Abstract
Leber's hereditary optic neuropathy (LHON) is a debilitating mitochondrial disease characterised by bilateral painless vision loss. Despite being the most prevalent mitochondrial disorder, the precise pathophysiological mechanisms underlying the penetrance of LHON remain poorly understood. Nuclear modifier genes have been long suspected to affect phenotype-severity, however, specific cellular pathways implicated in the disease penetrance have been only suggested recently. In recent years, autosomal recessive variants in nuclear genes involved in complex I function and metabolic pathways were recognised to cause a typical LHON phenotype. This was proposed as a new autosomal recessive disease mechanism for LHON (arLHON). The association between nuclear variants and the LHON phenotype makes the nuclear pathways disrupted in arLHON the strongest candidates to act as modifiers of mitochondrial LHON (mLHON). In this study we systematically investigated a large cohort of 23 symptomatic and 28 asymptomatic individuals carrying one of the three primary mitochondrial LHON variants. We identified several heterozygous pathogenic nuclear variants amongst the affected individuals that were consistently linked to metabolic and complex I related pathways, mirroring those disrupted in arLHON. Our findings are consistent with the presence of a second hit in specific biological pathways impairing ATP production. We propose that in addition to the primary mitochondrial variants, disruption in these nuclear-encoded pathways drives the clinical manifestation of LHON. Genes involved in the same pathways also emerge as exciting candidates for future association with arLHON. The present study deepens our understanding of LHON's pathophysiology and provides a new framework for identifying novel disease-modifying targets.