title: Systemic oxidative stress in classic Rett syndrome.
abstract: Rett syndrome (RS), a progressive severe neurodevelopmental disorder mainly caused by de novo mutations in the X-chromosomal MeCP2 gene encoding the transcriptional regulator methyl-CpG-binding protein 2, 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 intraerythrocyte non-protein-bound iron (NPBI; i.e., free iron), plasma NPBI, F2-isoprostanes (F2-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 intraerythrocyte NPBI (2.73-fold), plasma NPBI (x 6.0), free F(2)-IsoP (x1.85), esterified F2-IsoP (x 1.69), total F2-IsoP (x 1.66), and protein carbonyl (x 4.76) concentrations were evident in RS subjects and associated with reduced (-10.53%) arterial oxygen levels 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.
authors.affiliation: Neonatal Intensive Care Unit, University Hospital AOUS of Siena, I-53100 Siena, Italy. claudiodefelix@hotmail.it
authors.forename: Claudio
authors.initials: C
authors.lastname: De Felice
authors.forename: Lucia
authors.initials: L
authors.lastname: Ciccoli
authors.forename: Silvia
authors.initials: S
authors.lastname: Leoncini
authors.forename: Cinzia
authors.initials: C
authors.lastname: Signorini
authors.forename: Marcello
authors.initials: M
authors.lastname: Rossi
authors.forename: Laura
authors.initials: L
authors.lastname: Vannuccini
authors.forename: Gianni
authors.initials: G
authors.lastname: Guazzi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Latini
authors.forename: Mario
authors.initials: M
authors.lastname: Comporti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Valacchi
authors.forename: Joussef
authors.initials: J
authors.lastname: Hayek
mesh_terms: D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D004912:Erythrocytes / Q000378:metabolism* / Q000473:pathology; D028441:F2-Isoprostanes / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability; D007501:Iron / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D009154:Mutation; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D050050:Protein Carbonylation; D015518:Rett Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D014692:Ventilation-Perfusion Ratio
chemical_list: D028441:F2-Isoprostanes; D051783:Methyl-CpG-Binding Protein 2; D007501:Iron; D010100:Oxygen