Genotype-Phenotype Correlations in OPA1-Positive Autosomal Dominant Optic Atrophy

Abstract

Purpose : Autosomal dominant optic atrophy (DOA) is the commonest inherited optic neuropathy with ~ 60% of patients carrying pathogenic variants in the nuclear-encoded OPA1 gene (3q29, OMIM:605290). The majority of patients present with isolated optic atrophy (DOA) whilst some develop a syndromic form of the disease (DOA+). A lack of natural history data for DOA limits the development of outcome measures for therapeutic studies. This study sought to establish the natural history of DOA in a large patient cohort with a confirmed molecular diagnosis of a pathogenic OPA1 variant.

Methods : We performed a retrospective multicentre observational study which included all optic neuropathy patients who carried a pathogenic or candidate pathogenic OPA1 variant. Visual acuity (VA), visual fields, and optical coherence tomography (OCT) imaging data was collected from clinical records. OPA1 variant data was retrieved from diagnostic reports. Patients with compound OPA1 variants were excluded as were patients with variants of unknown significance. A mixed-effects model was used to develop a predictive tool for visual acuity decline.

Results : Of the 304 patients recruited into this study, 282 had isolated DOA and 22 had systemic features (DOA+). 45.5% of DOA+ patients harboured a missense variant compared with 20.6% of DOA patients (OR 3.22; P<0.01). Mean (± standard deviation) rate of visual decline was 0.035±0.162 logMAR/year and was shown to decline linearly for all subgroups. Final VA and rate of decline was significantly worse in the DOA+ group vs DOA group (1.544±0.817 vs 0.802±0.441; p<0.001); in patients who had a missense variant vs a loss of function variant (1.208±0.512 vs 0.758±0.470; p<0.001); and in patients with a variant in the GTPase domain vs other functional domains (0.985±0.535 vs 0.751±0.473; p<0.001). Patients with missense and GTPase variants demonstrated a faster rate of RNFL and GCL thinning on OCT. A visual acuity predictive model based on presenting features accounted for 80.2% of the logMAR variance.

Conclusions : We have identified several genotype-phenotype correlations in a large cohort of OPA1 mutation carriers that can be used for patient counselling and clinical trial design. The rate of visual decline in DOA is best modelled linearly and it can be predicted using patient demographics, the presence of DOA+ features and OPA1 mutation type.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.