Natural history of retinitis pigmentosa based on genotype, vitamin A/E supplementation, and an electroretinogram biomarker

Abstract

BACKGROUNDA randomized clinical trial from 1984 to 1992 indicated that vitamin A supplementation had a beneficial effect on the progression of retinitis pigmentosa (RP), while vitamin E had an adverse effect.METHODSSequencing of banked DNA samples from that trial provided the opportunity to determine whether certain genotypes responded preferentially to vitamin supplementation.RESULTSThe genetic solution rate was 587 out of 765 (77%) of sequenced samples. Combining genetic solutions with electroretinogram outcomes showed that there were systematic differences in severity and progression seen among different genetic subtypes of RP, extending findings made for USH2A, RHO, RPGR, PRPF31, and EYS. Baseline electroretinogram 30-Hz flicker implicit time was an independent, strong predictor of progression rate. Using additional data and baseline implicit time as a predictor, the deleterious effect of vitamin E was still present. Surprisingly, the effect of vitamin A progression in the cohort as a whole was not detectable, with or without data from subsequent trials. Subgroup analyses are also discussed.CONCLUSIONOverall, genetic subtype and implicit time have significant predictive power for a patient's rate of progression, which is useful prognostically. While vitamin E supplementation should still be avoided, these data do not support a generalized neuroprotective effect of vitamin A for all types of RP.TRIAL REGISTRATIONClinicalTrials.gov NCT00000114, NCT00000116, and NCT00346333.FUNDINGFoundation Fighting Blindness and the National Eye Institute: R01 EY012910, R01 EY031036, R01 EY026904, and P30 EY014104.

Keywords: Ophthalmology; Retinopathy.

Figure 1. Histogram showing the number of study participants with a genetic solution in each gene.

Bars are labeled with the number of participants. Participant counts are reported separately for each study because the participants from the vitamin A study were recruited before any genetic solutions for RP were known, and therefore the distribution of genes in that study should be the most unbiased. Participants without a genetic solution (n = 178) are not shown.

Figure 2. Natural history of retinitis pigmentosa by age among major genotypes.

Visual acuity (A), central visual field equivalent diameter (B), and ERG cone flicker amplitude (C) are shown for the 5 largest genetic subgroups. A linear curve fit is shown for the data for each participant. The dashed line in C represents 0.5 μV, below which the decay of the response amplitude is less reliably estimated. The lack of points below the blue arrow demonstrates the absence of RPGR participants with normal visual acuity after age 40. USH2A participants have relatively steep visual field declines starting at a variety of ages (red arrow), but can maintain visual acuity into older ages (black arrow). A subset of RHO participants has particularly mild deficits in the ERG amplitudes even at older ages (green arrow).

Figure 3. Individual cone flicker ERG amplitude decay rates were calculated for each study participant (y axis), and plotted by baseline ERG cone flicker implicit time (x axis), for all participants (top).

A spline fit shows the trend toward worse progression rates with increasing baseline implicit time. Participants from the largest gene subgroups are shown below. (One outlier point beyond the y axis is not shown.)

Figure 4. Gene-specific estimates of the baseline (time = 0) cone flicker ERG amplitude (y axis) and the yearly ERG amplitude progression rate (x axis).

Both x- and y-axis values are adjusted to remove any vitamin E treatment effect. The results are presented without (A) and with (B) adjustment for baseline implicit time. A negative value on the x axis represents a decrease in amplitude over time.