Orphanet Journal of Rare Diseases
Retinitis pigmentosa Christian Hamel*
0 Address: Inserm U. 583, Physiopathologie et therapie des deficits sensoriels et moteurs, Institut des Neurosciences de Montpellier, Hopital Saint- Eloi , BP 74103, 80 av. Augustin Fliche, 34091 Montpellier Cedex 05 , France
Retinitis pigmentosa (RP) is an inherited retinal dystrophy caused by the loss of photoreceptors and characterized by retinal pigment deposits visible on fundus examination. Prevalence of non syndromic RP is approximately 1/4,000. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. Some extreme cases may have a rapid evolution over two decades or a slow progression that never leads to blindness. In some cases, the clinical presentation is a cone-rod dystrophy, in which the decrease in visual acuity predominates over the visual field loss. RP is usually non syndromic but there are also many syndromic forms, the most frequent being Usher syndrome. To date, 45 causative genes/loci have been identified in non syndromic RP (for the autosomal dominant, autosomal recessive, X-linked, and digenic forms). Clinical diagnosis is based on the presence of night blindness and peripheral visual field defects, lesions in the fundus, hypovolted electroretinogram traces, and progressive worsening of these signs. Molecular diagnosis can be made for some genes, but is not usually performed due to the tremendous genetic heterogeneity of the disease. Genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, so the visual prognosis is poor. The therapeutic approach is restricted to slowing down the degenerative process by sunlight protection and vitaminotherapy, treating the complications (cataract and macular edema), and helping patients to cope with the social and psychological impact of blindness. However, new therapeutic strategies are emerging from intensive research (gene therapy, neuroprotection, retinal prosthesis).
Retinitis pigmentosa (RP) belongs to the group of
pigmentary retinopathies, a generic name that covers all
retinal dystrophies presented with a loss of photoreceptors
and retinal pigment deposits. RP is a retinal degenerative
disease characterized by pigment deposits predominant in
the peripheral retina and by a relative sparing of the
central retina. In most of the cases of RP, there is a primary
degeneration of the photoreceptor rods, with secondary
degeneration of cones. Thus, the typical RP is also
described as a rod-cone dystrophy, photoreceptor rods
being more affected than cones. This sequence of
photoreceptor involvement explains why patients initially present
with night blindness, and only in the later life would
suffer visual impairment in diurnal conditions.
Night blindness (nyctalopia) is the earliest symptom
Photophobia appears later
The visual acuity is preserved in early and mid stages
Patchy losses of peripheral vision evolving to
Ring shape scotoma, and eventually
Attenuation of the retinal vessels
Waxy pallor of the optic disc
Various degrees of retinal atrophy
Dramatic diminution in a- and b-wave's amplitudes
Scotopic system (rods) predominates over photopic
Non syndromic retinitis pigmentosa
RP is a long lasting disease that usually evolves over
several decades. However, there are extreme cases with a
rapid evolution over two decades or a slow progression
that never leads to blindness. The disease course can be
conveniently divided into three stages.
In the early stage, night blindness is the main symptom.
It may be present from the first years of life or may appear
during the second decade, or even later. Mild night
blindness is often ignored by the patients and becomes
apparent in the teen age, at evening parties. At this stage, there
may be peripheral visual field defects in dim light.
However, these defects do not exist or are minimal in day light,
thus patients have normal life habits and the disease may
appear stable. Diagnosis is difficult to establish at this
stage, particularly when there is no familial history (about
half of the cases). Visual acuity is normal or subnormal.
Fundus examination (Figure 1) may seem normal, as
bone spicule-shaped pigment deposits are not present or
rare. Morevover, the attenuation of retinal arterioles is
modest and the optic disc is normal. The visual field test
reveals scotomas only in scotopic conditions, while the
test is usually done in mesopic conditions. Color vision is
normal. The electroretinogram (ERG) is the key test. In
most cases, it shows a decreased amplitude of the b-wave
that predominates in scotopic conditions. However, ERG
may appear normal when the retina is only partially
affected, though the decrease in maximum ERG
In the mid stage, the clinical picture is complete. Night
blindness is obvious, with difficulties to drive during the
night, and to walk at evening and in dark staircases.
Patients become aware of the loss in the peripheral visual
field in day light conditions through stereotypic
situations: while driving, they do not see pedestrians or
sidecoming cars, they miss hands in handshaking and
frequently step into various objects. Consequently, patients
adapt themselves by avoiding night driving and
circulation in unfamiliar places. Dyschromatopsia to pale colors
(particularly blue and yellows hues) is often present. In
addition, patients become photophobic, especially in
presence of diffuse light (white cloudy weather). This
leads to reading difficulties, with a narrow window
between insufficient and too bright light. Difficulties with
reading are due also to decreased visual acuity, partly
because of macular involvement (macular edema or mild
foveomacular atrophy) and subcortical posterior cataract.
Fundus examination (Figure 2) reveals the presence of
bone spicule-shaped pigment deposits in the mid
periphery, along with atrophy of the retina. Narrowing of the
retinal vessels is evident and the optic disc is moderately
pale. In contrast, the extreme periphery and the macular
region appear relatively spared, although mild macular
FFuignudures o1f patient with retinitis pigmentosa, early stage
Fundus of patient with retinitis pigmentosa, early stage.
FFuignudures o2f patient with retinitis pigmentosa, mid stage
Fundus of patient with retinitis pigmentosa, mid stage (Bone
spicule-shaped pigment deposits are present in the mid
periphery along with retinal atrophy, while the macula is
preserved although with a peripheral ring of depigmentation.
Retinal vessels are attenuated.)
involvement is frequent. The ERG is usually unrecordable
in scotopic conditions (rods) and the cone responses
(30Hz flickers, bright light) are markedly hypovolted.
Phenotypic features of the disease should be carefully registered
to guide towards mutation searches. At this stage,
evaluation of the rate of the disease progression, based on
several year-to-year examinations (visual acuity, ERG and
most importantly visual field testing), is mandatory.
Indeed, visual field testing shows mild periphery
scotomas that tend to enlarge towards extreme periphery and
macular area. Cataract, which usually blurs the optic
center, should be removed even when there is macular
In the end stage, patients can no longer move
autonomously, as a result of peripheral vision loss (classical
tunnel vision), with few degrees of remaining visual field
around the fixation point. Reading is difficult and
magnifying glasses are necessary. Photophobia is intense.
Fundus examination (Figure 3) reveals widespread pigment
deposits reaching the macular area. Vessels are thin and
the optic disc has a waxy pallor. Fluorescein angiography
detects chorioretinal atrophy in the periphery and also in
the foveomacular area. The ERG is unrecordable. Even at
this stage, the disease progression remains slow, with
patients being able to read short passages for years, while
being totally incapable to move. However, reading
becomes impossible when the central visual field
vanishes. Usually, patients continue to perceive light, often in
the peripheral visual field.
FFuignudures o3f patient with retinitis pigmentosa, end stage
Fundus of patient with retinitis pigmentosa, end stage
(Pigment deposits are present all over the retina. Retinal vessels
are very thin and optic disc is pale.)
Age of onset
Early onset RP is diagnosed when symptoms of mid stage
RP are already present at the age of two years. These forms
may be difficult to distinguish from Leber's congenital
amaurosis (LCA) in which a severe visual impairment is
present from birth or at least in the first year of life. In fact,
mutations in RPE65, CRB1, CRX and TULP1 genes cause
retinal dystrophies that are diagnosed as either LCA or RP,
depending on the age of onset .
Alternatively, late onset RP is diagnosed when symptoms
of early stage RP are apparently beginning at or after mid
life. One possibility is that moderate night blindness from
infancy is ignored by the patient and slowly worsens to
the point where it becomes clinically apparent. Another
possibility is RP truly to begin late. In this case, one must
search for a non genetic cause of similar phenotype such
as ocular trauma or inflammation/infection,
paraneoplasic syndromes, association with a spinocerebellar ataxia,
particularly if there is a rapid evolution of the symptoms.
Absence or scarcity of pigment deposits may occur. This
is frequent in myopia because of the retinal pigment
atrophy linked to this condition. In other cases, the amount of
pigment deposits may vary and does not necessarily
reflect the severity of the disease.
Localization of the lesions. There are regional or
sectorial forms in which only one or two quadrants are affected
(RHO, PRPF31 mutations). The lesions may also be
localized as a ring around the macula (pericentral), the optic
disc (parapapillary) or predominantly along retinal veins
(paraveinous). In some cases, there is paraarteriolar
retinal pigment epithelium preservation (CRB1 mutations).
Finally, there are rare cases of unilateral RP for which a
local cause (trauma) should be actively searched.
Other lesions. White dots or whitish spots can be
present as in retinitis punctata albescens (RLBP1
mutations). Macular atrophy can be quite prominent from the
mid stage of the disease (RDS and CRX mutations).
Mode of inheritance
Autosomal dominant forms are usually the mildest
forms, with some cases starting after the age of 50,
although severe disease can also appear. Variations in
penetrance are frequent, particularly in case of PAP1,
PRPF31 and RP1 mutations. In genetic counseling, one
should always suspect autosomal dominance in
apparently sporadic mild cases, especially when ascendants
have not been thoroughly examined or are unknown.
Autosomal recessive forms start typically during the first
decade, although some mild forms can be encountered.
X-linked forms also start early and are frequently
associated with myopia. Although transmission is recessive in
most cases, there are some families in which dominant
inheritance with affected females is found.
Digenic form: rare cases have been described in which
heterozygous mutations in ROM1 in combination with
heterozygous mutations in RDS cause digenic RP. These
forms are inherited in a pseudo-dominant pattern (1/4
Usher syndrome is the most frequent syndromic form
in which typical RP is associated with neurosensory
deafness. About 14% of all RP cases are, in fact, Usher
syndrome . Deafness, generally congenital and stable, may
be profound (type 1) or moderate/medium (type 2). In
some cases deafness occurs during the first decade and
worsens progressively (type 3). Mutations in at least 11
genes are responsible for Usher syndrome (for review see
Bardet Biedl syndrome (BBS) is less frequent than
Usher syndrome (prevalence 1/150,000 ). The
phenotype is characteristic and associates RP (often of cone-rod
dystrophy type) with obesity already present in
childhood, mental retardation or mild psychomotor delay,
post axial polydactyly, hypogenitalism and renal
abnormalities that lead to renal failure. BBS is due to mutations
in at least 11 genes [10,11], with cases of triallelic digenic
inheritance . The rare Alstrm syndrome (due to
ALMS1 gene mutation) resembles BBS and presents with
deafness, diabetes mellitus and acanthosis nigricans.
Less frequent syndromes
Senior Loken syndrome (SLS) associates an usually
severe RP (sometimes diagnosed as LCA) with
nephronophtisis (renal atrophy frequently evolving towards
renal failure requiring transplantation), or sometimes a
milder RP that is discovered later in life. At least four genes
(NPHP1, NPHP3-5) encoding nephrocystins are involved
in this disease .
Alport syndrome: deafness and progressive nephritis
are associated with yellow flecks around the macula,
rather than with an authentic RP.
Cohen syndrome associates RP to a particular facial
dysmorphism (prominent upper incisors) with short stature,
mental retardation, long and narrow hands, and
neutropenia. One causative gene (COH1) that encodes a protein
involved in vesicular trafficking, is related to this
Jeune syndrome associates RP with a thoracic
hypoplasia, brachydactyly and chronic nephritis. One locus has
been identified (asphyxiating thoracic dystrophy, ATD).
Cockayne syndrome is characterized by dwarfism,
progeria, mental retardation, and retinopathy with fine
Methylmalonic aciduria with homocystinuria is
caused by genetic defects in enzymes that metabolize
vitamin B12. Rare cases present with macular atrophy,
saltand-pepper retinopathy, and vascular attenuation.
Abetalipoproteinemia (Bassen Korntzweig disease) is
characterized by progressive ataxia, steatorrhea, reduction
of plasma lipids and pigmentary retinopathy that
resembles retinitis punctata albescens in some cases.
Bietti's disease shows characteristic microcrystalline
deposits in fundus and cornea. Patients undergo
progressive RP evolving towards chorioretinal atrophy. The
causative gene, encoding a form of cytochrome P450
(CYP4V2), has been recently discovered .
Cystinosis presents with typical crystal deposits in the
cornea and pigmentary retinopathy in a highly
photophobic patients with short stature. Accumulation of cystine in
other body parts leads to hypothyroidism, diabetes
mellitus, and renal failure. The causative gene (CTNS) encodes
a protein (cystinosin) involved in the lysosomal
transmembrane transport of cystein .
Mucopolysaccharidoses are characterized by facial and
bony changes, mental retardation and corneal clouding.
Only types I, II and III show pigmentary retinopathy.
Zellweger (cerebro-hepato-renal) syndrome.
Hyperoxaluria type I with retinal atrophy in spots.
Neonatal adrenoleukodystrophy with leopard spots
Infantile Refsum disease (caused by mutation in the
PEX1, PEX2 or PEX26 genes) presents with elevated
phytanic acid and pigmentary retinopathy with characteristic
prominent macular involvement.
Adult Refsum disease caused by mutation in the gene
encoding phytanoyl-CoA hydroxylase (PAHX or PHYH)
or the gene encoding peroxin-7 (PEX7) presents with
highly elevated phytanic acid, anosmia, deafness, and RP.
Peroxisomal disorders other than Refsum disease:
except for the rhizomelic chondrodysplasia punctata, all
children with disorders of peroxisomal assembly who
survive long enough develop pigmentary retinopathy.
Neuronal ceroid lipofuscinosis (also called Batten
disease or amaurotic idiocies), associates mental retardation,
seizures, ataxia and retinal degeneration. The retinal
disease starts with macular involvement (red-cherry spot)
and later spreads to peripheral retina. The protein,
encoded by CLN3, is found in the lysosomes and in
Joubert syndrome (JBTS) is a phenotypically
heterogenous syndrome that associates various central nervous
system (CNS) developmental abnormalities including the
so-called "molar tooth sign", cerebellar vermis hypoplasia
and cerebral cortex defects, with renal cysts, and
pigmentary retinopathy. There are overlaps with Senior Loken
syndrome, as NPHP1 is a causative factor in about 2% of
JBTS4. Another causative gene, AHI1, has been recently
discovered in the JBTS3 form [18,19]. There are two other
Autosomal dominant cerebellar ataxia type II (SCA7)
shows a retinal disease, which often begins with a
granular macula and then spreads out to the whole retina. It is
due to trinucleotide expansions in the transcription factor
ataxin-7 and anticipation effect is found .
Myotonic dystrophy shows cataract and sometimes
Hallervorden-Spatz syndrome shows progressive
dysarthria and dementia, iron deposition, and flecked type
retinopathy with bull's eye maculopathy.
RP are genetic disorders inherited as mendelian traits in
most cases. Except for mutation in a few genes that can
cause both autosomal dominant and recessive forms of
RP (NRL, RP1 and, exceptionally, RHO), most genes
involved in the disease are linked to only one form of
inheritance. There are also some rare RP cases due to
mitochondrial DNA mutations  and to digenic diallelic
inheritance involving RDS and ROM1 genes .
Uniparental isodisomy and incomplete penetrance have also
been described (reviewed in ).
In 1990, the first gene involved in RP, Rhodopsin, has been
identified . It encodes the rod visual pigment. Since
then, it has been established that mutations in many
genes may cause RP . To date, 45 known genes/loci
have been identified in non syndromic RP, including 15 for
autosomal dominant- (14 cloned, one mapped), 24 for
autosomal recessive- (18 cloned, six mapped), five for
Xlinked- inheritance (two cloned, three mapped), and one,
ROM1, which has been found mutated only in digenism
with RDS. It has been estimated that the cloned genes
account for about 50% of dominant RP, 40% of recessive
RP and approximately 80% of X-linked RP, indicating that
many genes remain to be identified .
The gene products localize in rods (sometimes in rods and
cones), being involved in various metabolic pathways.
They include proteins of the rod visual transduction
(rhodopsin, and subunits of the rod phosphodiesterase,
and subunits of the rod cGMP gated channel, arrestin,
guanylate cyclase activating protein 1B), cytoskeleton
proteins (peripherin/RDS, ROM1, fascin 2), proteins
presumably involved in trafficking (RPGR, RP1, RP2,
promininlike 1), in photoreceptor differentiation (NRL, NR2E3,
CRX), in mRNA splicing (PRPC8, HPRP3, PRPF31, PAP1),
in the composition of extracellular matrices (USH2A),
and in lipid (ABCA4, CERKL), nucleotide (IMPDH1) or
other (TULP1, CRB1, MITS2, CA4, SEMA4A) metabolic
pathways. In addition, RP is also caused by mutations of
genes expressed in the photoreceptor supporting tissue,
i.e. the retinal pigment epithelium (RPE), the encoded
proteins being involved in the retinol metabolism (the
retinol isomerase RPE65, the 11-cis retinoid transporter
CRALBP, the lecithin retinol acyl transferase LRAT, RGR)
or in the phagocytosis of the photoreceptor outer
Specificities of photoreceptors
The genetic heterogeneity of RP is difficult to correlate
with the fairly homogeneous phenotype of the disease.
Photoreceptors, and particularly rods, may require a
highly regulated environment to function properly and
any alteration of this environment may render these cells
prone to apoptosis, causing loss of rods and cones. Rods
have a very elongated outer segment that contains several
hundreds of membrane discs in which visual transduction
occurs. Discs contain huge amounts of visual transduction
proteins, particularly rhodopsin (~4 107 molecules per
rod) and cytoskeleton proteins. Discs of the apex of the
rod outer segment are phagocytosed daily by the retinal
pigment epithelium (RPE), and this phenomenon is
compensated by a daily boost of disc synthesis at the base of
the outer segment. This requires an intense activity of
mRNA and protein synthesis, as well as an important
protein trafficking from the rod inner segment, through the
connecting cilium, to the rod outer segment. This cellular
activity generates an important energy consumption,
requiring high content of mitochondria and oxygen, and
mechanisms to protect the cell against the oxidative stress.
Possible common pathways to photoreceptor cell death
Loss of the rod outer segment may be caused by mutations
that lead to its destabilization (mutations in cytoskeleton
or trafficking proteins). This would considerably shorten
the photoreceptor layer and expose the photoreceptor cell
body to high pressure levels in oxygen, hence oxygen
toxicity. Mutations that lead to diminution in the ability to
respond to high demand of energy or mRNA/protein
synthesis may somewhat destabilize the outer segment. Other
mechanisms that may be involved are calcium toxicity or
metabolic exhaustion by permanent opening of the
cGMP-gated channel, due to defective visual transduction
proteins, or, conversely, due to low calcium when visual
transduction permanently activated . Finally,
alterations in critical RPE functions, such as disc phagocytosis
or retinol metabolism, may also deregulate the fine
balance of photoreceptor metabolism.
Identification of the causative genes is a necessary step
towards the understanding of RP pathophysiology. With
the use of genetic databases, it can be reasonably assumed
that most genes responsible for autosomal dominant and
X-linked RP will be known within the next few years. This
will not be as straightforward in autosomal recessive RP
and some sporadic cases, as these forms seem to be
associated with an extreme genetic diversity. For each gene, we
then need to explore what causes the decrease in the visual
performance on the one hand, and how the mutated or
absent protein causes the loss in photoreceptor, on the
other hand. This implies the development of animal
models and long lasting experiments based on cell and
molecular biology techniques. From this knowledge,
therapeutic trials are being conducted.
Clinical diagnosis is based on the presence of night
blindness and peripheral visual field defects, lesions in fundus,
hypovolted ERG traces, and progressive worsening of
these signs. Full field ERG is the key test, particularly when
patients are asymptomatic and show normal fundus at
early stages of the disease or in autosomal dominant
forms with variable penetrance, since it is usually
hypovolted before the appearance of clinical signs (night
blindness). It is important to ascertain the diagnosis by
repeating the examination one or two years after it has
been first established. Multifocal ERG and
electrooculogram are not essential to establish the diagnosis.
At present, a systematic molecular diagnosis is not
routinely performed, due to the tremendous genetic
heterogeneity of the disease. However, rapid and large-scale
mutation screening techniques are developing and several
laboratories perform search for mutations in the most
frequently involved genes, including:
RPGR that accounts for at least 10% of all cases of non
syndromic RP, including 55% of X-linked RP and until
25% of sporadic RP. It is also involved in cases of X-linked
cone or macular dystrophies.
USH2A may account for 1/3 to 1/2 of cases with Usher
syndrome and may be involved in at least 16% of cases
with recessive non syndromic RP .
In some instances, molecular diagnosis for certain genes is
performed by the laboratories that have discovered them.
The currently known genes responsible for RP account for
5060% of the cases, and strategies to test in a short time
several dozen of genes for a single patient DNA are
Leber's congenital amaurosis (LCA), which also belongs
to the group of pigmentary retinopathies, must be
differentiated from RP, although some genes are involved in
both LCA and RP. RP is also clearly different from the
macular dystrophies in which the extent of the lesions are
limited to the macula. Cone dystrophies, due to cone
degeneration while rods remain unaffected or only
moderately affected, must also be excluded, although some
genes cause either cone dystrophies or RP. Finally,
conerod dystrophies that are usually viewed as a subclass of RP
should be distinguished from typical RP (rod-cone
Various entities resemble RP:
Congenital stationary night blindness. In autosomal
forms, symptoms are limited to night blindness, while
Xlinked forms are associated with a limited visual acuity.
Fundus albipunctatus is a rare condition in which fine,
white deposits are visible in fundus. The fundus aspect is
similar to retinitis punctata albescens (see above), but
there is usually no signs of degeneration (narrowing of
retinal vessels, retinal atrophy), although some cases may
undergo macular degeneration .
Vitamin A deprivation syndrome mimics the signs of RP
with night blindness and is associated with keratitis. If
vitamin A supplementation is given early, the symptoms
disappear but after a certain point the lesions become
Non evolving pigmentary retinopathies
The aspect of the fundus is often that of salt-and-pepper
pigmentary retinopathy or deposits of pigment with
various shape, often dot-like.
Congenital infections like rubella (salt-and-pepper
retinopathy) or syphilis (pseudo-retinitis pigmentosa or
leopard skin retinopathy).
Carriers of X-linked disorders like choroideremia, ocular
albinism, RP. This helps to recognize carriers, in particular
for RP in which a yellowish reflex may be present in
Mitochondrial diseases like Kearns-Sayre syndrome
(ophthalmoplegia), although there may be progressive
degeneration of photoreceptors.
Grouped congenital hypertrophy of the retinal pigment
epithelium with characteristic bear-like footprints in
In all cases there is a marked atrophy of the
choriocapillaris that is readily diagnosed by the absence of fluorescence
in fluorescein angiography.
Choroideremia, an X-linked disorder, due to mutations
in CHM encoding the Rab Escort Protein 1 (REP1) and
accounting for about 2% of pigmentary retinopathies.
Gyrate atrophy, a very rare autosomal recessive disorder,
due to deficiency in ornithine aminotransferase.
In these conditions, the vitreous and inner layers of the
retina are also affected. Retinal detachment and retinal
vasculopathy are often present.
Retinoschisis, in most cases the juvenile X-linked
retinoschisis with typical spoke-wheel-like lesions in the fovea,
is due to mutations in XLRS1 encoding a protein involved
in the adhesion of retinal cells. End stage X-linked
retinoschisis are difficult to distinguish from RP because of the
macular degeneration and frequent pigmented lesions in
peripheral retina. There is also the autosomal recessive
Goldman Favre syndrome in which patients have night
blindness from infancy and show foveal retinoschisis in
fundus. It is the same disease as the Enhanced S-Cone
Syndrome (ESCS) due to mutations in NR2E3, that presents
with characteristic whitish and secondarily round
pigmented lesions in retinal periphery when evolved.
Hereditary vitreoretinopathies, the most frequent ones
being several autosomal dominant conditions: familial
exudative vitreoretinopathy, Wagner disease and Stickler
Inflammatory diseases of the eye, birdshot
choroidoretinopathy, serpiginous retinopathy, multifocal
placoid pigment epitheliopathy, sarcoidosis. The
presentation and fundus are clearly different from RP but there
may be a secondary degeneration mimicking RP.
Stargardt disease, due to mutations in ABCA4. Null
mutations in this gene can also be responsible for
Cone dystrophies, in some cases presenting with a
minimal rod involvement.
Sorsby's disease, in extended cases.
Intoxication with various drugs including thioridazine
and chloroquine. Although chloroquine usually leads to
"bull's eye maculopathy", there are some cases of RP-like
pigmentary retinopathies that may continue to progress
even after discontinuation of the drug intake.
Inflammation (pars planitis, Behcet disease, sarcoidosis,
subacute diffuse unilateral neuroretinitis) may rarely be
complicated with RP.
Sequelae of severe gravidic toxemia, uveal effusion
syndrome or trauma.
Parasitic infections such as onchocercosis.
Once the diagnosis is made, patients should be informed
and familial surveys recommended. Genetic counseling is
always advised since all genetic forms can be encountered
in RP. A precise phenotypic diagnosis is always mandatory
and is particularly useful in the absence of familial history
or in sporadic cases.
Prenatal diagnosis (amniocentesis or chorionic biopsy)
raises an ethical issue: whether the investigative risks
associated with these invasive prenatal procedures are justified
in a non life-threatening disease is questionable. Prenatal
diagnosis can be performed in families in which the
responsible gene has been identified, particularly in
families with early onset and severe RP.
Management including treatment
Currently, there is no therapy that stops the evolution of
pigmentary retinopathies or restores the vision. However,
there are several therapeutic strategies aimed at slowing
down the degenerating process, treating the
complications and helping patients to cope with the social and
psychological impact of blindness.
Slowing down the degenerating process
Clinical evidence and data from animal studies indicate
that some genetic types of pigmentary retinopathies are
partly light-dependent . Thus, patients with
pigmentary retinopathies are recommended to wear dark glasses
outdoor. Wearing of yellow-orange spectacles minimizes
photophobia. Eyeshade and lateral protection help to
protect against dazzling side-coming light rays.
Vitamins A and E may protect the photoreceptors by
trophic and anti-oxidant effects, respectively. Previous
studies have demonstrated that long term (512 years)
vitamin A supplementation at doses of 15,000 units per
day slightly slowed down the loss in ERG amplitude,
while vitamin E at 400 units per day had adverse effects
. However, the conclusions of this study were debated
, thus there is no consensus about the usefulness of
vitamin A treatment. If vitamin A supplementation is
proposed, levels of serum retinol (normal <3.49 mol/l, i.e.
<1 mg/l) and triglyceridemia (normal <2.13 mmol/l, i.e.
<0.19 g/l) should regularly be checked, as well as liver
enzymes (aspartate aminotransferase, alanine
aminotransferase and alkaline phosphatase) since vitamin A
storage occurs mainly in this organ. Vitamin A should not
be given to RP patients with mutations in ABCA4. In a
recent study, patients were given docosahexaenoic acid
(DHA) supplementation at 1200 mg/day, in addition to
vitamin A. It was shown that the course of the disease was
initially slowed down by the addition of DHA, but this
beneficial effect did not last over 2 years .
It is a posterior central subcapsular cataract with a clear
nucleus, which is usually present at mid stage in the
evolution of the disease. Although the cataract is not
widespread, its central position blurs the remaining central
visual field. Therefore, cataract provokes a sight restriction
and generates photophobia. Phacoemulsification with
implantation of intraocular lens is thus required.
Macular edema occurs frequently, causing a decrease in
the visual acuity. Acute episodes of macular edema may be
successfully treated with carboanhydrase inhibitors such
as acetazolamide sodium at a daily dose of 500 mg or less.
However, the macular edema in RP patients is most often
chronic and does not improve with this treatment .
Topical administration of dorzolamide is inefficient .
Mild inflammatory reactions occur frequently in the
vitreous and are often associated with macular edema, vascular
diffusion visible on fluorescein angiogram, and early
cataract. Although these reactions do not require a specific
treatment, some cases present with large exsudates in the
peripheral retina (pseudo Coats) that leads to retinal
detachment and rapid evolution towards blindness. This
latter complication has been found recurrently in RP
linked to CRB1 mutations . Cryotherapy or laser
treatment are required for resorption of the exudates.
Myopia associated with X-linked RP requires
management and routine examinations as for non RP patients.
Glaucoma is not associated with RP but the presence of
increased intraocular pressure in RP patients should be
cautiously checked in order to prevent more rapid
deterioration of the visual field.
Management of blind patients
Psychological help is often necessary at milestones in the
course of the disease: announcement, occurrence of
moving difficulties and loss of reading. This support can be
provided by either professionals or supportive patients'
associations. Patients should be oriented towards
institutions that help them to rehabilitate (short- and
mediumstay stages and others  and to obtain new professional
Enormous efforts have been invested to identify the
involved genes, to unravel the underlying
pathophysiological mechanisms, and to find efficient treatments.
Search for new therapies follows several strategies, which
may be non exclusive. None of these future treatments is
currently operating in humans.
Treating the cause of the disease
This approach requires the implicated genes to be
identified and therefore, the availability of efficient genotyping
methods. The strategy is relatively simple for RP due to
loss-of-function (usually recessively inherited). In this
case, one expect that the expression of the wild-type cDNA
in the appropriate cell (photoreceptor or RPE) will avoid
cell death. However, it is more complicated for RP due to
dominant negative pathogenic mechanisms in which the
expression of the mutated gene should be inhibited, by
use of ribozymes or siRNA for example. In the last 10
years, studies have been carried out in several animal
models. Although all showed a significant rescue of
photoreceptors, there was still progressing photoreceptor cell
death, which could be due to an inappropriate expression
level of the therapeutic gene and to an insufficient
percentage of transduced photoreceptors. The most advanced
studies have been performed for LCA in a large animal
model (the Briard dog) in which the surgical
administration in the subretinal space of AAV vectors carrying the
RPE65 cDNA allowed to restore vision in four month-old
dogs in USA [39,40] and in France . Five years later,
the dog vision seems stable, although the very long-term
efficiency still remained to be ascertained. Promising
results have been obtained in a mouse model of X-linked
retinoschisis . It is expected human trials in RPE65
patients to be carried out soon in the USA, UK, France,
and other countries.
In those cases where some aspects of the
pathophysiological mechanism are known, pharmacological treatment
may be a good choice, as it offers the advantages of using
available drugs with known toxicity that can be
modulated. Pharmacological agents can compensate for a
biochemical defect, and enhance or inhibit the activity of
various effectors. Calcium-channel blockers have been
tried in several animal models of RP , yet with limited
success . Another example is Stargardt disease in
which the use of visual cycle inhibitors has been shown to
slow down the toxic accumulation of lipofuscin in the
RPE in a mouse model [45,46]. Supply of 9-cis retinal has
been shown to restore the rod activity in a Rpe65-/- mouse
model of LCA . NAD analogues supply in RP due to
IMPDH1 defects may also be efficient . It might be
speculated that the alternative of pharmacological
treatments would be explored in more details in the future, as
the mechanisms of the various forms of RP will be
Coping with photoreceptor cell death
A general problem with the treatment of the primary cause
of the disease is that beyond certain stage in the evolution,
non-cell autonomous mechanisms leading to cell death
may overwhelm the potential benefits of gene- or
pharmacological therapies. Cell death may be due to the
release of proapoptotic signals in the photoreceptor
environment, or to the lack of survival factors normally
produced by the living cells. The latter has been confirmed by
the discovery that rods produce factors that are necessary
for cone survival . Thus, in typical RP, rods die
because they express a mutated gene, and cones, which do
not express the mutated gene, are secondarily
degenerating because of the lack of rod factors. Therefore, the
supply of rod factors in the retina would protect cones against
Neuroprotection using growth factors
Several growth factors, including ciliary neurotrophic
factor (CNTF), glial-derived neurotrophic factor (GDNF),
cardiotrophin-1, brain-derived neurotrophic factor
(BDNF) and basic fibroblast growth factor (bFGF) have
some efficacy in animal models, that varies from one
model to another. Their short half-life requires their
delivery in situ. Since iterative intravitreal injections are not
recommended, several strategies like use of encapsulated
cells producing bFGF placed in the vitreous cavity 
and gene transfer of GDNF in resident cells  have been
tried. These factors, however, have side effects including
retinal neovascularization and cataract. For example,
CNTF allows an excellent preservation of retinal integrity
in several animal models, but it causes a decrease in the
ERG response of the retina by yet unknown toxic
mechanism . Nevertheless, encapsulated cells releasing
CNTF of vitreous of patients with RP is currently under
Phase I clinical investigation .
Neuroprotection using antiapoptotic factors
In animal models, gene transfer of anti-apoptotic bcl-2
slows down the photoreceptor cell death  as well as
the use of an inhibiting peptide of caspase-3 .
Rod-derived cone viability factor
Lveillard et al.  identified a rod-derived cone viability
factor (RdCVF) that appears to be a truncated
thioredoxinlike protein which significantly delays cone death in the
rd1 mouse model of RP. Studies are ongoing to test
whether this factor will be efficient in other forms of RP.
Restoration of visual function
Beside therapies aimed at preserving visual function and
preventing cell death, one would like to find out ways of
restoring the visual function. This is a tremendous
challenge since (as a general rule for neurons in the CNS)
human photoreceptors are not produced and do not
divide after birth, therefore, their loss is irreversible. In
addition, the loss of photoreceptors leads to a dramatic
remodeling of the retinal circuits which would probably
modify the visual information process if correct
implantation of new photoreceptors was possible. Nevertheless,
numerous teams are now working to achieve visual
restoration either by photoreceptor replacement or by means
of artificial devices.
Cell or tissue transplantation
Experiments have been tried to transplant retinal cells
from fetuses or adult retina in humans, and layers of
photoreceptors or even entire retina in animals models (rats
and rabbits). Generally, the survival of transplanted
photoreceptors is readily observed, but they do not properly
organize in the retina (forming rosettes) and lack, with
rare exceptions, functional synapses. Researchers are also
becoming interested by using stem cells, embryonic or
adult, from retina or from other tissues. Although very
interesting to study, these therapeutic approaches are still
far from realistic use in a near future.
Conversely to photoreceptors, it has been proven that the
RPE grafts rescue the photoreceptors in Royal College of
Surgeons (RCS) rat model, in which a mutation in c.Mertk
causes a retinal dystrophy by lack of outer segment
phagocytosis of the RPE, and in rare cases of RP in humans
[57,58]. In RP due to RPE defects, RPE transplantation is
then theoretically possible, but one has to resolve the
immunogenic reaction against allogenic, wild type RPE.
Microphotodiodes arrays that replace degenerated
photoreceptors or more sophisticated devices that capture
light and stimulate the retina, optic nerve or visual cortex
have been developed. Several clinical trials have
essentially demonstrated the tolerance of the implanted
devices. Today, they represent the basis for further studies
towards improvement of the future devices resolution.
Evaluation of the prognosis is not an easy task as the
quality of vision is depending on several features such as
peripheral visual field, visual acuity and perception of
contrasts which may not change in concert. For example,
one patient with a long-evolved RP may feel fortunate
because of a relatively good visual acuity to 4/10, even if
his/her tiny visual field limited to 5 around the fixation
point does not allow autonomous walking outside, while
a younger patient, with a better visual field will feel
unfortunate with a visual acuity less than 1/10 due to macular
Few studies have addressed the question about the disease
prognosis, even though this is a very important concern
for patients. The rate of decline in visual performance is
depending on many parameters that include the gene and
type of mutations as well as other genetic and
environmental factors. It has been recently established that the
disease course in patients with pericentral RP is slower
that those with typical RP . There are also several
clues, such as the Optical Coherence Tomography (OCT)
third high-reflectance band, which may help to predict
which patients are more likely to lose visual acuity with
the decline of the retinal thickness .
Overall, we clearly need to use standardized tests over
extended periods of time to precisely determine clinical
subgroups who will be relevant for clinical trials, in
particular to appreciate the efficacy of treatments.
Cloned genes account for 40 to 54% of the autosomal
dominant cases, 61 to 89% of the X-linked cases, and
probably less than 1/3 of the autosomal recessive cases,
not taking into account all the sporadic cases (45% of all
RP cases). Therefore, it can be broadly estimated that half
the genes have yet to be discovered. It is anticipated that
modifier genes play important roles, in particular in
incomplete penetrance of autosomal dominant RP and in
sporadic cases. Those modifier genes, that could also be
used for therapeutic prospects, remain to be discovered.
The understanding of the role of the encoded proteins
often requires many years. Today, for a number of
proteins, substantial information about their function is
available, while some of them remain poorly known.
A challenging issue is the elucidation of the precise steps
leading from a gene mutation to photoreceptor
degeneration. Data from animal models and clinical studies
suggest that photoreceptors die by apoptosis at a linear rate
throughout life (named the one-hit hypothesis), implying
that they have a given probability to undergo apoptosis
that remains constant from early to late stages of the
disease . For certain genes or severe mutations, this
probability will be high, while for others it will be lower. The
results of experimental and clinical studies clearly indicate
that the mechanisms of photoreceptor degeneration are
multiple. In all genetic forms of RP studied till now, data
are incomplete. In addition, it is likely that several
apoptotic pathways are involved in the photoreceptor loss,
sometimes concurrently, and this also needs to be
carefully investigated. This knowledge is crucial to design
therapies. The efficacy of various potential treatments has to
be proven in large animal models and in humans. For
example, gene replacement therapy for RDS in mouse
improves photoreceptor ultrastructure, but there is no
significant effect on photoreceptor cell loss .
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