Clinical, Genetic, Imaging and Electrophysiological Findings in a Cohort of Patients With GUCA1A-Associated Retinopathy

Abstract

Purpose: To report findings in GUCA1A-associated retinopathy, a rare autosomal-dominant retinopathy.

Methods: Clinical features and investigations from molecularly confirmed patients at a large referral center were analyzed (retrospective cohort study).

Results: Nineteen patients (14 families), with five different variants, were included: p.(Tyr99Cys) in 10 families and p.(Leu84Phe), p.(Ile107Thr), p.(Glu111Ala), and p.(leu176Phe) in 1 family each. Mean (SD) ages at first and last visits were 38 (17) and 48 (15) years, respectively. Mean (SD) logMAR visual acuities at the first and last visits were 0.67 (0.61) and 0.94 (0.58) for right eyes and 0.63 (0.63) and 0.95 (0.74) for left eyes. Acuities ranged from 0.00 logMAR to no light perception. Most described progressive problems with central and color vision. Across 144 patient visits, logMAR acuity correlated with age (Spearman coefficients of 0.43 and 0.54 for right and left eyes, P < 0.001), with a high interocular correlation (coefficient 0.90, P < 0.001). Optical coherence tomography showed irregularity and then loss of the central ellipsoid zone. Ultra-widefield imaging showed peripheral degeneration in some patients. Electrophysiology (n = 13) was consistent with cone dystrophy (n = 11) or macular dystrophy (n = 2). Compared with the common p.(Tyr99Cys) variant, patients with p.(Glu111Ala) (n = 2) had worse vision; those with p.(Leu84Phe) (n = 3) were younger with earlier-onset visual loss. Patients with p.(Ile107Thr) (n = 2) showed later presentation, with milder acuity reduction.

Conclusions: We present genotypic and phenotypic findings from the largest cohort with GUCA1A retinopathy. Most had progressive visual loss and electrophysiologic evidence of cone dystrophy. Possible genotype-phenotype correlations emerged, but subgroups were small for four of five variants.

Figure 1.

Pedigrees for the 14 families with variants shown for each individual who underwent genetic testing.

Figure 2.

Visual acuities across 144 patient visits plotted against age for right eyes (A) and left eyes (B). Each color denotes a different genetic variant (shown in legend in upper panel). Within each color group, each symbol denotes an individual patient. The dashed line shows a simple linear fit (fitted across all patient visits and both eyes). LogMAR acuity correlated positively with age, indicating worse visual acuities in older patients overall, although several exceptions are seen. Findings from a mixed-effects model are described in the text.

Figure 3.

Right eye pseudocolor fundus imaging for patients where available. The age at examination is denoted in parentheses.

Figure 4.

Right eye ultra-widefield pseudocolor fundus imaging for patients where available. The age at examination is denoted in parentheses.

Figure 5.

Right eye fundus short-wavelength (488 nm) autofluorescence imaging for all patients where available. The age at examination is denoted in parentheses.

Figure 6.

Right eye optical coherence tomography imaging for all patients where available. The age at examination is denoted in parentheses.

Figure 7.

Longitudinal multimodal imaging showing visual acuity measurements, fundus autofluorescence, and optical coherence tomography findings in a single individual (I-b) across a 15-year follow-up period. The age at examination is denoted in parentheses. OCTs were available from age 25.

Figure 8.

Full-field ERG parameters in 13 subjects tested according the International Society for Clinical Electrophysiology of Vision standard methods. (A) The amplitudes of the DA 0.01 ERG, DA 10 ERG a- and b-waves, LA 30-Hz ERG, and LA 3 ERG b-wave are plotted as a percentage of the age-matched lower limit of the (“normal”) reference range (horizontal broken line), with values arranged in ascending order of the cone-mediated LA 3 ERG b-wave amplitude for clarity. Data points for DA 0.01 ERGs are plotted slightly to the right of other data for clarity. (B) The LA 30-Hz peak times as a difference from the age-matched upper limit of normal timing with corresponding GUCA1A variants highlighted. (C) The age of the patients at the time of testing and time since presentation. Patient numbering is consistent in all three panels.

Figure 9.

Representative International Society for Clinical Electrophysiology of Vision standard full-field and pattern ERGs. (A) Recordings from ERG patients 1 (aged 55 years), 7 (23 years), and 10 (51 years) corresponding to the patient numbering used in Figure 8. Representative control (“normal”) recordings are shown for comparison (N). Data are shown for the right eyes only, as all showed a high degree of interocular symmetry. Patient traces are superimposed to demonstrate reproducibility. (B) Recordings from patient 12, who was tested using different equipment, and single-flash and PERG recordings include a 20-ms prestimulus delay. There is ERG evidence of a severe (patient 1), moderate (patient 7), and mild (patients 10 and 12) cone dystrophy. Undetectable PERG P50 components are consistent with severe macular involvement, except in patient 12, who showed a normal PERG P50 in keeping with spared macular function.

Figure 10.

Comparison of the main ERG component amplitudes at initial testing with those obtained at follow-up for four patients. These are ERG patients 5 (top left), 7 (top right), 8 (bottom left), and 9 (bottom right), monitored over 1.5, 4, 2, and 11 years, respectively. Ages at the time of testing are shown on the x-axis. Final follow-up DA 0.01 ERGs in case 9 were distorted by eye movement and are excluded. LA 30-Hz ERG peak times were stable in all four individuals (data not shown).