Inflammatory Lung Disease in Rett Syndrome

Abstract

Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly linked to mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Respiratory dysfunction, historically credited to brainstem immaturity, represents a major challenge in RTT. Our aim was to characterize the relationships between pulmonary gas exchange abnormality (GEA), upper airway obstruction, and redox status in patients with typical RTT (n = 228) and to examine lung histology in a Mecp2-null mouse model of the disease. GEA was detectable in ~80% (184/228) of patients versus ~18% of healthy controls, with “high” (39.8%) and “low” (34.8%) patterns dominating over “mixed” (19.6%) and “simple mismatch” (5.9%) types. Increased plasma levels of non-protein-bound iron (NPBI), F2-isoprostanes (F2-IsoPs), intraerythrocyte NPBI (IE-NPBI), and reduced and oxidized glutathione (i.e., GSH and GSSG) were evidenced in RTT with consequently decreased GSH/GSSG ratios. Apnea frequency/severity was positively correlated with IE-NPBI, F2-IsoPs, and GSSG and negatively with GSH/GSSG ratio. A diffuse inflammatory infiltrate of the terminal bronchioles and alveoli was evidenced in half of the examined Mecp2-mutant mice, well fitting with the radiological findings previously observed in RTT patients. Our findings indicate that GEA is a key feature of RTT and that terminal bronchioles are a likely major target of the disease.

Respiratory morbidity in Rett syndrome: an observational study

“…Evidence is accumulating that systems additional to the central nervous system are affected in Rett syndrome. The respiratory system is no exception, with evidence of lower airway inflammation and a mismatch in ventilation and perfusion in healthy individuals with Rett syndrome . Ventilation and perfusion mismatch is the most common cause of hypoventilation and shunt resulting in hypoxaemia and could in part be caused by lower airway inflammation.…”

“…However, in an Italian case series ( n =27) each with observed autonomic breathing abnormalities, abnormal findings on high‐resolution computed tomography scans were identified in over half the cases, with bronchiolectasis identified in one‐third despite no clinically recognizable lung disease . Several years later, the same group identified abnormalities in pulmonary gas exchange in approximately three‐quarters of their study population ( n =228) and reported that a chronic mismatch in ventilation and perfusion seemed related to oxidative stress . In the same study, lung histology was investigated in a mouse model, and diffuse inflammatory infiltrate of the terminal bronchioles and alveoli was identified in two of four MECP2 ‐mutant mice .…”

Unexpected cellular players in Rett syndrome pathology

“…While many neurodevelopmental conditions are associated with increased respiratory infection due to oropharyngeal dysfunction, it was importantly shown that intrinsic immune defects may underlie these infections in the context of MeCP2 duplication syndrome, supporting a direct role for MeCP2 in epigenetic control of immune cells (Yang et al, 2012). Given the involvement of respiratory infection in MeCP2 duplication syndrome it is interesting to note a recent report that the lungs of Mecp2-null mice display an inflammatory infiltrate, which may contribute to the respiratory phenotypes observed in the context of Mecp2-deficiency (De Felice et al, 2014); this may raise the question as to what role MeCP2 may play more globally in the regulation of immune responses in the respiratory tract. Together, these findings suggest that MeCP2 is critical for healthy immune system function, and therefore warrant further investigation into the possible contributions of the immune system in Rett syndrome.…”

Gene Therapy for Rett Syndrome: Prospects and Challenges

“…It might be the case that lack of MeCP2 in the peripheral tissue produced an effect that is masked by the profound CNS-related phenotype. Indeed there is clinical and mouse data pointing to several phenotypes (bone, liver, lung) that may be peripheral in origin [97][98][99][100][101]. However, delivery of exogenous MECP2 directly to the brain using ssAAV9 [11], emphasizes the crucial role of the brain in ameliorating most of the gross aspects of the phenotype.…”