Progressive encephalopathy in m.3243A > G/MT-TL1 mutation carriers: a quantitative EEG analysis

Objective: The m.3243A > G/MT-TL1 mutation underlies a broad spectrum of clinical manifestations, varying from the mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome to incomplete phenotypes without stroke-like episodes (SLE), termed MELAS-Spectrum Syndrome (MSS). We systematically analyzed the longitudinal EEG changes in individuals carrying the m.3243A > G/MT-TL1 mutation through visual inspection of paroxysmal abnormalities and quantitative analysis of background activity. Methods: Adults with the m.3243A > G/MT-TL1 mutation and at least two EEG recordings during their follow-up were included. For each EEG, we obtained: 1) delta-theta/alpha energy ratio (ER); 2) Higuchi fractal dimension (HD); 3) paroxysmal activities (AR), quantified by two experienced clinicians. A linear mixed model assessed the effect of early SLE phases as a time-dependent covariate. Results: Sixteen patients (9 females) were recruited. ER significantly increased over time in temporal-parieto-occipital regions. EEG traces recorded shortly after SLEs showed significantly higher ER, lower HD, and an increasing AR trend. Conclusions: Quantitative EEG metrics revealed a gradual disruption of posterior background rhythms in both MSS and MELAS. Early consequences of SLEs include background activity slowing, reduction of brain states complexity, and recrudescence of paroxysmal abnormalities. Significance: Neurophysiological signs of progressive brain dysfunction emerged in all individuals with m.3243A > G/MT-TL1 mutation, independently of SLEs.