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Genetics A-Z: Retinitis Pigmentosa
NURS 6233 -DE
Debosree Banerjee Jayaram
The George Washington University
October 28, 2018
Genetics A to Z
Name of Disease
Retinitis Pigmentosa
Inheritance Pattern and Family History
Retinitis Pigmentosa (RP), also known as non-syndromic RP, was first identified in 1990 as an autosomal dominant inheritance pattern, and this accounts for 30%-40% of reported cases; the number of mutations have increased in more than 80 genes since then, and the number of mutations continues to grow each year (Verbakel et al., 2018). It has also been found that there are patterns of autosomal recessive inheritance (50%-60% of reported cases), x-linked inheritance (5%-15% of reported cases), and sporadic/simplex traits (30% of reported cases) (Verbakel et al., 2018).
Chromosomal location of gene mutation if known
There are currently 83 known mutated gene locations that contribute to RP, each denoted as a subtype of RP (i.e. RP1, RP2, RP3, RP4, etc.) (Verbakel et al., 2018). In a study that examined 423 subjects, 206 had automsomal dominant RP, 238 had isolated/recessive RP, and 79 had RP of an unknown source, because there was no family history available (Verbakel et al., 2018). The majority of RP was found on the rhodopsin gene, which consisted of 59 out of the 423 subjects (Verbakel et al., 2018).
OMIM number
Incidence in population
As the most common inherited retinal dystrophy (IRD), RP has a worldwide prevalence of 1:3000 to 1:5000 people, and though there is no propensity in a particular sex, X-linked RP is expressed only in males, and they are more affected than women (Verbakel et al., 2018). It has been reported that the prevalence rate of RP is different according to certain ethnicities and regions of the world (Verbakel et al., 2018). These prevalence rates include: 1:5260 people in American and European populations, 1:2086 in the Jerusalem region, and it was higher for Arab Muslims (1:1798) than it was for Jews (1:2230) (Verbakel et al., 2018).
Type of mutation (s) if known
When RP manifests early in life, it tends to progress more rapidly. Patients with the autosomal dominant form of RP have the best overall prognosis in terms of retaining their vision, whereas patients with autosomal recessive RP have a worse course of the disease, and X-linked RP patients have the most severe disease course (Verbakel et al., 2018). The rhodopsin (RHO), USH2A, and RPGR genes contribute the most number of mutations that cause RP, but because there is no single mutation that accounts for 10% of unrelated patients, it is important to conduct genetic testing to screen for a group of genes (Verbakel et al., 2018).
Pathophysiology of the disease
RP causes visual disability and blindness, caused by progressive degeneration of rod receptors and retinal pigment epithelium (RPE), followed by the loss of cone receptors (Verbakel et al., 2018). Also seen throughout the different stages of RP are diminishing of the blood vessels, cystoid macular edema, disc pallor, and peripheral bone-spicule development (Verbakel et al., 2018). In an enucleated eye of a patient with autosomal RP showed that in the area of visual loss, rod and cone outer segments were shortened, and these disorganized the patient’s best field of vision; it also led to a total loss of outer segments and decrease in the number of photoreceptors (Verbakel et al., 2018, p. 173). Typical RPE cells were found to be moving away from the retinal pigment epithelial layer, and the cells that resembled macrophages that contained melanin were found to be invading the retina. For patients with autosomal dominant RP, findings included poorly organized, shortened, or even absent outer segments (Verbakel et al., 2018).
As mentioned previously, the most frequent mutations are in the RHO (phototransduction cascade), the USH2A (photoreceptor structure), or RPGR (maintenance of cilia or ciliated cells) genes (Verbakel et al., 2018). The phototransduction cascade is a series of reactions that are triggered by the stimulation of the opsin molecule by a photon, “resulting in an electrical signal that is transmitted via the optic nerve to the visual cortex, leading to the perception of an image” (Verbakel et al., 2018). The phototransduction cascade is similar to rods and cones, however have difference in function when it comes to dim light versus bright light. In terms of the USH2A gene, induced pluripotent cells stem cells taken from a patient’s keratinocytes and compared to the human retinal precursor cells (Verbakel et al., 2018). By looking at the USH2A gene’s mutation, it showed that these cells cause exonification of intron 40, which is a premature stop codon as well as protein misfolding (Verbakel et al., 2018). The RPGR gene is essential for making a protein that leads to normal vision, and involves the cell structures of cilia, which are finger-like projections that protrude off of the cell surface (Verbakel et al., 2018). The protein produced from RPGR contains a segment called the ORF15 exon, which helps maintain photoreceptors (Verbakel et al., 2018). However, this is the segment by which the mutation is caused, which disrupts the normal function of the cilia in the photoreceptor cells causing abnormally short, malfunctioning protein (Verbakel et al., 2018).
Diagnosis – genotype and phenotype
There are three main clinical features associated with RP: bone spicule pigmentation, retinal vessel degradation, and a waxy appearance of the optic nerve (Verbakel et al., 2018). Symptoms include night blindness also known as nyctalopia and the loss of peripheral vision (Verbakel et al., 2018). In addition to these symptoms, the following findings could lead to a diagnosis of RP: bilateral involvement (can be asymmetric), rod dysfunction evidenced by elevated rod final threshold on dark adaptation, and progressive loss in photoreceptor function (Verbakel et al., 2018). During adolescence, the fundus may appear normal, but an affected patient may undergo difficulty with adaptation to light and night blindness, which may then progress to tunnel vision and the loss of central vision in young adulthood (Verbakel et al., 2018). Later in life, the patient may develop retinal arteriolar attenuation, bone spicule pigmentation, and a waxy pallor of the optic discs (Verbakel et al., 2018).
Genetic testing for RP could provide more specifics of the disease and mutations, and could potentially provide diagnostic and prognostic information (Ruben, Park, Duong, Mahajan, ; Tsang, 2018). Currently, there is a number of screening technologies, and even though they are not necessarily burdensome, they are considered inefficient (Ruben et al., 2018). These screening technologies include: conformation sensitive gel electrophoresis, denaturing high performance liquid chromatography, and direct DNA sequencing (Ruben et al., 2018). Another method, called DNA micro-array technology, uses a disease chip that contains all of the known disease alleles, however it only detects known mutations and overlooks the mutations that are rare (Ruben et al., 2018).
Treatment/Gene Therapy
Because RP is a genetic disorder, there is no preventative measure for the manifestations that exist. Several studies have suggested that diet-based prevention by taking vitamin A or the fish oil docosahexaenoic acid can be used to prevent or decrease disease progression, however there has been no confirmed evidence that these can be used as treatment (Dias et al., 2017). However, there have been several trials regarding other modes of treatment for RP, and because the focus has been on the genetic causes of the disease, there has been significant progress with gene therapy (Dias et al., 2017).
One promising technique that is still being studied for safety, long-term survival, and function of the graft is the approach of transplantation of stem cell-derived RPE cells and/or photoreceptor cells (Dias et al., 2017). The technique would include cell replacement of the retinal progenitor cells (RPCs) or non-ocular derived stem cells into the vitreous body or subretinal space (Dias et al., 2017). Even though the donor cells of RPCs are hard to acquire, they are easy to process and the donor does not require immunosuppression therapy (Dias et al., 2017). But it takes a longer time to process stem cells. Sometimes, the cell therapy process itself can correct the genetic defect before transplantation is even required by using the technique of genome editing (Dias et al., 2017).
Another new technique for patients with little or no light perception with end-stage RP includes using electronic retinal implants, and there are two that are currently being used called the Argus II epiretinal implant, which works by mounting a miniature camera on a pair of eyeglasses, stimulating the retinal ganglion cells, and the Alpha AMS subretinal implant, which works by stimulating the bipolar cell layer (Dias et al., 2017). Both implants stimulate the inner retinal layers and require the inner retina to be intact, helping to restore basic vision, help with vision tests, and improve the patients’ daily mobility (Dias et al., 2017).
Another emerging approach to help patients that have lost photoreceptor or RPE cells is the use of optogenetics, which also uses gene therapy “to express light-activated ion channels in the residual retinal neurons, thereby restoring photosensitivity” (Verbakel et al., 2018, p. 178). However, since this is a newer technique, it needs to be studied and researched further before it can be approved for treatment.
Support groups and websites
Foundation Fighting Blindness is a foundation that supports research and grants that could lead to preventative measures, treatments, and cures. The website contains various events to show support for those affected like the Vision Walk, and conferences for researchers and physicians who strive to develop emerging approaches and research. The website also contains a blog called “Eye on the Cure” where fellow RP patients can show support for each other. https://www.blindness.org/
Prevent Blindness America is a website that provides contact information in each state for patients who want to reach out to a representative regarding RP and blindness. It also contains fact sheets regarding safety, eye health, and prevention. There is also a section that contains resources for professionals pertaining to initiatives, webinars, publications and research, and training materials. https://www.preventblindness.org/
Retina International is a website that has information on volunteer groups, charities, and foundations on an international level all to promote the research for retinal diseases such as RP. It has extensive information on rare eye conditions as well as a database that contains all of the retinal mutations that exist. It also contains information on several conferences that are held internationally that promote retinal research. http://www.retina-international.org/
Long-term outcome
Specialists are able to identify patients with progressive forms of RP, although there is limited research that shows that there are various uncertainties involving long-term visual prognoses in patients with RP. Researchers and specialists have found that the age of patients with RP varies when it comes to the severity of the disease, whether it is 30 years of age or 80 years of age (Verbakel et al., 2018). Usually, a slow rate of progression exists for patients with the condition, whether they will be able to see for another 10 years or another 40 years (Verbakel et al., 2018). Based on the severity of the condition, some patients may have a good prognosis, considering that they might be able to retain useful vision their entire lives without treatment. It is recommended that patient with RP should return for doctors’ visits three to four times per 2-3 years to assess their rate of disease progression (Verbakel et al., 2018).
References
Dias, M., Joo, K., Kemp, J., Fialho, S., da Silva Cunha, A., Woo, S., and Kwon, Y. (2017). Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives. Progress in Retinal and Eye Research 63, 107-131. DOI: 10.1016/j.preteyeres.2017.10.004
Lewin, A., Rossmiller, and Mao, H. (2014). Gene augmentation for adRP mutations in RHO. Cold Spring Harbor Perspectives in Medicine 4, 1-14. DOI: 10.1101/cshperspect.a017400
Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 26800: 08/07/2018. World Wide Web URL: https://omim.org/
Ruben, J., Park, K., Duong, J., Mahajan, V., and Tsang, S. (2018) Quantitative progression of retinitis pigmentosa by optical coherence tomography angiography. Scientific Reports 8(12130), 1-7. DOI: 10.1038/s41598-018-31488-1
Verbakel, S., van Huet, R., Boon, C., den Hollander, A., Collin, R., Klaver, C.,… Klevering, J.

(2018). Non-syndromic retinitis pigmentosa. Progress in Retinal and Eye Research
66, 157-186. DOI: 10.1016/j.preteyeres.2018.03.005

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