Exploratory and comprehensive description of an italian cohort of patients affected by leber hereditary optic neuropathy carrying the pathogenic variants m.11778G > A/MT‐ND4 and m.3460G > A/MT‐ND1

Aims/Purpose: This is an observational study to track the disease course of patients affected by Leber Hereditary Optic Neuropathy (LHON), regularly attending the neurophthalmological clinic of the IRCCS ISNB (Bologna).

Methods: To satisfy inclusion criteria, subjects needed a confirmed genetic diagnosis for 2 of the 3 primary LHON mutations (m.11778G > A/MT‐ND4; m.3460G > A/MT‐ND1). There was no restriction on age, and patients could have received idebenone or any other treatment.

Results: 397 subjects from 137 families were enrolled, 196 symptomatic (49%; male: 79%), 201 asymptomatic (51%; male: 40%). Of these, 66 (17%; symptomatic: 55%) carried the m.3460G > A/MT‐ND1 variant, 331 (83%; symptomatic: 48%) the m.11778G > A/MT‐ND4, with a ratio of affected male: female of 2: 1 for the first, and 4: 1 for the m.11778G > A/MT‐ND4 carriers.

Of the 196 symptomatic patients, 37 had LHON childhood onset and 3 had unilateral LHON.

106 patients (54%) were treated with idebenone and/or lenadogene nolparvovec.

For both mutations the distribution of age at onset is multimodal, and different between males and females. LHON females showed later age at onset (post‐menopausal peak) in the m.11778G > A/MT‐ND4 subgroup, while the m.3460G > A/MT‐ND1 density plot showed a peak in the fertile young age.

Then, visual acuities of both eyes were collected from 1252 outpatient visits. The resulted best‐fitted LOWESS curve depicting the evolution of BCVA over time did not show a difference between m.11778G > A/MT‐ND4 and m.3460G > A/MT‐ND1 symptomatic patients.

Conclusions: We highlight the highest penetrance in females of the m.3460G > A/MT‐ND1 variant, for which females had an age of onset more similar to males at difference with the m.11778G > A/MT‐ND4 for which females had a delayed peak of onset, after menopause. Clinically, the two variants seem to behave similarly. This “real world” study is a precious tool to define genotype/phenotype relationships and highlight the most appropriate subpopulations for clinical trials.