PMC4063355_01
Family pedigree of RPGR ORF15 X-linked retinitis pigmentosa. Affected men from five known generations of the family suffer from severe retinitis pigmentosa and are typically blind in their fourth decade. The disease-causing family mutation in RPGR ORF15 was identified with molecular genetic analysis of one affected male subject (fourth generation, third individual from the left). A woman with the mutation examined at the age of 44 years had retinitis pigmentosa-like fundus abnormalities, tunnel vision, night blindness, and subnormal visual acuity (third generation, sixth individual from the left). The proband is a non-obligate carrier who at 16 years of age presented with a tapetal-like reflex in the light adapted state, but at reexamination at 22 years of age showed marked attenuation of the tapetal-like reflex in the light adapted state and reappearance of the tapetal-like reflex with prolonged dark adaptation.
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The mutation results in removal of adenosine 62 bp upstream of the ORF15 stop codon, thus inducing a frameshift and subsequently a premature stop codon affecting the last 21 amino acids of the RPGR gene product (Figure 1). The proband was a nullipara who at the age of 6 years had been treated for hypermetropia and strabismic and astigmatic amblyopia in her left eye (Figure 1, Table 1).
Color fundus photographs of the right eye of female carrier of RPGR ORF15 X-linked retinitis pigmentosa. A: After light exposure at the age of 16 years, a tapetal-like reflex is present, most conspicuously temporal of the fovea. B: After light exposure at the age of 22 years, no tapetal-like reflex can be seen. C: After 2 h of dark adaptation at the age of 22 years, a discreet tapetal-like reflex is present. D: After 12 h of dark adaptation at the age of 22 years, a clearly visible tapetal-like reflex is present, most conspicuously temporal of the fovea, in a pattern similar to the initial presentation at the age of 16 years.
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No fundus hyperpigmentation or atrophy was seen (Figure 2A-D). This finding was confirmed with color fundus photography (Figure 2B). Renewed ophthalmoscopy after 2 h of dark adaptation showed that the tapetal-like reflex had reappeared in a discrete pattern resembling that seen 6 years earlier (Figure 2C). At the age of 22 years, after 12 h of dark adaptation, a pronounced tapetal-like reflex with a pattern identical to that seen at age 16 years was found in both eyes (Figure 2D).
Goldmann-Weeker dark adaptation curves at the age 16 and 22 in a female carrier of RPGR ORF15 X-linked retinitis pigmentosa. The rod sensitivity after 30-min dark adaptation is similar at age 16 and age 22. The threshold value is about 2.6 for both curves. However, there is a delay of 3-5 min in the blue curve performed at age 22. This delay occurs about 10 min after the dark adaptation and lasts for about 7 min. Furthermore, at age 16, the dark adaptation final threshold is reached after 14 min, compared to 17 min at age 22. This may indicate a progressive delay in the rod activation kinetics.
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Goldmann visual fields (object sizes IV/4e and I/4e) were normal, Goldmann-Weekers dark adaptometry showed a normal biphasic response (Table 1, Figure 3), and standard full-field ERG showed normal scotopic and photopic response configurations, implicit times, and amplitudes (Table 2, Figure 4). She had no visual complaints, slit-lamp biomicroscopy was unremarkable, Goldmann fields (object sizes IV/4e and I/4e) were normal, and the patient had a biphasic Goldmann-Weekers dark adaptometry response, albeit delayed in reaching the final threshold (Table 1, Figure 3).
Full-field electroretinography (ffERG) performed at the age of 16 and six years later in a female carrier of RPGR ORF15 X-linked retinitis pigmentosa. At the age of 22, ffERG was performed twice: after 30 min and 6 h of dark adaptation, respectively. Compared to the ffERG at age 16, rod response was reduced by 28% at the age of 22. The combined rod-cone response a wave (resulting from activity of the photoreceptors) and b wave (resulting from activity of the bipolar and Muller cells) were reduced by 39% and 17%, respectively. Under photopic conditions, single flash cone response was reduced by about 41% and 30-Hz flicker response by 36%. No significant changes were recorded after the 6-h dark adaptation. The figure corresponds to Table 2. cd.s/m2=candela seconds per square meter. microV=microvolts. ms=milliseconds.
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Goldmann visual fields (object sizes IV/4e and I/4e) were normal, Goldmann-Weekers dark adaptometry showed a normal biphasic response (Table 1, Figure 3), and standard full-field ERG showed normal scotopic and photopic response configurations, implicit times, and amplitudes (Table 2, Figure 4). The amplitudes were, however, generally lower when examined at 22 years compared to 16 years of age (Table 2, Figure 4).
Multifocal electroretinography of the right eye female carrier of RPGR ORF15 X-linked retinitis pigmentosa demonstrates normal first-order latencies and amplitude values for all 103 hexagons, within 20 degrees eccentricity. ms=milliseconds. nV/deg2=nanovolts per degree squared.
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Multifocal electroretinography on the right eye after light exposure showed normal first-order latencies and amplitude values throughout the 103 hexagons, within 20 degrees eccentricity (Figure 5).
Spectral-domain optical coherence tomogram and fundus autofluorescence in a female carrier of RPGR ORF15 X-linked retinitis pigmentosa. Horizontal transfoveal spectral-domain optical coherence tomogram (A) from the left eye of the female carrier of XLRP after 2 h of dark adaptation at the age of 22 years. An ordered configuration of the photoreceptor/retinal pigment epithelium complex is seen. Except a slightly undulating ellipsoid line, there seems to be no obvious difference compared to the normal optical coherence tomogram of a healthy subject. Retina layers from bottom upward: RPE=retinal pigment epithelium/Bruch's membrane complex, ISe=inner segment ellipsoid, ONL=outer nuclear layer, OPL=outer plexiform layer, INL=inner nuclear layer, IPL=inner plexiform layer, NFL=nerve fiber layer. Autofluorescence fundus photography was performed at the age of 22 years. No abnormal pattern and thus no reminiscence of tapetal-like reflex was noted on imaging obtained in the light adapted state (B, last image in a series of five images), or after 2 h of dark adaptation (C, first image in a series of five images). The patient's autofluorescence fundus images displayed a sensitivity to dark adaptation that is also known from subjects with normal eyes. Thus, a progression was seen from the first to the last image in that the intensity of autofluorescence gradually increased, except in the fovea. This phenomenon is believed to reflect the bleaching of the photoreceptor photopigment as the result of continued exposure to blue light and the shielding of the foveal fluorophores by the xanthophyll pigment. The autofluorescence images showed no trace of the tapetal reflex pattern, neither before nor after bleaching.
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Spectral-domain optical coherence tomography after 2 h of dark adaptation appeared to be unchanged (Figure 6A). Autofluorescence fundus photography in the light-adapted state at 22 years showed no abnormal pattern and thus no reminiscence of tapetal-like reflex (Figure 6B), and the same was true after 2 h of dark adaptation (Figure 6C).