This cohort study analyzes the association of best-corrected visual acuity loss with foveal phenotype and genotype in patients with Stargardt disease.
Key Points
Question
Is best-corrected visual acuity an appropriate outcome measure for treatment trials in Stargardt disease?
Findings
In this multicenter longitudinal cohort study (the ProgStar Study), the mean rate of best-corrected visual acuity loss was clinically small at 0.55 letters per year during 2 years. The rate varied by baseline best-corrected visual acuity and by fovea phenotype (defined as fovea with normal, increased, questionably decreased, or definitely decreased autofluorescence).
Meaning
For trials of Stargardt disease with 2 years of duration, it may be difficult to show efficacy using best-corrected visual acuity as an end point owing to its slow rate of change over this time.
Abstract
Importance
Limited data from prospective studies are available to understand the natural history of ABCA4-related Stargardt disease (STGD1). Such data are important for determining appropriate outcome measures for future STGD1 trials.
Objective
To estimate the rate of loss of best-corrected visual acuity (BCVA) during 2 years and to estimate the associations of BCVA loss with foveal phenotype and genotype in patients with STGD1.
Design, Setting, and Participants
This multicenter prospective cohort study included 259 participants (489 study eyes) with molecularly confirmed STGD1 who were 6 years or older. The participants were enrolled at 9 centers in the United States and Europe and were followed up every 6 months for 2 years.
Exposures
Baseline BCVA and presence and type of foveal lesion (determined via fundus autofluorescence images) and genotype (classified into 4 groups based on the number and pathogenicity of ABCA4 mutations).
Main Outcomes and Measures
Rate of BCVA change per year.
Results
The mean (SD) age was 33 (15) years. Of 259 the participants, 141 (54%) were female, and 222 (85%) were white. The overall rate of BCVA loss was 0.55 (95% CI, 0.20-0.90) letters per year during the 2 years. Eyes with baseline BCVA worse than 20/200 showed an improvement of 0.65 (95% CI, 0.1-1.2) letters per year. At baseline, the mean BCVA for eyes without foveal lesion was 20/32, and their BCVA change rate over time was 0.1 (95% CI, −1.2 to 1.35) letters per year (P = .89). Eyes with a foveal lesion but having BCVA of 20/70 or better at baseline lost BCVA at a rate of 3 (95% CI, 1.5-4.4) letters per year (P < .001). Genotype was neither associated with baseline BCVA nor with the rate of BCVA change during the follow-up.
Conclusions and Relevance
A clinically small BCVA loss was observed during 2 years, and the change rate varied depending on baseline BCVA. Eyes without lesion in the fovea had better BCVA at baseline and showed minimal change of BCVA throughout 2 years. Eyes with no or modest acuity impairment but with a foveal lesion at baseline had the fastest loss rate. For trials of STGD1 with 2 years of duration, it may be difficult to show efficacy using BCVA as an end point owing to its slow rate of change over this time.
Introduction
Stargardt disease (STGD1; OMIM: 248200) is the most common juvenile macular dystrophy.1 It is inherited as an autosomal-recessive trait associated with mutations in the ABCA4 gene,2 and more than 900 disease-associated sequence variants are reported.3 Clinically, STGD1 is characterized by fundus flecks in the retinal pigment epithelium and by macular atrophic lesions. Visual acuity (VA) in individuals with STGD1 often deteriorates progressively in a nonlinear fashion,4,5,6,7,8,9 with a faster rate of loss at the early stage when a degree of foveal vision is still present. Some patients may present with a fovea sparing phenotype in which the fovea is not involved with any lesion initially, and such patients may maintain relatively good VA for decades.3,9
Currently there is no approved treatment for STGD1. The international multicenter Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study aimed to understand the natural history of disease progression to help determine appropriate outcome measures for future treatment trials.3,10,11,12,13,14 Previously, we have reported no significant change of best-corrected VA (BCVA) during a 12-month follow-up in the ProgStar study.6 Herein we reported the rate of BCVA loss throughout 2 years, assessed whether BCVA loss was linear throughout 2 years, and identified associated risk factors. In particular, we estimated the associations of BCVA loss with baseline foveal involvement and with genotype group defined by the pathogenicity and the number of ABCA4 variants detected.
Methods
This analysis used data from the prospective ProgStar study (ClinicalTrials.gov Identifier: NCT01977846), which was approved by the Western Institutional Review Board, local institutional review boards, and the Human Research Protection Office of the United States Army Medical Research and Materiel Command.
Details of the prospective ProgStar study have been described elsewhere.14 In brief, participants were enrolled at 9 sites from September 2013 to March 2015. Eligibility criteria included patients 6 years or older, those with 2 pathogenic mutations in the ABCA4 gene, or those with 1 pathogenic mutation in the ABCA4 gene at the time of genetic testing plus a typical Stargardt phenotype.14 Relevant inclusion criteria for the current analysis were study eyes with BCVA of 20 or higher Early Treatment of Diabetic Retinopathy Study letter score (ie, 20/400 Snellen equivalent or better), and at least 1 well-demarcated area of atrophy on fundus autofluorescence (AF) imaging with a diameter of 300 μm or more and the sum of all lesions of 12 mm2 or less. All participants gave written informed consent prior to study enrollment and were followed semiannually for 2 years.
At each visit, refraction and BCVA were obtained following the Early Treatment of Diabetic Retinopathy Study protocol.15 Baseline fovea lesion status was assessed by 2 graders independently (R.W.S. and E.S.) (adjudicated by a third senior grader [M.A.]) using fundus AF images,14,16 and near-infrared reflectance images were referenced for eyes with decreased foveal AF, to tease out the confounding AF decrease due to normal macular pigmentation.17 Then presence of a lesion in the foveal center and type of the lesion (increased AF, definitely decreased AF [DDAF], or questionably decreased AF [QDAF]), as previously described,4 was recorded to define fovea phenotypes.
Data on participant genetic characteristics were abstracted from genetic screening reports. Screenings were conducted for clinical diagnosis between 2000 and 2014, using polymerase chain reaction enrichment–based targeted next-generation sequencing, gene chip array, single-strand conformation polymorphism, or direct sequencing technology. All detected variants were confirmed by direct sequencing in 2016 for the ProgStar study, and their pathogenicity was predicted through in silico analysis. Owing to the large number of ABCA4 variants identified, participants’ genetic characteristics were categorized into 4 groups based on the estimated pathogenicity reported in the literature (as of June 2017) and the number and the severity of the predicted functional impact of the ABCA4 variants (Box).18
Box. Genotypes Defined Based on the Pathogenicity, Number, and Severity of the Predicted Functional Impact of Detected ABCA4 Mutationsa.
Genotype A: Patients with ≥2 severe/null variants.b
Genotype B: Patients with 1 severe/null variant and ≥1 variant that are missense or in-frame insertion/deletion.
Genotype C: Patients with no severe/null variant, but ≥2 variants that are missense or in-frame insertion/deletion.
Genotype D: Patients with 1 missense or in-frame insertion/deletion variant or with only variants predicted as less likely pathogenic or uncertain.
Statistical Analysis
Early Treatment of Diabetic Retinopathy Study letter scores of BCVA were converted to the logMAR scale for analysis. Best-corrected VA was used as a continuous variable and also categorized per the World Health Organization’s International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (Table 1).19
Table 1. Genotype and Baseline Characteristics of Participants and Study Eyes of the Prospective ProgStar Study.
Characteristics | Participants, No. (%) |
---|---|
Total No. | 259 |
Genotypea | |
A | 8 (3.1) |
B | 98 (37.8) |
C | 99 (38.2) |
D | 54 (20.9) |
Age at baseline visit, median (IQR) [range], y | 31 (21-44) [7-69] |
Sex | |
Male | 118 (45.6) |
Female | 141 (54.4) |
Race/ethnicity | |
White | 222 (85.7) |
Black/African descent | 20 (7.7) |
Asian/Indian | 10 (3.9) |
Other (Pakistan, near east, or multiple races) | 3 (1.2) |
Do not know | 4 (1.5) |
Age at symptom onset, y | |
Asymptomatic | 2 (0.8) |
Unknown | 16 (6.2) |
Known | 241 (93.0) |
Age at symptom onset among known, median (IQR) [range], y | 19 (12-29) [4-64] |
Duration since symptom onset at the baseline visit, median (IQR) [range], y | 9 (5-15) [0-55] |
Eye-level clinical characteristics | |
No. of study eyes | 489 |
Fovea point lesion involvement statusb | |
Definitely decreased AF | 130 (29.1) |
Questionable decreased AF | 260 (58.2) |
Increased AF | 21 (4.7) |
Normal AF | 36 (8.1) |
BCVA, median (IQR) [range] | |
VA in ETDRS letter score | 41 (35-52) [20-88] |
Equivalent logMAR | 0.88 (0.66 to 1.00) [−0.06 to 1.30] |
Categorized BCVA | |
No VI (≥Snellen 20/25 or logMAR ≤0.1) | 17 (3.5) |
Mild VI (<Snellen 20/25-20/70 or logMAR 0.1-0.54) | 83 (17.0) |
Moderate VI (<Snellen 20/70-20/200 or logMAR 0.54-1.0) | 267 (54.6) |
Severe VI (<Snellen 20/200-20/400 or logMAR 1.0-1.3) | 122 (25.0) |
Blindness (<20/400 or logMAR >1.3) | 0 |
Dilated fundus examination results | |
Total, No.c | 483 |
RPE pigmentary abnormality | |
No | 159 (32.9) |
Yes | 324 (67.1) |
Flecks outside arcades | |
No | 262 (54.2) |
Yes | 220 (45.6) |
Cannot determine | 1 (0.2) |
Abbreviations: AF, autofluorescence; BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; IQR, interquartile range; RPE, retinal pigment epithelium; VA, visual acuity; VI, visual impairment.
Genotype group is defined in the Box.
Fovea point lesion status was graded for 447 study eyes from participants with a known age of onset.
Fundus examination was completed in 483 eyes, and results also included results on presence of nerve pallor, nerve cupping, macula edema, RPE atrophy, vascular attenuation, and peripheral abnormalities. These variables did not show much variability in distribution and were reported in our prior article,4 and thus are not presented here.
Cross-sectional analysis of baseline data used bivariable linear models with generalized estimating equations to compare BCVA by genotype group and by fovea lesion status. If the variable had a P value of more than .10 in the bivariable model, a multivariable model was built to adjust for factors associated with baseline BCVA identified in our prior report,6 including age at symptom onset, duration of symptoms, presence of retinal pigment epithelium pigmentary abnormality, and presence of flecks outside arcades.
To estimate the longitudinal BCVA change rate (logMAR/y), linear mixed-effects modeling (LMM) with a random intercept was used, accounting for intereye and intraeye correlations. To assess whether BCVA change was linear during a 2-year period, a piecewise LMM was used to compare the BCVA change rate during the first and second year.
To further identify baseline variables associated with the BCVA change rate, LMMs were used by including each variable and its interaction with time. The baseline variables included participant demographics, genotype group, and clinical characteristics, as well as the baseline BCVA level. The univariate association of each variable with the BCVA change rate was first estimated. Adjusted associations were also estimated using multivariable LMMs including variables either associated with BCVA change at P less than .10 or associated with baseline BCVA at P less than .10.
All analyses were conducted in SAS version 9.3 (SAS Institute Inc), and 2-sided P values from Wald tests were reported. For multivariable models, raw P values with no adjustment for multiple comparisons were reported. Model fit was assessed using aggregated residuals for generalized estimating equations models20 and was inspected visually and based on plots of scaled residuals for LMMs.21
Results
The prospective ProgStar study enrolled 259 participants with 489 study eyes. Retention rate was more than 88% at all visits (eFigure 1 in the Supplement). There were 200 sequence ABCA4 variants identified, including 166 variants predicted as likely pathogenic.
Table 1 summarizes genotype, demographics, and baseline clinical characteristics. The median (interquartile range [IQR]) age at baseline was 31 (21-44) years, 141 (54%) were female, and 222 (86%) were white. The median (IQR) age at symptom onset was 19 (12-29) years, and the median (IQR) duration since symptom onset at baseline was 9 (5-15) years. Eight participants (3.1%) were in genotype group A, 98 (37.8%) in group B, 99 (38.2%) in group C, and 54 (20.9%) in group D. In the foveal center, 36 eyes (8%) had no lesion (normal AF), 130 eyes (29%) had DDAF, 260 eyes (58%) had QDAF, and 21 (5%) had increased AF. The median (IQR) BCVA was 41 (35-52) letters (logMAR = 0.88), and 100 eyes (21%) had no or mild impairment, 267 eyes (55%) were moderately impaired, and 122 eyes (25%) were severely impaired.
Cross-sectionally at baseline, compared with eyes without a foveal lesion, eyes with abnormal foveal AF had worse BCVA (Figure, A and Table 2). In adjusted analysis, the mean BCVA for eyes with increased AF, QDAF, and DDAF at the fovea was 0.36 (95% CI, 0.17-0.55), 0.47 (95% CI, 0.38-0.56), and 0.50 (95% CI, 0.40-0.60) logMAR worse than the mean BCVA for eyes without foveal lesion, respectively. Best-corrected VA was not significantly different by genotype group (Figure, B and Table 2).
Table 2. Cross-sectional Comparisons of Baseline Best-Corrected Visual Acuity (logMAR) by Foveal Phenotype and Participant Genotype.
Characteristic | Mean VA (logMAR) | Univariate Model | Multivariate Model | ||
---|---|---|---|---|---|
Difference in BCVA Compared With Reference Group (95% CI) | P Valuea | Adjusted Difference Compared With Reference Group (95% CI) | P Valuea | ||
Fovea lesion involvement status | |||||
No lesion (ie, normal AF) | 0.21 | 1 [Reference] | <.001 | 1 [Reference]b | <.001 |
Increased AF | 0.62 | 0.39 (0.23 to 0.56) | 0.36 (0.17 to 0.55) | ||
QDAF | 0.78 | 0.56 (0.48 to 0.63) | 0.47 (0.38 to 0.56) | ||
DDAF | 0.95 | 0.63 (0.55 to 0.72) | 0.50 (0.40 to 0.60) | ||
Genotype | |||||
A | 0.79 | 1 [Reference] | .26 | NAc | NAc |
B | 0.83 | 0.05 (−0.12 to 0.21) | NAc | ||
C | 0.77 | −0.01 (−0.17 to 0.16) | NAc | ||
D | 0.72 | −0.06 (−0.24 to 0.12) | NAc |
Abbreviations: AF, autofluorescence; BCVA, best-corrected visual acuity; DDAF, definitely decreased AF; NA, not applicable; QDAF, questionably decreased AF; VA, visual acuity.
The P value is for testing whether there was a significant difference in BCVA comparing the different groups.
The multivariate model adjusted for other variables that were significantly associated with baseline BCVA, including age at symptom onset, duration of symptoms, presence of retinal pigment epithelium pigmentation abnormality, and presence of flecks outside the arcade. Their associations were reported in our prior ProgStar report.4
Not applicable in multivariate model because the variable was not associated with baseline VA in the univariate analysis at P < .10.
Longitudinally, during the 2 years, 71 eyes (16.4%) lost 1 or more lines (ie, ≥5 letters) and 16 eyes (3.7%) lost 3 or more lines (≥15 letters). Overall, BCVA declined at a rate of 0.011 logMAR per year (−0.55 letters/y) (95% CI, 0.004-0.018; P = .004). The BCVA change rate was 0.006 logMAR per year (−0.3 letters/y) (95% CI, −0.009 to 0.021) during the first year and 0.015 logMAR per year (−0.75 letters/y) (95% CI, 0-0.031) during the second year. However, the rate difference between the second and the first year (0.009 logMAR/y) was not significant (95% CI, −0.01758 to 0.03592; P = .50).
Table 3 presents the rates of BCVA change by subgroups. The BCVA loss rate differed by baseline BCVA level (eFigure 2 in the Supplement): the rate was 0.025 logMAR per year (−1.3 letters/y) (95% CI, −0.002 to 0.051; P = .07), 0.038 logMAR per year (−1.9 letters/y) (95% CI, 0.025-0.050; P < .001), and 0.012 logMAR per year (−0.6 letters/y) (95% CI, 0.004-0.019; P = .002) in eyes with no VI, mild VI, and moderate VI, respectively. Eyes with severe visual impairment at baseline showed a gain of BCVA (rate = −0.013 logMAR/y [0.65 letters/y]; 95% CI, −0.023 to −0.002; P = .02).
Table 3. Rates of Visual Acuity Change (logMAR/y) by Participant Characteristics.
Characteristic | Mean BCVA Change Rate, logMAR/y, (95% CI) | Univariate Model | Multivariate Model | ||
---|---|---|---|---|---|
Difference in Change Rate Compared With Reference Group (95% CI) | P Valuea | Adjusted Difference Compared With Reference Group (95% CI) | P Valuea | ||
Baseline BCVA | <.001b | <.001b | |||
No VIc | 0.025 (−0.002 to 0.051) | 1 [Reference] | NAd | 1 [Reference] | NAd |
Mild VI | 0.038 (0.025 to 0.050) | 0.013 (−0.017 to 0.042) | .39 | −0.017 (−0.052 to 0.019) | .36 |
Moderate VI | 0.012 (0.004 to 0.019) | −0.013 (−0.041 to 0.015) | .35 | −0.061 (−0.099 to −0.024) | .001 |
SevereVI | −0.013 (−0.023 to −0.002) | −0.037 (−0.066 to 0.008) | .01 | −0.098 (−0.139 to −0.058) | <.001 |
Fovea lesion involvement status | .44b | .005b | |||
No lesion (ie normal AF) | 0.002 (−0.024 to 0.027) | 1 [Reference] | NAd | 1 [Reference] | NAd |
Increased AF | 0.020 (−0.013 to 0.052) | 0.018 (−0.023 to 0.059) | .39 | 0.064 (0.020 to 0.107) | .004 |
QDAF | 0.015 (0.006 to 0.024) | 0.013 (−0.014 to 0.040) | .34 | 0.066 (0.034 to 0.098) | <.001 |
DDAF | 0.003 (−0.010 to 0.017) | 0.002 (−0.027 to 0.031) | .91 | 0.066 (0.032 to 0.100) | <.001 |
Genotype | .66b | ||||
A | 0.008 (−0.030 to 0.045) | 1 [Reference] | NAd | NAd | NAd |
B | 0.005 (−0.007 to 0.017) | −0.002 (−0.042 to 0.037) | .91 | NAd | NAd |
C | 0.012 (0.001 to 0.024) | 0.005 (−0.034 to 0.044) | .81 | NAd | NAd |
D | 0.017 (0.002 to 0.032) | 0.010 (−0.031 to 0.050) | .65 | NAd | NAd |
Age at baseline visit, y | .25b | ||||
≤18 | 0.004 (−0.011 to 0.020) | 1 [Reference] | NAd | NAd | NAd |
>18-50 | 0.009 (0 to 0.019) | 0.005 (−0.013 to 0.023) | NAd | NAd | NAd |
>50 | 0.023 (0.006 to 0.041) | 0.019 (−0.004 to 0.042) | NAd | NAd | NAd |
Sex | |||||
Female | 0.008 (−0.002 to 0.018) | 1 [Reference] | NAd | NAd | NAd |
Male | 0.014 (0.003 to 0.024) | 0.005 (−0.009 to 0.020) | .46 | NAd | NAd |
Race/ethnicity | |||||
White | 0.011 (0.003 to 0.018) | 1 [Reference] | NAd | NAd | NAd |
Nonwhite | 0.010 (−0.010 to 0.029) | −0.001 (−0.022 to 0.020) | .94 | NAd | NAd |
Age at symptom onset, y | .83b | NAd | .70b | ||
≤14 | 0.007 (−0.006 to 0.020) | 1 [Reference] | NAd | 1 [Reference] | NAd |
15-20 | 0.008 (−0.007 to 0.024) | 0.001 (−0.019 to 0.021) | .55 | −0.007 (−0.022 to 0.009) | .41 |
21-30 | 0.016 (0 to 0.031) | 0.008 (−0.012 to 0.029) | .42 | −0.003 (−0.018 to 0.013) | .76 |
>30 | 0.013 (−0.002 to 0.029) | 0.006 (−0.014 to 0.026) | .92 | −0.009 (−0.027 to 0.008) | .29 |
Duration since symptom onset at the baseline visit, y | .57b | .14b | |||
0-2 | 0.017 (−0.004 to 0.038) | 1 [Reference] | NAd | 1 [Reference] | NAd |
2-6 | 0.011 (−0.004 to 0.026) | −0.006 (−0.032 to 0.020) | .63 | 0 (−0.027 to 0.027) | .99 |
6-11.5 | 0.002 (−0.012 to 0.017) | −0.015 (−0.041 to 0.011) | .26 | −0.006 (−0.032 to 0.021) | .67 |
>11.5 | 0.015 (0.003 to 0.027) | −0.003 (−0.027 to 0.022) | .83 | 0.009 (−0.017 to 0.036) | .48 |
RPE pigmentary abnormality | .66b | ||||
No | 0.011 (−0.001 to 0.023) | 1 [Reference] | NAd | 1 [Reference] | NAd |
Yes | 0.011 (0.003 to 0.020) | 0 (−0.015 to 0.015) | .97 | 0.004 (−0.012 to 0.020) | NAd |
Flecks outside arcades | .61b | ||||
No | 0.020 (0.011 to 0.030) | 1 [Reference] | NAd | 1 [Reference] | NAd |
Yes | 0 (0.010 to 0.011) | −0.020 (0.006 to 0.034) | .006 | −0.004 (−0.021 to 0.012) | NAd |
Abbreviations: AF, autofluorescence; BCVA, best-corrected visual acuity; DDAF, definitely decreased AF; NA, not applicable; QDAF, questionably decreased AF; RPE, retinal pigment epithelium; VI, visual impairment.
Each P value is testing compared with the reference group whether there was significant difference (except for the P values noted with footnote b).
The P value is for testing overall whether there was any difference in the change rate associated with the variable.
No VI: VA ≥20/25; mild VI: VA <20/25 to 20/70; moderate VI: VA <20/70 to 20/200; severe VI/blindness: VA <20/200.
NA, the variable was not included in the multivariate model because it was not associated with BCVA change with P < .10 in univariate analysis nor was associate with baseline BCVA level.
Eyes with normal foveal AF did not have significant BCVA change (rate = 0.002 logMAR/y [−0.2 letters/y]; P = .89) (Table 3 and eFigure 3 in the Supplement). Eyes with a DDAF foveal lesion also showed no significant change (rate = 0.003 logMAR/y [−0.15 letters/y]; P = .62). Eyes with increased foveal AF lost 1 letter per year (rate = 0.020 logMAR/y [−1 letter/y]; P = .23), but it was not statistically significant. The rate of BCVA loss was 0.015 logMAR per year ( −0.8 letters/y) (95% CI, 0.006-0.024; P = .002) in eyes with a QDAF foveal lesion at baseline. After adjusting for baseline BCVA status, the rates of BCVA loss in eyes with QDAF, DDAF, and increased AF foveal lesion were 0.064 logMAR per year (95% CI, 0.020-0.107; P = .004), 0.066 (95% CI, 0.034-0.098; P < .001), and 0.066 (95% CI, 0.032-0.100, P < .001) faster, respectively, than the rate in eyes with normal foveal AF (Table 3).
Considering that a foveal lesion and no or mild visual impairment at baseline were both associated with faster loss of BCVA, a subset analysis was conducted for the eyes with no or mild visual impairment but with abnormal foveal AF at baseline, and the estimated rate of BCVA loss was 0.059 logMAR per year (−3 letters/y) (95% CI, 0.0307-0.088; P < .001).
The rate of BCVA change was not significantly associated with genotype group, age at baseline, sex, or race/ethnicity (Table 3). While age at symptom onset, duration since symptom onset, presence of retinal pigment epithelium pigmentary abnormality, and presence of flecks outside arcades were associated with baseline BCVA,6 they were not associated with BCVA change rate during the 2 years.
Discussion
We previously reported that BCVA did not change significantly during the first year of follow-up in the prospective ProgStar study.6 Over 2 years of follow-up, there was a statistically significant but clinically small loss of BCVA. Prior evidence has suggested that VA loss in STGD1 is not linear,5,6,9 where loss is faster when vision is minimally or mildly impaired despite accompanying retinal degeneration,22,23,24 followed by slower VA loss after foveal vision is lost and fixation becomes eccentric. In this analysis, the BCVA change rate during the second year more than doubled that during the first year, but the difference in the rate between the 2 years was not statistically different. This suggests that we may not have had the power to detect a nonlinear change of BCVA over 2 years and that using a linear model to describe the change process of BCVA for over 2 years may not be appropriate.
Consistent with our prior findings,4,5,6 the starting level of VA was predictive of subsequent speed of VA loss. For eyes worse than 20/25 at baseline, the better the starting VA, the faster the VA loss subsequently. For those with VA better than 20/25 at baseline, there was no significant loss of VA over 2 years. This was partly due to the small sample size in this group (n = 17), but it may also be attributable to the greater proportion in this subgroup that had no foveal lesion (eTable in the Supplement). For the subset of eyes with no or mild VA loss (ie, BCVA, ≤20/70) but having foveal lesion involvement, their BCVA loss was approximately 3 letters per year, suggesting patients with STGD1 with such attributes are likely to lose vision more quickly.
Patients with STGD1 with a foveal sparing phenotype often can maintain good VA3,25,26,27 over a long time. Such clinical observations are supported by our data showing that at baseline, eyes with no lesion in the fovea had much better BCVA than eyes with abnormal AF (Figure, A) and that these eyes had minimal change in VA during the follow-up.
Visual acuity as a measure of central vision highly depends on the intactness of the fovea. This is supported by the dose-response association between foveal lesion status and BCVA (Figure, A), in which eyes with no lesion in the fovea had the best BCVA, followed by eyes with increased AF, QDAF, and DDAF in the fovea. Increased AF is thought to reflect the early stage of pathogenesis in STGD1, which involves accumulation of lipofuscin fluorophores.28 Such accumulation, detectable on AF images as increased intensity, can lead to loss of photoreceptor cells, which were graded in this study into 2 levels: QDAF (ie, partial loss) and DDAF (ie, complete loss).
This analysis of 2-year data estimated a statistically significant rate of BCVA change of 0.011 logMAR per year (ie, 0.55 letters/y), which was slower than the VA loss rate (0.03 logMAR or 1.5 letters/y) estimated from the retrospective ProgStar cohort. The rates in the subgroups of eyes with no impairment (0.025 logMAR/y) or mild impairment at baseline (0.038 logMAR/y) were also slower than the rates of these subgroups in the retrospective cohort (0.096 and 0.094 logMAR/y, respectively).5 These differences are most likely owing to the retrospective cohort having longer and variable follow-up times (range, 1-6 and median, 3.6 years), plus the potential problem of lack of standardization in VA measures in the retrospective study, which were obtained from review of medical records.
Consistent with our prior findings,5,6 we found a clinically small but statistically significant improvement of VA in eyes with severe impairment at baseline (VA worse than 20/200). Measuring vision reliably in this group is difficult, and regression to the mean is likely. The improvement for some eyes could also be a result of change of the location of the preferred retinal locus, as observed in geographic atrophy and inherited macular dystrophies.29,30,31,32 In STGD1, fixation stability may improve33 as the preferred retinal locus moves to the parapapillary region while scotoma expands,34 and VA with poor fixation stability may improve once fixation stabilizes. The rate of BCVA improvement over 2 years (0.65 letters/y) was smaller than the rate of improvement that we reported in the first year (2.3 letters/y),6 suggesting with longer time since baseline and more measurements to estimate change, the estimate of improvement becomes more stable and closer to 0.
We did not find any association of genotype with baseline VA or with the VA change rate. Understanding the genotype-phenotype correlation in STGD1 is challenging because of the large number of ABCA4 mutations having been associated with STGD1. In silico analysis predicting the potential impact of each variant on protein functioning is a necessary step for further examining the clinical impact of the genotype. Following prior literature,35 we classified our participants into 4 genotype groups based on the number of mutations identified and their predicted pathogenicity. The prevalence of genotype A, the group for which the pathogenicity of the mutations is best known and expected to have the most severe clinical manifestations, was low (8 [3%]). We found no evidence of differences in VA at baseline by genotype group.
Limitations
The above observations may reflect our imperfect knowledge of the pathogenicity of certain mutations and also the limitations in our genetic data. Additionally, the genotype grouping criteria adopted here are clearly a simplification to summarize the complex genetic profiles of the participants and may not be sensitive enough to capture differences in VA loss over 2 years. A limitation in our genetic data is that the data were abstracted from participants’ genetic screening reports. The screenings occurred during 2000 to 2014 for clinical diagnosis and used different sequencing platforms depending on the clinical center. All detected mutations were confirmed by direct sequencing in 2016 through ProgStar, but because the sensitivity in identifying mutations and the sequencing target regions of ABCA4 had changed over time and varied across platforms, it is still possible that disease-relevant mutations were missed in screening. Additionally, it is also possible that participants carry disease-causing mutations in other genes that were not screened but were associated with Stargardt (eg, ELOVL4, PRPH2, or PROM1).36,37 For example, genotype D participants had a large range of baseline BCVA (Figure, B), suggesting they could carry disease-causing mutations in ABCA4 or other relevant genes, which were not screened in our cohort. These limitations emphasize the importance of considering the enrollment criteria of ProgStar participants when generalizing the results to all patients with Stargardt disease in the population.
Earlier age at symptom onset was associated with worse VA in our cross-sectional analyses5,6 and it was associated with faster VA decline in our ProgStar retrospective cohort.5 However, in our current analysis of the prospective cohort, the VA change rate did not differ significantly by age at symptom onset. This may be because compared with the early-onset cases in the retrospective cohort, the early-onset cases in the prospective cohort had poorer vision at baseline, and thus their VA change was also slower. Moreover, 2 years of follow-up may not be long enough to observe the effect of age of onset on the speed of VA decline.
Conclusions
Although BCVA is an important visual function outcome directly associated with participants’ daily activities38 and is often the primary end point in trials for retinal diseases,39 it is probably not a practical outcome measure for STGD1 treatment trials of 2-year duration given the very small rate of change during the period. For a new therapy or treatment aiming to slow down acuity loss in STGD1, the clinical trial should consider no less than 3 years of follow-up and enroll patients with only moderate loss of VA at the outset to optimize the chance of showing efficacy. Such trials should also be careful in using models with linear assumptions on the change process when estimating efficacy on visual acuity. Although BCVA may not show a clinically significant change over 2 years, this reflects the relatively slow course of the natural history of the disease. Even if a large change may be observed within a structural parameter (eg, increased AF40), the structural change may not be correlated with a functional decline of BCVA. Therefore, it remains important to examine whether and under what situations structural changes entail functional impact in STGD1. The associations of foveal phenotype and current BCVA level with subsequent rate of BCVA change may be also important for future trial designs. Fast progressors in STGD1 (in terms of BCVA) are most likely those who currently have good or mildly impaired acuity but have foveal lesion involved in the eyes. For patients with a relatively intact fovea, other visual function measures (eg, macular sensitivity) may be needed to track their visual function change.
Footnotes
All variants refer to mutations on the ABCA4 gene.
Severe/null variants were defined as those that were predicted to affect splicing or to introduce a premature truncating codon in the protein if translated, such as stop, frame shift, intronic variants in splice regions with significant splice site alteration, exonic synonymous variants with significant splice site alteration, or missense variants with significant splice site alteration (eg, nucleotide change at the start/end of exon).
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