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RP2-Associated Retinitis Pigmentosa

Title: RP2-Associated Retinitis Pigmentosa
Author (s): Eleanor Burton, 4th year medical student, JHUSOM
Date: 9/7/2021
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).

Fundus exam revealed a “beaten metal” macula and lightly pigmented peripheral retina (Figure 1-1)Fundus exam revealed a “beaten metal” macula and lightly pigmented peripheral retina (Figure 1-2)

Optic nerves were normal. Fundus autoflurorescence demonstrated parafoveal hyperautoflurescence (Figure 2).

Optic nerves were normal. Fundus autoflurorescence demonstrated parafoveal hyperautoflurescence (Figure 2-1) Optic nerves were normal. Fundus autoflurorescence demonstrated parafoveal hyperautoflurescence (Figure 2-2)

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).

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 3-1).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 3-2).

Full-field electroretinography demonstrated poor rod and cone function OU (Figure 4).

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 (, 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:


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Faculty Approval by: Paul Bernstein, MD, PhD
Identifier: Moran_CORE_26959
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