Quantifying mitochondrial stress in LHON patients – an exploratory study of flavoprotein autofluorescence

Abstract Purpose Leber Hereditary Optic Neuropathy (LHON) is a primary mitochondrial disorder, where retinal ganglion cell dysfunction typically leads to sequential blindness. Although targeted gene therapies have shown promise, clinical trials have struggled to show efficacy using traditional biomarkers. Flavoprotein autofluorescence (FPF) is able to quantify mitochondrial oxidative stress in vivo , and warrants exploration as a potential biomarker for future clinical trials. Methods This was a cross-sectional exploratory study examining FPF in 13 LHON patients (24 eyes) and 18 controls (36 eyes). Raw FPF was quantified at the optic nerve head rim (Garway-Heath sectors) and the macula (ETDRS sectors). Corrected values were also calculated accounting for tissue loss. Mixed effects models were used to compare LHON and control groups and to examine other covariables. Correlation with other established metrics was also examined. Results Both raw (t = 5.68, p < 0.001) and corrected (t = 7.63, p < 0.001) FPF values were significantly higher in LHON patients at the optic nerve head. This was confirmed for all individual rim segments. In contrast, only when corrected for tissue loss was macula FPF significantly higher (t = 6.65, p < 0.001). Symptom duration, disease severity and age all variably influenced regression models. FPF was variably correlated with other visual metrics. Conclusions FPF is significantly higher in LHON patients than controls both at the optic nerve head rim and central macula. Tissue loss is a critical factor which must be taken into account. FPF may offer additional information beyond traditional biomarkers, and shows good structure-function correlation.