Retinitis pigmentosa and related disorders

Clinical background

The term retinitis pigmentosa (RP) is used to describe a group of inherited disorders in which vision loss is caused by degeneration of the rod and cone photoreceptor cells of the retina. RP occurs in nonsyndromic and syndromic forms. It has recently been recognized that in many of the syndromic disorders of which RP is a part, the common link between the affected tissues is cilia, as the light-sensitive outer segments of photoreceptor cells are specialized sensory cilia ( Figure 74.1 ).

Figure 74.1

Retina and photoreceptor cell structure. Left, cross-section of human retina, showing retinal layers. Right, drawing of rod photoreceptor cell, showing different portions of the cell. The photoreceptor sensory cilium is indicated. Ch, choroid; GC, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; RPE, retinal pigment epithelium.

Symptoms and signs

In all types of RP, nyctalopia (night blindness) is often the first symptom noticed. This is due to dysfunction and death of rod photoreceptor cells, which mediate vision under conditions of dim illumination. This symptom is often noticed in adolescence, but the age of onset can be variable, ranging from early childhood to adulthood. Loss of peripheral visual field follows, and is progressive, resulting in constriction of visual fields. Central vision, mediated predominantly by cone photoreceptor cells, is ultimately lost in many cases as well, often in later adulthood.

The progression of visual symptoms is associated with dysfunction and death of photoreceptor cells and consequent changes in the retinal pigment epithelium, which is visible on fundus exam. For example, in childhood, the fundus may appear relatively healthy, or small regions of depigmentation may be noted prior to the detection of the typical bone spicule pigmentation in the midperiphery ( Figure 74.2A ). As more photoreceptor cells die, and visual field is lost, fundus abnormalities become more notable, with more prominent bone spicule pigmentation and associated retinal atrophy ( Figure 74.2B ). Eventually, attenuation of retinal blood vessels and optic atrophy are evident, as further loss of photoreceptor cells and secondary loss of retinal ganglion cells occurs ( Box 74.1 ).

Figure 74.2

Fundus appearance in retinitis pigmentosa (RP). (A) Fundus images from a patient with early RP. Note the presence of both depigmented areas (black arrow) and early bone spicule pigment (white arrow). (B) Fundus images from a patient with more advanced RP. Note increased bone spicule pigmentation in the midperiphery, attenuation of retinal blood vessels, and early pallor of the optic nerves. Note: these fundus photos were taken with the Optos fundus imaging system, which provides a wide-angle view of the fundus. This scanning laser ophthalmoscope system uses red and green lasers, and thus produces images with slightly different colors than standard fundus cameras.

Box 74.1

Retinitis pigmentosa – clinical features


  • Nyctalopia

  • Peripheral field loss

  • Progressive loss of central vision later in disease

Exam findings

  • Diminished electroretinograms, rod greater than cone

  • Bone spicule pigmentation

  • Vascular attenuation

  • Optic atrophy

Other degenerations

In addition to RP, many other inherited retinal degenerations have been described. These have been classified clinically by their age of onset, the types of photoreceptor cells affected, the region of the retina involved, and rates of progression. Leber congenital amaurosis (LCA) is a severe early-onset form of retinal degeneration, in which poor vision associated with nystagmus is evident early in childhood. Cone and cone–rod dystrophies are characterized by early-onset cone dysfunction, in contrast to RP, in which rods are typically affected first. Congenital stationary night blindness is characterized by early-onset night -blindness like RP, but has a more stable clinical course.


The prevalence of RP in the USA, Europe, and Japan is approximately 1 in 4000. This translates into ∼1.5 million individuals affected with RP worldwide. Data from the Beijing Eye Study suggest that the prevalence in China may be higher, at approximately 1 in 1000. These data predict approximately 1.3 million people affected with RP in China alone, although this estimate is based on a relatively small sample size compared to the total Chinese population. Data from studies in Japan and Denmark and Kuwait indicate that RP is among the leading causes of blindness or visual impairment, especially in working-aged people, accounting for 25–29% cases in that age group (21–60 years).

Diagnostic workup

Clinical evaluation of a patient with symptoms of RP, such as nyctalopia and decreased visual fields, involves thorough ophthalmic examination, testing of visual function, consideration of systemic evaluations, and genetic testing. Visual acuity may remain normal even in later stages of classic RP, in which rod photoreceptors are affected first. Early loss of central acuity suggests the possibility of early cone photoreceptor dysfunction. Anterior-segment exam is important to rule out other causes of vision loss, and to look for posterior subcapsular cataracts, which develop in up to 50% of patients with RP.

Visual field testing is important both for detecting field loss for diagnostic purposes, and for following disease status over time. Full-field evaluations using a Goldmann perimeter or Humphrey field analyzer are useful for detecting the midperipheral scotomas typically observed in patients with RP. Progression of field loss is associated with loss of rod and cone photoreceptor function, resulting in small residual islands of vision.


Electroretinogram (ERG) testing is an important diagnostic tool for patients with RP. The ERG measures the function of rod and cone photoreceptors. It is a measure of the field potential generated by the circulating ion currents in photoreceptor cells. Standards for the performance of ERGs have been established by the International Society for Clinical Electrophysiology of Vision (ISCEV). In the ISCEV standard ERG evaluation, five steps are used to evaluate rod and then cone function: the rod ERG, the combined rod–cone ERG, oscillatory potentials, single flash cone ERG, and 30-Hz flicker ERG. Responses to low levels of white or blue light in dark-adapted subjects are used to evaluate rod photoreceptor function. A brighter standard flash of white light is then used to elicit a maximal or combined response from both the rod and cone photoreceptors. A typical response includes a negatively deflected a -wave, followed by a positive b -wave ( Figure 74.3 ). The a -wave is a measure of the photoreceptor response; the b -wave is thought to be generated by cells in the inner retina.

Figure 74.3

Standard scotopic electroretinograms (ERGs). Example traces of ERG results from a normal subject, a patient with moderate retinitis pigmentosa (RP), and a patient with severe RP. (A) Rod ERGs generated response to dim flashes of white light. (B) Combined rod–cone ERGs generated in response to a brighter flash of white light. The negatively deflected a -wave, and positive b -wave are indicated. The time to peak (implicit time) and amplitude of the responses are decreased.

Following light adaptation, cone responses to a single white flash are recorded in the presence of background illumination. Finally, flicker ERGs recorded at approximately 30 flashes per second (30 Hz) are used to measure responses from cones; rod photoreceptors cannot recover rapidly enough to respond to the rapid flashes ( Figure 74.4 ).

Figure 74.4

Standard photopic electroretinograms (ERGs). Example traces of ERG results from a normal subject, a patient with moderate retinitis pigmentosa (RP) and a patient with severe RP. (A) Cone ERGs generated response to a single flash of white light. (B) 30-Hz flicker cone ERGs.

In patients with RP, ERG responses are decreased. Indeed, decreased photoreceptor function can be detected by ERG in children who remain asymptomatic until young adulthood. In RP, decreased rod photoreceptor responses are typically noted first, followed by decreases in cone responses. A typical young adult with RP will have reduced amplitudes of both rod and cone responses, and delays in the response times ( Figures 74.3 and 74.4 ). Patients with more severe retinal degeneration, such as early-onset forms of RP or LCA, may have nondetectable ERG responses ( Figures 74.3 and 74.4 ).

ERG amplitudes can provide objective measures of retinal function, and thus are useful for accurate diagnosis and for tracking the course of disease. It has also been suggested that the amplitudes of the 30-Hz cone response can be used to provide information about visual prognosis. The dark adaptation threshold can also be a useful assessment of rod photoreceptor function. This test measures the lowest intensity of white light that can be perceived in a dark- adapted state. Optical coherence tomography (OCT) can be useful for monitoring the thickness of the retina in patients with RP.

Genetic testing

Genetic testing to identify the mutations which cause an individual patient’s disease has become an important part of clinical care of patients with RP and related disorders. This is important because it can help confirm the diagnosis, assist with family planning, and provide more detailed information about the prognosis of the specific form of RP identified. Genetic diagnoses will also be increasingly important as genetic treatments for RP and related disorders are developed.

Clinical genetic testing for RP is improving, and several clinical labs now provide relevant testing. An up-to-date list can be found at . Identification of pathogenic mutations in patients with RP can be challenging, due in part to the polygenic nature of these disorders (see below). New developments with high-throughput mutation detection and sequencing will hopefully simplify this process in the relatively near future.

Systemic evaluation

As discussed below, RP and related retinal degenerations are often associated with systemic disorders. It is therefore important to consider potential disease associations when evaluating patients with RP. This is especially true for children. Common systemic associations include defects in other sensory or primary cilia, such as hearing loss in Usher syndrome, cystic renal disease in Alstrom, Bardet–Biedl, Joubert, and Senior Loken syndromes. Retinal degeneration can also occur in the setting of mitochondrial disease, and metabolic disorders. Three specific forms of RP that are important to consider in children are Refsum’s disease (phytanic acid oxidase deficiency), Bassen–Kornzweig syndrome (abetalipoproteinemia), and RP with ataxia caused by α-tocopherol transport protein deficiency, as early intervention can be beneficial in these disorders.

Differential diagnosis

Other retinal degenerative disorders can present with visual symptoms like those caused by RP. The fundus appearance in gyrate atrophy is distinct from that of RP, with patches of choroidal and retinal atrophy in the midperiphery. Plasma ornithine levels are elevated in this disease, which is caused by deficiency of the ornithine aminotransferase ( OAT ) gene. Fundus appearance is also helpful for distinguishing choroideremia from RP. In this X-linked condition, RPE and choroidal atrophy are evident on fundus exam.


Several studies have been performed to assess the value of nutritional supplements for patients with RP. A randomized clinical trial demonstrated that vitamin A supplementation slowed the decline of photoreceptor cell loss as measured by 30-Hz cone ERG amplitude in patients with RP. Vitamin A supplementation was also associated with slower loss of visual field in the subset of trial patients who performed the visual field tests with the greatest precision. Studies of dietary supplementation with the omega-3 fatty acid docosahexaenoic acid (DHA), which is present at relatively high levels in photoreceptor outer-segment membranes, did not show a clear benefit.

Several promising treatments for RP and related disorders are nearing or in clinical trials. The value of sustained intraocular release of the neurotrophic factor ciliary neurotrophic factor (CNTF) is being evaluated in a phase II trial, after being found to be safe in a small phase I study. Gene augmentation therapy for specific forms of RP, LCA, and related disorders has shown promise in preclinical and early phase I research studies. Based on these results, further clinical trials of gene therapy for LCA2, caused by mutations in the RPE65 gene, are currently in progress in England and the USA. RNA interference-mediated knockdown of mutant alleles that cause disease via dominant negative mechanisms is also being evaluated. Several approaches to using stem cells for the treatment of inherited retinal degenerations have also shown promise, including the use of RPE-like cells derived from human embryonic stem cells.


Several clinicopathologic studies of the pathology of RP have been reported. These studies show that loss of vision in end-stage RP correlates with widespread loss of photoreceptors. In samples from patients with retained vision, a single layer of cones with shortened outer segments was observed in the macula, reflecting the slower loss in cones in most types of RP. Bone spicule pigmentation is caused by migration of RPE cells into the retina, where they cluster around blood vessels. Pathologic studies also show that the neural retina undergoes significant remodeling in human RP. Loss of photoreceptors, especially cones, appears to trigger retinal remodeling, with changes in cell organization and connections. These include neuronal and glial migration, rewiring of retinal circuits with elaboration of new neurites and synapses, and glial hypertrophy. These remodeling changes may affect the success of potential therapeutic strategies for RP and related disorders.


Genetics of RP and related disorders

Nonsyndromic RP

RP and related disorders are caused by mutations in genes which encode proteins that are required for photoreceptor cell function. These disorders are genetically heterogeneous, with over 80 disease genes identified to date ( Tables 74.1–74.3 ). Indeed, it has recently been pointed out that photoreceptor cells are subject to more genetic diseases than any other cell type. The website RetNet provides a curated listing of disease genes and loci for retinal degenerative disorders.

Table 74.1

Summary of disease genes and loci

Disease category Inheritance pattern Total number of genes and loci Number of identified genes
Cone–rod dystrophy AD 7 5
Cone–rod dystrophy AR 5 3
Leber congenital amaurosis AR 15 14
Retinitis pigmentosa AD 16 15
Retinitis pigmentosa AR 18 13
Retinitis pigmentosa XL 6 2
Ciliopathy syndromes
Alstrom syndrome AR 1 1
Bardet–Biedl syndrome AR 12 12
Nephronophthisis-associated AR 9 8
Usher syndrome AR 11 9
Other syndromic disorders
Lipofuscinoses 2 2
Mitochondrial disorders 4 4
Refsum disease 4 4

AR, autosomal recessive; AD, autosomal dominant; XL, X-linked.

Table 74.2

Genetics of nonsyndromic retinitis pigmentosa (RP)

Gene symbol Protein name % 1 Function/mechanism of disease 2
RHO Rhodopsin 25 Phototransduction, cilia structure
RP1 Retinitis pigmentosa 1 5.5 Cilia structure
PRPF31 Pre-mRNA processing factor 31 5 RNA splicing
PRPF3 Pre-mRNA processing factor 3 4 RNA splicing
PRPH2 Peripherin 2 2.5 Cilia structure
PRPF8 Pre-mRNA processing factor 8 2 RNA splicing
IMPDH1 Inosine monophosphate dehydrogenase 1 2 Nucleotide biosynthesis
NRL Neural retina leucine zipper 1 Overexpression of rhodopsin
CRX Cone–rod homeobox protein 1 Cilia structure – transcription factor
CA4 Carbonic anhydrase IV pH balance
FSCN2 Fascin 2 Cilia structure
GUCA1B Guanylate cyclase activator 1B Phototransduction
SEMA4A Semaphorin B Cilia structure
TOPORS Topoisomerase I binding, arginine/serine-rich RNA splcing
RP9 Retinitis pigmentosa 9 RNA splicing
NR2E3 Photoreceptor-specific nuclear receptor Cilia structure – transcription factor
Unknown 45
USH2A Usherin 8 Cilia structure
ABCA4 ATP-binding cassette, subfamily A member 4 5.6 Visual cycle
CNGB1 Cyclic nucleotide gated channel beta 1 4 Phototransduction
PDE6B Phosphodiesterase 6B, cGMP-specific, rod, beta 3.5 Phototransduction
PDE6A Phosphodiesterase 6A, alpha subunit 3.5 Phototransduction
RPE65 Retinal pigment epithelium-specific protein 65 kDa 2 Visual cycle
CNGA1 Cyclic nucleotide gated channel alpha 1 1 Phototransduction
CRB1 Crumbs homolog 1 1 Retinal organization
LRAT Lecithin retinol acyltransferase 1 Visual cycle
MERTK MER receptor tyrosine kinase 1 Retinal pigment epithelium function
TULP1 Tubby-like protein 1 1 Cilia structure
RHO Rhodopsin 1 Phototransduction, cilia structure
RLBP1 Retinaldehyde binding protein 1 1 Visual cycle
CERKL Ceramide kinase-like 1 Sphingolipid metabolism
RGR Retinal G-protein-coupled receptor 0.5 Visual cycle
NR2E3 Photoreceptor-specific nuclear receptor 0.25 Cilia structure – transcription factor
SAG S-arrestin Phototransduction
NRL Neural retina leucine zipper Overexpression of rhodopsin
RP1 Retinitis pigmentosa 1 Cilia structure
PRCD Progressive rod–cone degeneration
PROM1 Prominin 1 Cilia structure
Unknown 60–70
X-linked RP
RPGR Retinitis pigmentosa GTPase regulator Cilia structure
RP2 XRP2 protein
Unknown 10–20
CEP290 Centrosomal protein 290 kDa 15 Cilia structure
GUCY2D Guanylate cyclase 2D, membrane (retina-specific) 12 Phototransduction failure
CRB1 Crumbs homolog 1 10 Retinal organization
IMPDH1 Inosine monophosphate dehydrogenase 1 8 Nucleotide biosynthesis
RPE65 Retinal pigment epithelium-specific protein 65 kDa 6 Visual cycle
AIPL1 Aryl hydrocarbon receptor interacting protein-like 1 5 Cilia structure – chaperone
RPGRIP1 Retinitis pigmentosa GTPase regulator interacting protein 1 4 Cilia structure
RDH12 Retinol dehydrogenase 12 ( all -trans and 9- cis ) 3 Visual cycle
LCA5 Leber congenital amaurosis 5 2 Cilia structure
CRX Cone–rod homeobox protein 1 Cilia structure – transcription factor
TULP1 Tubby-like protein 1 1 Cilia structure
MERTK MER receptor tyrosine kinase RPE function
LRAT Lecithin retinol acyltransferase Visual cycle
RD3 Retinal degeneration 3
Unknown 20–30

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Aug 26, 2019 | Posted by in OPHTHALMOLOGY | Comments Off on Retinitis pigmentosa and related disorders

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