Breathing disorders in Rett syndrome: progressive neurochemical dysfunction in the respiratory network after birth

Abstract

Disorders of respiratory control are a prominent feature of Rett syndrome (RTT), a severely debilitating condition caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2). RTT patients present with a complex respiratory phenotype that can include periods of hyperventilation, apnea, breath holds terminated by Valsalva maneuvers, forced and deep breathing and apneustic breathing, as well as abnormalities of heart rate control and cardiorespiratory integration. Recent studies of mouse models of RTT have begun to shed light on neurologic deficits that likely contribute to respiratory dysfunction including, in particular, defects in neurochemical signaling resulting from abnormal patterns of neurotransmitter and neuromodulator expression. The authors hypothesize that breathing dysregulation in RTT results from disturbances in mechanisms that modulate the respiratory rhythm, acting either alone or in combination with more subtle disturbances in rhythm and pattern generation. This article reviews the evidence underlying this hypothesis as well as recent efforts to translate our emerging understanding of neurochemical defects in mouse models of RTT into preclinical trials of potential treatments for respiratory dysfunction in this disease.

Figures

Figure 1

Breaths and breath-holds in a representative child with Rett Syndrome obtained during the day and night using inductance plethysmography waveforms: sum amplitude (AMP), rib cage (RC), abdomen (AB), and heart rate (HR) are shown. Note that respiratory irregularities and characteristic heart rate changes occur during both the day and night. Adapted from Weese-Mayer et al. 2006, .

Figure 2

Plethysmographic recordings from P35 WT (Mecp2+/y) and Mecp2 null (Mecp2−/y) mice (Mecp2tm1.1Jae strain). Each horizontal trace = 10s quiet breathing in room air. Adapted from Ogier et al., (2007).