Systemic oxidative stress in classic Rett syndrome
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 pathog...
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Veröffentlicht in: | Free radical biology & medicine 2009-08, Vol.47 (4), p.440-448 |
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Sprache: | eng |
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Zusammenfassung: | 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, 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 intraerythrocyte NPBI (2.73-fold), plasma NPBI (×
6.0), free F
2-IsoP (×
1.85), esterified F
2-IsoP (×
1.69), total F
2-IsoP (×
1.66), and protein carbonyl (×
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. |
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ISSN: | 0891-5849 1873-4596 |
DOI: | 10.1016/j.freeradbiomed.2009.05.016 |