- The condition
- Current research in RP
- Practical advice
- Referral to a specialist centre
- Further information and support
- A patient’s perspective
- Retinitis pigmentosa: for professionals
Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies that primarily affects the normal function of rod photoreceptor cells in the retina. It causes a gradual but permanent visual impairment in both eyes, and is estimated to affect 1 in 4,000 individuals. There are over 80 genes associated with this condition and can be inherited in a variety of patterns.
There are two types of photoreceptor cells in humans, known as rods and cones. The rods are responsible for vision in dim light and peripheral vision (side vision) while cones are responsible for central (reading) vision, along with helping us to see colour and objects in detail under bright light. In RP, the rods are affected earlier and more severely compared to cones.
As a result, patients tend to notice difficulties seeing in dim light/at night (night blindness) initially along with “blind spots” in their peripheral vision. Later on, they will notice issues with their central vision (things appearing blurry/not able to read) and colour vision as the cones start to degenerate as well. Symptoms usually begin during adolescence to young adulthood with progressive deterioration of visual function over time. However, the age of symptom onset, severity of sight impairment and rate of disease progression are highly variable among patients depending on the causative gene.
While the majority of patients only have visual symptoms, RP can be part of a wider systemic condition that affects other parts of the body in approximately 20-30% of cases. The most common systemic conditions associated with RP are Usher syndrome and Bardet-Biedl syndrome.
Patients with RP experience the following initial symptoms related to rod photoreceptor degeneration:
- Night blindness and difficulty to adapt to dark/dim environments (impaired dark adaptation)
- Blind spots in the peripheral vision causing them to bump into things appearing at either side of their vision. Over time, these blind spots gradually enlarge and constrict inwards towards the centre of their vision, eventually only leaving a small area of central vision to see out of, like seeing through a tunnel (tunnel vision)
As the disease progresses, the cone photoreceptors start to degenerate as well, causing the central vision to become blurry or the image sharpness (known as visual acuity) reduced. These symptoms gradually deteriorate over time, leading to difficulties in everyday activities such as reading or watching TV. During this stage, patients may also notice that they cannot distinguish colours as clearly as before.
Due to the large number of genes associated with RP, the age of symptom onset, severity and rate of disease progression are highly variable among patients, even those from within the same family.
In addition, some of the following symptoms/eye conditions may be present as well that can cause further visual deterioration:
- Light sensitivity (photophobia)
- Flashes of light in the field of vision (photopsia)
- Involuntary movements of the eyes (nystagmus)
- Extreme short-sightedness (myopia—unable to see distant objects); typically associated with RP caused by mutations in the RPGR or RP2 genes
- Early-onset cataracts (fairly common among RP patients)
- Swelling of the macula due to leakage of the retinal blood vessels (cystoid macular oedema/CMO); up to 50% of RP patients are affected by CMO
2) Systemic (other body systems)
Most patients only have isolated visual symptoms but in 20-30% of cases, RP is part of a wider systemic condition that affects other organs as well. The most common medical conditions associated with RP are:
- Usher syndrome (characterised by hearing loss and progressive visual loss with/without balancing problems)
- Bardet-Biedl syndrome (characterised by childhood obesity, progressive vision loss, extra finger/toes, learning difficulties, kidney problems and genital abnormalities)
The retina is a complex structure comprised of different type of cells working smoothly together to help us see. Over 80 genes so far have been implicated to cause RP, accounting for about 50-70% of cases, with the most common being RHO, USH2A and RPGR.[2-5] The genes associated with RP provide instructions to make proteins vital to the healthy development and functioning of retinal cells. A defect in any of these genes disrupt the smooth working of the retina and leads to sight loss.
How is it diagnosed?
1) Eye examination
An ophthalmologist is able to diagnose RP based on the presenting symptoms, clinical examination and the results of numerous investigations that assess the structure and function of the retina. When examining the retina, the ophthalmologist will look for typical features of RP, one of which is the presence of dispersed dark spots towards the outside areas of the retina as a result of photoreceptor degeneration.
Patients also tend to undergo the following tests as part of their assessment:
- Colour vision testing
- Visual field testing to reveal the extent of peripheral vision loss. Patients are asked to press a button when they detect flashing lights and a map of their visual field is created.
- Optical coherence tomography (OCT), a camera that allows detailed visualisation of all the retinal layers and reveal abnormalities in the retinal structure if present; it is useful for monitoring disease progression and detecting the presence of macular oedema
- Autofluorescence imaging (FAF) is another camera that can visualise and assess the health of the retina; it is a useful tool to monitor disease progression together with OCT
- Electroretinogram (ERG)–an electrodiagnostic test to assess the overall function of the photoreceptor cells; the rod function is severely reduced compared to cone function in RP
Genetic testing can help confirm the diagnosis by identifying mutations in one of the genes associated with RP.
2) General medical assessment
RP may occasionally be associated with medical conditions that affect other parts of the body. If this is suspected, a referral to the relevant specialist is made for further assessment. This may include but not limited to:
- General physical examination including assessment of height, weight (BMI), head circumference and overall development (for children)
- Hearing assessment
- MRI (magnetic resonance imaging) of the brain
- Blood tests
- Ultrasound scans of the kidney and heart
How is it inherited?
The most common causative gene inherited in this manner is RHO. Only one faulty gene copy (inherited from either parent) is required to cause disease. This means that each newborn of the patient has a 50% chance of inheriting the condition regardless of gender.
The most common causative gene inherited in this manner is USH2A. In contrast to AD inheritance, two faulty copies of a gene are required to cause disease. Both parents are usually unaffected carriers (who only carry one faulty copy of the gene) while the patient inherits has two faulty gene copies (one faulty copy inherited from each parent). This means that every newborn has the following risks regardless of gender:
- 25% chance of being affected by RP
- 25% chance of being unaffected and not a carrier
- 50% chance of being a carrier with no symptoms
The most common causative gene inherited in this manner is RPGR. In this type of inheritance, the faulty gene is located on the X chromosome (determines our gender together with the Y chromosome). Males inherit the X chromosome from their mothers and the Y chromosome from their fathers. Females inherit one X chromosome from each parent.
As a result, males are usually affected in conditions inherited in an X-linked manner as they only have one X-chromosome containing the faulty gene copy. On the other hand, some cells in females contain the second functioning X chromosome and thus do not display any symptoms (heterozygous carrier). However, a small portion of female carriers may present with severe visual deterioration, or have asymmetrical disease (one eye more affected than the other).
If the mother is a carrier and the father is healthy:
- Each son has a 50% chance of being affected
- Each daughter has a 50% chance of being a carrier like the mother
If the father is affected and the mother is healthy:
- None of his sons will be affected
- All of his daughters will be carriers
4) No family history/sporadic
Up to 50% of RP patients do not know of any other family members affected by RP.[1,7,8] This may be because their relatives are unaffected carriers and therefore do not show any symptoms. Genetic testing is the only method to find out how the condition is inherited in such situations, which will ultimately assist in family planning. Most sporadic cases turn out to be inherited in an autosomal recessive manner after genetic testing.
If you or your child is affected by RP, it is advisable to see a genetic counsellor to obtain more information and advice on inheritance and family planning options.
Is there any treatment?
1) Gene therapy
Gene therapy aims to halt retinal degeneration by replacing the mutated gene with a normal healthy copy. This enables the affected cells to regain some of their function and produce functioning proteins.
As of 2019, patients in the UK with inherited retinal dystrophies caused by mutations in the RPE65 gene are able to receive a treatment called Luxturna (voretigene neparvovec) under the NHS in four treatment centres:
- Great Ormond Street Hospital for Children, London (for children < 10 years of age)
- Moorfields Eye Hospital, London (for children and adults)
- Manchester Royal Eye Hospital
- Oxford Eye Hospital
This followed the approval by the US Food and Drug Administration (FDA) in 2017 after the success of a phase 3 trial conducted by Russell and colleagues. Patients with RPE65 genetic mutations typically have significant night blindness from birth. The trial showed that those patients treated with Luxturna in both eyes (sequentially at different periods) have improved visual function and navigational abilities at low light levels compared to those who did not receive treatment.
In Luxturna, a normal copy of the mutated RPE65 gene is “packaged” into a harmless virus called the adeno associated virus (AAV) which is then surgically injected into the retina (subretinal injection). This way, the affected retinal cells are maximally exposed to the viruses containing the normal gene.
- Further information about retinal degeneration caused by changes in the RPE65 gene
- Safety of gene therapy
- NHS news on the first UK patients receiving Luxturna treatment
- Explanation of different phases of clinical trials
2) Supportive treatment
There is no approved treatment for other types of RP at present but several clinical trials are ongoing. In the meantime, treatment is focused on alleviating symptoms and optimising remaining sight by treating other associated eye conditions. These include:
- Regular monitoring of visual function and prescribing glasses (if required) to optimise development of remaining vision
- Referral to low vision services
- Utilising visual aids and assistive technology to improve quality of life
- Having a healthy diet consisting of fresh fruits and green leafy vegetables
- Using blue light screen protectors on mobile devices or computer screens*
- Wearing hats/UV protected sunglasses and placing sunlight diffusers at the back window of cars to ease light sensitivity
- Regular check-ups to monitor for other eye conditions frequently associated with RP such as cataracts and cystoid macular oedema
*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.
Cataract surgery is an effective way to improve vision but up to 50% of RP patients do not experience any benefit due to extensive damage of the retina caused by RP.[11-13] Therefore, if you are interested in undergoing surgery, we recommend that you have a thorough discussion with your ophthalmologist beforehand to understand about the procedure, possible complications and the potential visual benefits so that you can make a well-informed decision.
Cystoid macular oedema is a common complication of RP and can be observed in up to 50% of patients. It usually resolves on its own and does not affect visual function. However, treatment may be commenced if patients are symptomatic. Eye drops is usually the first line of treatment before proceeding to oral medications if the drops are not working adequately. Response to treatment is highly variable among patients. Some may notice a significant improvement in vision while others may only experience mild or even no improvement despite treatment.
3) Systemic treatment
Patients presenting with RP in the context of an underlying medical condition often require input from a number of healthcare professionals.
If the onset of visual impairment occurs in early childhood, it can have a negative impact on their early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.
The Developmental Journal for babies and young children with visual impairment (DJVI), developed by Great Ormond Street Hospital Developmental Vision team is a structured early intervention programme designed to track developmental and vision progress in children from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents. Children with VI may be referred to developmental services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.
1) Gene therapy
The approval of Luxturna has intensified research in this specific area. Several clinical trials are currently underway for the following genes:
- MERTK (NCT 01482195, phase 1)
- PDE6B (NCT 03328130, phase 1/2)
- RLBP1 (NCT 03374657, phase 1/2)
- RPGR (NCT 03116113 [XIRIUS]; NCT 03316560; NCT 03252847, phase 1/2)
The MERTK trial with 2-year follow-up data demonstrated that it is a safe and well-tolerated procedure but no significant improvement in visual function or photoreceptor structure were reported in most of the participants during this period. However, only 6 participants were included in this report which preclude us from drawing a concrete conclusion about its effectiveness. The trial is still currently ongoing to monitor the long-term safety of MERTK gene therapy.
In other studies, only the 1-month and 6-month interim data are available in two RPGR trials (XIRIUS and NCT 03316560) respectively. These treatments will continue to progress through testing but it could take several years before they are generally available to patients.
2) Antisense RNA oligonucleotides (AONs)
AONs are small molecules genetically engineered to correct a disease-causing genetic mutation. It is being investigated as a therapeutic option for specific changes in two of the most common RP genes, RHO and USH2A.
The AURORA trial (NCT 04123626) aims to study the safety, tolerability and efficacy of an AON called QR-1123. It is injected intravitreally (a common outpatient procedure performed by ophthalmologist worldwide) in patients with a particular mutation (P23H) in the RHO gene that is highly prevalent in the US among those of European origin.
The STELLAR trial (NCT 03780257) is studying another AON called QR-421a. It is injected intravitreally into patients with mutations in a particular region of the USH2A gene (exon 13). The most common mutations in USH2A causing Usher syndrome and isolated RP are both located in this region. So far, the interim analysis has shown promising results, so the treatments will continue to progress through testing. However, more extensive trials will be required and it will be a few years before this treatment could be generally available.
3) Stem cell replacement
Stem cells are cells in the body that can develop into different specialised cell types (photoreceptors, liver, nerves etc) and multiply unlimited times (self-replication) to produce new stem cells. Using stem cells to replace damaged cells in the body has been researched in multiple areas of medicine, including inherited retinal dystrophies.
The photoreceptors in our retina are supported by a single layer of cells called the retinal pigment epithelium (RPE). RPE have been successfully cultured from stem cells and transplanted into patients with Stargardt disease and age-related macular degeneration.[15-18] A similar approach can be used in RP to replace the damaged photoreceptors but the ability of the transplanted cells to integrate successfully and signal correctly with other retinal cells remain a challenge that needs to be overcome.
A slightly different type of stem cell known as progenitor cells are also being investigated as a therapeutic option for RP. Progenitor cells are similar to stem cells but have limited ability in self-replication and can only develop into one or a few specialised cell types. In animal studies, retinal progenitor cells have been shown to protect surviving photoreceptors by releasing a type of protein called neurotrophic factors. This is currently being studied in two RP trials:
Preliminary data from both studies (ReNeuron and jCyte) have shown that both treatments are safe and well-tolerated, with some improvement in visual function observed. Further testing is needed over the coming months and years.
4) Other potential therapies for RP under research
- Types of stem cells
- Stem cells as potential treatment for eye diseases
- Research Opportunities at Moorfields Eye Hospital UK
- Searching for current clinical research or trials
Living with RP
Patients are still able to lead fairly independent lives through maximising their available vision and having access to social support. Here are some ideas:
- Attending the low vision clinic which provides access to low vision specialists, Eye Clinic Liaison Officers (ECLOs), visual aids and visual rehabilitation services
- Getting in touch with the local education authority for access to qualified teachers for children with visual impairment (QTVI) and special educational needs co-ordinator (SENCO)
- Registering your child as sight impaired (SI) or severely sight impaired (SSI) if eligible for access to social support and financial concessions
- Getting in touch with national or local charities for advice and peer support
- Coping with sight loss
- Education and learning
- Employment support
- Family support service
- Driving and alternative transport
If you are based in the UK and would like to be seen in the nearest specialist centre for your eye condition, either to receive a more comprehensive genetic management or just to find out more about current research, you can approach your GP to make a referral or alternatively arrange for a private appointment.
More information can be found in our “How to see a genetic eye specialist?” page.
- Retina UK
- Usher Kids UK
- Bardet-Biedl syndrome UK
- Royal National Institute of Blind People (RNIB)
- Guide Dogs for the Blind Association
- Look UK
- Retina International
- Foundation Fighting Blindness
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- Huang XF, Huang F, Wu KC, et al. Genotype-phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing. Genet Med. 2015;17(4):271-278
- Birtel J, Gliem M, Mangold E, et al. Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa. PLoS One. 2018;13(12):e0207958
- Ge Z, Bowles K, Goetz K, et al. NGS-based Molecular diagnosis of 105 eyeGENE((R)) probands with Retinitis Pigmentosa. Sci Rep. 2015;5:18287
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- Fahim AT, Daiger SP, Weleber RG. Nonsyndromic Retinitis Pigmentosa Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews(®). Seattle (WA): University of Washington, Seattle Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 2017
- Dryja TP, Hahn LB, Kajiwara K, Berson EL. Dominant and digenic mutations in the peripherin/RDS and ROM1 genes in retinitis pigmentosa. Invest Ophthalmol Vis Sci. 1997;38(10):1972-1982
- Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860
- Jackson H, Garway-Heath D, Rosen P, Bird AC, Tuft SJ. Outcome of cataract surgery in patients with retinitis pigmentosa. Br J Ophthalmol. 2001;85(8):936-938
- Yoshida N, Ikeda Y, Murakami Y, et al. Factors affecting visual acuity after cataract surgery in patients with retinitis pigmentosa. Ophthalmology. 2015;122(5):903-908
- Dikopf MS, Chow CC, Mieler WF, Tu EY. Cataract extraction outcomes and the prevalence of zonular insufficiency in retinitis pigmentosa. Am J Ophthalmol. 2013;156(1):82-88.e82
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- Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet. 2015;385(9967):509-516
- Mehat MS, Sundaram V, Ripamonti C, et al. Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration. Ophthalmology. 2018;125(11):1765-1775
- da Cruz L, Fynes K, Georgiadis O, et al. Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration. Nat Biotechnol. 2018;36(4):328-337
- Kashani AH, Lebkowski JS, Rahhal FM, et al. A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration. Sci Transl Med. 2018;10(435)
- Klassen H. Stem cells in clinical trials for treatment of retinal degeneration. Expert Opin Biol Ther. 2016;16(1):7-14
- Terrell D, Comander J. Current Stem-Cell Approaches for the Treatment of Inherited Retinal Degenerations. Semin Ophthalmol. 2019;34(4):287-292