Retinal Degeneration in Choroideremia follows an Exponential Decay Function
Authors: James W. Aylward, Kanmin Xue, Maria I. Patrício, Jasleen K. Jolly, Jonathan C. Wood, Jonathan Brett, Kirti M. Jasani, Robert E. MacLaren
Journal: Ophthalmology (2018)

Fundus autofluorescence (AF) arises from lipofuscin, which is derived from retinoid byproducts of the visual cycle and accumulates within retinal pigment epithelial cells. Alterations in AF pattern are seen in a wide range of retinal degenerations. Choroideremia is an X-linked retinal dystrophy caused by loss-of-function mutations within the CHM gene, encoding Rab escort protein-1.1van den Hurk J.A. Schwartz M. van Bokhoven H. et al.Molecular basis of choroideremia (CHM): mutations involving the Rab escort protein-1 (REP-1) gene.Hum Mutat. 1997; 9: 110-117Crossref PubMed Scopus (134) Google Scholar It is uniquely characterized by a central “island” of residual AF that undergoes gradual shrinkage with disease progression. The decrease in AF area is correlated precisely with loss of overlying photoreceptors, leading to progressive visual field restriction and blindness around the fifth decade. Retinal gene replacement therapy using an adeno-associated viral vector could potentially slow down or stop disease progression in choroideremia.2MacLaren R.E. Groppe M. Barnard A.R. et al.Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial.Lancet. 2014; 383: 1129-1137Abstract Full Text Full Text PDF PubMed Scopus (571) Google Scholar, 3Edwards T.L. Jolly J.K. Groppe M. et al.Visual acuity after retinal gene therapy for choroideremia.N Engl J Med. 2016; 374: 2016-2018Crossref Scopus (152) Google Scholar Although visual acuity may be improved by gene therapy, it is affected relatively late in the disease; therefore, the area of residual AF may provide an alternative anatomic biomarker for monitoring progression at earlier stages. A previous cross-sectional study suggested an exponential decrease in AF area with age in choroideremia.4Jolly J.K. Edwards T.L. Moules J. et al.A qualitative and quantitative assessment of fundus autofluorescence patterns in patients with choroideremia.Invest Ophthalmol Vis Sci. 2016; 57: 4498-4503Crossref PubMed Scopus (49) Google Scholar However, longitudinal data on natural disease progression is lacking. For instance, it is uncertain whether individuals progressed at different rates depending on genetic, epigenetic, or environmental factors, and whether the rate of progression varied between early and late stages of the disease. We performed a retrospective, longitudinal analysis of AF images from 62 eyes of the youngest 31 confirmed patients with choroideremia (mean age, 28 years; range, 12–43 years), who have relatively large and therefore measurable AF areas, and were seen as part of the screening process for gene therapy trials approved by the UK Research Ethics Committee (ref: GTAC171 & 15/LO/1379; Table S1, available at www.aaojournal.org). BluePeak 55° AF images were captured on the Spectralis confocal scanning laser ophthalmoscope (Heidelberg Engineering, Heidelberg, Germany) at baseline, and 1 and 2 years. The central contiguous AF island was outlined manually using the area tool within Heidelberg Eye Explorer (HEYEX) by 2 independent graders (J.W.A. and J.C.W.) to provide a mean. Area outlines from follow-up visits were transferred onto the baseline image using the internal image registration function of HEYEX, thereby overcoming discrepancies arising from small changes in focus, orientation, and edge distortion. Correlation between baseline AF area and age suggested an exponential decline of AF area over time (R2 = 0.5; P < 0.0001; n = 56 eyes), consistent with a previous report (Fig 1A).4Jolly J.K. Edwards T.L. Moules J. et al.A qualitative and quantitative assessment of fundus autofluorescence patterns in patients with choroideremia.Invest Ophthalmol Vis Sci. 2016; 57: 4498-4503Crossref PubMed Scopus (49) Google Scholar The percentage of AF area loss over 2 years in each eye showed a weak correlation with age (slope, 0.28; R2 = 0.11; P =0.03; n = 44 eyes; Fig 1B). The absolute AF area loss over 2 years was, however, strongly correlated with AF area at baseline (R2 = 0.97; P < 0.0001; n = 44 eyes; Fig 1C). Because age and baseline AF area are not independent variables in a progressive retinal degeneration, multiple regression analysis was performed. This analysis showed a strong overall correlation between AF area loss over 2 years and baseline AF area and age (R2 = 0.94; P < 0.0001; n = 44 eyes). However, age alone was not a significant correlate (R = −0.005; 95% confidence interval, −0.01 to 0.00; P = 0.06), whereas baseline AF area was a highly significant positive correlate (R = 0.81; 95% confidence interval, 0.72–0.89; P < 0.0001). Altogether, the rate of AF area reduction seemed to depend on the baseline area, with larger areas progressing more quickly, in keeping with exponential decay. Hence, the slowing of degeneration in later years is due to the small baseline area remaining rather than any protective effect of ageing. If AF area undergoes steady exponential decay, the rate of degeneration in the first year should predict the rate of degeneration in the second, which seemed indeed to be the case (Fig 1D). Because a good degree of intereye symmetry was observed (paired t-test: P = 0.53; t = 0.64; degrees of freedom [df] = 20; n = 21 patients), the AF data from both eyes were combined to calculate the AF half-life in each individual (Fig 1E). The mean AF area half-life for the cohort was 5.53 years (95% confidence interval, 5.0–6.1). Therefore, the exponential decay constant (λ) was 0.125, using the equation N(t) = N(0)e−λt. No correlation was found between AF half-life and age (P = 0.2; n = 28), further confirming that the rate of disease progression is independent of age. Our estimate of AF half-life is slightly shorter than that predicted by the cross-sectional study (8.7 years).4Jolly J.K. Edwards T.L. Moules J. et al.A qualitative and quantitative assessment of fundus autofluorescence patterns in patients with choroideremia.Invest Ophthalmol Vis Sci. 2016; 57: 4498-4503Crossref PubMed Scopus (49) Google Scholar A possible explanation is that the latter extrapolated half-life from a regression line fitted to the whole cohort and constrained to the maximum measurable area of the 55° field at age zero. However, it can take several variable years before the AF defects progress to within the central 55° field. We propose an alternative model, whereby the degeneration of AF follows a “one-hit” model such that the probability of retinal pigment epithelial/photoreceptor cell death remains constant over time. The implication is that the time of onset of detectable AF loss may be the critical factor that determines eventual disease severity, because once the degeneration starts, it progresses at a similar exponential rate. By extrapolating individual half-lives, the range of age of onset of AF degeneration involving the 55° posterior pole were predicted to be 0 to 20 years (Fig 1F). Our human data are consistent with the kinetics of photoreceptor degeneration in mouse models of retinitis pigmentosa, which followed exponential decreases with similar λ constants.5Clarke G. Collins R.A. Leavitt B.R. et al.A one-hit model of cell death in inherited neuronal degenerations.Nature. 2000; 406: 195-199Crossref PubMed Scopus (258) Google Scholar The data suggest that the majority of patients with choroideremia undergo retinal degeneration with a similar rate of exponential decay. Possible modifiers that may account for some of the variation in AF half-life are area measurement errors, and variability in developmental anatomy of the retina/choroid and AF island shapes. Bland-Altman analysis of test–retest variability in AF area measurements between our 2 graders showed a 95% limits of agreement of −0.80 to 0.68 mm2 (n = 22) and bias of −0.06 (standard deviation, 0.38). Comparisons of the shapes of the AF islands between fellow eyes revealed a remarkable degree of mirror symmetry and islands with more “craggy” outlines seemed to shrink at a slightly higher rate (Fig S1, available online at www.aaojournal.org). Overall, the results support the use of fellow eyes as controls in clinical trials, particularly when baseline AF areas are symmetrical. Alternatively, individuals can be observed for a period of time to determine their baseline AF half-life before a therapeutic intervention is given to 1 eye. Download .pdf (.8 MB) Help with pdf files Figure S1 Download .pdf (.1 MB) Help with pdf files Table S1