Central Visual Function and Genotype-Phenotype Correlations in PDE6A-Associated Retinitis Pigmentosa

Abstract

Purpose: Autosomal recessive retinitis pigmentosa (arRP) can be caused by mutations in the phosphodiesterase 6A (PDE6A) gene. Here, we describe the natural course of disease progression with respect to central retinal function (i.e., visual acuity, contrast sensitivity, and color vision) and establish a detailed genotype--phenotype correlation.

Methods: Forty-four patients (26 females; mean age ± SD, 43 ± 13 years) with a confirmed genetic diagnosis of PDE6A-associated arRP underwent comprehensive ophthalmological examinations including best-corrected visual acuity (BCVA) with Early Treatment Diabetic Retinopathy Study charts, contrast sensitivity (CS) with Pelli-Robson charts at distances of 3 m and 1 m, and color vision testing using Roth 28-Hue and Panel D-15 saturated color cups.

Results: The most frequently observed variants were c.998+1G>A/p.?, c.304C>A/p.R102S, and c.2053G>A/p.V685M. Central retinal function in patients homozygous for variant c.304C>A/p.R102S was better when compared to patients homozygous for variant c.998+1G>A/p.?, although the former were older at baseline. Central retinal function was similar in patients homozygous for variant c.304C>A/p.R102S and patients heterozygous for variants c.304C>A/p.R102S and c.2053G>A/p.V685M, although the latter were younger at baseline. Annual decline rates in central retinal function were small.

Conclusions: We conclude that the severity of the different disease-causing PDE6A mutations in humans with respect to central visual function may be ranked as follows: c.2053G>A/p.V685M in homozygous state (most severe) > c.998+1G>A/p.? in homozygous state > c.304C>A/p.R102S and c.2053G>A/p.V685M in compound-heterozygous state > c.304C>A/p.R102S in homozygous state (mildest). The assessment of treatment efficacy in interventional trials will remain challenging due to small annual decline rates in central retinal function.

Figure 1.

Variant distribution. (A) The 22 exons of PDE6A (NM_000440.3) are represented by gray boxes. Note that exons and the intervening intronic sequences (represented by black horizontal lines) are not drawn to scale. Each variant identified in our cohort is shown above the respective exon (for missense, nonsense, and indel variants) or below the respective intron (for splice site variants). (B) Protein structure with the non-catalytic cGMP-binding domain and the PDEase I catalytic domain.

Figure 2.

Pedigree of family ARRP 291 carrying variant c.998+1G>A/p.? homozygously. Circles indicate female family members, squares indicate male family members. Affected family members are indicated by black symbols. Note that the father of the six siblings also carries the respective variant homozygously. Also note the consanguinity in the parents.

Figure 3.

Correlation between contrast sensitivity at distances of 3 m and 1 m (r = 0.91; P < 0.01; n = 71 measurements) and between Roth 28-Hue and Panel D-15 saturated tests (r = 0.90; P < 0.01; n = 61 measurements) in PDE6A-associated arRP. Note the ceiling effect in Panel D-15 saturated color vision testing.

Figure 4.

Genotype-associated age, visual acuity, contrast sensitivity, and color vision in PDE6A-associated arRP. Baseline findings of right eyes. Group 1 was comprised of patients homozygous for variant c.998+1G>A/p.? (n = 7); group 2, patients homozygous for variant p.R102S (n = 5); and group 3, patients heterozygous for variants c.304C>A/p.R102S and c.2053G>A/p.V685M (n = 5). The two siblings carrying the variant c.2053G>A/p.V685M homozygously are indicated with a black asterisk. The remaining patients are sub-summarized by “other.” Note that the central retinal function in group 2 was better when compared to group 1, although patients were older at baseline. Also note that central retinal function was similar in groups 2 and 3, although patients in group 3 were younger at baseline.

Figure 5.

Estimated progression rates in visual acuity, contrast sensitivity, and color vision in PDE6A-associated arRP. The dashed lines indicate the 95% confidence intervals.