Establishing risk of vision loss in Leber hereditary optic neuropathy

M Isabel G Lopez Sanchez,Lisa S Kearns,Sandra E Staffieri,Linda Clarke,Myra B Mcguinness,Wafaa Meteoukki,Sona Samuel,Jonathan B Ruddle,Celia Chen,Clare L Fraser,John Harrison,Alex W Hewitt,Neil Howell,David A Mackey

doi:10.1016/j.ajhg.2021.09.015

Abstract

SummaryWe conducted an updated epidemiological study of Leber hereditary optic neuropathy (LHON) in Australia by using registry data to establish the risk of vision loss among different LHON mutations, sex, age at onset, and mitochondrial haplogroup. We identified 96 genetically unrelated LHON pedigrees, including 56 unpublished pedigrees, and updated 40 previously known pedigrees, comprising 620 affected individuals and 4,948 asymptomatic carriers. The minimum prevalence of vision loss due to LHON in Australia in 2020 was one in 68,403 individuals. Although our data confirm some well-established features of LHON, the overall risk of vision loss among those with a LHON mutation was lower than reported previously—17.5% for males and 5.4% for females. Our findings confirm that women, older adults, and younger children are also at risk. Furthermore, we observed a higher incidence of vision loss in children of affected mothers as well as in children of unaffected women with at least one affected brother. Finally, we confirmed our previous report showing a generational fall in prevalence of vision loss among Australian men. Higher reported rates of vision loss in males with a LHON mutation are not supported by our work and other epidemiologic studies. Accurate knowledge of risk is essential for genetic counseling of individuals with LHON mutations. This knowledge could also inform the detection and validation of potential biomarkers and has implications for clinical trials of treatments aimed at preventing vision loss in LHON because an overestimated risk may lead to an underpowered study or a false claim of efficacy.

Highlights

Leber hereditary optic neuropathy (LHON [MIM: 535000])is a primary mitochondrial disease characterized by optic atrophy due to degeneration of retinal ganglion cells in the retina.[1]
This knowledge could inform the detection and validation of potential biomarkers and has implications for clinical trials of treatments aimed at preventing vision loss in LHON because an overestimated risk may lead to an underpowered study or a false claim of efficacy
We identified 96 genetically unrelated LHON pedigrees, including 56 new pedigrees, and updated 40 previously

Summary

Introduction

Is a primary mitochondrial disease characterized by optic atrophy due to degeneration of retinal ganglion cells in the retina.[1] LHON is caused by point mutations in mitochondrial DNA (mtDNA) genes encoding subunits of oxidative phosphorylation complex I. Most people with vision loss from LHON harbor one of three primary LHON mutations in MT-ND4 (m.11778G>A [p.Arg340His]),[2] MT-ND6. (m.14484T>C [p.Met64Val]),[3,4] or MT-ND1 (m.3460G>A [p.Ala52Thr]).[5,6] The presence of a LHON mutation is not in itself sufficient to cause vision loss. Studies have suggested an association between mtDNA haplogroup and risk of vision loss.[7,8,9] some environmental risk factors, including tobacco smoking, heavy alcohol consumption, and exposure to toxic drugs, may trigger vision loss in some LHON mutation carriers.[10,11,12] Additional genetic risk factors remain unidentified, and it is currently unknown why only some carriers lose vision.[13]

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