AFG3L2 and ACO2-linked Dominant Optic Atrophy: genotype-phenotype characterization compared to OPA1 patients

Purpose: Heterozygous mutations in AFG3L2 gene (encoding a mitochondrial protease indirectly reflecting on OPA1 cleavage) and ACO2 gene (encoding the mitochondrial enzyme aconitase) are associated to isolated forms of Dominant Optic Atrophy (DOA). We aimed at describing their neuro-ophthalmological phenotype as compared with classic OPA1-related DOA. Design: Cross-sectional study. Methods: The following neuro-ophthalmological parameters were collected: Log MAR visual acuity (VA), color vision, mean deviation and foveal threshold at visual fields, average and sectorial retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness at optic coherence tomography. ACO2 and AFG3L2 patients were compared with an age- and gender-matched group of OPA1 patients with 1:2 ratio. All eyes were analysed using Clustered Wilcoxon rank sum test using Rosner-Glynn-Lee method. Results: 44 eyes from 23 ACO2 and 26 eyes from 13 AFG3L2 patients were compared with 143 eyes from 72 OPA1 patients. All cases presented with bilateral temporal-predominant optic atrophy with various degree of visual impairment. Comparison between AFG3L2 and OPA1 failed to reveal any significant difference. ACO2 patients compared to both AFG3L2 and OPA1 presented overall higher values of nasal RNFL thickness (p=0.029, p=0.023), average (p=0.012, p=0.0007) and sectorial GCL thickness. These results were confirmed also comparing separately affected and subclinical patients. Conclusions: Clinically, DOA remains a fairly homogeneous entity despite the growing genetic heterogeneity. ACO2 seems associated to an overall better preservation of retinal ganglion cells, probably depending on the different pathogenic mechanism involving mtDNA maintenance, as opposed to AFG3L2, which is involved in OPA1 processing and resulted virtually indistinguishable from classic OPA1-DOA.