Genotype–phenotype heterogeneity of ganglion cell and inner plexiform layer deficit in autosomal‐dominant optic atrophy

Purpose To describe the thickness of the combined ganglion cell and inner plexiform layers (GC-IPL) and the peripapillary retinal nerve fibre layer (RNFL) in patients with OPA1 c.983A>G or c.2708_2711delTTAG autosomal-dominant optic atrophy (ADOA). Methods The study included 20 individuals with c.983A>G and nine individuals with c.2708_2711delTTAG. Data for comparison were drawn from 49, previously published, individuals with OPA1 c.2826_2836delinsGGATGCTCCA and 51 individuals with no OPA1 mutation. Subjects underwent refraction, best-corrected visual acuity assessment, axial length measurement and high-definition optical coherence tomography. Results There was overlap in GC-IPL thickness in subjects younger than 20–30 years between the two new groups of ADOA patients and controls. Numerical decreases in GC-IPL thickness with age did not reach statistical significance in individuals with c.983A>G (p = 0.18) or in healthy controls (p = 0.22), but it did in individuals with c.2708_2711delTTAG (p = 0.02). Visual acuity decreased with decreasing GC-IPL thickness (p = 0.0006 in c.983A>G and p = 0.0084 in c.2708_2711delTTAG). Unlike c.2826_2836delinsGGATGCTCCA, individuals with c.983A>G or c.2708_2711delTTAG did not show a pattern of maximum GC-IPL deficit inferonasal of the fovea. Conclusion Genotype–phenotype heterogeneity in OPA1 ADOA is evident when inner retinal atrophy is examined as a function of age. Thus, a pronounced decline with age in GC-IPL thickness is observed in c.2708_2711delTTAG ADOA, an intermediate decline with age is observed in c.983A>G ADOA, whereas little or no change with age is observed in c.2826_2836delinsGGATGCTCCA ADOA. This genotype–phenotype heterogeneity may explain why some patients have progressive visual loss while others have a relatively stable prognosis.