Inflammatory lung disease in Rett syndrome

Area of Science:

• Neuroscience
• Pulmonology
• Genetics

Background:

• Rett syndrome (RTT), a neurodevelopmental disorder, is primarily caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene.
• Respiratory dysfunction is a significant clinical challenge in RTT, often attributed to brainstem immaturity.

Purpose of the Study:

• To investigate the connection between pulmonary gas exchange abnormality (GEA), upper airway obstruction, and redox status in RTT patients.
• To analyze lung histology in a Mecp2-null mouse model to understand disease mechanisms.

Main Methods:

• Characterized GEA in 228 RTT patients and compared them to healthy controls.
• Measured plasma and intraerythrocyte levels of iron, F2-isoprostanes, and glutathione redox status (GSH/GSSG).
• Examined lung histology in Mecp2-null mice.

Main Results:

• Gas exchange abnormalities were detected in approximately 80% of RTT patients.
• Elevated markers of oxidative stress (non-protein-bound iron, F2-isoprostanes) and altered glutathione status were observed in RTT patients.
• Apnea severity correlated with oxidative stress markers and inversely with the GSH/GSSG ratio.
• Lung histology of Mecp2-mutant mice showed inflammation in terminal bronchioles and alveoli.

Conclusions:

• Pulmonary gas exchange abnormality is a prominent feature of Rett syndrome.
• Oxidative stress and inflammation, particularly affecting terminal bronchioles, play a crucial role in RTT-associated respiratory dysfunction.