Late-onset Leber Hereditary Optic Neuropathy: disease triggers and prognostic factors in a large Italian cohort.

PURPOSE: To characterize the clinical and genetic features, investigate disease triggers, and explore factors associated with visual recovery in late-onset Leber Hereditary Optic Neuropathy (LHON).

DESIGN

Retrospective cohort study.

SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Seventy-seven patients with late-onset LHON (onset ≥ 40 years of age) were identified from a larger cohort of 398 Italian LHON patients. Full clinical and genetic analyses were performed on 67 of these patients, while an internal control group of 562 healthy individuals was utilized for mitochondrial haplogroup comparisons.

METHODS, INTERVENTION, OR TESTING: Patient medical records were retrospectively reviewed to assess demographics, environmental exposures (smoking history), hormonal status (menopause, hormonal therapy), systemic comorbidities, and idebenone treatment data. Genetic testing evaluated primary mitochondrial DNA (mtDNA) mutations, mitochondrial haplogroups, and NQO1 polymorphisms. Statistical relationships were investigated using an exploratory chi-square automatic interaction detection (CHAID) analysis to generate hypothesis-generating decision tree models.

MAIN OUTCOME MEASURES: The primary outcome measures were the identification of precipitating factors (disease triggers) for LHON conversion and the rate of visual recovery, which was defined as an improvement of at least 0.3 LogMAR or a change from off-chart to on-chart visual acuity.

RESULTS

The m.11778G>A variant was the predominant mtDNA mutation (62.7%), and the male-to-female ratio was lower than in canonical LHON (1.48:1). Smoking history was present in 58.2% of patients, and 85.2% of women were postmenopausal. Other relevant factors included primary open-angle glaucoma (6%) and the LHON 'plus' phenotype (7.5%). The overall visual recovery rate was 38.8%. Exploratory CHAID analysis suggested that idebenone treatment at a dosage of ≥900 mg/day and the presence of a J or T mitochondrial haplogroup were associated with a higher probability of visual recovery.

CONCLUSIONS

Late-onset LHON represents a clinically relevant subset in which environmental and hormonal factors may contribute to disease conversion. In this retrospective cohort, high-dose idebenone treatment was associated with a higher probability of visual recovery, particularly among patients with a J or T haplogroup background. These exploratory findings should be considered hypothesis-generating and warrant confirmation in prospective studies.