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(Investigative Ophthalmology and Visual Science. 2007;48:1298-1304.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.06-0971
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Disease Course of Patients with X-linked Retinitis Pigmentosa due to RPGR Gene Mutations

Michael A. Sandberg,1 Bernard Rosner,1 Carol Weigel-DiFranco,1 Thaddeus P. Dryja,2 and Eliot L. Berson1

1From the The Berman-Gund Laboratory for the Study of Retinal Degenerations and 2The Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
PURPOSE. To measure the rates of visual acuity, visual field, and ERG loss in patients with X-linked retinitis pigmentosa due to RPGR mutations and to determine whether these rates differ from those of patients with dominant retinitis pigmentosa due to RHO mutations.

METHODS. Snellen visual acuities, Goldmann visual field areas (V4e white test light), and 30 Hz (cone) full-field ERG amplitudes were recorded for an average of 9.8 years in 113 patients with RPGR mutations. After censoring data to eliminate ceiling and floor effects, we used longitudinal regression to estimate mean rates of change and to compare these rates with those of a previously studied cohort of 134 patients with dominant retinitis pigmentosa due to RHO mutations, who were followed for an average of 8.9 years. Survival analysis was used to compare the age distribution of legal blindness in these two groups. To explain group differences in visual acuity, optical coherence tomograms were recorded in some patients to visualize central retinal structure.

RESULTS. Mean annual exponential rates of decline for the patients with RPGR mutations were 4.0% for visual acuity, 4.7% for visual field area, and 7.1% for ERG amplitude. Each of these rates was significantly different from zero (P < 0.001). The rates of visual acuity and visual field loss were significantly faster than the corresponding rates in the RHO patients (1.6%, P < 0.001 and 2.9%, P = 0.002, respectively), whereas the rate of ERG amplitude loss was comparable to that in the RHO patients (7.7%, P = 0.39). The median age of legal blindness was 32 years younger in the RPGR patients than in the RHO patients, due primarily to loss of visual acuity rather than to loss of visual field. Loss of acuity in RPGR patients appeared to be associated with foveal thinning.

CONCLUSIONS. Patients with X-linked retinitis pigmentosa due to RPGR mutations lose visual acuity and visual field more rapidly than do patients with dominant retinitis pigmentosa due to RHO mutations.

In retinitis pigmentosa, it is commonly thought that the X-linked form progresses most rapidly and that the dominant form progresses least rapidly, but this impression is primarily based on single visits and not on observing the same patients over time. In 1985 a longitudinal study showed that patients with dominant retinitis pigmentosa as a group were half as likely to lose cone electroretinogram (ERG) amplitude over a 3-year time interval as were patients with autosomal recessive, X-linked, and isolated disease combined.1 However, the number of patients was too small and the follow-up too short in that study to consider similar comparisons with respect to loss of visual acuity and visual field area, which progress more slowly than loss of ERG amplitude, or to compare the X-linked form with other genetic types.

The discovery of the molecular bases for different forms of retinitis pigmentosa has allowed us and others to reclassify patients according to their responsible gene defects. We recently reported mean rates of decline in ocular function for a large cohort of patients with dominant retinitis pigmentosa due to mutations in the rhodopsin (RHO) gene.2 In the present study we report mean rates of decline in a similar-sized cohort of patients with X-linked retinitis pigmentosa due to mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, the protein of which is expressed in the connecting cilia of cones as well as rods,3 and compare these rates with those of patients with RHO mutations.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Patients
This study adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Boards of the Massachusetts Eye and Ear Infirmary and Harvard Medical School. We measured visual acuities, visual fields, and ERGs from 113 males (mean age at baseline: 26.1 years, age range at baseline, 5–61 years) with X-linked retinitis pigmentosa due to an RPGR mutation and at least 3 years of follow-up. The methods used to identify the RPGR mutations in these patients and the DNA sequences of the mutations have been reported.4 5 The RPGR dataset was derived from the results of an average of 7.2 ocular examinations per patient performed from 1975 to 2005 with the same test conditions; follow-up ranged from 3 to 28 years with a mean of 9.8 years. The RHO dataset, derived from a previous study,2 was also limited to patients with at least 3 years of follow-up. This yielded a sample of 134 patients (mean age at baseline: 36.0 years, age range at baseline: 8–66 years) who had been observed for 3 to 24 years, with an average follow-up of 8.9 years based on an average of 6.2 examinations per patient. The mean age at baseline of the patients with RPGR mutations was significantly younger than that of the patients with RHO mutations (P < 0.001).

Clinical Evaluation
The patients with RPGR mutations and those with RHO mutations underwent identical ocular examinations. We recorded best corrected visual acuity by using a projected Snellen chart and coded them in decimal form (e.g., 20/40 = 0.5). Kinetic visual fields were measured to the V4e white test light and to one or more smaller test lights in the Goldmann perimeter against the standard background of 31.5 apostilbs, bringing the test light from nonseeing to seeing areas. Fields were plotted with a digitizing tablet or scanned by custom software and converted to areas in square degrees. Although a cartographic distortion arises from projecting the curved surface of the perimeter onto the flat visual field chart6 and the projection of the visual field onto the retina is nonlinear based on a schematic eye,7 most longitudinal studies of visual field progression in retinitis pigmentosa have not applied corrections to their chart data,1 2 8 9 10 and we elected to do the same for consistency. We elicited full-field cone ERGs with 10-µs, 30-Hz flashes of white light (0.2 cd-s/m2) after pupillary dilation, 45 minutes of dark adaptation, and having recorded responses in the dark to 0.5 Hz flashes of light. ERGs were monitored with a contact lens electrode on the topically anesthetized cornea and differentially amplified. Consecutive responses to 30-Hz flashes greater than 10 µV in amplitude were photographed from the screen of an oscilloscope or digitized and quantified by computer. Smaller responses were digitized, smoothed with a band-pass filter, and averaged. Waveforms in response to 30-Hz flashes were quantified with respect to trough-to-peak amplitudes, and amplitudes <0.05 µV, considered nondetectable, were recoded as 0.05 µV. In this study, we limited our analyses to the V4e white test light for measuring visual fields and to 30-Hz white flashes for eliciting ERGs, because only these conditions of testing provided us with sufficiently large data sets to estimate rates of change with high precision.

As part of a separate program,11 we had recorded optical coherence tomograms (OCTs) from 5 of the patients with RPGR mutations (age range, 19–47 years) and from 10 of the patients with RHO mutations (age range, 20–52 years). The RPGR patients had visual acuities of 20/30 to 20/200, and the RHO patients had visual acuities of 20/20 to 20/60 (excluding an eye of one patient with a history of deep amblyopia). We evaluated these tomograms to search for a structural basis for visual acuity differences in these two groups.

Statistical Analyses
For estimating mean rates of change, we censored visual acuities of 20/20, except those that followed a lower value, to minimize a ceiling effect, because on our coding sheet we had constrained Snellen visual acuities to be ≤20/20. To minimize floor effects, we also censored patients with baseline visual acuities <20/100 and follow-up data after visual acuity declined to <20/100. For patients who became aphakic or pseudophakic in either eye at follow-up, those follow-up visits were excluded from visual acuity analyses. We also censored baseline visual field areas <78 deg2 (i.e., equivalent to a diameter of 10°) and follow-up data after the first occurrence of an area <78 deg2 to minimize floor effects. To minimize floor effects, we censored baseline ERG amplitudes <0.68 µV and follow-up data after the amplitude decreased to <0.34 µV. The censoring criteria were those applied in a previous study of patients with dominant RHO mutations.2 After applying these criteria, we eliminated patients from a given analysis if their residual follow-up was <3 years.

We converted all measures of ocular function to natural logarithms, because an exponential model has been shown to be optimal for evaluating cell loss over time in animal models of retinitis pigmentosa,12 provides a good fit for describing short-term disease progression in patients with retinitis pigmentosa,2 and has been used in several longitudinal studies of retinitis pigmentosa.1 2 8 9 10 13 14 Repeated-measures longitudinal regression (performed with PROC MIXED of SAS, ver. 9; SAS Institute, Cary, NC) was used to estimate the mean rate of change for each outcome measure, based on the average loge value for both eyes at each visit (when data for both eyes were available). By including terms for genotype (i.e., RPGR versus RHO mutation) and the cross-product of time x genotype, we compared mean slopes in patients with RPGR mutations versus mean slopes in patients with RHO mutations. We also used longitudinal regression to compare the mean rates of progression in patients with RPGR mutations in exons 1 to 14 (n = 33) with the mean rates in patients who had RPGR mutations in open reading frame (ORF) 15 (n = 80), because a previous analysis had suggested differences in ocular function between these two groups based on single visits.5

We used the commercial software (PROC LIFEREG of SAS) to fit a Weibull function to survival data and compare the age distribution of legal blindness in patients with RPGR mutations to the corresponding distribution in patients with RHO mutations. These plots provide a visualization of the long-term course of disease, and the model allows inclusion of left-censored data (i.e., a patient failing at baseline) and right-censored data (i.e., a patient not failing during follow-up) as well as interval-censored data (i.e., a patient failing between exams occurring at ages x1 and x2). For this purpose, we applied failure criteria (i.e., a visual acuity ≤20/200 or a visual field area ≤314 deg2 in one eye and a visual acuity ≤20/200 or a visual field area ≤314 deg2 in the fellow eye) to the entire dataset. The area of 314 deg2 corresponds to an equivalent diameter of 20° (i.e., a criterion for legal blindness) and was used in lieu of measuring the linear extent of each remaining visual field directly from charts. We also used a visual acuity ≤20/200 alone and a visual field area ≤314 deg2 alone as failure criteria, to determine which was the critical factor that led to legal blindness in each group.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Baseline Ocular Function
Tables 1 and 2 list the baseline raw data and mean values for the RPGR patients with mutations in exons 1 to 14 and with ORF15 mutations, respectively. None of the mean values in one group is significantly different from the corresponding mean value in the other group.


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  		TABLE 1. Baseline Ocular Function of Patients with RPGR Mutations in Exons 1 to 14

 

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  		TABLE 2. Baseline Ocular Function of Patients with RPGR Mutations in ORF15

 
Mean Rates of Change
Table 3 shows the mean annual loge rates of change in the patients with RPGR mutations, with standard errors and significance levels. The mean loge values correspond to mean annual exponential rates of decline of 4.0% for Snellen visual acuity, 4.7% for visual field area to the V4e test light, and 7.1% for cone ERG amplitude to 30-Hz flashes. In comparison, the RHO patients had a mean annual exponential rate of visual acuity decline (1.6%) and a mean annual exponential rate of visual field decline (2.9%) that were slower than the corresponding rates in the patients with RPGR mutations (P < 0.001 and P = 0.002, respectively). In contrast, the RHO patients had a mean annual exponential rate of decline in ERG amplitude (7.7%) that was not significantly different from that of the RPGR patients (P = 0.39).


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  		TABLE 3. Annual Rates of Change in Patients with RPGR Mutations

 
When we divided our patients with RPGR mutations into those with mutations in exons 1 to 14 and those with mutations in ORF15, we found a significant group difference in the mean annual exponential rates of decline in ERG amplitude (9.5% versus 6.3%, respectively; P = 0.005), but no significant difference in the rates of decline in visual acuity (3.4% versus 4.3%, respectively; P = 0.17) or visual field (4.9% versus 4.6%, respectively; P = 0.78).

Median Age to Reach Legal Blindness
We found a significant effect of genotype on the age distribution for legal blindness (P < 0.001). Figure 1 shows that our patients with RPGR mutations reached legal blindness, based on loss of acuity and/or field, at a median age (45 years) that was 32 years younger than that of our patients with RHO mutations (77 years). Figure 2 shows that the development of legal blindness was driven primarily by visual acuity loss in the patients with RPGR mutations and by visual field loss in the patients with RHO mutations. That is, in the patients with RPGR mutations, the survival curve based on a visual acuity of 20/200 or less is shifted to younger ages compared with the survival curve based on a visual field area of 314 deg2 or less. In contrast, the visual field survival curve is shifted to younger ages compared with the visual acuity survival curve of the patients with RHO mutations.


Figure 1
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  		FIGURE 1. Weibull plot survival analysis for legal blindness (i.e., loss of acuity and/or field) by genotype. The effect of genotype was significant (Wald {chi}2 test, P < 0.001). Vertical lines: median age of legal blindness in patients with RPGR mutations (left) and in patients with RHO mutations (right).

 

Figure 2
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  		FIGURE 2. Weibull plot survival analysis for a visual acuity >20/200 (blue curves) or a visual field area >314 deg2 (i.e., an equivalent diameter of 20°, green curves) by genotype. Visual field survival is also shown for the central field, excluding peripheral islands (red curves). The effect of genotype was significant for visual acuity (P < 0.001) and for central field (P < 0.001), but not for total field (P = 0.29).

 
Figure 2 also shows that, although the time course for surviving visual acuity was markedly different by genotype, the time course for surviving visual field was not significantly different in the two groups of patients. Because our clinical impression has been that patients with X-linked retinitis pigmentosa are left with a small central island of vision at a younger age than patients with dominant retinitis pigmentosa, we repeated the visual field survival comparison after subtracting peripheral islands from field area and then censoring baseline field areas >4915 deg2, to exclude fields with large peripheral areas connected by a narrow bridge to the central field. We found a significant effect of genotype on the age distribution for retaining central field (P < 0.001, Fig. 2 ). The median age for central field area decreasing to 314 deg2 or less was 22 years younger in the RPGR patients (37 years) than in the RHO patients (59 years).

Optical Coherence Tomography
Five of the 10 RHO patients with available OCTs had reduced visual acuity associated with macular cysts and were not considered further. Of the remaining patients with tomograms, the five with RHO mutations had a mean visual acuity of 20/22 and the five with RPGR mutations had a mean visual acuity of 20/53 (Table 4) . This difference was significant (P = 0.002). Their mean retinal thicknesses at the foveal center were 171 and 104 µm, respectively. The thickness in the RHO patients is similar to the normal mean thickness for our test system (167 µm),11 and that in the RPGR patients is significantly smaller than that in the RHO patients (t-test for unequal variances, P = 0.03). Figure 3 shows a tomogram from a 40-year-old RHO patient with a visual acuity of 20/25 and from a 38-year-old RPGR patient with a visual acuity of 20/100. The patient with the RHO mutation had a normal retinal thickness profile, whereas the patient with the RPGR mutation had a broad foveal depression with attenuation of the outer nuclear layer centrally, indicating loss of central foveal cones.


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  		TABLE 4. Visual Acuity and Central Foveal Thickness by Genotype in Retinitis Pigmentosa

 

Figure 3
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  		FIGURE 3. Tomograms subtending 20° (Stratus High-resolution Optical Coherence Tomographer [OCT3], Carl Zeiss Meditec, Inc., Dublin, CA) from the right eye of a 40-year-old woman with dominant retinitis pigmentosa due to an RHO mutation (Pro23His) and visual acuity of 20/25 (left) and from the right eye of a 38-year-old man with X-linked retinitis pigmentosa due to an RPGR mutation (ORF15Gly308;Ter@492) and visual acuity of 20/100 (right). ONL, outer nuclear layer.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The present study, based on data from two large cohorts observed for an average of 8 and 9 years, shows that patients with retinitis pigmentosa due to RPGR mutations lost Snellen visual acuity at more than twice the mean rate of patients with retinitis pigmentosa due to RHO mutations. Our survival analyses over the long term showed that the median age of legal blindness was much younger age in patients with RPGR mutations than in patients with RHO mutations. Our data also showed that becoming legally blind was due primarily to loss of visual acuity in RPGR patients and to loss of visual field in RHO patients.

OCT recordings revealed that the difference in mean visual acuity between these two groups may be attributable to photoreceptor loss. The tomograms of one RPGR patient showed a broad thinning of the fovea resembling that in the tomograms of patients with Stargardt’s disease17 or occult macular dystrophy.18 When visual acuity was reduced in patients with RHO mutations, it tended to be associated with macular cysts. Study of OCTs from additional RHO patients and RPGR patients who have reduced visual acuity will reveal whether these features are characteristic of these two groups.

We also found that patients with RPGR mutations lost visual field area to the V4e stimulus at a mean rate that was approximately 50% faster than that in patients with RHO mutations and were left with a central island of vision ≤20° at a younger median age than the RHO patients. This result suggests that the faster loss of visual acuity by the RPGR patients may be a consequence of their faster loss of central field, consistent with a significant correlation between visual acuity and central visual field diameter in retinitis pigmentosa.19 However, the two groups had similar age distributions for retaining 20° of total visual field and had nearly identical mean rates of progression of the full-field cone ERG, which derives mostly from the peripheral retina.

In a previous study based on single visits with adjustment for differences in age, we reported that patients with RPGR mutations in exons 1 to 14 had a borderline smaller mean visual field area (P = 0.04) and mean cone ERG amplitude (P = 0.06) than did patients with RPGR mutations in ORF15,5 suggesting that the former group had more severe disease at a given age than did the latter group. In the present study we evaluated whether mean rates of disease progression were different in these two groups. We found that patients with exon 1 to 14 mutations lost ERG amplitude 50% faster than did patients with ORF15 mutations, whereas visual acuity and visual field area declined comparably in the two groups. We, therefore, conclude that RPGR mutations in exons 1 to 14 tend to cause a more rapid loss of peripheral cone retinal function than do mutations in ORF15.


   Acknowledgements
 
The authors thank Terri L. McGee for help in compiling the list of RPGR mutations.


   Footnotes
 
Supported by National Eye Institute Grants EY00169, EY08683, and EY14104 and The Foundation Fighting Blindness.

Submitted for publication August 16, 2006; revised October 31, 2006; accepted January 23, 2007.

Disclosure: M.A. Sandberg, None; B. Rosner, None; C. Weigel-DiFranco, None; T.P. Dryja, None; E.L. Berson, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Michael A. Sandberg, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114; masandberg{at}aol.com.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Berson EL, Sandberg MA, Rosner B, et al. Natural course of retinitis pigmentosa over a three-year interval. Am J Ophthalmol. 1985;99:240–251.[ISI][Medline][Order article via Infotrieve]
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  3. Hong D, Pawlyk BS, Shang J, et al. A retinitis pigmentosa GTPase regulator (RPGR)-deficient mouse model of X-linked retinitis pigmentosa (RP3). Proc Natl Acad Sci USA. 2000;97:3649–3654.[Abstract/Free Full Text]
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  5. Sharon D, Sandberg MA, Rabe VW, Stillberger M, Dryja TP, Berson EL. RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa. Am J Hum Genet. 2003;73:1131–1146.[CrossRef][ISI][Medline][Order article via Infotrieve]
  6. Kirkham TH, Meyer E. Visual field area on the Goldmann hemispheric perimeter surface: correction of cartographic errors inherent in perimetry. Curr Eye Res. 1981;1:93–99.[ISI][Medline][Order article via Infotrieve]
  7. Drasdo N, Fowler CW. Non-linear projection of the retinal image in a wide-angle schematic eye. Br J Ophthalmol. 1974;58:709–714.[Free Full Text]
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  10. Iannaccone A, Kritchevsky SB, Ciccarelli ML, et al. Kinetics of visual field loss in Usher Syndrome type II. Invest Ophthalmol Vis Sci. 2004;45:784–792.[Abstract/Free Full Text]
  11. Sandberg MA, Brockhurst RJ, Gaudio AR, Berson EL. The association between visual acuity and central retinal thickness in retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2005;46:3349–3354.[Abstract/Free Full Text]
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  17. Ergun E, Hermann B, Wirtitsch M, et al. Assessment of central visual function in Stargardt’s disease/fundus flavimaculatus with ultrahigh-resolution optical coherence tomography. Invest Ophthalmol Vis Sci. 2005;46:310–316.[Abstract/Free Full Text]
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