Course:MEDG550/Student Activities/Non-syndromic Retinitis Pigmentosa

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Non-Syndromic Retinitis Pigmentosa

Overview

Non-syndromic retinitis pigmentosa (RP) is a group of genetic conditions that cause vision loss over time. Loss of vision in these conditions is caused by the gradual breakdown of parts of the retina, called cones and rods. There are many genes involved in the functioning of the cones and rods that are implicated in RP. Other types of RP include Syndromic RP and Systemic RP, where different body systems are involved[1]. Non-syndromic RP will be the focus of this review, and the effects of this condition are confined to the eyes.  

Pathophysiology

Diagram showing different parts of the eye. The rods and cones are not pictured but are located inside of the retina.

To understand RP, it is important to understand what the retina is and how it is impacted in this condition.

The retina is a layer of nerves in the eye that sense light and allow the brain to process that light. Within the retina, there are two types of photoreceptors. Photoreceptors are cells that convert light into signals for the brain to use for vision. Without photoreceptors, someone would not be able to see. There are two types of photoreceptors in the retina: rods and cones. Rods allow a person to see in low light and night vision because they are sensitive to small amounts of light. Cones allow a person to see colour. They are less sensitive to light than rods are, so they are more active during the day or in brightly lit areas. Another difference between the two is that cones are mostly located in the centre of the retina (so are more associated with central vision) and rods are located all over the retina (associated with central and peripheral vision).

In RP, rods and cones break down, causing vision to gradually decrease. Rods begin to degenerate first, which is why the initial symptoms most people experience are trouble with night vision and loss of peripheral vision. In the later stages of the condition, cones break down, eventually leading to blindness[1],[2].

Characteristics

The prevalence of RP is approximately 1:4000 globally[3].

Age of onset can vary based on the specific gene involved, but more than ¾ of people with RP experience symptoms before the age of 30[4].

Common characteristics of RP include[1],[2],[5]:

  • Night blindness: Oftentimes this symptom becomes apparent in adolescence. The time of onset of night blindness can often indicate how severe the RP will be (i.e. an earlier onset of night blindness may indicate a more severe case of RP). Night blindness is the result of loss of rod function.
  • Loss of peripheral vision: This is also a result of loss of rod function and tends to be one of the initial symptoms, in addition to night blindness.
  • Clarity of vision: Related to cone function. Clarity of the central vision is typically preserved until the end stages of RP. At this time, individuals may experience “tunnel vision” where they can only see clearly with their central vision. This vision is usually preserved until the end stages of RP, after which an individual becomes completely blind.
  • Photophobia: In both the early and later stages of the condition, individuals can become very sensitive to bright light.
  • Changes in the appearance of the fundus: The fundus is an area in the back of the eye which contains the retina, blood vessels, and nerves. The fundus looks different depending on the progression of the RP. As RP progresses, blood vessels in the fundus may become narrower, the fundus can have changes in pigmentation, and the retina begins to break down. Additionally, the optic nerve, which is an important nerve within the fundus, appears to be pale in colour and takes on a waxy appearance.

Genetics

RP is a genetic condition. Typically, every person has two copies of each gene in their body, one copy is inherited from their biological father and one copy is inherited from their biological mother. When there is a genetic change in a gene, it can cause the gene to not function properly.

Changes or differences in our genes can also be inherited from our parents. These changes can be inherited in different ways. The way a change is inherited is called its “inheritance pattern”. The genetic changes that cause RP can be inherited in three different ways: 1) Autosomal dominant, 2) Autosomal recessive, and 3) X-linked recessive[4],[6],[7].

Autosomal dominant inheritance of RP showing the likelihood of children inheriting the genetic change when one parent has RP

Depending on the inheritance pattern of a genetic change, the chance that it gets passed down to an individual’s children can be calculated. This is called the recurrence risk. The inheritance pattern can also provide information about which other family members may be at risk for developing RP. If a genetic change is found in someone with RP, genetic testing to look for the same change may be available for themselves or their partner when they become pregnant. This test will tell parents if the baby will also have RP.

Autosomal dominant RP

Autosomal dominant inheritance means that to be affected, an individual only needs to have a genetic change on one copy of a gene associated with RP. Approximately 30-40% of RP cases are thought to be inherited in this way6,7.

Children of a person with autosomal dominant RP will each have a 50% chance of inheriting the genetic change and being affected with RP. Each child will also have a 50% chance of inheriting the gene without the change.

Both biological parents of this individual will have a 50% risk of having this same genetic change. By the time their child is diagnosed, the parent with the genetic change will likely have experienced symptoms of RP.  

Each full sibling of an individual with RP will have a 50% chance of having the same genetic change.

Autosomal recessive RP

Autosomal recessive inheritance of RP showing the likelihood of children having RP when both parents are carriers

Autosomal recessive means that to be affected, an individual must have a genetic change on both copies of a gene associated with RP. About 50-60% of RP cases are inherited in this way[6],[7]. A person who has a change in one gene but not the other can be called a carrier and usually does not experience symptoms of RP.

If an individual with autosomal recessive RP has children with a carrier of the condition, each child will have a 50% chance of inheriting both genetic changes and having RP. Each child has a 50% chance of inheriting one of the two genetic changes, making them a carrier. Children of carriers have a 25% chance of inheriting both genetic changes, meaning they will have RP, a 50% chance of being a carrier themselves, and a 25% of not inheriting either genetic change.

When someone is diagnosed with an autosomal recessive type of RP, it is most likely that each of their parents are carriers. Their siblings each have a 25% chance of having inherited both genetic changes, which would mean they also have RP. Siblings each have a 50% chance of having inherited one of the two genetic changes. In this case, they would be a carrier of RP.

Something unique about autosomal recessive RP is that patients tend to begin having symptoms in adolescence, which is younger than the typical presentations for the other inheritance patterns[4].


X-linked recessive inheritance of RP showing the likelihood of children having RP when a male has RP


X-Linked recessive RP

X-linked recessive inheritance means that to be affected, an individual must have a genetic change on both of their X chromosomes (if they have two, as people assigned female at birth do) or on their only X chromosome (people assigned male at birth have an X and a Y chromosome). Approximately 5-15% of RP cases are inherited in this way[6],[7].

In X-linked recessive RP, people assigned male at birth are primarily affected as they have only one X chromosome. In an affected patient who is assigned male at birth, their sons will not be at risk of inheriting the genetic change, since sons will inherit the Y chromosome from their father, not the X. Their daughters will have a 100% chance of inheriting the genetic change but will likely not be affected unless their biological mother also has a genetic change in a gene associated with RP, in which case each daughter would have a 2/3 chance of being affected.

A male with X-linked RP will have inherited the genetic change from his mother since he receives his X chromosome from his biological mother and his Y chromosome from his biological father.

Male siblings of a male with X-linked RP have a 50% chance of having inherited the genetic change and being affected with RP. Female siblings of a male with X-linked RP have a 50% chance of being carriers.


Diagnosis

Someone with RP may have a test where a specialized doctor examines a part of their eye called the fundus. The fundus is the back section of the eye and contains important parts of the eye including the retina. The doctor may see differences in the fundus, which could allow them to make a diagnosis of RP.

Clinical diagnosis can be established when the three main signs of RP are observed during an eye exam. These three signs are[5]:

  • A change in pigmentation of the fundus
  • Narrowing and fewer blood vessels in the retina than expected
  • A pale and waxy appearance of the optic nerve

A diagnosis of RP can be genetically confirmed using a test that reads through genes that are known to be associated with RP. 50-80% of people with RP will have a change known to cause RP in their genes that a test can detect[8],[9]. If someone does not have a genetic change detected, they still have RP if they have the three main signs of RP (listed above).

Family members of someone with RP can also be tested genetically for RP if the person with RP has a change identified in their genes.

Management

There is no cure for RP. RP is primarily managed by monitoring vision and the function of the retina and by treating complications when/if they arise. Vision aids, like special glasses, can also help to retain vision for as long as possible[10].

To monitor vision, someone with RP would ideally have an appointment at least once a year with a specialized eye doctor. The doctor will perform tests to assess vision and look for signs of any complications.

Examples of complications that can arise are cataracts (cloudy areas in the eye that make it difficult to see) and swelling in the eye[10].

There is currently ongoing research into gene therapies and medications for RP, but none of these treatments are widely available at this time.

Resources for Patients

Fighting Blindness Canada[11]

  • Fighting Blindness Canada is a nonprofit organization that provides information on retinal diseases affecting Canadians, including retinitis pigmentosa. Their website has educational tools for patients, updates about current research, and is equipped with accessibility features like text-to-audio features for the website content.

National Eye Institute[12]

  • The National Eye Institute is an organization that provides patient-friendly information on eye-related conditions, including retinitis pigmentosa. The website contains information about the condition, directs interested patients to current clinical trials they may be eligible for, and printable and downloadable PDFs of information about the condition and tips for individuals with low vision.

References

  1. ↑ Jump up to: 1.0 1.1 1.2 Fahim AT, Daiger SP, Weleber RG. Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [Updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1417/
  2. ↑ Jump up to: 2.0 2.1 Verbakel SK, van Huet RAC, Boon CJF, den Hollander AI, Collin RWJ, Klaver CCW, Hoyng CB, Roepman R, Klevering BJ. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res. 2018 Sep;66:157-186.
  3. ↑ Berson, E. L. (1993). Retinitis pigmentosa. the friedenwald lecture. Investigative Ophthalmology & Visual Science, 34(5), 1659.
  4. ↑ Jump up to: 4.0 4.1 4.2 Cross N, van Steen C, Zegaoui Y, Satherley A, Angelillo L. Retinitis Pigmentosa: Burden of Disease and Current Unmet Needs. Clin Ophthalmol. 2022;16:1993-2010.
  5. ↑ Jump up to: 5.0 5.1 Hamel, C. Retinitis pigmentosa. Orphanet J Rare Dis 1, 40 (2006). https://doi.org/10.1186/1750-1172-1-40
  6. ↑ Jump up to: 6.0 6.1 6.2 Li, C., Zhang, C., Bai, D., & Cui, Y. (2024). Clinical and molecular findings in children with retinitis pigmentosa. Ophthalmic Genetics, 45(5), 441–451. https://doi.org/10.1080/13816810.2024.2357305
  7. ↑ Jump up to: 7.0 7.1 7.2 Bunker, Clareann H. et al. Prevalence of Retinitis Pigmentosa in Maine. American Journal of Ophthalmology. 1984 March; 97(3): 357 – 365. Doi: 10.1016/0002-9394(84)90636-6
  8. ↑ Corton M, Nishiguchi KM, Avila-Fernández A, Nikopoulos K, Riveiro-Alvarez R, Tatu SD, Ayuso C, Rivolta C. Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis. PLoS One. 2013 Jun 14;8(6):e65574. doi: 10.1371/journal.pone.0065574. Erratum in: PLoS One. 2016 Mar 31;11(3):e0153121. doi: 10.1371/journal.pone.0153121. PMID: 23940504; PMCID: PMC3683009.
  9. ↑ Xu Y, Guan L, Shen T, Zhang J, Xiao X, Jiang H, Li S, Yang J, Jia X, Yin Y, Guo X, Wang J, Zhang Q. Mutations of 60 known causative genes in 157 families with retinitis pigmentosa based on exome sequencing. Hum Genet. 2014 Oct;133(10):1255-71. doi: 10.1007/s00439-014-1460-2. Epub 2014 Jun 18. PMID: 24938718.
  10. ↑ Jump up to: 10.0 10.1 Nguyen, X.-T.-A., Moekotte, L., Plomp, A. S., Bergen, A. A., van Genderen, M. M., & Boon, C. J. F. (2023). Retinitis Pigmentosa: Current Clinical Management and Emerging Therapies. International Journal of Molecular Sciences, 24(8), 7481. https://doi.org/10.3390/ijms24087481
  11. ↑ Retinitis Pigmentosa. (September 2020). Fighting Blindness Canada. Retrieved on January 30, 2025, from https://www.fightingblindness.ca/eyehealth/eye-diseases/retinitis-pigmentosa/
  12. ↑ Retinitis Pigmentosa. (November 2023). The National Eye Institute. Retrieved on January 30, 2025, from https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/retinitis-pigmentosa
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