AFG3L2 and ACO2-Linked Dominant Optic Atrophy: Genotype-Phenotype Characterization Compared to OPA1 Patients

Giulia Amore; Martina Romagnoli; Michele Carbonelli; Maria Lucia Cascavilla; Anna Maria De Negri; Arturo Carta; Vincenzo Parisi; Antonio Di Renzo; Costantino Schiavi; Chiara Lenzetti; Corrado Zenesini; Danara Ormanbekova; Flavia Palombo; Claudio Fiorini; Leonardo Caporali; Valerio Carelli; Piero Barboni; Chiara La Morgia

doi:10.1016/j.ajo.2024.01.011

AFG3L2 and ACO2-Linked Dominant Optic Atrophy: Genotype-Phenotype Characterization Compared to OPA1 Patients

Am J Ophthalmol. 2024 Jan 24:262:114-124. doi: 10.1016/j.ajo.2024.01.011. Online ahead of print.

Authors

Giulia Amore¹, Martina Romagnoli², Michele Carbonelli³, Maria Lucia Cascavilla⁴, Anna Maria De Negri⁵, Arturo Carta⁶, Vincenzo Parisi⁷, Antonio Di Renzo⁷, Costantino Schiavi⁸, Chiara Lenzetti⁹, Corrado Zenesini¹⁰, Danara Ormanbekova², Flavia Palombo², Claudio Fiorini², Leonardo Caporali², Valerio Carelli¹¹, Piero Barboni⁴, Chiara La Morgia¹²

Affiliations

¹ From the Department of Biomedical and Neuromotor Sciences (G.A., M.C., V.C., C.L.M.), University of Bologna, Bologna, Italy; Ophthalmology Unit (G.A., C.S.), IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy. Electronic address: giulia.amore4@unibo.it.
² IRCCS Istituto delle Scienze Neurologiche di Bologna (M.R., D.O., F.P., C.F.L.C.V.C.), Programma di Neurogenetica, Bologna, Italy.
³ From the Department of Biomedical and Neuromotor Sciences (G.A., M.C., V.C., C.L.M.), University of Bologna, Bologna, Italy.
⁴ Department of Ophthalmology (M.L.C., P.B.), University Vita-Salute, IRCCS Ospedale San Raffaele, Milan, Italy.
⁵ Azienda Ospedaliera San Camillo-Forlanini (A.M.D.N.), Rome, Italy.
⁶ Ophthalmology Unit (A.C.), University Hospital of Parma, University of Parma, Parma, Italy.
⁷ IRCCS Fondazione Bietti (V.P. A.D.R.), Rome, Italy.
⁸ Ophthalmology Unit (G.A., C.S.), IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
⁹ Department of Surgery and Translational Medicine (C.L.), Eye Clinic, Careggi University Hospital, University of Florence, Florence, Italy.
¹⁰ IRCCS Istituto delle Scienze Neurologiche di Bologna (C.Z.), Unità di Epidemiologia e Statistica, Bologna, Italy.
¹¹ From the Department of Biomedical and Neuromotor Sciences (G.A., M.C., V.C., C.L.M.), University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna (M.R., D.O., F.P., C.F.L.C.V.C.), Programma di Neurogenetica, Bologna, Italy.
¹² From the Department of Biomedical and Neuromotor Sciences (G.A., M.C., V.C., C.L.M.), University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna (C.L.M.), UOC Clinica Neurologica, Bologna, Italy.

PMID: 38278202
DOI: 10.1016/j.ajo.2024.01.011

Abstract

Purpose: Heterozygous mutations in the AFG3L2 gene (encoding a mitochondrial protease indirectly reflecting on OPA1 cleavage) and ACO2 gene (encoding the mitochondrial enzyme aconitase) are associated with 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: logMAR 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 on optical coherence tomography. ACO2 and AFG3L2 patients were compared with an age- and sex-matched group of OPA1 patients with a 1:2 ratio. All eyes were analyzed using a clustered Wilcoxon rank sum test with the Rosner-Glynn-Lee method.

Results: A total of 44 eyes from 23 ACO2 patients 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 = .029, P = .023), average thickness (P = .012, P = .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 to be associated with 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 is virtually indistinguishable from classic OPA1-DOA.