Authors: Henry Liu, Chiara La Morgia, Lidia Di Vito, Samir Nazarali, Isabelle Gauthier, Maleeha Syed, Alexander Pearson, Jasdeep Chahal, Mike Ammar, Michelle Carbonelli, Piero Barboni, Anna Maria De Negri, Frederico Sadun, Valerio Carelli, Alfredo Sadun, Rustum Karanjia
Author Disclosure Block: H. Liu: None. C. La Morgia: None. L. Di Vito: None. S. Nazarali: None. I. Gauthier: None. M. Syed: None. A. Pearson: None. J. Chahal: None. M. Ammar: None. M. Carbonelli: None. P. Barboni: None. A. De Negri: None. F. Sadun: None. V. Carelli: None. A. Sadun: None. R. Karanjia: None.

Abstract Body:

Purpose: Leber’s hereditary optic neuropathy (LHON) is an inherited mitochondrial disease characterized by a painless, subacute loss of central vision with over 95% of affected patients harbouring one of three mitochondrial DNA (mtDNA) classical point mutations (G11778A, G3460A and T14484C). The purpose of this study was to compare the age of disease onset and time interval between affected eyes by mutation.

Study Design: Retrospective chart review

Methods: Age of onset, unilateral versus bilateral presentation, interval between the first and second eye, and the mtDNA mutation were retrieved from two separate database registries consisting of 268 Italian and 71 U.S. patients.

Results: Clinical data from 339 patients with LHON mutations were evaluated (G11778A, n = 216; G3460A, n = 40; T14484C, n = 44; non-dominant mutations, n = 39). Bilateral eye involvement was clinically documented in 99.4% of cases with 50.3% of all patients demonstrating sequential onset. In these latter cases the median inter-eye delay was 12.8 weeks. Comparing the age of onset across mutation subtypes, the T14484C mutation resulted in the lowest age at onset (19.2 ± 10.6 years) compared to G11778A (25.8 ± 15.3 years), G3460A (20.9 ± 14.5 years) and non-dominant mutations (22.9 ± 12.1 years) (p < 0.05). The M:F ratio for G11778A, G3460A, T14484C and non-dominant mutations were 3.5:1, 1.7:1, 4.5:1 and 3.8:1 respectively. Interestingly, the T14484C mutation exhibited more simultaneous than sequential onsets compared with the other mutation subtypes (p < 0.001). Moreover, T14484C showed a shorter and more reproducible interval between eyes (inter-eye onset range = 1-44 weeks) versus G11778A (range = 1-2016 weeks), G3460A (range = 2-816 weeks), non-dominant mutations (range = 1-108 weeks) for sequential presentations.

Conclusions: The T14484C mutation, though least penetrant, manifested at an earlier age and resulted in a smaller inter-eye delay interval range and higher incidence of simultaneous involvement compared to the other classical and non-dominant mutations in LHON.