Institut de Neurosciences Cognitives et Intégratives d'Aquitaine (UMR5287)

Aquitaine Institute for Cognitive and Integrative Neuroscience

Université de Bordeaux

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Obstructive Apneas in a Mouse Model of Congenital Central Hypoventilation Syndrome

by Loïc Grattier - published on

Obstructive Apneas in a Mouse Model of Congenital Central Hypoventilation Syndrome

Amélia Madani*, Gabriel Pitollat*, Eléonore Sizun, Laura Cardoit, Maud Ringot, Thomas Bourgeois, Nelina Ramanantsoa, Christophe Delclaux, Stéphane Dauger, Marie-Pia d’Ortho, Muriel Thoby-Brisson, Jorge Gallego, Boris Matrot
Am J Respir Crit Care Med . 2021;
*: first co-authors
Gabriel Pitollat (PhD student at INCIA) is funded with a Cifre grant in association with Atmos R

Congenital Central Hypoventilation Syndrome (CCHS) is characterized by a loss of ventilatory chemosensitivity and life-threatening hypoventilation. Patients require lifelong mechanical ventilation, at least nocturnally. Central apneas are commonly reported in CCHS patients, whereas obstructive apneas may remain unnoticed due to tracheostomy and positive pressure ventilation. CCHS is caused by mutations in the paired-like homeobox 2B gene (PHOX2B), the master gene of the autonomic nervous system. In mice, introduction of the most prevalent mutation observed in human (7-alanine expansion, PHOX2B27Ala/+) is associated with the main symptoms of CCHS, and agenesis of the retrotrapezoid nucleus, known to provide a major excitatory drive to breathing.

In this publication in AJRCCM we present our work, performed in collaboration with Dr. Jorge Gallego and Boris Matrot (Inserm U1141, Hôpital Robert Debré, Université de Paris, Paris) providing new insights in breathing disorders associated with CCHS. Combining pneumotachography and laser detection of abdominal movements to classify apneas, we demonstrate that newborn Phox2b27Ala/+ mice display an abnormally high degree not only of central apneas, but also of obstructive and mixed apneas. Furthermore, these mice show dysgenesis and dysfunction of the hypoglossal nucleus, a non-Phox2b expressing structure critical to the maintenance of upper airway patency. These results broaden the spectrum of neuroanatomical and neurofunctional disorders caused by Phox2b mutations, and point to the clinical importance of also detecting obstructive events in CCHS patients.

Different types of apneas detected in CCHS mutant pups

Abnormal hypoglossus nucleus in the CCHS mutant