Oxidative stress in Rett syndrome: Natural history, genotype, and variants

Abstract

Objectives

Rett syndrome (RTT) is an X-linked autism spectrum disorder caused by mutations in the MeCP2 gene in the great majority of cases. Evidence suggests a potential role of oxidative stress (OS) in its pathogenesis. Here, we investigated the potential value of OS markers (non-protein-bound iron (NPBI) and F₂-isoprostanes (F₂-IsoPs)) in explaining natural history, genotype-phenotype correlation, and clinical heterogeneity of RTT, and gauging the response to omega-3 polyunsaturated fatty acids (ω-3 PUFAs).

Methods

RTT patients (n = 113) and healthy controls were assayed for plasma NPBI and F₂-IsoPs, and intraerythrocyte NPBI. Forty-two patients with typical RTT were randomly assigned to ω-3 PUFAs supplementation for 12 months. NPBI was measured by HPLC and F₂-IsoPs using a gas chromatography/negative ion chemical ionization tandem mass spectrometry (GC/NICI-MS/MS) technique.

Results

F₂-IsoPs were significantly higher in the early stages as compared with the late natural progression of classic RTT. MeCP2 mutations related to more severe phenotypes exhibited higher OS marker levels than those of milder phenotypes. Higher OS markers were observed in typical RTT and early seizure variant as compared with the preserved speech and congenital variants. Significant reduction in OS markers levels and improvement of severity scores were observed after ω-3 PUFAs supplementation.

Discussion

OS is a key modulator of disease expression in RTT.

Keywords:

• Autism spectrum disorders
• F₂-isoprostanes
• MeCP2 gene
• Non-protein-bound iron
• Oxidative stress
• Rett syndrome

Acknowledgments

The study was partially supported by grants from the Toscana Life Sciences (Orphan_0108 Call; title: ‘Nuovi approcci terapeutici nella sindrome di Rett’), Siena, Italy.

This paper is dedicated to professional singer Matteo Setti (Reggio Emilia, Italy, official web site: http://www.matteosetti.it) as his precious collaboration surprisingly triggered our studies on oxidative stress in Rett syndrome.

We thank the Azienda Ospedaliera Universitaria Senese Hospital Administration for mass spectrometer purchasing, and Roberto Faleri (Central Medical Library, University of Siena, Siena, Italy) for online bibliographic assistance.

We acknowledge ‘Cell Lines and DNA Bank of Rett syndrome and other X mental retardation’ (Prof. A. Renieri, Medical Genetics Unit-Siena) for gene mutations analyses.

Conflicts of interest: All authors declare that they have no conflicts of interest related to the present study.