Autonomic Nervous System Dysregulation: Breathing and Heart Rate Perturbation During Wakefulness in Young Girls with Rett Syndrome

Abstract

This study characterizes cardiorespiratory dysregulation in young girls with MECP2 mutation-confirmed Rett syndrome (RS). Respiratory inductance plethysmography of chest/abdomen and ECG was obtained during daytime wakefulness in 47 girls with MECP2 mutation-confirmed RS and 47 age-, gender-, and ethnicitymatched controls (ages 2-7 y). An in-home breath-to-breath and beat-to-beat characterization was conducted and revealed that breathing was more irregular, with an increased breathing frequency, mean airflow, and heart rate in RS versus controls. There was a decreased correlation between normal breathing and heart rate variability, and an exaggerated increase in heart rate response to breathholds in RS versus controls. We conclude that girls with RS have cardiorespiratory dysregulation during breathholds as well as during "normal" breaths and during breaths before and subsequent to breathholds. This dysregulation may offer insight into the mechanisms that render girls with RS more vulnerable to sudden death. R S is one of a growing number of disorders characterized by autonomic nervous system dysfunction/dysregulation (1). Diagnosis of RS is based on clinical criteria (2-4), with more than 85% of identified girls having mutations in MECP2 on the X chromosome (5; B. Roa, personal communication). The RS phenotype includes normal development until 6 -18 mo of age, then regression with slowing of head circumference growth, loss of language, development of stereotypical hand movements, gait and truncal apraxia, EEG abnormalities, seizures, spasticity, and scoliosis (2).Breathing irregularities consistent with autonomic dysregulation in RS include characteristic patterns variably described as hyperventilation, Valsalva maneuvers, apnea, apneusis, breathholding, and rapid shallow breathing (6 -17). These irregularities are reported to occur near-exclusively during wakefulness (8,17). Age may play a role, as more breathholds and forceful breathing are reported in 5-10-y-old patients compared with more of a Valsalva pattern in young adults (13). Conclusions regarding imbalance of sympathovagal input have been made primarily from heart rate and blood pressure monitoring during spontaneously occurring breathholds, coupled with analytical measures derived from these signals (4,11,13). Julu and others proposed a disturbance in cardiovascular and respiratory system integration, describing their findings as central autonomic dysfunction (4,11,13). Further support for autonomic dysregulation comes from observations of decreased heart rate variability, longer corrected QT intervals, sinus bradycardia, gaseous abdominal distension, sweating, cool extremities (3,7,18 -23), flushing and temperature dysregulation (M. Coenraads, personal communication).Despite survival into adulthood, Kerr and colleagues (24,25) reported that 20 -26% of RS deaths are sudden and unexpected, and that the deaths occur primarily during wakefulness. QT prolongation and nonspecific ST changes in RS suggest cardiac causes for sudden death, though ...

Effect of desipramine on patients with breathing disorders in RETT syndrome

“…Several reasons could explain the lack of clinically significant effects of DMI on breathing patterns in RTT girls. First, as described by several authors, breathing dysfunction in RTT is very complex and highly variable 5, 6, 7, 8, 22. We monitored the breathing disorders in awake patients at each visit and found similar results on AHI to those reported in two patients with atypical Rett 23.…”

“…Among the symptoms of RTT, breathing dysrhythmia may represent a life‐threatening event 3. Breathing disorders are present in 65 to 93% of the patients and characterized by hyperventilation, hypoventilation, breath holds and apneic events 4, 5, 6, 7, 8. Studies in validated mouse models of RTT have shown that Mecp2 null male and heterozygous female mice exhibited breathing disturbances with different level of severity 9, 10, 11.…”

The Integrative Role of the Sigh in Psychology, Physiology, Pathology, and Neurobiology

“…Various neurological conditions are associated with severe breathing disturbances. These disorders include multiple system atrophy (Schwarzacher et al, 2011), Rett syndrome (Ramirez et al, 2013b; Weese-Mayer et al, 2006, 2008b), Familial Dysautonomia (Carroll et al, 2012; Weese-Mayer et al, 2008a), sudden infant death syndrome (Garcia et al, 2013; Kinney et al, 2009; Paterson, 2013), congenital central hypoventilation syndrome (Ramanantsoa and Gallego, 2013), sleep apnea (Gozal and Kheirandish-Gozal, 2008; Ramirez et al, 2013a), Pitt Hopkins Syndrome (Gallego, 2012), and sudden death of epilepsy (Kalume, 2013; Sowers et al, 2013). Thus, understanding how breathing is generated within the nervous system and how the CNS controls ventilatory functions is of great clinical interest.…”

Breathing abnormalities in animal models of Rett syndrome a female neurogenetic disorder

“…Abnormal breathing is common in people with RTT, including irregular breathing, breath-hold or apnea, gasping, alternative hyper- and hypoventilation (Bissonnette and Knopp, 2006; Weese-Mayer et al, 2006). In some patients, these breathing abnormalities are more frequent and severe during wakefulness or sleep.…”