Variant and clinical landscape of Leber hereditary optic neuropathy based on 1516 families with mtDNA variants in a tertiary centre.

Aims: To investigate the clinical characteristics of Leber hereditary optic neuropathy (LHON) with mtDNA primary mutations to better understand features associated with prognosis.

Methods: This study enrolled 1540 LHON patients from 1516 unrelated families genetically confirmed by Sanger or whole-mitochondrial sequencing between 1997 and 2022. The spectrum of variants was summarised and compared in different ethnic groups. Clinical data from outpatients were collected, including onset age, disease course, optic disc categories and the corresponding visual acuity.

Results: Of the 1516 LHON families, 13 pathogenic mtDNA variants were detected, in which the proportion of m.11778G>A, m.3460G>A and m.3635G>A was significantly different from non-East Asians (p<0.0001). About 95% (1075/1131) of patients were between 8 and 40 years old at onset, with a median onset age of 16. The eyes of m.14484T>C patients presented with better visual acuity and slower progression across patients with different onset ages and initial severity. Eyes (N=439) with available fundus images were divided into four categories (C1-C4). The progression grades were derived from the category and the corresponding time course, where a higher grade (C3-C4 within 1 year) was associated with greater visual impairment than a lower grade (C1-C2 over 1 year) (p=4.60E-05) . A prognostic matrix showed that later onset and a higher progression grade are associated with higher risk of blindness.

Conclusion: Compared with non-East Asians, Chinese LHON patients had higher proportions of m.11778G>A and m.3635G>A and lower m.3460G>A mutations. A novel progression grade derived from optic disc category was proposed. The prognostic matrix indicated that lower grade and younger-onset age are the most favourable prognostic factors.