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.

Introduction

Rett syndrome (RTT) is a complex neurodevelopmental disorder whose underlying pathogenic mechanisms remain poorly understood. RTT affects approximately 1 in 10,000 live female births and is characterized by apparently normal early postnatal development followed by neurological decline around 6–18 months of age. The disorder has a highly variable course and affected individuals exhibit a broad array of symptoms that generally includes loss of acquired speech, head growth deceleration, autistic features such as emotional withdrawal and diminished eye contact, motor stereotypies, early hypotonia followed by rigidity, epileptiform seizures, exaggerated responses to stress and severe respiratory and autonomic (cardiac and gastrointestinal) dysfunction (Hagberg et al., 1983, Shahbazian et al., 2002, Vorsanova et al., 2004, Chahrour and Zoghbi, 2007, Chahrour et al., 2008, Ogier and Katz, 2008, Weese-Mayer et al., 2006, Weese-Mayer et al., 2008). Approximately 25% of RTT patients may die prematurely of cardiorespiratory failure (Kerr et al., 1997).

At least 95% of typical RTT cases result from loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2; Amir et al., 1999, Shahbazian et al., 2002), one of a number of methyl-binding proteins (Klose and Bird, 2006) that regulate gene expression by repressing transcription at methylated promoters. Over 200 different MECP2 mutations have been found in RTT patients and tend to cluster within two functional domains of the protein; a methyl-binding domain that recognizes methylated CpG dinucleotides with particular flanking sequences (Klose and Bird, 2006), and a transcription repression domain. The MECP2 gene is X-linked, and homozygous mutation in females (or hemizygous mutation in males) is invariably lethal. Thus, affected females are heterozygotes and somatic mosaics for MeCP2, i.e., cells in which the mutated allele occurs on the inactive X are phenotypically normal, whereas cells in which the mutated allele occurs on the active X are mutant. Disease phenotype is therefore affected not only by the specific MECP2 mutation but by the skewing of X chromosome inactivation; individuals in which inactivation is skewed towards the mutant allele are less severely affected, and vice versa. For a more detailed discussion of molecular genetic aspects of RTT the reader is referred to an excellent recent review by Chahrour and Zoghbi (2007).