Abstract
Purpose :
A critical threshold of mutant mitochondrial DNA(mtDNA) is necessary to manifest symptoms both in carriers of Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes(MELAS)-associated m.3243A>G/MT-TL1 mutation and Myoclonic Epilepsy with Ragged-Red Fibers(MERRF)-associated m.8344A>G/MT-TK mutation. However, correlations between heteroplasmy and specific clinical phenotypes are poorly documented. Since MELAS and MERRF present with different ocular phenotypes, we performed a prospective study to compare neuro-ophthalmological features and correlate them with mtDNA heteroplasmy levels.
Methods :
We compared 33 MELAS and 8 MERRF patients. The heteroplasmic mutant load was assessed on available samples from peripheral blood, urinary sediment and muscle biopsies using SnapShot technology. A comprehensive neuro-ophthalmological assessment included Optic Coherence Tomography(OCT) to measure Retinal Nerve Fiber Layer(RNFL) and Ganglion Cell Layer(GCL) thickness. Heteroplasmy levels were compared using Mann-Whitney U test. Neuro-ophthalmological results were analyzed with Clustered Wilcoxon rank sum test using Rosner-Glynn-Lee method. Pearson’s correlation was used to relate mutant load to neuro-ophthalmologic data.
Results :
Retinopathy was the most common neuro-ophthalmological manifestation in 51% MELAS patients, while optic atrophy was present in 87% MERRF patients, reflecting in significantly thinner RNFL compared to MELAS (p=0.021). Heteroplasmy in MERRF was significantly higher than in MELAS in blood (p<0.001) and muscle (p=0.049), but not in urinary sediment (p=0.31). A significant negative correlation between blood heteroplasmy with age was confirmed in MELAS (p=0.011), warranting for a correction, but not in MERRF (p=0.43). We failed to demonstrate a significant correlation between mutant load and neuro-ophthalmological findings in MELAS, while heteroplasmy was negatively correlated with both RNFL (p=0.002) and GCL (p=0.030) thickness in MERRF.
Conclusions :
MELAS and MERRF present with a clearly distinct ocular phenotype, respectively retinopathy in MELAS and optic atrophy in MERRF, the latter correlating with mtDNA heteroplasmy levels. This may reflect a selective susceptibility of different retinal cell types, namely photoreceptors in MELAS and retinal ganglion cells in MERRF, possibly in relation to a global energy defect in MELAS as opposed to oxidative stress in MERRF.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.