Clinical features and temporal trends in a large Japanese LHON cohort, 1995-2024: a retrospective study

Leber hereditary optic neuropathy (LHON) exhibits population-specific characteristics in Japan, but long-term temporal changes remain unclear.

We retrospectively analysed 179 patients with genetically confirmed LHON at Inoue Eye Hospital (1995-2024). Age at onset was evaluated using median (τ = 0.5) quantile regression, with temporal effects expressed per decade. Female proportion, m.11778 G > A frequency, and-among adults ( ≥ 20 years)-smoking and alcohol use were assessed using logistic regression. Age-band distributions (10-year intervals) were compared between 1995-2012 and 2013-2024 using a χ² test.

The median age at onset was 33 years (interquartile ranges, 18.5-48.0); 83.2% were male. Mutation frequencies were m.11778 G > A, 88.8%; m.14484 T > C, 9.5%; and m.3460 G > A, 1.7%. Age at onset increased by 4.29 years per decade (95% confidence interval [CI], 0.16-8.41; p = 0.043). Temporal changes were not significant for female sex (odds ratio [OR]/decade, 1.39; 95% CI, 0.80-2.40; p = 0.24) or for m.11778 G > A (OR/decade, 1.38; 95% CI, 0.74-2.56; p = 0.31). Among adults with available data, smoking showed a nonsignificant decrease and alcohol use a nonsignificant increase; however, these exploratory estimates were limited by missingness, retrospective exposure ascertainment, and complete-case analysis. After 2013, the age distribution shifted (p = 0.0436), with more patients aged 30-49 years, fewer aged 0-9 years, and emerging cases at 70-79 years.

Age at onset increased over time, whereas sex ratio and m.11778 G > A predominance remained stable. Wider availability of genetic testing, together with improved recognition of optic neuropathy in routine practice, may have reduced under-recognition in older adults, partly explaining the upward shift in age at onset.