Analysis of genotype and phenotype in Leber Hereditary Optic Neuropathy-affected patients and asymptomatic maternal relatives

Abstract

Analysis of genotype and phenotype in Leber Hereditary Optic Neuropathy-affected patients and asymptomatic maternal relatives MD in Clinical Medicine: Dr Clare Quigley Supervisor: Prof Lorraine Cassidy Introduction: Leber Hereditary Optic Neuropathy (LHON) affects a minority of carriers of causative mitochondrial DNA mutations, and the underlying reasons for visual loss or preservation are not fully understood. We aimed to investigate LHON-affected families for disease expression patterns and potential associations of visual loss. Methods: We investigated a cohort of patients with LHON, including m.11778G>A, m.3460G>A, m.14484T>C and DNAJC30 c.152A>G variants, and their asymptomatic maternal carrier relatives. We assessed optic nerve function including visual acuity, perimetry, and visually evoked potential testing, and also evaluated vision-related quality of life. We assessed optic nerve head anatomy including retinal nerve fibre layer thickness and perfusion, measured as vessel density (VD), via optical coherence tomography angioraphy (OCTA) of the peripapillary retinal nerve fibre layer (RNFL), with comparison to a control sample. We also carried out full mitochondrial genome sequencing. A 12-lead electrocardiogram was conducted on the study subjects. Comparison was made with a reference standard for OCT; European Descent, Heidelberg Engineering; and electrophysiology measurements with in-house normative ranges. Results: In the LHON group the median visual acuity in the better sighted eye was 1.6 logMAR, IQR 1.2, 2.1 (n = 12), and in the asymptomatic carrier relatives median VA was logmar 0.0 (n=16). The optic nerve head RNFL thickness was significantly reduced in the LHON-affected group (median 51 microns, p=0.003), and in asymptomatic relatives (median 90 microns, p=0.01), compared to controls (median 101 microns, n=10). The LHON-affected group had significantly reduced peripapillary VD (median 7.9%, p=0.046), but not the LHON asymptomatic relatives, who showed no significant change in peripapillary VD (p=0.166). The presence of RNFL thinning had greater specificity compared to the presence of reduced perfusion for an association with optic nerve dysfunction in asymptomatic carriers (92% versus 66%). Optic nerve dysfunction was associated with mitochondrial haplogroup H and HV, versus non-H haplogroups, in the asymptomatic carriers (Fisher's exact test, p=0.05). Cardiac conduction abnormalities were identified in 56% of asymptomatic maternal relatives of LHON patients. Conclusions: Optic nerve abnormalities may be identified in asymptomatic LHON mitochondrial mutation carriers, which may be associated with optic nerve dysfunction. For asymptomatic carriers these findings were associated with mitochondrial haplogroup H and HV. Optic nerve head perfusion was lower in LHON but was normal overall in relatives, where evidence of optic neuropathy was found to be associated more closely with nerve fibre layer atrophy than with reduced optic nerve head perfusion. Larger studies are warranted to investigate cardiac conduction in asymptomatic carriers of LHON associated pathogenic variants.