Breathing disturbances in Rett syndrome

Abstract

Rett Syndrome is an X-linked neurological disorder characterized by behavioral and neurological regression, seizures, motor deficits, and dysautonomia. A particularly prominent presentation includes breathing abnormalities characterized by breathing irregularities, hyperventilation, repetitive breathholding during wakefulness, obstructive and central apneas during sleep, and abnormal responses to hypoxia and hypercapnia. The condition and pathology of the respiratory system is further complicated by dysfunctions of breathing-motor coordination, which is reflected in dysphagia. The discovery of the X-linked mutations in the MECP2 gene has transformed our understanding of the cellular and molecular mechanisms that are at the root of various clinical phenotypes. However, the genotype-phenotype relationship is complicated by various factors which include not only X-inactivation but also consequences of the intermittent hypoxia and oxidative stress associated with the breathing abnormalities.

Keywords: Apnea; Breathing; Rett Syndrome.

Fig. 1.

MECP2 s expressed largely throughout the brainstem, including areas within the pons and medulla involved in the neural control of breathing. In healthy cells, MECP2 locates to CPG islands to influence transcription regulation. Studies have shown deficiencies in MECP2 expression in patients presenting with Rett syndrome. This deficiency has been suggested to alter normal respiration and result in abnormal breathing patterns accompanied by overactive expirations, known as breatholding.

Fig. 2.

Examples of breathing patterns and breath holds in a representative child with Rett Syndrome during the day and night using inductance plethysmography. Respiratory irregularities and heart rate changes are observed during both the day and night. Sum amplitude (AMP), rib cage (RC), abdomen (AB), and heart rate (HR). Adapted from (49, 55).

Fig. 3.

A: A 30-second epoch from nocturnal polysomnographic recording. A representative central apnea event (highlighted in red) arising from NREM N3 sleep stage in a 6yr old girl with Rett syndrome. This event is characterized by a cessation of flow with associated lack of effort on the chest (CHEST channel) and abdomen (ABD channel) bands, followed by mild oxygen desaturation (highlighted in pink) and subsequent mild tachycardia. B: A 30-second epoch from nocturnal polysomnographic recording. A representative obstructive apnea event (highlighted in orange), arising from NREM N3 sleep stage in a 6yr old girl with Rett syndrome. This event is characterized by cessation of flow associated with increased effort (CHEST channel) and abdomen (ABD channel) bands, followed by mild oxygen desaturation (highlighted in pink) and subsequent mild tachycardia. Abbreviations: NREM: Non-rapid Eye Movement; PFLOW: Pressure flow from thermistor; FLOW: Flow signal from thermistor; SUM FLOW: Summatory of PFLOW and FLOW channel signals; CHEST: Signal from chest band; ABD: Signal from abdominal band; OSAT: Oxygen saturation (%); PR: Pulse rate (BPM)