Original articleDisturbances in Cardiorespiratory Function During Day and Night in Rett Syndrome
Introduction
Rett syndrome is a severe neurodevelopmental disorder that almost exclusively affects females. After Down syndrome, Rett syndrome is the most common specific cause of severe cognitive impairment in females [1], affecting 1 in 10,000 [2]. Rett syndrome is caused by a dominant de novo mutation in the MECP2 gene on the X-chromosome in 85-90% of cases [3]. Thus, Rett syndrome serves as a model for how a specific genetic mutation can affect postnatal neurodevelopment [4]. The syndrome is characterized by neurodevelopmental stagnation starting at around 6-18 months of age, accompanied by motor deterioration and slowing growth of the head circumference. Pronounced autonomic dysfunction was found to underlie breathing and cardiac disturbances of various kinds. Cardiorespiratory morbidity is characterized by hypoventilation, breath-holding spells, apnea, episodic hyperventilation, air swallowing (bloating), Valsalva maneuvers [5], tachycardia, and poor peripheral circulation. Kerr et al. [6] reported that 26% of the deaths attributed to Rett syndrome are sudden and unexpected, and respiratory dysrhythmia was suggested as a contributory factor. Breathing disturbances in children with Rett syndrome were reported to occur almost entirely during wakefulness [7], [8], [9], with normal respiration during sleep.
Respiration is controlled by a variety of complex mechanisms and stimuli, and undergoes dramatic changes during both wakefulness and sleep. Respiratory control mechanisms in the brainstem dominate when the waking drive for respiration is withdrawn, e.g., during sleep. The hypothesis that patients with Rett syndrome have a brainstem dysfunction is supported by several studies. A mouse model of Rett syndrome revealed breathing disturbances that probably originated from a deficiency in noradrenergic and serotonergic modulation of the medullary respiratory network [10]. In addition, an analysis of sleep-wake rhythm during polysomnography [11] and autopsy findings [12], [13] suggest that patients with Rett syndrome suffer from serotonergic and noradrenergic hypofunction at brainstem level.
To date, despite thorough studies involving sleep recordings of patients with Rett syndrome, most conclusions have been based on one-night polysomnographic recordings [7], [8], [9]. Therefore, we decided to monitor respiratory movements and heart rate, day and night, for 1 week in 12 children with Rett syndrome in their home environment. We hypothesized that: (1) the cardiorespiratory dysfunction in Rett syndrome is present, independent of behavioral state, in sleep, and (2) there is a correlation between severity of clinical symptoms and cardiorespiratory dysfunction.
Section snippets
Clinical Data and Subjects
The parents of 18 girls with Rett syndrome (aged 7-20 years) in Stockholm County were asked by letter to take part in a clinical, neuropaediatric assessment. The parents of 12 of these 18 girls agreed to let their child participate in our cardiorespiratory monitoring study. The data of individual patients are presented in Table 1.
Our clinical evaluation took place at the Department of Neuropediatrics at Karolinska University Hospital, and each child was seen by two or three neuropediatricians
Results
The total recording time for all patients was 1114 hours (535 during wakefulness, and 579 during sleep). Each girl was monitored for 77 ± 22 hours (median ± SEM).
Discussion
The main findings of the present study on Rett syndrome can be summarized as follows: (1) cardiorespiratory disturbances were present during sleep as well as wakefulness, (2) all children manifested respiratory dysfunction, and the majority also had heart-rhythm abnormalities, and (3) there were pronounced intraindividual and interindividual differences with regard to cardiorespiratory function.
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