RP2-Associated Retinitis Pigmentosa
Title: RP2-Associated Retinitis Pigmentosa
Author (s): Eleanor Burton, 4th year medical student, JHUSOM
Keywords/Main Subjects: Retinitis Pigmentosa, Cone-Rod Dystrophy, RP2
Diagnosis: X-linked Retinitis Pigmentosa associated with RP2 gene mutation
Description of Case: A 20-year-old man presented with bilateral central vision loss and decreased contrast sensitivity. Past ocular history was notable for amblyopia status post strabismus surgery at ages 5, 13, and 15 years, myopia (-3.25 OD, -4.00 OS), and contact lens-associated corneal ulcer with peripheral corneal scarring OD. Medical history was unremarkable. Family history was notable for poor night vision and keratoconus in his father, but no history of retinal disease.
On exam, the patient had bilateral central scotomas, best corrected visual acuity (BCVA) of 20/30 OU, and scored 2/11 OU on the Ishihara test for color blindness. Slit lamp exam was notable only for anterior stromal scar at the mid-periphery OD. Fundus exam revealed a “beaten metal” macula and lightly pigmented peripheral retina (Figure 1).
Optic nerves were normal. Fundus autoflurorescence demonstrated parafoveal hyperautoflurescence (Figure 2).
On Goldmann perimetry, the patient had superior and nasal constriction of his visual fields and diminished central vision OU with a paracentral scotoma in his left eye (Figure 3).
Full-field electroretinography demonstrated poor rod and cone function OU (Figure 4).
Given the concern for an inherited cone-rod dystrophy, the patient was referred for genetic testing, which revealed hemizygous RP2 c.934C>T, p.(Gln312*), which is a nonsense mutation that results in a premature stop codon and that is likely pathogenic.
Epidemiology: Retinitis pigmentosa (RP) is an inherited, degenerative disease of the photoreceptors and retinal pigmented epithelium (RPE) that affects about 1 in 750 to 9000 people worldwide, with estimates of prevalence varying widely by geographic location.1–6
Genetics: About half of patients with RP have no significant family history and are considered sporadic.2 Among patients with a clear pattern of inheritance, the majority (~50-60%) are autosomal recessive, ~30-40% autosomal dominant, and ~10-15% X-linked recessive (XL).7–10 According to the Retinal Information Network, there are now more than 130 genes known to cause RP (https://sph.uth.edu/retnet/, accessed September 22, 2021) and hundreds of different mutations within these genes contributing to significant genetic, allelic, phenotypic, and clinical variability.7,11–17 Mutations in the retinitis pigmentosa GTPase regulator (RPGR, 70-90% of cases) and RP2 (10-20%) genes comprise the majority of cases of XLRP.7,17,18 RP2 is located on the short arm of the X chromosome and encodes a GTPase-activating protein primarily found in the plasma membrane of photoreceptors.19,20 RP2 plays a vital role in mediating photoreceptor intraflagellar transport, and RP2-knockout zebrafish models exhibit rapid retinal degeneration.21–23
Clinical Presentation: Most patients with RP initially present with nyctalopia and progressive mid-peripheral visual field loss by age 30.2,18 Estimates of the rate of visual field loss vary,24,25 but most patients deteriorate to legal blindness by age 40.1 Given the predominant involvement of rods over cones, RP is typically considered a rod-cone dystrophy. Fundus exam typically reveals attenuated retinal vessels, optic disc pallor, and bone spicule pigmentary changes.18,26
Interestingly, RP2-XLRP presents differently, as demonstrated in the case presented above. RP2-XLRP tends to present at a younger age and progress more rapidly than other forms of RP. Although there is significant phenotypic variability among patients with RP2-XLRP, a cohort study of 18 patients with RP2-XLRP found several commonalities, including BCVA worse than 20/40, high myopia (greater than –6.00 D), and early-onset (before age 12) macular atrophy resulting in central scotoma.27 Most patients in this study had a rod-cone dystrophy pattern on ERG, but one patient had cone-rod dystrophy (similar to the patient described above). On fundus exam, patients with RP2-XLRP often have perimacular golden metallic luster known as the “tapetal-like reflex” (TLR), peripheral pigmentary changes, and macular atrophy.28 Female carriers of pathogenic RP2 mutations may have the characteristic TLR on fundus exam but are usually asymptomatic or, in very severe cases, may develop symptoms similar to their male counterparts.27,29,30
Diagnosis: Diagnosis is typically based on patient symptoms, fundus exam, ERG, and Goldmann perimetry.2,18 However, as genetic testing has become more widely available and less expensive, patients with a clinical diagnosis of RP are now commonly referred for genetic testing for confirmation of the diagnosis, more individualized counseling, and entry into genetics databases.
Management: Currently, the only effective treatment or cure for any form of RP is gene therapy for RPE65-related mutations.31 Ongoing research in animal models and clinical trials show promise for the future. Stem cell therapy in photoreceptor-deficient mice induced development of RPE and partially restored light perception.32–34 Retina transplants in both animal and human models yielded improvements in visual acuity.35 For RP2-XLRP, specifically, gene therapy studies in mouse models demonstrated restoration of cone function in RP2-knockout mice receiving subretinal adeno-associated viral (AAV) RP2.36 Further studies are needed to optimize these promising treatments for human use.
Summary of the Case:
- Retinitis pigmentosa is an inherited degenerative disease of the photoreceptors and retinal pigmented epithelium.
- There is significant variability in the clinical presentation of patients with RP, but most progress to legal blindness by age 40.
- Compared with other forms of RP, patients with RP2-XLRP often present at a younger age with worse visual acuity, central vision loss, and, rarely, a cone-rod dystrophy pattern.
- Current treatment is limited to RPE65-related RP, but studies exploring additional gene therapy, stem cell transplantation, and retinal transplantation show promise for the future.
- Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006;368(9549). doi:10.1016/S0140-6736(06)69740-7
- O’Neal TB and LEE. Retinitis Pigmentosa. StatPearls [Internet] Treasure Isl StatPearls Publ. January 2021.
- Bessant D. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev. 2001;11(3). doi:10.1016/S0959-437X(00)00195-7
- Pagon RA. Retinitis pigmentosa. Surv Ophthalmol. 1988;33(3). doi:10.1016/0039-6257(88)90085-9
- Na K-H, Kim HJ, Kim KH, et al. Prevalence, Age at Diagnosis, Mortality, and Cause of Death in Retinitis Pigmentosa in Korea—A Nationwide Population-based Study. Am J Ophthalmol. 2017;176. doi:10.1016/j.ajo.2017.01.014
- Nangia V, Jonas JB, Khare A, Sinha A. Prevalence of retinitis pigmentosa in India: the Central India Eye and Medical Study. Acta Ophthalmol. 2012;90(8). doi:10.1111/j.1755-3768.2012.02396.x
- Schwahn U, Lenzner S, Dong J, et al. Positional cloning of the gene for X-linked retinitis pigmentosa 2. Nat Genet. 1998;19(4). doi:10.1038/1214
- Hardcastle AJ, Thiselton DL, Van Maldergem L, et al. Mutations in the RP2 Gene Cause Disease in 10% of Families with Familial X-Linked Retinitis Pigmentosa Assessed in This Study. Am J Hum Genet. 1999;64(4). doi:10.1086/302325
- Miano MG, Testa F, Filippini F, et al. Identification of novel RP2 mutations in a subset of X-linked retinitis pigmentosa families and prediction of new domains. Hum Mutat. 2001;18(2). doi:10.1002/humu.1160
- Evans RJ, Schwarz N, Nagel-Wolfrum K, Wolfrum U, Hardcastle AJ, Cheetham ME. The retinitis pigmentosa protein RP2 links pericentriolar vesicle transport between the Golgi and the primary cilium. Hum Mol Genet. 2010;19(7). doi:10.1093/hmg/ddq012
- Koyanagi Y, Akiyama M, Nishiguchi KM, et al. Regional differences in genes and variants causing retinitis pigmentosa in Japan. Jpn J Ophthalmol. 2021;65(3). doi:10.1007/s10384-021-00824-w
- Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations causing retinitis pigmentosa. Clin Genet. 2013;84(2). doi:10.1111/cge.12203
- Rosenfeld PJ, Cowley GS, McGee TL, Sandberg MA, Berson EL, Dryja TP. A Null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa. Nat Genet. 1992;1(3). doi:10.1038/ng0692-209
- McLaughlin ME, Sandberg MA, Berson EL, Dryja TP. Recessive mutations in the gene encoding the β–subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nat Genet. 1993;4(2). doi:10.1038/ng0693-130
- Dryja TP, Finn JT, Peng YW, McGee TL, Berson EL, Yau KW. Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa. Proc Natl Acad Sci. 1995;92(22). doi:10.1073/pnas.92.22.10177
- Daiger SP. Perspective on Genes and Mutations Causing Retinitis Pigmentosa. Arch Ophthalmol. 2007;125(2). doi:10.1001/archopht.125.2.151
- Sahel J-A, Marazova K, Audo I. Clinical Characteristics and Current Therapies for Inherited Retinal Degenerations. Cold Spring Harb Perspect Med. 2015;5(2). doi:10.1101/cshperspect.a017111
- Wang AL, Knight DK, Vu TT, Mehta MC. Retinitis Pigmentosa: Review of Current Treatment. Int Ophthalmol Clin. 2019;59(1). doi:10.1097/IIO.0000000000000256
- Veltel S, Gasper R, Eisenacher E, Wittinghofer A. The retinitis pigmentosa 2 gene product is a GTPase-activating protein for Arf-like 3. Nat Struct Mol Biol. 2008;15(4). doi:10.1038/nsmb.1396
- Bartolini F, Bhamidipati A, Thomas S, Schwahn U, Lewis SA, Cowan NJ. Functional Overlap between Retinitis Pigmentosa 2 Protein and the Tubulin-specific Chaperone Cofactor C. J Biol Chem. 2002;277(17). doi:10.1074/jbc.M200128200
- Kannabiran C. Review: Intraflagellar transport proteins in the retina. Mol Vis. 2020;26.
- Zhang J, Gao F, Du C, et al. A novel RP2 missense mutation Q158P identified in an X-linked retinitis pigmentosa family impaired RP2 protein stability. Gene. 2019;707. doi:10.1016/j.gene.2019.05.006
- Liu F, Chen J, Yu S, et al. Knockout of RP2 decreases GRK1 and rod transducin subunits and leads to photoreceptor degeneration in zebrafish. Hum Mol Genet. 2015;24(16). doi:10.1093/hmg/ddv197
- Berson EL, Sandberg MA, Rosner B, Birch DG, Hanson AH. Natural Course of Retinitis Pigmentosa Over a Three-Year Interval. Am J Ophthalmol. 1985;99(3). doi:10.1016/0002-9394(85)90351-4
- Holopigian K, Greenstein V, Seiple W, Carr RE. Rates of Change Differ among Measures of Visual Function in Patients with Retinitis Pigmentosa. Ophthalmology. 1996;103(3). doi:10.1016/S0161-6420(96)30679-9
- Pruett RC. Retinitis pigmentosa: clinical observations and correlations. Trans Am Ophthalmol Soc. 1983;81.
- Jayasundera T. RP2 Phenotype and Pathogenetic Correlations in X-Linked Retinitis Pigmentosa. Arch Ophthalmol. 2010;128(7). doi:10.1001/archophthalmol.2010.122
- Genead MA, Fishman GA, Lindeman M. STRUCTURAL AND FUNCTIONAL CHARACTERISTICS IN CARRIERS OF X-LINKED RETINITIS PIGMENTOSA WITH A TAPETAL-LIKE REFLEX. Retina. 2010;30(10). doi:10.1097/IAE.0b013e3181dde629
- Comander J, Weigel-DiFranco C, Sandberg MA, Berson EL. Visual Function in Carriers of X-Linked Retinitis Pigmentosa. Ophthalmology. 2015;122(9). doi:10.1016/j.ophtha.2015.05.039
- Misky D, Guillaumie T, Baudoin C, et al. Pattern dystrophy in a female carrier of RP2 mutation. Ophthalmic Genet. 2016;37(4). doi:10.3109/13816810.2015.1081253
- Darrow JJ. Luxturna: FDA documents reveal the value of a costly gene therapy. Drug Discov Today. 2019;24(4). doi:10.1016/j.drudis.2019.01.019
- Uy HS, Chan PS, Cruz FM. Stem cell therapy: a novel approach for vision restoration in retinitis pigmentosa. Med hypothesis, Discov Innov Ophthalmol J. 2013;2(2).
- Li T, Lewallen M, Chen S, Yu W, Zhang N, Xie T. Multipotent stem cells isolated from the adult mouse retina are capable of producing functional photoreceptor cells. Cell Res. 2013;23(6). doi:10.1038/cr.2013.48
- Li Y, Tsai Y-T, Hsu C-W, et al. Long-term safety and efficacy of human-induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa. Mol Med. 2012;18. doi:10.2119/molmed.2012.00242
- Seiler MJ, Aramant RB. Cell replacement and visual restoration by retinal sheet transplants. Prog Retin Eye Res. 2012;31(6). doi:10.1016/j.preteyeres.2012.06.003
- Mookherjee S, Hiriyanna S, Kaneshiro K, et al. Long-term rescue of cone photoreceptor degeneration in retinitis pigmentosa 2 ( RP2 )-knockout mice by gene replacement therapy. Hum Mol Genet. 2015;24(22). doi:10.1093/hmg/ddv354
Faculty Approval by: Paul Bernstein, MD, PhD
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