OBSTRUCTIVE APNEAS IN A MOUSE MODEL OF CONGENITAL CENTRAL HYPOVENTILATION SYNDROME

Abstract

AbstractRationaleCongenital Central Hypoventilation Syndrome (CCHS) is characterized by life-threatening sleep hypoventilation, and is caused by PHOX2B gene mutations, most frequently the PHOX2B27Ala/+ mutation, with patients requiring lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome.ObjectivesTo determine whether Phox2b27Ala/+ mice, which present the main symptoms of CCHS and die within hours after birth, also express obstructive apneas, and to investigate potential underlying mechanisms.MethodsApneas were classified as central, obstructive or mixed by using a novel system combining pneumotachography and laser detection of abdominal movement immediately after birth. Several respiratory nuclei involved in airway patency were examined by immunohistochemistry and electrophysiology in brainstem-spinal cord preparation.Measurements and Main ResultsThe median (interquartile range) of obstructive apnea frequency was 2.3/min (1.5-3.3) in Phox2b27Ala/+ pups versus 0.6/min (0.4-1.0) in wildtypes (P < 0.0001). Obstructive apnea duration was 2.7s (2.3-3.9) in Phox2b27Ala/+ pups versus 1.7s (1.1-1.9) in wildtypes (P < 0.0001). Central and mixed apneas presented similar, significant differences. In Phox2b27Ala/+ preparations, the hypoglossal nucleus had fewer (P < 0.05) and smaller (P < 0.01) neurons, compared to wildtypes. Importantly, coordination of phrenic and hypoglossal motor activities was disrupted, as evidenced by the longer and variable delay of hypoglossal with respect to phrenic activity onset (P < 0.001).ConclusionsThe Phox2b27Ala/+ mutation predisposed pups not only to hypoventilation and central apneas, but also to obstructive and mixed apneas, likely due to hypoglossal dysgenesis. These results thus demand attention towards obstructive events in infants with CCHS.