Disorders of Sleep and Ventilatory Control in Prader-Willi Syndrome

Abstract

Prader-Willi syndrome (PWS) is an imprinted genetic disorder conferred by loss of paternal gene expression from chromosome 15q11.2-q13. Individuals with PWS have impairments in ventilatory control and are predisposed toward sleep disordered breathing due to a combination of characteristic craniofacial features, obesity, hypotonia, and hypothalamic dysfunction. Children with PWS progress from failure to thrive during infancy to hyperphagia and morbid obesity during later childhood and onward. Similarly, the phenotype of sleep disordered breathing in PWS patients also evolves over time from predominantly central sleep apnea in infants to obstructive sleep apnea (OSA) in older children. Behavioral difficulties are common and may make establishing effective therapy with continuous positive airway pressure (CPAP) more challenging when OSA persists after adenotonsillectomy. Excessive daytime sleepiness (EDS) is also common in patients with PWS and may continue after OSA is effectively treated. We describe here the characteristic ventilatory control deficits, sleep disordered breathing, and excessive daytime sleepiness seen in individuals with PWS. We review respiratory issues that may contribute to sudden death events in PWS patients during sleep and wakefulness. We also discuss therapeutic options for treating sleep disordered breathing including adenotonsillectomy, weight loss, and CPAP. Lastly, we discuss the benefits and safety considerations related to growth hormone therapy.

Requirements for improving health and well‐being of children with Prader‐Willi syndrome and their families

“…Hyperphagia may also be associated with inadequate chewing and eating unusual foods and non‐food items, contributing to a greater risk of choking and respiratory aspiration . Poor oromotor co‐ordination and gag reflexes, hypotonia and difficulties producing an adequate cough to expel excess secretions or airway foreign bodies could further explain these increased risks . Recent videofluoroscopy swallow studies suggest aspiration is common and often silent in infants with PWS .…”

“…) and a small naso‐ and oro‐pharynx are common in affected individuals, resulting in a relatively narrow upper airway . The presence of obesity can further increase upper airway resistance and is another well‐known risk factor for obstructive sleep apnoea syndrome . Obstructive sleep apnoea is found in almost 80% of children with PWS, and those with moderate to severe obstructive sleep apnoea exhibit more hypoventilation and more severe desaturation during sleep than typically developing children with a similar severity of obstructive sleep apnoea .…”

“…Central sleep apnoea is also frequently reported in PWS, particularly in children younger than 2 years of age . Contributors to central sleep apnoea include respiratory muscle hypotonia, abnormal arousal and ventilatory control mechanisms and may also be a downstream effect of hypothalamic dysfunction related to hypocretin deficiencies . The presence of excessive daytime sleepiness in individuals with PWS in the context of adequate quality and quantity of sleep, even in the absence of or sufficient treatment for sleep disordered breathing and hypothyroidism, suggests hypersomnolence is related to hypothalamic dysfunction, particularly hypocretin (also known as orexin) deficiencies, causing a narcolepsy phenotype with or without cataplexy …”

Analysis of airflow indices in paediatric respiratory disorders

“…If obstructive sleep apnoea develops, another treatment is non-invasive ventilation (NIV) using continuous positive airway pressure (CPAP). Yet, the expected AHI, hypoventilation, or carbon dioxide level, for timing of initiation of treatment or to monitor treatment are not described for this cohort [3,18]. Timing of treatment of growth hormone and/or non-invasive ventilation is left to the judgement of the reporting sleep clinician as there are no clinical guidelines related to paediatric patients with PWS and initiation of treatment.…”

“…Given the complex inter-relationship between controller and mechanical pathology in patients with PWS or DMD, these parameters may beneficially characterize breathing patterns in these disorders and give an indication of disorder progression. Indeed, in a study of [16][17][18][19][20][21][22] year olds, the FIT was higher in patients with advanced DMD than in healthy controls [122], and this is likely to be explained by diaphragm muscle insufficiency in late stage patients with DMD [123]. However, there is no data for paediatric patients with DMD as they progress from the relative normality of early stage disorder to the REM-related hypoventilation and then respiratory instability of older adolescence/early adulthood.…”