F4-neuroprostanes mediate neurological severity in Rett syndrome

Background: Rett syndrome (RTT) is a pervasive development disorder, mainly caused by mutations in the methyl-CpG binding protein 2 (MeCP2) gene. No reliable biochemical markers of the disease are available. Here we assess F₄-neuroprostanes (F₄-NeuroPs), lipid peroxidation products of the docosahexaenoic acid, as a novel disease marker in RTT and correlate it with clinical presentation, MeCP2 mutation type, and disease progression. In addition, we investigate on the impact of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) supplementation on F₄-NeuroPs levels. Methods: A case-control study design was used. A cohort of RTT patients (n=144) exhibiting different clinical presentations, disease stages, and MeCP2 gene mutations were evaluated. F₄-NeuroPs were measured in free form using a GC/NICI-MS/MS technique. Plasma F₄-NeuroPs levels in patients were compared to healthy controls and related to RTT forms, disease progression, and response to ω-3 PUFAs supplementation. Results: Plasma F₄-NeuroPs levels were i) higher in RTT than in controls; ii) increased with the severity of neurological symptoms; iii) significantly elevated during the typical disease progression; iv) higher in MeCP2-nonsense as compared to missense mutation carriers; v) higher in typical RTT as compared to RTT variants; and vi) decreased in response to 12months ω-3 PUFAs oral supplementation. Conclusions: Quantification of plasma F₄-NeuroPs provides a novel RTT marker, related to neurological symptoms severity, mutation type and clinical presentation.