RPGR-Associated Dystrophies: Clinical, Genetic, and Histopathological Features

Abstract

This study describes the clinical, genetic, and histopathological features in patients with RPGR-associated retinal dystrophies. Nine male patients from eight unrelated families underwent a comprehensive ophthalmic examination. Additionally, the histopathology of the right eye from a patient with an end-stage cone-rod-dystrophy (CRD)/sector retinitis pigmentosa (RP) phenotype was examined. All RPGR mutations causing a CRD phenotype were situated in exon ORF15. The mean best-corrected visual acuity (BCVA, decimals) was 0.58 (standard deviation (SD)): 0.34; range: 0.05-1.13); and the mean spherical refractive error was -4.1 D (SD: 2.11; range: -1.38 to -8.19). Hyperautofluorescent rings were observed in six patients. Full-field electroretinography responses were absent in all patients. The visual field defects ranged from peripheral constriction to central islands. The mean macular sensitivity on microperimetry was 11.6 dB (SD: 7.8; range: 1.6-24.4) and correlated significantly with BCVA (r = 0.907; p = 0.001). A histological examination of the donor eye showed disruption of retinal topology and stratification, with a more severe loss found in the peripheral regions. Reactive gliosis was seen in the inner layers of all regions. Our study demonstrates the highly variable phenotype found in RPGR-associated retinal dystrophies. Therapies should be applied at the earliest signs of photoreceptor degeneration, prior to the remodeling of the inner retina.

Keywords: Retinitis Pigmentosa GTPase Regulator (RPGR), cone-rod dystrophy; genotype-phenotype; histopathology; natural history; retinal dystrophies; retinitis pigmentosa.

Figure 1

Graph demonstrating the change in mean best-corrected visual acuity (BCVA) in relation to the age in years of this cohort. Snellen BCVA data were transformed into logMAR values. Data from the same subject are shown using interpolation lines connecting the points. All patients had a retinitis pigmentosa phenotype, except for patient H-9, who exhibited a cone-rod dystrophy phenotype.

Figure 2

Color fundus photographs (scale bar = 1 mm) and corresponding fundus autofluorescence (FAF, scale bar = 1 mm) and spectral-domain optical coherence tomography (SD-OCT, scale bar = 200 µm) images of patients carrying mutations in the RPGR gene. (A) The right eye of patient A-1, with a best-corrected visual acuity (BCVA) of 0.05, showing a tilted optic disc, vascular attenuation, and bone-spicule hyperpigmentation in the midperiphery. Degenerative changes are seen across the entire retina, with sparing of the central macula. An atrophic perifoveal ring is present, resembling a bull’s eye maculopathy. Correspondingly, FAF imaging in this patient showed hypo-autofluorescent (hypo-AF) lesions throughout the posterior pole, with sparing of the central macula, and some optic disc drusen. On SD-OCT imaging, atrophy of outer retinal layers is observed, with some relative preservation of the ellipsoid zone (EZ) at the fovea. (B) The composite fundus photograph of the left eye of patient B-2 (BCVA of 0.9), showing optic nerve head drusen, normal vessels, and bone-spicule hyperpigmentation in the periphery. FAF imaging showed hypo-AF regions along the vascular arcades and far periphery. A macular hyperautofluorescent (hyper-AF) ring is observed, which matches the extent of EZ loss seen on SD-OCT. (C) The right eye of patient C-4 (BCVA of 0.36) carrying the c.706C > T (p.[Gln236*]) mutation. In addition to bone-spicule hyperpigmentation in the periphery, the fundus of this patient also displayed atrophic changes in the macula. A hyper-AF ring was seen on FAF, encircled by a hypo-AF ring, which corresponded with the loss of outer retinal bands on SD-OCT. (D) The right eye of patient G-8, with a BCVA of 0.25. The accumulation of hyperpigmented clumps in the macular region is observed, as well as outside the retinal vascular arcades. On FAF imaging, granular hypo-AF lesions are seen in the posterior pole, and a large central hypo-AF area is seen. SD-OCT imaging shows atrophy of retinal layers, with increased choroidal visibility. Remnants of the outer retinal bands are present in the (para)fovea, together with hyperreflective elevations at the level of the retinal pigment epithelium (RPE) that seem to correspond to the hyperpigmented deposits on fundus photography. (E) The left eye of patient H-9 (BCVA of 0.76), with a cone-rod dystrophy phenotype. A bull’s eye appearance is seen in the macula on fundus examination, without the presence of bone-spicule-like deposits. Similar findings are seen on FAF imaging, with hyper-AF spot in the fovea, where the outer retinal layers are relatively preserved on SD-OCT, surrounded by a hypo-AF ring of outer retinal and RPE atrophy, which itself is surrounded by a hyper-AF ring.

Figure 3

Multimodal imaging and microperimetry in the left eye of patient G-8 (best-corrected visual acuity of the left eye: 0.10). (A) Microperimetry revealed reduced, but measurable sensitivity (red and orange sensitivity points) at the central 2° of the fovea, with nearly a complete absence of sensitivity outside this region (black sensitivity points). Superimposed microperimetry data on the fundus autofluorescence (FAF) image demonstrated that loss of retinal sensitivity on microperimetry aligned with hypo-autofluorescent lesions on FAF. Scale bar = 1 mm. (B) The corresponding fundus image showed clinical hallmarks of retinitis pigmentosa and macular atrophy. Scale bar = 1 mm. (C) Spectral-domain optical coherence tomography (SD-OCT) showed remnants of the outer retina at the (para)fovea. Scale bar = 200 µm.

Figure 4

Clinical characteristics and postmortem histopathological examination in patient I-10 at the age of 94, who carried the p.Glu1031Glyfs*58 (c.3092del) mutation in RPGR. (A) A line graph detailing the best-corrected visual acuity (logMAR) course regression in this patient. A cataract extraction was performed at the age of 66 (left eye; OS) and 74 (right eye; OD). For hand movement vision, light perception vision, and no light perception, logMAR values of 2.7, 2.8, and 2.9 were used, respectively. (B) A fundus examination of the right eye at age 89 showed a pale optic disc with extensive peripapillary and macular atrophy. Retinal vessels were attenuated or obliterated. Bone-spicule-like pigmentation is mainly seen in the inferior-nasal quadrant. The green line illustrates the spectral-domain optical coherence tomography (SD-OCT) section line. Scale bar = 1 mm. (C) Goldmann kinetic perimetry at the age of 67 showed a superior hemifield defect. (D) SD-OCT imaging revealed profound degeneration of all retinal layers. Scale bar = 200 µm. (E) A macroscopic examination of the right eye. A schematic drawing indicating the approximate macular (I) and peripheral (II and III) regions sectioned and processed for further examination. (F) A section of the macular region (I) showing the loss of photoreceptor segments and the closing of the subretinal space. The retinal pigment epithelium (RPE) layer is atrophic, but still visible in this section (hematoxylin-eosin (H&E), 200×). (G) A complete absence of photoreceptor outer segments and RPE cells is observed in this peripheral section (II). The inner layers are highly atrophic and disorganized. The migration of RPE cells into retinal vessels is shown (yellow arrowhead; H&E, 200×). (H) A clear disruption of the normal topology and stratification is also seen in this section (III), although there are still some RPE cells remaining (red arrowhead (H&E, 200×)). (I–K) A positive immunoreactivity for glial fibrillary acid protein (GFAP) is seen across all retinal layers in both macular and peripheral regions (GFAP, 200×).