Genetic Diseases: Congenital Central Hypoventilation, Rett, and Prader‐Willi Syndromes

Abstract

The present review summarizes current knowledge on three rare genetic disorders of respiratory control, congenital central hypoventilation syndrome (CCHS), Rett syndrome (RTT), and Prader‐Willi syndrome (PWS). CCHS is characterized by lack of ventilatory chemosensitivity caused by PHOX2B gene abnormalities consisting mainly of alanine expansions. RTT is associated with episodes of tachypneic and irregular breathing intermixed with breathholds and apneas and is caused by mutations in the X‐linked MECP2 gene encoding methyl‐CpG‐binding protein. PWS manifests as sleep‐disordered breathing with apneas and episodes of hypoventilation and is caused by the loss of a group of paternally inherited genes on chromosome 15. CCHS is the most specific disorder of respiratory control, whereas the breathing disorders in RTT and PWS are components of a more general developmental disorder. The main clinical features of these three disorders are reviewed with special emphasis on the associated brain abnormalities. In all three syndromes, disease‐causing genetic defects have been identified, allowing the development of genetically engineered mouse models. New directions for future therapies based on these models or, in some cases, on clinical experience are delineated. Studies of CCHS, RTT, and PWS extend our knowledge of the molecular and cellular aspects of respiratory rhythm generation and suggest possible pharmacological approaches to respiratory control disorders. This knowledge is relevant for the clinical management of many respiratory disorders that are far more prevalent than the rare diseases discussed here. © 2012 American Physiological Society. Compr Physiol 2:2255‐2279, 2012.

Facing the challenge of mammalian neural microcircuits: taking a few breaths may help

“…Conditions in which neural circuits controlling breathing are disturbed (recently reviewed in Feldman et al 2013), e.g. in single gene disorders (Amir et al 1999;Amiel et al 2003;Weese-Mayer et al 2003;Gallego, 2012), with sleep apnoea (Javaheri & Dempsey, 2013), following opiate intoxication (Stuth et al 2012), or in sudden infant death syndrome (Lavezzi & Matturri, 2008;Weese-Mayer et al 2008) have severe consequences for human health. Despite the development of rodent models for these conditions (Dubreuil et al 2008;Calfa et al 2011;Davis & O'Donnell, 2013), our current understanding of such disturbances of respiratory behaviour is insufficient for developing effective therapies or treatments and will depend on a better grasp of basic mechanisms underlying the neural control of breathing, including respiratory rhythmogenesis.…”

“…; Weese‐Mayer et al . ; Gallego, ), with sleep apnoea (Javaheri & Dempsey, ), following opiate intoxication (Stuth et al . ), or in sudden infant death syndrome (Lavezzi & Matturri, ; Weese‐Mayer et al .…”

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.…”

Inflammatory Lung Disease in Rett Syndrome

“…However, the breath-holding/obstructive apnea phenotype of RTT is often confused in the related clinical literature with central apnea, which has fundamentally distinct neurological mechanisms [9, 15–26]. The wide spectrum of respiratory disorders detectable in RTT patients has been historically credited to brainstem immaturity and/or cardiorespiratory autonomic dysautonomia [9, 27, 28]. However, as the pathogenesis of the respiratory dysfunction in RTT appears far from being completely understood, alternative or complementary hypotheses can be formulated [29].…”