A prospective longitudinal study of retinal structure and function in achromatopsia

Abstract

Purpose: To longitudinally characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical gene therapy trials.

Methods: Thirty-eight molecularly confirmed ACHM subjects underwent serial assessments, including spectral domain optical coherence tomography (SD-OCT), microperimetry, and fundus autofluorescence (FAF). Foveal structure on SD-OCT was graded and compared for evidence of progression, along with serial measurements of foveal total retinal thickness (FTRT) and outer nuclear layer (ONL) thickness. Fundus autofluorescence patterns were characterized and compared over time.

Results: Mean follow-up was 19.5 months (age range at baseline, 6-52 years). Only 2 (5%) of 37 subjects demonstrated change in serial foveal SD-OCT scans. There was no statistically significant change over time in FTRT (P = 0.83), ONL thickness (P = 0.27), hyporeflective zone diameter (P = 0.42), visual acuity (P = 0.89), contrast sensitivity (P = 0.22), mean retinal sensitivity (P = 0.84), and fixation stability (P = 0.58). Three distinct FAF patterns were observed (n = 30): central increased FAF (n = 4), normal FAF (n = 11), and well-demarcated reduced FAF (n = 15); with the latter group displaying a slow increase in the area of reduced FAF of 0.03 mm(2) over 19.3 months (P = 0.002).

Conclusions: Previously published cross-sectional studies have described conflicting findings with respect to the age-dependency of progression. This study, which constitutes the largest and longest prospective longitudinal study of ACHM to date, suggests that although ACHM may be progressive, any such progression is slow and subtle in most patients, and does not correlate with age or genotype. We also describe the first serial assessment of FAF, which is highly variable between individuals, even of similar age and genotype.

Keywords: achromatopsia; gene therapy; optical coherence tomography; retinal degeneration; retinal dystrophy.

Figure 1

Longitudinal SD-OCT scans in achromatopsia. Left: Baseline scans indicating genotype, patient number, and age at initial scan. Right: Follow-up scans indicating patient number and interval between baseline and follow-up scans in months. Center: Foveal magnification (×3) of corresponding scan (gray arrows). Shown are the left eyes of a typical subject from each of the five SD-OCT categories, all of whom demonstrated no change in SD-OCT structure over the study period (from the top row down: patient 35 with a continuous ISe band at both time points; patient 21 with a disrupted ISe layer at both time points; patient 11 with an absent ISe layer at both time points; patient 12 with an HRZ at both time points; and patient 30 with outer retinal atrophy at both time points). Nonmagnified images represent 4500 μm horizontally and 1000 μm vertically; image scaling has been corrected for axial length. Scale bar: 200 μm.

Figure 2

The left and right eye scans of the two achromatopsia subjects who demonstrated a change in SD-OCT appearance over the time course of the study. Layout is as in Figure 1. Top two rows: Patient 2 showed a continuous ISe layer at the fovea at initial scan in both the OS and OD eyes, and subsequently a disrupted ISe layer in both eyes at follow-up scan 20 months later (black arrows). Bottom two rows: Patient 31 showed a disrupted ISe layer at initial scan in both eyes and an HRZ 20 months later (black arrows). Nonmagnified images represent 4500 μm horizontally and 1000 μm vertically; image scaling has been corrected for axial length. Scale bar: 200 μm.

Figure 3

The microperimetry findings in patient 5, who developed a scotoma during this study. (A) Microperimetry findings at baseline. Numbers indicate retinal sensitivity (dB) at that location. (B) Microperimetry findings 16 months later indicate an absolute scotoma at two locations.

Figure 4

Longitudinal FAF in achromatopsia, demonstrating the three patterns observed (patient number, genotype, and age at baseline acquisition indicated at left; patient number and follow-up interval in months indicated at right). Top: Pattern 1: reduced FAF signal centrally with a well-demarcated border. Middle: Pattern 2: normal FAF appearance. Bottom: Pattern 3: a central increase in FAF. These patterns were not statistically significantly age dependent. All of the three above patients harbor CNGA3 disease-causing alleles and are of a similar age, which serves to highlight both the wide phenotypic variation seen in achromatopsia even within the same genotype, and also the lack of strict age-dependency.