing the mobility of the patient, with
Goldmann perimetry providing quantitative data on the extensive remaining
(photopic) visual field in this typical RP
patient.
Figure 6. Visual fields of Patient 2 using W/4e target on the Goldmann perimeter. The only
area of absolute visual field loss under photopic conditions was an annular scotoma centring
around the 15-degree meridian.
71
HOW DO YOU MANAGE THE

PATIENT WITH RETINITIS
PIGMENTOSA?
Most patients with RP are likely to present
for an eye examination when night vision
and/or mobility are affected and therefore
the critical age estimate of Massof and colleagueP is a useful guide. Early adulthood
is the most likely presentation time for an
optometric examination.
The diagnosis should be confirmed by
electrophysiology and genetic counselling
should be undertaken, as well as low vision
service delivery. Other family members
should be examined, particularly the
mother of a male RP sufferer who may
have an X-linked inheritance pattern.
Goldmann visual field assessment
should be used (loss occurs in the mid- to
far-periphery) and visual fields should be
followed for a minimum of two years to
estimate the time constant for visual field
loss. An estimate of the visual field progression rate is given by the time constant
estimate of tc = 8.4 f 4.9 years when using
the V/4e target.
Time of onset of visual field loss can be
combined with the time constant to obtain a reasonable predictor of remaining
duration of functional photopic vision.
When using broad classifications such
as autosomal dominant or X-linked,
genetic subtype is not a reasonable predictor of severity and progression.
MECHANISMS OF RETINAL
DEGENERATION
The location of the gene

mutation leads to different
functional deficits
Mutations on the rhodopsin gene lead to
autosomal dominant forms of retinitis
pigmentosa in humans and a canine
model, and introducing this human gene
in the rat or mouse genome leads to
transgenic rodent models of retinitis
example,
p i g r n e n t o ~ a ~(for
~.~
~ - ~ ~ P23H rat).
Why a rhodopsin gene mutation causes
retinal degeneration is unclear. Rhodopsin
is an integral membrane protein that comprises the bulk of the outer segment pro-
teins. The gene mutation may change the

tertiary structure of the protein and alter
the structural role of rhodopsin.23 Using
the P23H rat model of RP, Illing and associatesMshowed that rhodopsin was prone
to form high molecular weight oligomeric
species in the cytoplasm of transfected
cells, accumulating in aggresomes
(pericentiolar inclusion bodies). These
cellular changes make rhodopsin susceptible to degradation by the ubiquitindependent proteosome system. In effect,
mutated P23H rhodopsin is a potential
cytotoxin mimicking neurodegenerative
diseases of the central nervous system.
On one hand, gene mutations that encode structural proteins, such as
peripherin (peripherin/RDS) and rod
outer segment protein 1 (ROM-1) lead to
RP characterised by 'slower' degeneration
in rodent models (hence the term retinal
degeneration slow or rds mouse) and may
account for about five per cent of autosoma1 dominant RP in human^.^^^^^^ On the
other hand, the mutant rhodopsin may
have an alteration to protein structure that
subsequently modifies the phototransduction role of this protein. Based on the
modelling of the a-wave in RP, Birch and
associates6* proposed that the reduced
maximum response, low gain and slower
activation are due to an abnormality within
the activation stages of the transduction
cascade. They suggest a prolonged lifetime
of activated rhodopsin (Rh*)and may reflect a mechanism similar to light-induced
retinal damage. Other findings suggesting
abnormal photopigment kinetics include
reduced rod bwave amplitude and delayed
implicit time54and delayed time course of
dark adaptation after large bleach.63In s u p
port of this concept of abnormal activation, in a model of congenital night blindness due to rhodopsin gene mutations, the
mutant rhodopsin remained constitutively
activated and thus would cause desensitisation of photoreceptors.M
Photoreceptor degenerations such as a
human form of autosomal recessive retinitis pigmentosa, the rd mouse and Irish
Setter dog model are caused by defects in
photoreceptor cCMP-phosphodiesterase
a ~ t i v i t y ~(Figure
- ~ ~ . ~7).
~ In the rd mouse
model, a substantial increase in retinal
72
cGMP appears to precede both photoreceptor and inner retinal

In vitro experiments have demonstrated a
causal link between increases in cCMP
levels and retinal d e g e n e r a t i ~ n . ~ ~ . ~ . ~ ~ ~ ~
Incubation of isolated human retina, in
the presence of PDE inhibitors or cCMP
analogues, leads to degenerative changes
that are proportional to the concentration
of the drug used and the period of exposure. Over an eight-hour period, the
presence of high concentrations of PDE
inhibitor or cGMP analogue induced
vesiculation of rod inner segments, and
cone morphological changes. A combination of PDE inhibitor and cGMP analogue
in the incubation medium virtually destroyed every rod in the specimen over the
same incubation p e r i ~ d . ~T'h e use of
iodoacetate, a known inhibitor of
glycolysis, which also inhibits sulfhydrylcontaining enzymes such as PDE, results
in elevated cGMP levels (within 35 minutes) and visible photoreceptor degeneration within a day.72
Despite such studies and the established
elevation of cGMP in animal models of
RP,67*68the mechanism by which cCMP
leads to photoreceptor degeneration remains unresolved. Elevated cyclic nucleotide (cGMP) levels in the outer segment
of photoreceptors would place photoreceptors effectively in a state of high
activity or 'constant darkness'. The functional significance of 'constant darkness' is
that photoreceptors must maintain their
dark current at a considerable energy cost.79
It has been established by S t e i r ~ b e r gthat
~~
photoreceptors are in a state of physiological hypoxia in the dark: a hypoxia that does
not lead to functional deficits, presumably
due to the lowered energy demands during the light cycle.
Anomalies in the delivery or recycling
of the chromophore leads to a spectrum
of RP conditions including a well characterised form of Leber's congenital amaurosis involving RPE65, an RPE protein
associated with c h r o m o p h o r e recyling.^.^^ The Royal College of Surgeons
(RCS) rat, is an established model for
retinal degeneration with the primary
defect being a failure of phagocytosis of
photoreceptor outer segments by the
RPE.76R"In both humans and the RCS rat,

a mutation in a tyrosine kinase receptor
gene (Mertk"'."') has been identified as
the genetic defect.
In a chimeric model, where both normal rhodopsin and mutated rhodopsin
were present in the same retina, uniform
retinal degeneration was evident, although
the progression was slower than in the corresponding transgenic mice.RgThe finding
of Huang and associatesHShas important
implications for the autosomal dominant
form of RP. I t implies that the gene mutation per se does not lead to photoreceptor
degeneration but that the mutant product triggers other not yet fully understood
events (see discussion earlier), leading to
degeneration of photoreceptors that do
not have defective rhodopsin. These findings for the rhodopsin gene mutation differ from previous work using chimeras, for
rds mouse6' and the
the RCS rat
rd mouse.a In these three chimeric models (RCS, rd, rds), the retinal degeneration
occurs in a patchy manner, implying that
the genetic defect is largely confined to
the anomalous cells, unlike the rhodopsin
gene mutation model of Huang and assoit was not clear whether
c i a t e ~However,
.~~
the chimeric models (RCS, rd, rds) were
followed to completion considering the
different time courses in the diverse animal models of RE4
From a clinical viewpoint, variations in
rod and cone sensitivity profiles suggest that
the diversity in photoreceptor degeneration is evident in human forms of the condition. Massof and Finkelsteins4 assessed
rod and cone sensitivity and reported the
existence of three groups of patients:
1. subjects with only cone mediated responses throughout their visual field
2. subjects with both rod and cone threshold elevation with the rod/cone threshold differences being similar to those
expected in normal subjects
3. subjects with cone mediated central
vision, rod and cone mediated midperipheral vision and far-peripheral
function mediated by rods.R4
When genetic classification was used in
three family groups displaying different
gene mutations of the peripherin/RDS
gene, all displayed similar psychophysical
Anatomy
Electroretinogram
+a-wave
Figure 7. Anatomical and physiological changes in degenerating (rd/rd and control C57 mouse
retina). Nissl stained sections of the trf mouse retina at post-natal age 49 shows an absent
photoreceptor layer with a few cone photoreceptors(asterisk).The inner nuclear layer (arrow)
is also reduced in size compared to the control adult retina (C57 mouse). The electroretinogram shows a normal appearance for the control (C57) animal with clear a- and
bwaves, whereas the degenerating mouse (rd/rd) at the same age had effectivelyno detectable
signal. Scale bar is 50 microns and stimulus intensity was 2.50 log cd.s.m-*(Gibson,Kalloniatis
and Vigrys, unpublished data).
and electrophysiological characteristics

with rod and cone threshold elevations for
the different gene mutations.44Although
there was variability in the degree of visual
dysfunction within each g r o u p , t h e
peripherin/RDS gene mutations appear
to fall within category two of Massof and
Finkel~tein.~~
Despite differences in the underlying
genetics causing the RP phenotype and
other proposed environmental mechan i s m ~ , ~the
~ *established
~'
pathway of cell
death is through apoptosis, a form of
programmed cell death.7R.R5
Although the
mechanism(s) leading to apoptosis in RP
is not fully understood, an area of interest
has been retinal metabolism.
Retinal metabolism
The major glial cell in the retina is the
Miiller cell, which spans the entire length
of the retina and is intricately related to
73
retinal function a n d development.86.RR

Normal retinal function is dependent on
tight metabolic coupling between neurons
and glia and the provision of oxygen and
g l u c ~ s eGlucose
.~~~~
is the major substrate
for retinal and brain metabolism but in
mammalian retina, the major product of
glucose utilisation is lactate, even under
aerobic ~ o n d i t i o n s . ~
The
' ~ ~dense
~
mitochondria] packing within photoreceptor
inner segments accounts for the high rate
of metabolism of the retina,92.94
with both
glycolytic and aerobic pathways used by
photore~eptors.9~
Photoreceptor cells have
a high energy demand because of:
1. the maintenance of an ionic gradient
via the Na/KATPase pump (maintains
the dark current)
2. the large turnover of cyclic nucleotides
in the outer segment including hydrolysis of guanyl tri-phosphate to form cCMP
3. multiple phosphorylations of photo-
pigment (an essential step in deactivation of opsins) .

One role of glial cells appears to involve
initial glucose catabolism with the carbon
skeleton provided to neurons predominantly in the form of lactate (with the last
step pyruvate to lactate catalysed by the
enzyme lactate dehydrogenase [LDHlYo).
Consequently, the major enzymes of
glycolysis and glycogen synthesis a r e
localised in Miiller cells and studies have
demonstrated Miiller cell metabolism of
glucose in mammalian retina,w,gfi
Lactate
is an essential metabolic substrate of retinal metabolism involving the trafficking of
the carbon skeleton of glucose between
glial cells and neurons, the 'lactate trafficking hypothesis' of Tsacopoulos and
Magi~tretti.9~
The hypothesis centres on the
contention that glial cells in the retina and
brain metabolise glucose and provide the
carbon skeleton (lactate) to neurons for
conversion to pyruvate, which fuels aerobic metabolism. In the retina, PoitryYamate, Poitry and Tsacopoulossg have
demonstrated tracking of lactate from
neurons to glia. Disruption of this shuttle
using a range of lactate transport inhibitors severely impairs retinal functiongs
however, the fact that photoreceptors can
use both glycolytic and aerobic metabolic
pathwdysy5suggests that lactate trafficking
reflects only part of the metabolic pathways available to retinal neurons.
A stable source of metabolic substrate is
required to maintain a high metabolic activity of the retina.w.y2.95,9H
One example of
high energy demand is the requirement
to maintain the cyclic nucleotide gated
channel in the open state in the dark. The
high metabolic demand is due to the high
activity of the sodium/potassium ATPase
in the inner segment.73In theory, the continuously high metabolic demand in cases
of elevated cGMP provides a parsimonious explanation for a mechanism inducing photoreceptor degeneration. In contrast, retinal degeneration caused by light
damage, or that due to continuously activated rhodopsin, would have a different
underlying cause because the cyclic nucleotide channel would not be makinga high
contribution to energy demand.
The interconversion of pyruvate/lactate
is catalysed by LDH, which comes in varishow major differences between normal

ous isoenzymes. Graymoreg9first reported
especially at P15 to P20.
and rd mice,108,Lo9
t h e metabolic alteration in LDH
T h e changes in oxygen consumption,
glucose utilisation and lactic acid producisoenzyme distribution in the RCS rat compared to control rat retina. He showed a
tionlo7identify an early metabolic dysfuncdramatic alteration in the distribution of
tion in the rd mouse, well before photoreLDH isoenzymes with a marked reduction
ceptor cells die through apoptosis at
of one of the LDH isoenzymes (LDH5) at
around P10 in the rd mouse."n The chief
P7, an age when photoreceptors have not
conclusion that can be drawn from such
differentiated in the rat retina and well
work is that in two disparate models of
before anatomical alterations are evident
retinal degeneration, the RCS rat (caused
in the RCS rat.7g*'w~Lo'
The RCS rat also disby a mutation of the tyrosine kinase gene
played little change in total LDH activity
(MERTK8i*82)
and the rd mouse (caused
before degenerationIo2 b u t t h e LDH
by a mutation of the PDE genem), both
display metabolic anomalies before phoisoenzyme distribution was altered early
(at P7), before photoreceptor degeneratoreceptor degeneration.
t i ~ n However,
. ~ ~
Bonavita, Ponte a n d
AmoreIo2demonstrated a major loss of
Adult onset retinal degeneration
LDH activity after degeneration in the RCS
mimicking RP
There are forms of adult onset photorerat retina indicating that LDH activity is a
ceptor degeneration mimicking RP assosensitive indicator of photoreceptor retinal function. In addition, the RCS rat
ciated with malignancies, including
shows altered glucose utilisation and transmelanoma associated retinopathy (MAR)
a n d cancer associated retinopathy
port 9s*105-105 and neurochemical studies
(CAR).1"-114
In these conditions, individuhave demonstrated alterations before,
during and after the d e g e n e r a t i ~ n . ' ~ . ' ~ ' als suffering from small-cell carcinoma of
the lung/breast or melanomas produce
Miiller cells display abnormal metabolism
of glutamate and altered neurochemistry
antibodies as part of the body's response
to cancer. These antibodies are produced
before degeneration that continue during
against epitopes on the cancer cells that
the degenerative phase involving the
also recognise a range of proteins in the
amino acids glutamate, GABA, aspartate,
retina.'"."2."5 Circulating serum antibodglutamine and arginine. The latter change
involves neurochemical changes during/
ies must enter the retina, presumably
after degeneration, involving the amino
through breaks in the blood retinal baracids glycine and taurine, as well as u p
rier and consequently destroy retinal neutake of glutamate, GABA and g l y ~ i n e . ~ ~ , " rons
' ~ leading to RP-like signs and symptoms
in these individuals. '"J"J~~
Although proMore recently, Kalloniatis and associates Io6
showed that cation channels are constituposed, a n immunological aetiology in
typical RP has not been supported by
tively open in many photoreceptors desexperimental data.llfiHeckenlively and cotined to degenerate, before apoptotic
markers are evident. Open cation chanworkerstJ7found eight instances of serum
anti-recoverin immunoglobulins in a samnels would place photoreceptors in a state
ple of 521 typical RP cases, implying that
of constant depolarisation increasing the
an immunological aetiology is not a likely
energy demand'* or may initiate apoptotic
mechanisms.
mechanism in most cases of RP.
I n the rd mouse model, metabolic
anomalies have also been demonstrated
TREATMENT OPTIONS: WHAT DO
before degeneration. NoellIo7showed an
YOU T E U YOUR PATIENT WITH
increase in oxygen uptake, glucose utiliINHERITED RETINAL DYSTROPHY?
sation and lactic acid production (aerobic)
In certain inherited forms of retinal dysdetectable at P8 in the rd mouse retina,
trophy, where biochemical pathway
followed by a rapid decrease from P12.
anomalies lead to the degeneration, diet
Metabolic substrate concentrations and
control of foods containing ornithine or
high energy phosphate compounds do not
74
increasing residual enzyme activity with

vitamin B6 has been beneficial in gyrate
atrophy or a diet to decrease phytanic acid
aids in Refsum disease.116.""The methods
undertaken to modify the progression of
retinal degeneration in RP include medical intervention, for example, vitamin A,
cardizem (diltiazem); activation of inhere n t protection systems, for example,
growth factors may reduce apoptosis; replacement of mutated gene; replacement
of affected cells, for example, RPE/neural
retinal transplants; and retinal prosthesis
(Sharma and Ehinger116and Lund and coworkers'lg provide comprehensive recent
reviews).
Modifying retinal degeneration in

animal models of RP
Photoreceptor degeneration in rodent
models can be affected through a variety
of measures, including modified oxygen
levels,'20-'22
retinal pigment epithelial transplant,IZ2creating chimera^,'^ growth facor differtors or apoptosis inhibitors123,124
ent light levels.'25Frasson and associates
reported an exciting development in the
treatment of RP using a calcium channel
blocker (D-cis-diltiazem) in the rd mouse
retina (PDE gene mutation). They reported that an L-type calcium channel
blocker slowed the progression of retinal
degeneration in the rd mouse. L-type calcium channels are present on photor e c e p t o r ~ although
,~~~
the physiology of
these channels in cones does not reflect
responses elicited by classic L-type calcium
channels.IZ8The fact that D-cis-diltiazem
modulated cone calcium channels is important because it means that pharmacological manipulation may be a viable treatment option (see Hart and colleagues12*
for discussion) but the exact mechanism
of action of calcium channel blockers is
unclear.12'i~lm
Frasson and associates proposed that elevated cGMP levels lead to
photoreceptor depolarisation, with calcium channel blockers preventing further
depolarisation via calcium entry into the
cell. Several other studies have not found
a beneficial effect of D-cis-diltiazem in the
rd mouse,"" in the P23H rat model"' or
the PDE6B mutant rcdl canine model.1s2
There are several explanations for these
negative findings, which include differences in experimental conditions, dosing

regime and animal strain.12"
Although at the experimental stage with
many problems to overcome, gene therapy
has led to some exciting results in animal
models. The benefits of gene therapy have
been hindered by problems including targeting the gene to the right cells, getting
the new gene integrated into the genome
and expressed, controlling the new gene
and suppressing expression of deleterious
genes in autosomal dominant RI?'33 In
autosomal recessive RP, introduction of a
healthy gene into dividing cells (in both
the rd mouse and rds mouse models) led
to modified photoreceptor degeneration,
although the technique was restricted to
in utero use.134,135
In a large animal model
of retinal degeneration, a canine with a
form of Leber's congenital amaurosis
(RPE65 gene mutation), Acland and cosuccessfully applied gene
therapy in congenital amaurosis. They reported ERG and other parameters consistent with improved visual function over 100
days post-treatment, providing the first
strong evidence of gene therapy for a condition causing a devastating early loss of
vision.'% This model also requires perinatal intervention.
Growth factors or apoptosis inhibitors,
for example, bFGF, are involved in nerve
cell differentiation and growth and have
proved useful in animal models such as
the rd mouse and rds mouse.'" Growth factors may work by reducing apoptosis but
other apoptosis retarding methods are in
experimental phases. They require repeated intra-vitreal injections and growth
factors may have other undesirable actions."' Even when rod death is delayed
by survival factors, photoreceptors still
experience deconstruction of their phenotypes and fail to function.
Attempts have been made to transplant
both RPE and neural retina but there is
little evidence that this can be made viable,
as the transplants must precede rod
death."9,13R
Surgery is still a challenge with
cell survival and the formation of meaningful contacts for the transplanted neural retina in doubt. More importantly, for
both retinal transplants, the degenerating
75
retina shows modified neuronal and glial

s t r u c t ~ r e , ' ~implying
~ J ~ ~ that new, rogue
circuits are being formed. In retinal remodelling secondary to rod-cone retinal
degeneration, there is neurite remodelling, followed by global remodelling (see
animation at the following address: http:/
/prometheus.med.utah.edu/-marclab/
PER-full-remodeling.htm1). One exciting outcome of this research139is that the
neural retina is 'plastic' secondary to degeneration. If the mechanism(s) for this
plasticity were understood, it would provide
a means to control the formation of retinal
circuitry secondary to retinal transplant.
TREATMENT OPTIONS AVAILABLE

TO HUMAN SUFFERERS OF RP
Treatments that do not work include:
1. the British therapy, where patients
undertook bee stings on the nape of the
neck
2. the Cuban therapy, which included
electric shock therapy, ozonation of the
blood, surgical implant of retrobulbar
fat, vasodilators and multivitamins
3. the Russian therapy, involving intramuscular and periorbital injection of
extracted RNA from y e a ~ t . ~ ~ . ' ~ ~
Treatment options with untested promise include the use of sunglasses and
hyperbaric oxygen. Although sunglasses,
particularly those with short-wavelength
filters, are useful to minimise discomfort
glare, there is conflicting evidence that
they modify progression rate in human
sufferers of RP.28,30
Hyperbaric oxygen levels, although modifying the ERG during
the treatment period, may not alter the
natural course of the disease.I4' In addition, high oxygen levels have been shown
to be detrimental in more advanced stages
of the disease.28
Two types of retinal implants have been
proposed, epiretinal and subretinal. Direct
retinal stimulation using epiretinal implants in RP patients'43resulted in patients
seeing spots of light that were usually
coloured (yellow/blue/yellow-green) .
Humayun and de Juan143proposed that
the resolution was up to about 1.8 degrees.
This group'44also reported that a patient
could detect spots of light and possibly the
Retinitis pigmentosa Kalloniatis and Fktcher
direction of movement using a 16-electrode array. In a study that included both

RP patients and a normal volunteer, a resolution limit of 2.25 degrees to 4.50 degrees
was achieved with an electrode array in
contact with the retina.'45z'46Often the
patients did not report percepts that
matched the stimulation pattern and frequently described multiple percepts when
one electrode was driven. The differing
results obtained from the normal-sighted
volunteer indicate that retinal degeneration alone does not explain the limited
results in blind p a t i e n t ~ , I ~providing
~.I~~
functional evidence supporting the retinal remodeling concerns of Marc and cow o r k e r ~ . ' "Subretinal
~~~~
electrodes have
been attempted in animal rn~dels,~~'.'*~
with
results indicating that cortical activity can
be induced by subcortical electrode stimulation. The long-term effect of such implants has not been assessed nor the effect
of electrodes placed between the neural
retina and the retinal pigment epithelium
on retinal metabolic function. In addition,
unlike the ear, there is considerable encoding of visual information before it is transmitted via ganglion cells and such sensory
encoding would be required by any prosthetic device. Technological development
is still required.
A large double-masked treatment trial
of vitamin A and/or vitamin E by Berson
and associates14g demonstrated a small but
significant slowing in the progression of
RP secondary to vitamin A (a daily dose of
15,000 IU). The use of 400 IU of vitamin
E was detrimental and the authors suggest
that the use of vitamin A may prolong useful vision by up to seven years. The lack of
data on functional improvement, such as
visual field progression, is a weakness of
the study and care should be used in advising patients on vitamin A considering
the known toxicity of this retinoid.l16This
mode of treatment has been shown to be
beneficial in other forms of retinal dystrophy and is currently recommended by the
National Institute of Health (USA)'I6
(http://www.nei.nih.gov/news/
subjects with RP for a further trial on the

benefits of vitamin A ( h t t p : / /
clinicaltrials.gov/ct/gui).
What do you advise your RP

patient regarding current
treatment options?
The complexity underlying the different
RP phenotypes may necessitate expert
genetic counselling. Particularly for patients with known autosomal dominant
mutations of RP, it may be possible to
eliminate the transfer of the mutated gene.
The use of pre-implantation genetic diagnosis (PGD), where the zygome that does
not contain the mutated gene is chosen
for implantation, ensures that the identified mutation is not transferred. This technique has been applied extensively to inherited conditions such as blood disorders
and neurodegenerative diseases, providing an additional 'treatment' option in
cases where the mutation is k n ~ w n . ' ~ " J ~ '
Vitamin A at 15,000 IU daily is the recommended dose from the National Eye
Institute, National Institutes of Health
(USA). This therapeutic option should be
undertaken after the patient consults
medical and ophthalmic practitioners.
The normal recommended daily intake is
2,500 IU, with three medium-sized carrots
providing around 6,000 IU,just under one
half the dose used in the study of Berson
and associate^.'^^ Even though Sibulesky
and co-workers152found that up to 25,000
IU per day was not detrimental to visual
function over five- to 12-year follow-up,
consideration should be given to the
following: vitamin A is contraindicated in
incipient, active or recent alcoholism; liver
disease, for example, history of hepatitis
A or C; in children; during pregnancy
(vitamin A is a teratogenic agent); during
breast feeding or in malnutrition.
Anti-oxidants such as vitamin E may be
detrimental.149
Other pharmacological agents may become available but other potential treatment options are at the laboratory experimental phase.
clinicalalerts/alert-rp.htm: http://
www.nei.nih.gov/news/pressreleases/
rppressrelease.htm). The National Institutes of Health is also currently recruiting
ACKNOWLEDGEMENTS
We thank Riki Gibson for compiling Figure 7 and contribution to the schematics
76
in Figures 2 and 3. We are also grateful

for helpful comments provided by Dr
Robert E Marc a n d two anonymous
reviewers.
GRANTS AND FINANCIAL SUPPORT
Some of the work outlined in this review

was conducted with grants from Retina
Australia and the National Health and
Medical Research Council of Australia.
Michael Kalloniatis holds a professorship
funded by the Robert G Leitl estate.
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Author's address:
Professor Michael Kalloniatis
Robert G Leitl Professor of Optometry
Department of Optometry and Vision
Science
The University of Auckland
Private Bag 92019
Auckland
NEW ZEALAND
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OPTOMETRY

Retinitis pigmentosa (RP) is a leading cause of human blindness due to degeneration

the basic structure of the retina and the key

Retinitis pigmentosa Kulloniutis and Fletcher

ing of Mata and colleagues14 that all trans

trinsic membrane protein (opsin) and a

multiple phosphorylations catalysed by

Activation of the visual pigment (Rh* in

Retinitis pigmentosa Kalloniatis and Fletcher

night blindness; g e n e mutations in

RP INHERITANCE PAITERNS AND

including mid-peripheral hone spicules,

averaged data from five studies (n = 2,406)

Retinitis pigmentosa Kalloniatis and Fletcher

reported 60 per cent with a known Mendelian inheritance pattern, whereas in a

ance of many conditions, including some

Retinitis pigmentosa Kalloniatis and Fletcher

view5' and those that found no significant

in a time constant = 8.4 f 4.9 years ( E D

Retinitis pigmentosa Kalloniatis and Fletcher

patients likely to be encountered in optometric practice.

ies was small, the characteristic of gene

years earlier with a 2/1000 white target

Retinitis pigmentosa Kalloniatis and Fletcher

elevated approximately 0.8 log units for

Clinical and Experimental Optometry 87.2 March 2004

Retinitis pigmentosa Kalloniatis and Fletcher

HOW DO YOU MANAGE THE

The location of the gene

teins. The gene mutation may change the

cGMP appears to precede both photoreceptor and inner retinal

Retinitis pigmentosa Kalloniatis and Fletcher

RPE.76R"In both humans and the RCS rat,

and electrophysiological characteristics

retinal function a n d development.86.RR

Retinitis pigmentosa Kulloniutis and Fletcher

pigment (an essential step in deactivation of opsins) .

is catalysed by LDH, which comes in varishow major differences between normal

Retinitis pigmentosa Kalloniatis and Fletcher

increasing residual enzyme activity with

Modifying retinal degeneration in

negative findings, which include differences in experimental conditions, dosing

retina shows modified neuronal and glial

TREATMENT OPTIONS AVAILABLE

Retinitis pigmentosa Kalloniatis and Fktcher

direction of movement using a 16-electrode array. In a study that included both

subjects with RP for a further trial on the

What do you advise your RP

in Figures 2 and 3. We are also grateful

Some of the work outlined in this review

Retinitis pigmentosa Kalloniatis and Fletcher

Physiology of the Eye, 10th ed. St Louis:

Ophthalmol Vis Sci 1998; 39: S295. Available

Clinical and Experimental Optometry 87.2 March 2004

unlinked peripherin/RDS and ROMl loci.

Retinitis pigmentosa Kalloniatis and Fletcher

ceptor cells in a transgenic rat model of

Dryja TP. Mutation spectrum of the gene

Clinical and Experimental Optometry 87.2 March 2004

Mutations in Mertk, the human orthologue

Retinitis pigmentosa Kulloniutis and Fletcher

K, Sato N. Vaccination with recoverin, a

Clinical and Experimental Optometry H7.2 March 2004

126. Frasson M, Sahel JA, Fabre M, Simonutti