September 2002
Volume 43, Issue 9
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Retina  |   September 2002
Disease Progression in Patients with Dominant Retinitis Pigmentosa and Rhodopsin Mutations
Author Affiliations
  • Eliot L. Berson
    From the Berman-Gund Laboratory for the Study of Retinal Degenerations and the
  • Bernard Rosner
    From the Berman-Gund Laboratory for the Study of Retinal Degenerations and the
  • Carol Weigel-DiFranco
    From the Berman-Gund Laboratory for the Study of Retinal Degenerations and the
  • Thaddeus P. Dryja
    Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
  • Michael A. Sandberg
    From the Berman-Gund Laboratory for the Study of Retinal Degenerations and the
Investigative Ophthalmology & Visual Science September 2002, Vol.43, 3027-3036. doi:
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      Eliot L. Berson, Bernard Rosner, Carol Weigel-DiFranco, Thaddeus P. Dryja, Michael A. Sandberg; Disease Progression in Patients with Dominant Retinitis Pigmentosa and Rhodopsin Mutations. Invest. Ophthalmol. Vis. Sci. 2002;43(9):3027-3036.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

purpose. To measure the rate of progression of retinal degeneration in patients with retinitis pigmentosa due to dominant rhodopsin mutations and to determine whether the rate of progression correlates with the location of the altered amino acid in the rhodopsin molecule.

methods. Change in ocular function was observed for an average of 8.7 years in 140 patients. After censoring data to eliminate “ceiling” and “floor” effects, longitudinal rates of change were compared, after weighting by follow-up time and number of visits, with rates inferred from cross-sectional analyses of the data from baseline visits. Mean rates of change were compared among groups of patients with mutations affecting the globule, plug, or C-terminal region of the protein after adjusting for age, gender, and baseline function.

results. Mean annual exponential rates of decline were 1.8% for visual acuity, 2.6% for visual field area, and 8.7% for ERG amplitude. The rates of visual acuity and ERG amplitude decline were significantly faster, and the rate of visual field area decline was significantly slower, than those inferred from baseline visits. Rates of acuity loss did not vary significantly with the region affected by the mutation. In contrast, the mean annual rate of field loss in the C terminus group (7.4%) was significantly faster than that in the globule (1.7%) or plug (1.1%) group. The mean annual rate of ERG decline was also significantly faster in the C terminus group (13.5%) than in the globule (8.5%) or plug (3.7%) groups and significantly faster in the globule group than in the plug group.

conclusions. Rates of decline in visual function for groups of patients with rhodopsin mutations cannot be accurately inferred from cross-sectional analyses of baseline visits. Average rates of decline of visual field area and ERG amplitude are fastest in patients with mutations affecting the C-terminal region.

Approximately 20% to 25% of patients with dominantly inherited retinitis pigmentosa have a mutation in the rhodopsin gene. 1 More than 100 different mutations have been described to date, all but a few of which are missense mutations (see RetNet, provided in the public domain by the University of Texas Houston Health Science Center, Houston, TX, and available at http://www.sph.uth.tmc.edu/retnet). In 1991 we evaluated disease severity at a given age by reviewing cross-sectional data from initial visits of patients with the two most common rhodopsin mutations—Pro23His and Pro347Leu—and found a milder disease on average in patients with the former mutation. 2 3 Those reports prompted a cross-sectional comparison of disease severity based on initial visits of 128 patients with 27 distinct rhodopsin mutations, with 9 altering residues in the intradiscal space, 12 altering residues in transmembrane regions, and 6 altering residues in the cytoplasm, 4 based on a two-dimensional model of rhodopsin. 5 Ocular function varied significantly by the region altered by the mutation: the disease appeared to be mildest with mutations altering residues in the intradiscal space and most severe with mutations altering residues in the cytoplasm. 4  
The cross-sectional plots of ocular function versus age showed best-fitting regression lines (slopes) in patients with mutations altering intradiscal residues that were similar to those in patients with mutations altering cytoplasmic residues. 4 This gave the impression that the differences in disease severity at a given age were due to differences in disease expression early in life and not to subsequent differences in disease course. However, slopes derived from cross-sectional data may not necessarily correspond to mean slopes derived from longitudinal data, because the former may be influenced by ascertainment biases (e.g., a patient may preferentially schedule the first visit when a visual symptom reaches a threshold shared by many other patients). 
In the present study, we measured the rates of disease progression based on longitudinal follow-up examinations of patients with rhodopsin mutations. We compared the mean longitudinal rates with those inferred from cross-sectional analyses of ocular function versus age at the patients’ first (“baseline”) visits. We next compared mean rates of progression in patients with altered residues in different regions of the rhodopsin molecule according to a new three-dimensional model derived from high-resolution crystallography. 6 7 We considered three of the regions in this report: the globular N terminus comprising residues 1 to 33, the plug (which supports the chromophore) comprising residue 110 (Krzysztof Palczewski, personal communication, June 2001) and residues 173 to 198 between helices IV and V, and the C terminus comprising residues 324 to 348 (Fig. 1)
Methods
Patients
We obtained visual acuity, visual field, and electroretinographic (ERG) data from 140 patients (78 males and 62 females; baseline ages, 6–67 years) with dominantly inherited retinitis pigmentosa due to a rhodopsin missense mutation or an in-frame deletion. All patients gave informed consent to participate in the study, which 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. The methods used to identify the rhodopsin mutations in these patients and the DNA sequences of the mutations have been reported. 8 9 Although some of these patients had sought consultation because of visual symptoms, most were relatives of probands. These relatives were found by DNA analysis to carry the rhodopsin mutation of the proband and, regardless of symptoms or stage of disease, were then asked to come for an ocular examination. All patients had progressive forms of retinitis pigmentosa based on history, clinical findings, and ERG abnormalities. The data set was derived from results of 826 ocular examinations performed from 1975 to 2000 under the same test conditions. Follow-up ranged from 2 to 25 years (mean, 8.7). The youngest patient was 6 years of age at baseline; the oldest was 79 years of age at final follow-up. 
Measures of Ocular Function
Best corrected visual acuities were obtained with a projected Snellen chart. Kinetic visual fields were measured to the V4e white test light of 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 and equivalent diameters. Full-field cone ERGs were elicited with 10-μs, 30-Hz flashes of white light (0.2 cd/sec per m2) after pupillary dilation and 45 minutes of dark adaptation. ERGs were monitored with a contact lens electrode on the topically anesthetized cornea and differentially amplified. Consecutive responses greater than 10 μV in amplitude were photographed from the screen of an oscilloscope or digitized and displayed on a computer screen. Smaller responses were digitized, smoothed with a band-pass filter, and averaged. Waveforms were quantified with respect to trough-to-peak amplitudes; amplitudes less than 0.05 μV, considered nondetectable, were recorded as 0.05 μV. Details of these procedures have been described previously. 2 3 4 10 11 We used the V4e white test light for measuring visual fields and 30-Hz white flashes for eliciting ERGs, because these conditions of testing provided us with large data sets for analysis. 
Statistical Analyses
Visual acuities were negatively skewed, and visual field areas and ERG amplitudes were positively skewed. To approximate normal distributions better, we converted visual acuities to minimum angles of resolution (MARs) and transformed all three measures to natural logarithms. Data from visits at which patients had aphakia or pseudophakia in either eye were excluded from visual acuity analyses. When data from both eyes were available at a given visit, the average was used. 
We compared demographic information and ocular function at baseline by region affected by the mutation, by χ2 test or ANOVA for all three regions (i.e., globule, plug, and C terminus) and Student’s t-test for pairs of regions. Because the distributions of baseline ocular function, as well as of follow-up time, differed significantly from normal, we also compared differences in continuous variables by region with the distribution-free Kruskal-Wallis test based on ranks. 
Linear regression analyses were performed with visual acuity, visual field area, or ERG amplitude as the dependent variable and age as the independent variable to derive a slope (rate of change) for each patient during follow-up. We analyzed these slopes for “ceiling” and “floor” effects (see the Results section), censored the longitudinal data to avoid these effects, and recalculated final slopes from the reduced data set. Otherwise, we did not exclude from analysis any data, unless they were statistical outliers, because we wanted our conclusions to be as representative as possible of patients whose functional level was appropriate to monitor change accurately. Outliers were identified from the longitudinal data by the generalized extreme studentized deviate test (P < 0.05) for univariate distributions. 12 Outliers for ocular function versus age at baseline were identified by applying the generalized extreme studentized residual test (P < 0.05) for linear regression. 13  
The average of each slope distribution was compared with the corresponding cross-sectional slope of ocular function versus age at baseline to determine whether single measurements in patients of different ages could be used to infer mean rates of change from longitudinal measurements. Multiple linear regression analyses were performed with slope for a given measure of ocular function as the dependent variable and region affected by the mutation as one independent variable and age–gender category and tertile of baseline ocular function as additional independent variables. We controlled for age, gender, and baseline ocular function, because the groups were not matched for age and ocular function at baseline (see below) and because rate of disease progression may depend on some or all of these factors. Linear contrasts were performed to identify significant differences between different pairs of regions affected by the mutations (e.g., globule versus plug). For both univariate and multivariate analyses, slopes were weighted by the square root of the product of the follow-up time in years and the number of visits, because estimates of rate of change are more precise in patients with longer follow-up and more measurements. Statistical analyses were performed on computer (JMP, ver. 3.2.2; SAS Institute, Inc., Cary, NC). 
Results
Baseline Ocular Function
Twenty-nine different rhodopsin mutations were found in this population of 140 patients. Table 1 lists the mutations, the number of patients with each mutation, their gender, mean age, and average ocular function at baseline by mutation and shows whether a given mutation affected an amino acid residue within the globule, plug, or C terminus. The table shows that the percentage of patients with mutations affecting the globule (38.6%) was greater than that of patients with mutations affecting the plug (13.6%) or C terminus (20%). The remaining patients (27.8%) had mutations that did not fall into one of these three groups. The location of the amino acid residues affected by these mutations is shown in Figure 1
Figure 2 displays stem-and-leaf plots of ln ocular function at baseline. Each of the distributions differed significantly from normal (see Fig. 2 legend): The distribution of ln MAR (i.e., ln [1/visual acuity]) was skewed toward higher ln MARs (i.e., lower acuities), the distribution of ln visual field area was skewed toward smaller areas, and the distribution of ln ERG amplitude was roughly rectangular. Each distribution included a large variation in values, only a small fraction of which could be explained by the variation in age. For example, the regression line in Figure 3 shows that ln visual field area declined with increasing age (P < 0.001), but the coefficient of determination (R 2) was 0.20, indicating that only 20% of the variation in ln visual field area could be explained by the variation in age. 
Table 2 presents the number of patients, mean age, percentage by gender, mean follow-up time, and mean ocular function by region of the rhodopsin molecule altered by the mutation. Although generally younger and with longer follow-up, patients with C terminus mutations had, on average, more advanced disease with respect to baseline visual acuity, visual field area, and ERG amplitude than patients with mutations in the other two regions. Patients with globule or plug mutations were similar in these respects. 
Overall Progression
Figure 4 shows the estimated annual change in ocular function versus baseline ocular function. The plots show the entire data set, including the statistical outliers (designated by x). None of the graphs shows that patients with normal baseline function (i.e., visual acuity of 1.0, visual field equivalent diameter ≥120°, or cone ERG amplitude ≥50 μV) were more likely than other patients to demonstrate zero change (designated by the dashed lines) that would be indicative of a ceiling effect. The presence of a floor effect is most obvious in the ERG data, in that regressors were as common as progressors at very impaired baseline amplitudes. 
Table 3 shows whether a given subgroup with normal baseline function or very impaired baseline function (excluding outliers) did not progress as tested. For visual acuity, visual field area, and ERG amplitude, the mean slopes in patients with normal baseline values were all significantly less than zero, ruling out the null hypothesis that these groups of patients did not progress and providing no evidence for a ceiling effect in our complete data set. Figure 5 illustrates this for visual field area. Included are the six patients from the cohort with normal baseline field areas, more than 8 measurements, and more than 10 years of follow-up. The figure shows that the patients lost visual field, even while their field areas remained above the lower normal limit, and that the rate of change above that limit was not evidently slower than that once the field area fell below the normal limit. Therefore, we did not exclude either the patients with normal baseline fields or their normal field data from the longitudinal analyses. In deriving rates of change we did elect to censor visual acuities of 20/20, except those that followed a lower value, because on our coding sheet we had constrained Snellen visual acuities to be 20/20 or less. 
The criteria that we selected to designate very impaired baseline function conformed to those adopted by previous studies (i.e., visual acuity <20/100, 11 visual field [equivalent] diameter <10°, 14 and cone ERG amplitude <0.68 μV 11 ). Table 3 shows that patients with very impaired baseline visual acuity or ERG amplitude had a mean rate of change that was positive and, therefore, not significantly less than zero, consistent with the idea that such patients, on average, demonstrated a floor effect. Although there were too few patients with very small visual fields at baseline to perform the same test, considering the data of Figure 4 and the acuity and ERG analyses of Table 3 , we elected to exclude from subsequent analyses patients with baseline function below all of these criteria. We censored follow-up data after a decline of visual acuity to ≤20/100, a decline of visual field equivalent diameter to ≤10°, and a decline of ERG amplitude to ≤0.34 μV 11 to reduce further the possibility of floor effects. 
Figure 6 displays stem-and-leaf plots showing the distributions of estimated annual change in ln ocular function in patients satisfying the described ocular function criteria and excluding statistical outliers. All three distributions were Gaussian (see Fig. 6 legend). The figure shows a large spread for change in ln visual field area and ln ERG amplitude. Standard deviations were 0.042 for visual acuity, 0.073 for visual field area, and 0.083 for ERG amplitude. The standard deviations for change in ln visual acuity and visual field area in the present study of patients with rhodopsin mutations were significantly less than the corresponding values (0.064 for visual acuity and 0.195 for visual field area) in a study of patients with different genetic types of retinitis pigmentosa combined 15 for which the individual data were provided (F-test for equality of variances: P = 0.007 for acuity and P < 0.001 for field). 
Estimated mean annual exponential rates of decline based on the distributions in Figure 6 were 1.8% for visual acuity, 2.6% for visual field area, and 8.7% for ERG amplitude (Table 4) . Table 4 shows the hypothetical rates of progression inferred from the linear regression of baseline function on baseline age (e.g., see Fig. 3 ). However, these cross-sectional rates did not predict the mean rates of progression calculated from the longitudinal data. Specifically, the rates inferred from the cross-sectional data were below the respective lower 95% confidence interval for the observed mean rates of progression for visual acuity and ERG amplitude and above the upper 95% confidence limit for the observed mean rate of progression for visual field area. In fact, the baseline data predicted that visual acuity would not decline with increasing age and that the rate of progression of visual field area would be faster than that of cone ERG amplitude, contrary to the evidence from the longitudinal follow-up data. 
Figure 7 illustrates how a cross-sectional slope can differ from the mean of the longitudinal slopes. The figure plots the longitudinal ERG data versus age from the 10 patients of the cohort with the fastest rates of progression and more than 10 years of follow-up; each patient’s disease course is fitted to an exponential function (solid lines). Also shown is the least-squares fit to the 10 baseline data points (i.e., baseline ln amplitude versus baseline age) from these same patients (dashed line). The slope of the line from initial visit data (−5.5%/year) is flatter than that of every follow-up line (ranging from −11.5%/year to −23.4%/year) and is about one third of the mean slope of the follow-up lines (−16.3%/year). Furthermore, the least-squares fits by patient have an average R 2 of 0.87, indicating that longitudinal ERG data from patients with retinitis pigmentosa, similar to that for visual field area data from patients with retinitis pigmentosa 16 and outer nuclear layer cell counts in animal models of retinitis pigmentosa (reviewed by Clarke et al. 17 ), are closely approximated by exponential functions. 
Rates of Progression by Region Affected by a Mutation
Figure 8 displays the annual percentage change in ocular function, including the statistical outliers (designated by x), by region affected by the mutation. The scatterplots show that there was considerable overlap between the three distributions for a given measure of ocular function. Nonetheless, for visual acuity the median value was slightly more negative (i.e., in the direction of progression) in patients with plug mutations (−2.8%/year) than in patients with globule mutations (−2.0%/year) or C terminus mutations (−0.4%/year) after excluding the statistical outliers. For visual field area, the median value was more negative in patients with C terminus mutations (−6.0%/year) than in patients with globule mutations (−2.0%/year) or plug mutations (−1.2%/year). For ERG amplitude the median value was also more negative in patients with C terminus mutations (−16.4%/year) than in patients with globule mutations (−8.4%/year) or plug mutations (−4.1%/year). 
Figure 9 compares the mean values by region for the data illustrated in Figure 8 after excluding the statistical outliers, weighted by follow-up time and number of visits and adjusted for age, gender, and baseline function by multiple linear regression. Figure 9 shows that the estimated exponential mean rates of change for visual field area and ERG amplitude, but not visual acuity, varied significantly by region. The mean rate of loss of remaining visual field area was faster in patients with mutations affecting the C-terminus region (7.4%/year) than in patients with mutations affecting the globule (1.7%/year) or plug (1.1%/year; P < 0.001 in both cases). The mean rate of loss of remaining ERG amplitude was faster in patients with mutations affecting the C terminus (13.5%/year) than in patients with mutations affecting the globule (8.5%/year) or plug (3.7%/year; P = 0.01 and P < 0.001, respectively), and ERG amplitude was lost more rapidly in patients with globule mutations than in patients with plug mutations (P = 0.01). 
Discussion
This study answers a question posed by a previous study of cross-sectional data from patients with rhodopsin mutations in which we reported that disease severity at a given age varies with the location of a mutant amino acid residue within the opsin molecule. 4 In that study, for each measure of ocular function, the slope of the regression line representing ocular function versus age in patients with mutations affecting the intradiscal region was similar to that in patients with mutations affecting the cytoplasmic region, raising the possibility that the differences in severity may reflect differences in disease expression early in life and not in subsequent disease course. The present results show that differences in disease severity at a given age among patients with rhodopsin mutations reflect in large part differences in disease course. When we compared rates of change inferred from our cross-sectional data (based on first visits to our center of patients examined at different ages) to mean rates of change calculated from our longitudinal data, we found that the former significantly differed from the latter, pointing to the importance of longitudinal studies to measure disease course in individual patients. 
We suspect that inferences about disease course based on cross-sectional data are flawed by ascertainment biases (e.g., on the part of patients seeking an evaluation when they first become symptomatic and on the part of investigators, as in this study, recruiting younger and older relatives, regardless of symptoms, because they were are found to carry a mutation). In the case of visual field progression, some patients who were ascertained for the first time late in life with small fields (see Fig. 3 ) may never have had a normal field and were recruited regardless of symptoms because of our molecular genetics analyses. This ascertainment bias may have contributed to a steeper slope inferred from our cross-sectional data than what we measured based on our longitudinal follow-up. Because it is impossible to explain fully or understand these ascertainment biases that may have a profound effect on estimates of rates of change from cross-sectional data, the only way to estimate reliably a rate of decline over time in an individual patient is to observe the same patient over time, as we did in our longitudinal analyses. 
Several previous studies have monitored the natural course of disease longitudinally in large cohorts of patients with retinitis pigmentosa. Unlike the present study, the sets of patients evaluated in those studies had unknown primary gene defects and probably were heterogeneous mixtures of patients with many of the dozens of genes that can cause retinitis pigmentosa. Based on those studies, the mean annual rate of decline of remaining visual acuity has been estimated at 1.0%, 18 3.7% (based on the individual data), 15 and 8.6% 19 in patients with retinitis pigmentosa in general and at 1.4% in patients with dominant retinitis pigmentosa. 19 Another study found that the median time to reach 20/200 was approximately 5 years in patients with a baseline visual acuity of 20/40. 20 Assuming that the mean would approximate the median, this corresponds to a 27% average annual rate of decline. Our rate of 1.8% in patients with rhodopsin mutations falls within the range of these values. The mean annual rate of decline of remaining visual field area has been estimated at 4.6%, 18 9.1%, 14 9.2% (based on the individual data), 15 and 13.5%. 16 Our rate of 2.6% is below the range of these values. The mean annual rate of decline of remaining cone ERG amplitude has been estimated at 13.3% 19 and 18.5% 18 in patients with retinitis pigmentosa in general and at 11.9% in patients with dominant disease. 19 Again, our rate of 8.7% is below these values. The results of the present study suggest that, on average, patients with rhodopsin mutations lose visual acuity at a rate similar to that observed in other patients with retinitis pigmentosa but lose peripheral retinal function, as monitored by visual field and full-field cone ERG testing, more slowly than other patients with retinitis pigmentosa. 
Some of our patients ascertained in middle age had normal visual fields at baseline in response to the V4e test light (e.g., see Fig. 5 ), consistent with the idea of a variable “critical age” 16 at which visual field loss begins with this test stimulus. However, we did not observe a ceiling effect in our cohort for change in visual field area and therefore did not exclude from longitudinal analysis patients with normal baseline visual fields or field data within the normal range. We similarly did not detect a ceiling effect for change in visual acuity or ERG amplitude, although we censored from longitudinal analysis visual acuities of 20/20 (except those that followed a lower value) because we did not code higher values. We excluded patients with rates of change that were identified as statistical outliers (who were as likely as not to show progression) and, as in prior studies, 11 14 15 19 patients with very low baseline values who, as a group, showed a floor effect. However, unlike some previous studies, 14 15 16 we included other patients who showed minimal or no progression, because we wanted our conclusions to be as representative as possible of patients with rhodopsin mutations and because our distributions for rate of change were Gaussian with these values included, thereby permitting us to use standard statistical methods to develop confidence limits for average rates of change and to compare rates of change between groups. It is likely that our observed mean rates of change for visual field and ERG progression were slower than those reported in some other studies, in part because of our inclusion of some patients who showed minimal or no progression. 
In this study we grouped patients according to the regions of the rhodopsin molecule affected by sets of mutations. These regions are based on a three-dimensional structure of rhodopsin. 6 7 Our results showed that in groups of patients with rhodopsin mutations, disease course varies according to the region within the opsin molecule of an altered amino acid residue. The globular N terminus is thought to enable the proper folding of opsin and to confer stability to rhodopsin in the outer segment. 21 22 The plug appears to support the chromophore, 11-cis retinal, in the pocket, while possessing some mobility to allow reconstitution of rhodopsin after bleaching. 7 The last five amino acids of the C terminus are necessary for proper sorting and vectorial transport of rhodopsin from the Golgi complex to the basal discs of the outer segment. 23 24 Transgenic mice, rats, and frogs with mutations affecting the C terminus have vesicles containing rhodopsin mislocalized to the inner segment cytoplasm and the plasma membrane or to the extracellular space adjacent to the border of the inner and outer segments. 25 26 27 The present study shows that patients with retinitis pigmentosa produced by rhodopsin mutations affecting the C terminus have more rapidly progressing disease with respect to visual field loss and ERG amplitude decline than patients with mutations affecting other regions. This suggests that impaired sorting and vectorial transport of rhodopsin are associated with a more rapid rate of photoreceptor degeneration than defects associated with impaired folding (i.e., the globule mutations) or the abnormal formation of a functional pocket for the binding of vitamin A (i.e., the plug mutations). 
Although significant differences were observed in the average rate of change by the region of rhodopsin affected by a given mutation, we noted considerable variation in disease course among patients with mutations affecting the same region. Our regression model, which included age, gender, baseline function, and affected region of rhodopsin, accounted for only 20% to 34% of the variation in rates of change. This suggests that some factor(s) other than the gene defect itself—for example, modifier genes, diet, general health, or light exposure—may affect the clinical course of this condition. Knowledge of a patient’s rhodopsin mutation helps to predict the disease course, but most of the variation in rate of progression among these patients remains unexplained. 
 
Figure 1.
 
Schematic representation of the structure of rhodopsin. The molecule is drawn with the amino terminus (residue 1) at the lower left in the intradiscal space, the carboxyl terminus (residue 348) in the cytoplasm at the top, and the transmembrane domains that span the outer segment disc membrane in the middle. The seven transmembrane domains are helical structures and are enclosed within rectangles. Another rectangle at the upper right encloses a helix in the cytoplasm that lies parallel to the disc membrane. Dotted lines encircle the globular region in the amino terminus and the plug region in the second intradiscal loop; these structures have been defined by high-resolution crystallography. 6 7 Two glycosylated residues in the globule region are designated. Circles are drawn around the amino acid residues that are altered by the rhodopsin mutations included in this study.
Figure 1.
 
Schematic representation of the structure of rhodopsin. The molecule is drawn with the amino terminus (residue 1) at the lower left in the intradiscal space, the carboxyl terminus (residue 348) in the cytoplasm at the top, and the transmembrane domains that span the outer segment disc membrane in the middle. The seven transmembrane domains are helical structures and are enclosed within rectangles. Another rectangle at the upper right encloses a helix in the cytoplasm that lies parallel to the disc membrane. Dotted lines encircle the globular region in the amino terminus and the plug region in the second intradiscal loop; these structures have been defined by high-resolution crystallography. 6 7 Two glycosylated residues in the globule region are designated. Circles are drawn around the amino acid residues that are altered by the rhodopsin mutations included in this study.
Table 1.
 
Mean Baseline Ocular Function by Rhodopsin Mutation
Table 1.
 
Mean Baseline Ocular Function by Rhodopsin Mutation
Mutation Cases (n) Sex (M/F) Age (y) Decimal Acuity* Equivalent Field Diameter* ERG Amplitude* Region of Molecule
Thr17Met 3 1/2 51.9 0.89 89.3 22.6 Globule
Pro23His 50 23/27 38.1 0.77 71.5 5.7 Globule
Pro23Leu 1 1/0 23.0 0.89 145.0 9.4 Globule
Phe45Leu 1 1/0 34.2 1.00 128.0 41.7
Gly51Arg 3 3/0 48.3 0.63 102.0 22.1
Gly51Val 3 2/1 31.8 0.70 108.0 29.0
Thr58Arg 2 1/1 35.1 0.95 107.0 39.4
Gly89Asp 9 5/4 36.3 0.58 61.9 0.99
Cys110Tyr 3 3/0 42.3 0.84 85.3 3.6 Plug
Gly114Asp 1 0/1 40.2 0.67 29.4 0.84
Gly114Val 2 0/2 33.7 0.18 25.9 1.9
Leu125Arg 1 1/0 25.0 0.48 40.9 0.19
Arg135Trp 4 2/2 26.3 0.26 81.3 0.98
Ala164Glu 1 1/0 40.6 0.12 92.5 29.3
Cys167Arg 1 1/0 33.8 0.58 26.3 0.66
Pro171Leu 4 3/1 24.0 0.45 77.3 0.61
Glu181Lys 4 2/2 41.2 0.87 61.1 1.4 Plug
Gln184Pro 1 0/1 49.6 0.89 84.2 12.8 Plug
Ser186Pro 1 1/0 37.6 0.27 20.3 0.17 Plug
Gly188Arg 1 1/0 35.5 0.40 56.6 2.5 Plug
Asp190Asn 6 4/2 46.0 0.57 78.7 11.1 Plug
Asp190Gly 3 2/1 29.0 0.96 124.0 31.1 Plug
Cys264del 4 3/1 32.6 0.03 35.9 0.2
Lys296Glu 2 0/2 41.0 0.27 14.4 0.16
Ser297Arg 1 0/1 40.4 0.73 20.9 0.37
Val345Leu 3 3/0 27.6 0.40 91.2 1.9 C-terminus
Val345Met 1 1/0 22.1 0.63 125.0 18.0 C-terminus
Pro347Leu 21 12/9 30.3 0.50 50.1 0.93 C-terminus
Pro347Ser 3 1/2 42.0 0.77 32.1 0.71 C-terminus
Figure 2.
 
Baseline ocular function in patients with rhodopsin mutations. The stem-and-leaf method of display allows presentation of data in grouped form while preserving the individual data points to at least two significant digits. Numbers of patients are 123 (visual acuity), 137 (visual field area), and 131 (ERG amplitude). Each distribution was significantly different from normal (Shapiro-Wilk test, P < 0.001 in each case). The rule for combining the stem and leaf is given at the bottom of the display. For example, in the bottom row (for ln ERG amplitude) the stem is −2 and the first leaf (to the right of the short vertical line) is 5. The stem is multiplied by 1 and the leaf is multiplied by −0.1 (because the stem is negative), and the two numbers are added together to obtain −2.5. This data point, therefore, represents −2.5 ln μV. The displays were generated with online software (provided in the public domain and available at http://www.ruf.rice.edu/∼lane/stat_analysis/descriptive.html).
Figure 2.
 
Baseline ocular function in patients with rhodopsin mutations. The stem-and-leaf method of display allows presentation of data in grouped form while preserving the individual data points to at least two significant digits. Numbers of patients are 123 (visual acuity), 137 (visual field area), and 131 (ERG amplitude). Each distribution was significantly different from normal (Shapiro-Wilk test, P < 0.001 in each case). The rule for combining the stem and leaf is given at the bottom of the display. For example, in the bottom row (for ln ERG amplitude) the stem is −2 and the first leaf (to the right of the short vertical line) is 5. The stem is multiplied by 1 and the leaf is multiplied by −0.1 (because the stem is negative), and the two numbers are added together to obtain −2.5. This data point, therefore, represents −2.5 ln μV. The displays were generated with online software (provided in the public domain and available at http://www.ruf.rice.edu/∼lane/stat_analysis/descriptive.html).
Figure 3.
 
Linear regression of ln visual field area on age at baseline in 137 patients with retinitis pigmentosa due to rhodopsin mutations.
Figure 3.
 
Linear regression of ln visual field area on age at baseline in 137 patients with retinitis pigmentosa due to rhodopsin mutations.
Table 2.
 
Baseline Ocular Function by Affected Region of Rhodopsin Molecule
Table 2.
 
Baseline Ocular Function by Affected Region of Rhodopsin Molecule
Globule Plug C Terminus P Kruskal-Wallis P
Number 54 19 28
Age (y) 38.6 ± 1.8 41.0 ± 2.8 31.0 ± 2.6 0.02* 0.01
Males/females (%) 46/54 68/32 61/39 0.18, †
Follow-up (y) 7.4 ± 0.6 9.3 ± 1.1 10.3 ± 1.1 0.04* 0.02
ln MAR (min) 0.25 ± 0.04 0.37 ± 0.11 0.67 ± 0.14 , § 0.01
 Snellen equivalent (20/26), ‡ (20/29), ‡ (20/39), ‡
ln visual field area (deg2) 8.35 ± 0.20 8.38 ± 0.26 7.69 ± 0.30 0.12* 0.13
 Equivalent diameter (73°), ‡ (74°), ‡ (53°), ‡
ln cone ERG amplitude (μV) 1.84 ± 0.25 1.63 ± 0.42 0.08 ± 0.37 <0.001* 0.001
(6.3 μV), ‡ (5.1 μV), ‡ (1.1 μV), ‡
Figure 4.
 
Plots of the estimated annual percentage change in ocular function by baseline function in patients with rhodopsin mutations. Dashed lines: zero change. The visual acuity plot (top left) shows data uncensored with regard to possible ceiling or floor effects from 123 patients, including 8 designated statistical outliers (x). The visual field plot (top right) shows uncensored data from 137 patients, including 2 outliers. The ERG plot (bottom) shows uncensored data from 131 patients including 1 outlier.
Figure 4.
 
Plots of the estimated annual percentage change in ocular function by baseline function in patients with rhodopsin mutations. Dashed lines: zero change. The visual acuity plot (top left) shows data uncensored with regard to possible ceiling or floor effects from 123 patients, including 8 designated statistical outliers (x). The visual field plot (top right) shows uncensored data from 137 patients, including 2 outliers. The ERG plot (bottom) shows uncensored data from 131 patients including 1 outlier.
Table 3.
 
Mean Annual Change in Ocular Function by Baseline Function in Patients with Rhodopsin Mutations
Table 3.
 
Mean Annual Change in Ocular Function by Baseline Function in Patients with Rhodopsin Mutations
Ocular Function Normal* P , † Very Low, ‡ P , †
ln visual acuity −0.0078 ± 0.0028, § (n = 27) 0.002 0.0039 ± 0.0191, § (n = 7) 0.50
ln visual field area −0.0449 ± 0.0076, § (n = 27) <0.001 , ¶ (n = 2) , ¶
ln ERG amplitude −0.0739 ± 0.0236, § (n = 6) 0.047 0.0128 ± 0.0155, § (n = 36) 0.71
Figure 5.
 
Scatterplot of ln visual field area versus age in the six patients with normal baseline fields, more than eight measurements, and more than 10 years of follow-up. The data for each patient have been fitted by a spline function to illustrate mean tendency as a function of age. Dashed line: lower limit of normal, corresponding to an equivalent diameter of 120°.
Figure 5.
 
Scatterplot of ln visual field area versus age in the six patients with normal baseline fields, more than eight measurements, and more than 10 years of follow-up. The data for each patient have been fitted by a spline function to illustrate mean tendency as a function of age. Dashed line: lower limit of normal, corresponding to an equivalent diameter of 120°.
Figure 6.
 
Estimated annual change in ln ocular function in patients with rhodopsin mutations. Censored were patients with baseline visual acuities less than 20/100, baseline visual field equivalent diameters less than 10°, and baseline ERG amplitudes less than 0.68 μV. Censored visual acuities were 20/20 that did not follow a lower value. Censored follow-up data were acuities after a value ≤20/100, visual field equivalent diameter after a value ≤10°, and ERG amplitudes after a value ≤0.34 μV. Excluded were statistical outliers from their respective plots (i.e., −54%, −28%, +14%, and +14% rates of change for visual acuity; −29%, −26%, +48%, and +61% rates of change for visual field area; and −42% and −34% rates of change for ERG amplitude). Numbers of patients were 83 (visual acuity), 131 (visual field area), and 92 (ERG amplitude). The distributions for visual acuity, visual field area, and ERG amplitude are not significantly different from normal (Shapiro-Wilk test, P = 0.52, P = 0.32, and P = 0.31, respectively). The rule for combining the stem and leaf is given at the bottom of the display (sample calculation in Fig. 2 ).
Figure 6.
 
Estimated annual change in ln ocular function in patients with rhodopsin mutations. Censored were patients with baseline visual acuities less than 20/100, baseline visual field equivalent diameters less than 10°, and baseline ERG amplitudes less than 0.68 μV. Censored visual acuities were 20/20 that did not follow a lower value. Censored follow-up data were acuities after a value ≤20/100, visual field equivalent diameter after a value ≤10°, and ERG amplitudes after a value ≤0.34 μV. Excluded were statistical outliers from their respective plots (i.e., −54%, −28%, +14%, and +14% rates of change for visual acuity; −29%, −26%, +48%, and +61% rates of change for visual field area; and −42% and −34% rates of change for ERG amplitude). Numbers of patients were 83 (visual acuity), 131 (visual field area), and 92 (ERG amplitude). The distributions for visual acuity, visual field area, and ERG amplitude are not significantly different from normal (Shapiro-Wilk test, P = 0.52, P = 0.32, and P = 0.31, respectively). The rule for combining the stem and leaf is given at the bottom of the display (sample calculation in Fig. 2 ).
Table 4.
 
Cross-Sectional Estimates Versus Longitudinal Measurements of Annual Rates of Change in Patients with Rhodopsin Mutations
Table 4.
 
Cross-Sectional Estimates Versus Longitudinal Measurements of Annual Rates of Change in Patients with Rhodopsin Mutations
Ocular Function n * Cross-Sectional Slope Longitudinal Slope Mean (95% CI), ‡
ln visual acuity 83 +0.0018 −0.0182 (−0.0103 to −0.0260)
+0.2% −1.8% (−1.0% to −2.6%)
ln visual field area 131 −0.0442 −0.0261 (−0.0147 to −0.0374)
−4.3% −2.6% (−1.5% to −3.7%)
ln ERG amplitude 92 −0.0098 −0.0911 (−0.0752 to −0.1069)
−1.0% −8.7% (−7.2% to −10.1%)
Figure 7.
 
Longitudinal ERG amplitude versus age in the 10 patients with rhodopsin mutations with the fastest rates of progression and more than 10 years of follow-up (symbols and solid lines) contrasted with the rate of progression inferred from the least-squares fit to their baseline values (circled symbols and dashed line).
Figure 7.
 
Longitudinal ERG amplitude versus age in the 10 patients with rhodopsin mutations with the fastest rates of progression and more than 10 years of follow-up (symbols and solid lines) contrasted with the rate of progression inferred from the least-squares fit to their baseline values (circled symbols and dashed line).
Figure 8.
 
Estimated annual exponential change in ocular function by region affected by the mutation in patients with rhodopsin mutations. Censoring criteria are provided in Fig. 6 . x, statistical outliers. Numbers of patients (including outliers) are 33, 13, and 18 for visual acuity; 53, 19, and 27 for visual field area; and 43, 15, and 14 for ERG amplitude for the globule, plug, and C terminus, respectively. The data points have been shifted horizontally to facilitate identification of individual values.
Figure 8.
 
Estimated annual exponential change in ocular function by region affected by the mutation in patients with rhodopsin mutations. Censoring criteria are provided in Fig. 6 . x, statistical outliers. Numbers of patients (including outliers) are 33, 13, and 18 for visual acuity; 53, 19, and 27 for visual field area; and 43, 15, and 14 for ERG amplitude for the globule, plug, and C terminus, respectively. The data points have been shifted horizontally to facilitate identification of individual values.
Figure 9.
 
The estimated annual change in visual function (mean + SE) by region altered by a rhodopsin mutation in patients with dominant retinitis pigmentosa. Rates of change have been weighted by the square root of the product of the follow-up time in years and the number of visits, and the data have been corrected for differences in age, gender, and baseline visual function (i.e., mean rates of decline are averages of estimated male and female rates for patients of an average age and baseline visual function). The analyses are based on the data illustrated in Figure 8 , after excluding outliers (i.e., 61 patients for visual acuity, 95 patients for visual field area, and 71 patients for ERG amplitude). Significant differences (P < 0.05) by region for a given measure of ocular function are indicated by different patterns (i.e., blank versus solid and blank versus solid versus diagonal stripes).
Figure 9.
 
The estimated annual change in visual function (mean + SE) by region altered by a rhodopsin mutation in patients with dominant retinitis pigmentosa. Rates of change have been weighted by the square root of the product of the follow-up time in years and the number of visits, and the data have been corrected for differences in age, gender, and baseline visual function (i.e., mean rates of decline are averages of estimated male and female rates for patients of an average age and baseline visual function). The analyses are based on the data illustrated in Figure 8 , after excluding outliers (i.e., 61 patients for visual acuity, 95 patients for visual field area, and 71 patients for ERG amplitude). Significant differences (P < 0.05) by region for a given measure of ocular function are indicated by different patterns (i.e., blank versus solid and blank versus solid versus diagonal stripes).
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Figure 1.
 
Schematic representation of the structure of rhodopsin. The molecule is drawn with the amino terminus (residue 1) at the lower left in the intradiscal space, the carboxyl terminus (residue 348) in the cytoplasm at the top, and the transmembrane domains that span the outer segment disc membrane in the middle. The seven transmembrane domains are helical structures and are enclosed within rectangles. Another rectangle at the upper right encloses a helix in the cytoplasm that lies parallel to the disc membrane. Dotted lines encircle the globular region in the amino terminus and the plug region in the second intradiscal loop; these structures have been defined by high-resolution crystallography. 6 7 Two glycosylated residues in the globule region are designated. Circles are drawn around the amino acid residues that are altered by the rhodopsin mutations included in this study.
Figure 1.
 
Schematic representation of the structure of rhodopsin. The molecule is drawn with the amino terminus (residue 1) at the lower left in the intradiscal space, the carboxyl terminus (residue 348) in the cytoplasm at the top, and the transmembrane domains that span the outer segment disc membrane in the middle. The seven transmembrane domains are helical structures and are enclosed within rectangles. Another rectangle at the upper right encloses a helix in the cytoplasm that lies parallel to the disc membrane. Dotted lines encircle the globular region in the amino terminus and the plug region in the second intradiscal loop; these structures have been defined by high-resolution crystallography. 6 7 Two glycosylated residues in the globule region are designated. Circles are drawn around the amino acid residues that are altered by the rhodopsin mutations included in this study.
Figure 2.
 
Baseline ocular function in patients with rhodopsin mutations. The stem-and-leaf method of display allows presentation of data in grouped form while preserving the individual data points to at least two significant digits. Numbers of patients are 123 (visual acuity), 137 (visual field area), and 131 (ERG amplitude). Each distribution was significantly different from normal (Shapiro-Wilk test, P < 0.001 in each case). The rule for combining the stem and leaf is given at the bottom of the display. For example, in the bottom row (for ln ERG amplitude) the stem is −2 and the first leaf (to the right of the short vertical line) is 5. The stem is multiplied by 1 and the leaf is multiplied by −0.1 (because the stem is negative), and the two numbers are added together to obtain −2.5. This data point, therefore, represents −2.5 ln μV. The displays were generated with online software (provided in the public domain and available at http://www.ruf.rice.edu/∼lane/stat_analysis/descriptive.html).
Figure 2.
 
Baseline ocular function in patients with rhodopsin mutations. The stem-and-leaf method of display allows presentation of data in grouped form while preserving the individual data points to at least two significant digits. Numbers of patients are 123 (visual acuity), 137 (visual field area), and 131 (ERG amplitude). Each distribution was significantly different from normal (Shapiro-Wilk test, P < 0.001 in each case). The rule for combining the stem and leaf is given at the bottom of the display. For example, in the bottom row (for ln ERG amplitude) the stem is −2 and the first leaf (to the right of the short vertical line) is 5. The stem is multiplied by 1 and the leaf is multiplied by −0.1 (because the stem is negative), and the two numbers are added together to obtain −2.5. This data point, therefore, represents −2.5 ln μV. The displays were generated with online software (provided in the public domain and available at http://www.ruf.rice.edu/∼lane/stat_analysis/descriptive.html).
Figure 3.
 
Linear regression of ln visual field area on age at baseline in 137 patients with retinitis pigmentosa due to rhodopsin mutations.
Figure 3.
 
Linear regression of ln visual field area on age at baseline in 137 patients with retinitis pigmentosa due to rhodopsin mutations.
Figure 4.
 
Plots of the estimated annual percentage change in ocular function by baseline function in patients with rhodopsin mutations. Dashed lines: zero change. The visual acuity plot (top left) shows data uncensored with regard to possible ceiling or floor effects from 123 patients, including 8 designated statistical outliers (x). The visual field plot (top right) shows uncensored data from 137 patients, including 2 outliers. The ERG plot (bottom) shows uncensored data from 131 patients including 1 outlier.
Figure 4.
 
Plots of the estimated annual percentage change in ocular function by baseline function in patients with rhodopsin mutations. Dashed lines: zero change. The visual acuity plot (top left) shows data uncensored with regard to possible ceiling or floor effects from 123 patients, including 8 designated statistical outliers (x). The visual field plot (top right) shows uncensored data from 137 patients, including 2 outliers. The ERG plot (bottom) shows uncensored data from 131 patients including 1 outlier.
Figure 5.
 
Scatterplot of ln visual field area versus age in the six patients with normal baseline fields, more than eight measurements, and more than 10 years of follow-up. The data for each patient have been fitted by a spline function to illustrate mean tendency as a function of age. Dashed line: lower limit of normal, corresponding to an equivalent diameter of 120°.
Figure 5.
 
Scatterplot of ln visual field area versus age in the six patients with normal baseline fields, more than eight measurements, and more than 10 years of follow-up. The data for each patient have been fitted by a spline function to illustrate mean tendency as a function of age. Dashed line: lower limit of normal, corresponding to an equivalent diameter of 120°.
Figure 6.
 
Estimated annual change in ln ocular function in patients with rhodopsin mutations. Censored were patients with baseline visual acuities less than 20/100, baseline visual field equivalent diameters less than 10°, and baseline ERG amplitudes less than 0.68 μV. Censored visual acuities were 20/20 that did not follow a lower value. Censored follow-up data were acuities after a value ≤20/100, visual field equivalent diameter after a value ≤10°, and ERG amplitudes after a value ≤0.34 μV. Excluded were statistical outliers from their respective plots (i.e., −54%, −28%, +14%, and +14% rates of change for visual acuity; −29%, −26%, +48%, and +61% rates of change for visual field area; and −42% and −34% rates of change for ERG amplitude). Numbers of patients were 83 (visual acuity), 131 (visual field area), and 92 (ERG amplitude). The distributions for visual acuity, visual field area, and ERG amplitude are not significantly different from normal (Shapiro-Wilk test, P = 0.52, P = 0.32, and P = 0.31, respectively). The rule for combining the stem and leaf is given at the bottom of the display (sample calculation in Fig. 2 ).
Figure 6.
 
Estimated annual change in ln ocular function in patients with rhodopsin mutations. Censored were patients with baseline visual acuities less than 20/100, baseline visual field equivalent diameters less than 10°, and baseline ERG amplitudes less than 0.68 μV. Censored visual acuities were 20/20 that did not follow a lower value. Censored follow-up data were acuities after a value ≤20/100, visual field equivalent diameter after a value ≤10°, and ERG amplitudes after a value ≤0.34 μV. Excluded were statistical outliers from their respective plots (i.e., −54%, −28%, +14%, and +14% rates of change for visual acuity; −29%, −26%, +48%, and +61% rates of change for visual field area; and −42% and −34% rates of change for ERG amplitude). Numbers of patients were 83 (visual acuity), 131 (visual field area), and 92 (ERG amplitude). The distributions for visual acuity, visual field area, and ERG amplitude are not significantly different from normal (Shapiro-Wilk test, P = 0.52, P = 0.32, and P = 0.31, respectively). The rule for combining the stem and leaf is given at the bottom of the display (sample calculation in Fig. 2 ).
Figure 7.
 
Longitudinal ERG amplitude versus age in the 10 patients with rhodopsin mutations with the fastest rates of progression and more than 10 years of follow-up (symbols and solid lines) contrasted with the rate of progression inferred from the least-squares fit to their baseline values (circled symbols and dashed line).
Figure 7.
 
Longitudinal ERG amplitude versus age in the 10 patients with rhodopsin mutations with the fastest rates of progression and more than 10 years of follow-up (symbols and solid lines) contrasted with the rate of progression inferred from the least-squares fit to their baseline values (circled symbols and dashed line).
Figure 8.
 
Estimated annual exponential change in ocular function by region affected by the mutation in patients with rhodopsin mutations. Censoring criteria are provided in Fig. 6 . x, statistical outliers. Numbers of patients (including outliers) are 33, 13, and 18 for visual acuity; 53, 19, and 27 for visual field area; and 43, 15, and 14 for ERG amplitude for the globule, plug, and C terminus, respectively. The data points have been shifted horizontally to facilitate identification of individual values.
Figure 8.
 
Estimated annual exponential change in ocular function by region affected by the mutation in patients with rhodopsin mutations. Censoring criteria are provided in Fig. 6 . x, statistical outliers. Numbers of patients (including outliers) are 33, 13, and 18 for visual acuity; 53, 19, and 27 for visual field area; and 43, 15, and 14 for ERG amplitude for the globule, plug, and C terminus, respectively. The data points have been shifted horizontally to facilitate identification of individual values.
Figure 9.
 
The estimated annual change in visual function (mean + SE) by region altered by a rhodopsin mutation in patients with dominant retinitis pigmentosa. Rates of change have been weighted by the square root of the product of the follow-up time in years and the number of visits, and the data have been corrected for differences in age, gender, and baseline visual function (i.e., mean rates of decline are averages of estimated male and female rates for patients of an average age and baseline visual function). The analyses are based on the data illustrated in Figure 8 , after excluding outliers (i.e., 61 patients for visual acuity, 95 patients for visual field area, and 71 patients for ERG amplitude). Significant differences (P < 0.05) by region for a given measure of ocular function are indicated by different patterns (i.e., blank versus solid and blank versus solid versus diagonal stripes).
Figure 9.
 
The estimated annual change in visual function (mean + SE) by region altered by a rhodopsin mutation in patients with dominant retinitis pigmentosa. Rates of change have been weighted by the square root of the product of the follow-up time in years and the number of visits, and the data have been corrected for differences in age, gender, and baseline visual function (i.e., mean rates of decline are averages of estimated male and female rates for patients of an average age and baseline visual function). The analyses are based on the data illustrated in Figure 8 , after excluding outliers (i.e., 61 patients for visual acuity, 95 patients for visual field area, and 71 patients for ERG amplitude). Significant differences (P < 0.05) by region for a given measure of ocular function are indicated by different patterns (i.e., blank versus solid and blank versus solid versus diagonal stripes).
Table 1.
 
Mean Baseline Ocular Function by Rhodopsin Mutation
Table 1.
 
Mean Baseline Ocular Function by Rhodopsin Mutation
Mutation Cases (n) Sex (M/F) Age (y) Decimal Acuity* Equivalent Field Diameter* ERG Amplitude* Region of Molecule
Thr17Met 3 1/2 51.9 0.89 89.3 22.6 Globule
Pro23His 50 23/27 38.1 0.77 71.5 5.7 Globule
Pro23Leu 1 1/0 23.0 0.89 145.0 9.4 Globule
Phe45Leu 1 1/0 34.2 1.00 128.0 41.7
Gly51Arg 3 3/0 48.3 0.63 102.0 22.1
Gly51Val 3 2/1 31.8 0.70 108.0 29.0
Thr58Arg 2 1/1 35.1 0.95 107.0 39.4
Gly89Asp 9 5/4 36.3 0.58 61.9 0.99
Cys110Tyr 3 3/0 42.3 0.84 85.3 3.6 Plug
Gly114Asp 1 0/1 40.2 0.67 29.4 0.84
Gly114Val 2 0/2 33.7 0.18 25.9 1.9
Leu125Arg 1 1/0 25.0 0.48 40.9 0.19
Arg135Trp 4 2/2 26.3 0.26 81.3 0.98
Ala164Glu 1 1/0 40.6 0.12 92.5 29.3
Cys167Arg 1 1/0 33.8 0.58 26.3 0.66
Pro171Leu 4 3/1 24.0 0.45 77.3 0.61
Glu181Lys 4 2/2 41.2 0.87 61.1 1.4 Plug
Gln184Pro 1 0/1 49.6 0.89 84.2 12.8 Plug
Ser186Pro 1 1/0 37.6 0.27 20.3 0.17 Plug
Gly188Arg 1 1/0 35.5 0.40 56.6 2.5 Plug
Asp190Asn 6 4/2 46.0 0.57 78.7 11.1 Plug
Asp190Gly 3 2/1 29.0 0.96 124.0 31.1 Plug
Cys264del 4 3/1 32.6 0.03 35.9 0.2
Lys296Glu 2 0/2 41.0 0.27 14.4 0.16
Ser297Arg 1 0/1 40.4 0.73 20.9 0.37
Val345Leu 3 3/0 27.6 0.40 91.2 1.9 C-terminus
Val345Met 1 1/0 22.1 0.63 125.0 18.0 C-terminus
Pro347Leu 21 12/9 30.3 0.50 50.1 0.93 C-terminus
Pro347Ser 3 1/2 42.0 0.77 32.1 0.71 C-terminus
Table 2.
 
Baseline Ocular Function by Affected Region of Rhodopsin Molecule
Table 2.
 
Baseline Ocular Function by Affected Region of Rhodopsin Molecule
Globule Plug C Terminus P Kruskal-Wallis P
Number 54 19 28
Age (y) 38.6 ± 1.8 41.0 ± 2.8 31.0 ± 2.6 0.02* 0.01
Males/females (%) 46/54 68/32 61/39 0.18, †
Follow-up (y) 7.4 ± 0.6 9.3 ± 1.1 10.3 ± 1.1 0.04* 0.02
ln MAR (min) 0.25 ± 0.04 0.37 ± 0.11 0.67 ± 0.14 , § 0.01
 Snellen equivalent (20/26), ‡ (20/29), ‡ (20/39), ‡
ln visual field area (deg2) 8.35 ± 0.20 8.38 ± 0.26 7.69 ± 0.30 0.12* 0.13
 Equivalent diameter (73°), ‡ (74°), ‡ (53°), ‡
ln cone ERG amplitude (μV) 1.84 ± 0.25 1.63 ± 0.42 0.08 ± 0.37 <0.001* 0.001
(6.3 μV), ‡ (5.1 μV), ‡ (1.1 μV), ‡
Table 3.
 
Mean Annual Change in Ocular Function by Baseline Function in Patients with Rhodopsin Mutations
Table 3.
 
Mean Annual Change in Ocular Function by Baseline Function in Patients with Rhodopsin Mutations
Ocular Function Normal* P , † Very Low, ‡ P , †
ln visual acuity −0.0078 ± 0.0028, § (n = 27) 0.002 0.0039 ± 0.0191, § (n = 7) 0.50
ln visual field area −0.0449 ± 0.0076, § (n = 27) <0.001 , ¶ (n = 2) , ¶
ln ERG amplitude −0.0739 ± 0.0236, § (n = 6) 0.047 0.0128 ± 0.0155, § (n = 36) 0.71
Table 4.
 
Cross-Sectional Estimates Versus Longitudinal Measurements of Annual Rates of Change in Patients with Rhodopsin Mutations
Table 4.
 
Cross-Sectional Estimates Versus Longitudinal Measurements of Annual Rates of Change in Patients with Rhodopsin Mutations
Ocular Function n * Cross-Sectional Slope Longitudinal Slope Mean (95% CI), ‡
ln visual acuity 83 +0.0018 −0.0182 (−0.0103 to −0.0260)
+0.2% −1.8% (−1.0% to −2.6%)
ln visual field area 131 −0.0442 −0.0261 (−0.0147 to −0.0374)
−4.3% −2.6% (−1.5% to −3.7%)
ln ERG amplitude 92 −0.0098 −0.0911 (−0.0752 to −0.1069)
−1.0% −8.7% (−7.2% to −10.1%)
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