Review
Breathing challenges in Rett Syndrome: Lessons learned from humans and animal models☆,☆☆

https://doi.org/10.1016/j.resp.2013.06.022Get rights and content

Highlights

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    Breathing disturbances in Rett Syndrome consist of hypo- and hyperventilation.

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    Disturbances exhibit large inter- and intraindividual variations.

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    Breath holds in human and mouse models of Rett Syndrome may involve overexcited expiration.

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    Irregular breathing is characterized by increased amplitude and frequency variability.

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    Animal models offer promising pre-clinical therapies, but so far no therapy has been translated to human patients.

Abstract

Breathing disturbances are a major challenge in Rett Syndrome (RTT). These disturbances are more pronounced during wakefulness; but irregular breathing occurs also during sleep. During the day patients can exhibit alternating bouts of hypoventilation and irregular hyperventilation. But there is significant individual variability in severity, onset, duration and type of breathing disturbances. Research in mouse models of RTT suggests that different areas in the ventrolateral medulla and pons give rise to different aspects of this breathing disorder. Pre-clinical experiments in mouse models that target different neuromodulatory and neurotransmitter receptors and MeCP2 function within glia cells can partly reverse breathing abnormalities. The success in animal models raises optimism that one day it will be possible to control or potentially cure the devastating symptoms also in human patients with RTT.

Introduction

Rett Syndrome (RTT) affects approximately 1 in 10,000 female births (Laurvick et al., 2006, Neul et al., 2010). Children with RTT develop apparently normal until the age of 18 months. At this age, most patients with RTT achieve the normal milestones with regards to motor functions and communication skills. But subsequently girls enter a stagnation phase (Hagberg, 2005) that is followed by a developmental regression (Neul, 2012). This regression is characterized by a loss of hand skills, mobility skills, and speech, and the girls typically show stereotypic hand movements, develop ataxia, gait apraxia and often seizures. Microcephaly, growth deficits, scoliosis are also characteristic features (Weng et al., 2011a). The loss of communication skills is one of the reasons why RTT is categorized as an autism spectrum disorder (Castro et al., 2013, Neul, 2012).

Among the core symptoms of RTT, severe disturbances in breathing are particularly devastating (Glaze, 2005, Katz et al., 2009, Kerr, 1992, Ogier and Katz, 2008, Rohdin et al., 2007, Weese-Mayer et al., 2008, Weese-Mayer et al., 2006). 65–93% of RTT patients display bouts of hypoventilation that alternate with irregular breathing or hyperventilation (Amir et al., 2000, Julu et al., 2001). But the breathing disturbances are variable and a large catalog of disturbances has been reported (Kerr, 1992). The breathing abnormalities have been categorized by various authors as periods of forced breathing, deep breathing, hyperventilation (rapid shallow breathing), hypoventilation, central and obstructive apneas, apneustic breathing, Valsalva's maneuvers, Biot's breathing, periodic breathing and breath holds (Julu et al., 2001, Weese-Mayer et al., 2008). Moreover, many of these breathing disturbances are associated with a significant dysregulation in cardio-respiratory coupling (Julu et al., 2001, Weese-Mayer et al., 2008). The complexity of the breathing phenotype in Rett Syndrome is in part explained by differences in the genotype/phenotype relationships, specifically the types of mutation and degree of X-chromosome inactivation (Amir et al., 2000).

Section snippets

The genetic basis of Rett Syndrome

Rett Syndrome is caused by a mutation in the methyl-CpG binding protein 2 (MECP2) gene (Amir et al., 1999). The genomic locus of MECP2 in humans is approximately 80 kb and consists of 4 exons from which two different isoforms of MeCP2 may be transcribed, differing in their inclusion of the second exon. The basic structure of the MECP2 locus and protein is conserved across species. Absence of the second intron allows for translation from the first exon and is referred to as the MeCP2e1 isoform,

Breath-holds and apneic events in Rett Syndrome

Breath holds or apneic events are consistently observed in RTT (Fig. 2, Fig. 3) (Weese-Mayer et al., 2008). These events have a periodic nature (Fig. 2A) and they are interspersed by bouts of hyperventilation and irregular breaths (Julu et al., 2001, Southall et al., 1988, Weese-Mayer et al., 2008).

Yet, defining these breathing cessations has been the source of considerable confusion. Indeed, the same type of events may have been described by different authors as “breath-hold”, “apnea” or

Hyperventilation and breath-to-breath irregularities

Hyperventilation associated with breath-to-breath irregularities is another characteristic disturbance in RTT patients (Southall et al., 1988, Weese-Mayer et al., 2008). The breaths in these patients are on average deeper, faster and more irregular in amplitude and timing (Weese-Mayer et al., 2008). However, the degree of these disturbances varies from individual to individual (Julu et al., 2001, Southall et al., 1988). Hyperventilation seems to be generated centrally as it is neither

Breathing disturbances in mouse models of RTT syndrome

The discovery that RTT is caused by a mutation in Mecp2 (Amir et al., 1999) facilitated animal studies aimed at mechanistically explaining the devastating symptoms of this disorder. Two mouse lines were developed in the laboratories of Rudolph Jaenisch and Adrian Bird in which Mecp2 was conditionally knocked-out: Mecp2™1Jae and Mecp2™1Bird (Chen et al., 2001, Guy et al., 2001). Initial characterization of breathing abnormalities was performed using null alleles of Mecp2 derived from the

Neuronal basis of breathing disturbances in RTT

Different aspects of breathing are controlled by different components of the respiratory network (Ramirez et al., 2011). By using conditional alleles of Mecp2 and monitoring the consequences in in vitro experiments it is possible to dissect which areas contribute to what aspects of RTT disturbances. Restoring MeCP2 to regions in the medulla and caudal pons restores a normal hypoxic breathing response (Ward et al., 2011). This is consistent with the role of the ventrolateral medulla, in

Disturbances in different interacting mechanisms may give rise to the RTT phenotype

The mouse models revealed a wide range of neuronal mechanisms that likely play a role also in human RTT patients (Fig. 5). Particularly important for the pathogenesis of breathing as well as other clinical phenotypes of RTT are (a) imbalances in synaptic transmission (Chao et al., 2010, Gatto and Broadie, 2010, Kron et al., 2012, Medrihan et al., 2008, Nelson et al., 2011, Shepherd and Katz, 2011, Zoghbi, 2003), and (b) alterations in a variety of neuromodulatory systems (Ladas et al., 2009,

Translational considerations

The complexity of the clinical phenotypes in RTT and the underlying mechanisms can be very discouraging to those trying to manage this devastating neurological disorder in human patients. Although, some improvement in the breathing disturbances have been reported in small trials and case reports (Andaku et al., 2005), large systematic clinical trials have not delivered reliable treatment avenues. Thus, there is a desperate need for novel therapies for the breathing disorder in RTT.

Several

Conclusions

Breathing abnormalities belong to the most detrimental clinical phenotype in RTT. These problems are associated with severe central dysautonomia that are worse during wakefulness. Other symptoms associated with RTT, such as increased anxiety further exacerbate the breathing disturbances. Although, disturbances in neuronal network functions can be observed early on, many symptoms become overt only later during postnatal development. Modern genetic and neurophysiological tools have led to a

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      Citation Excerpt :

      It is thought that MECP2 likely contributes to an imbalance in excitatory and inhibitory processing in the NTS, known to be critical for the hypoxic response (Tabata et al., 2001). The NTS-mediated afferent input regulates both medullary and pontine activity (Wittman et al., 2019), and the consequences of a MECP2 mutation may be even more far-reaching, given that the NTS receives important peripheral sensory inputs, not only from the carotid body, but also from lung mechanoreceptors (Kubin et al., 1985; Paton, 1998; Ezure et al., 2002; Moreira et al., 2007; Kline et al., 2010; Ramirez et al., 2013a). Interestingly, restoring MECP2 in the brainstem regions defined by the HOXB1 gene rescued only the hypoxic response, but not basal hyperventilation.

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    This paper is part of a special issue entitled “Clinical Challenges to Ventilatory Control”, guest-edited by Dr. Gordon Mitchell, Dr. Jan-Marino Ramirez, Dr. Tracy Baker-Herman and Dr. Dr. David Paydarfar.

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    Support: This work was supported by NIH grants P01HL090554 (JMR), R01HL107084 (JMR), F31NS066601 (CSW), and R01HD062553 (JLN).

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