Free Radic Biol Med. 2009 May 20. [Epub ahead of print]
Systemic oxidative stress in classic Rett syndrome.
De Felice C, Ciccoli L, Leoncini S, Signorini C, Rossi M, Vannuccini L, Guazzi G, Latini G, Comporti M, Valacchi G, Hayek J. Neonatal Intensive Care Unit.
Rett syndrome (RS), a progressive severe neurodevelopmental disorder mainly caused by de novo mutations in the X-chromosomal methyl-CpG-binding protein 2 (MeCP2) gene encoding for the transcriptional regulator methyl CpG binding protein 2 (MeCP2), is a leading cause of mental retardation with autistic features in females. However, its pathogenesis remains incompletely understood, and no effective therapy is available to date. We hypothesized that a systemic oxidative stress may play a key role in the pathogenesis of classic RS. Patients with classic RS (n = 59) and control subjects (n = 43) were evaluated. Oxidative stress markers included intra-erythrocyte non-protein-bound iron (NPBI, i.e., free iron), plasma NPBI, F(2)-isoprostanes (F(2)-IsoPs, as free, esterified and total forms) and protein carbonyls. Lung ventilation/perfusion (V/Q) ratio was assessed using a portable gas analyzer, and RS clinical severity was evaluated using standard scales. Significantly increased intra-erythrocyte NPBI (x 2.73-folds), plasma NPBI (x 6.0), free F(2)-IsoPs (x 1.85), esterified F(2)-IsoPs (x 1.69), total F(2)-IsoPs (x 1.66) and protein carbonyls (x 4.76) concentrations were evidenced in RS subjects, and associated with reduced (-10.53%) arterial oxygen levels as compared to controls. Biochemical evidence of oxidative stress was related to clinical phenotype severity and lower peripheral and arterial oxygen levels. Pulmonary V/Q mismatch was found in the majority of the RS population. These data identify hypoxia-induced oxidative stress as a key factor in the pathogenesis of classic RS, and suggest new therapeutic approaches based on oxidative stress modulation.
PMID: 19464363 [PubMed - as supplied by publisher]