F(2)-Dihomo-isoprostanes and brain white matter damage in stage 1 Rett syndrome

Oxidative damage has been reported in Rett syndrome (RTT), a pervasive development disorder mainly caused up to 95% of cases by mutations in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. We have recently synthesized F(2)-Dihomo-isoprostanes (F(2)-Dihomo-IsoP), peroxidation products from adrenic acid (C22:4 n - 6, AdA), a known component of myelin, and tested the potential value of F(2)-Dihomo-IsoPs as a novel disease marker and its relationship with clinical presentation, and disease progression. F(2)-Dihomo-IsoPs were determined by a gas chromatography/negative ion chemical ionization tandem mass spectrometry. The ent-7(RS)-F(2t)-Dihomo-IsoP and 17-F(2t)-Dihomo-IsoP were used as reference standards. The measured ions were the product ions at m/z 327 derived from the [M - 181](-) precursor ions (m/z 597) produced from both the derivatized ent-7(RS)-F(2t)-Dihomo-IsoP and 17-F(2t)-Dihomo-IsoP. Average plasma F(2)-Dihomo-IsoP levels in RTT were about 1 order of magnitude higher than in healthy controls, being higher in typical RTT as compared to RTT variants, with a remarkable increase of about 2 orders of magnitude in patients at the earliest stage of the disease followed by a steady decrease during the natural clinical progression. These data indicate for the first time that quantification of F(2)-Dihomo-IsoPs in plasma represents an early marker of the disease and may provide a better understanding of the pathogenic mechanisms behind the neurological regression in patients with RTT.