Abstract
Rationale Congenital 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.
Objectives To 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.
Methods Apneas 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 Results The 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).
Conclusions The 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Sources of support Institutional supports (Inserm and Université de Paris), Fonds de Recherche en Santé Respiratoire (F.R.S.R. grant to A.M.); Association Française du Syndrome d’Ondine (AFSO, grant to E.S.), Legs Poix (Chancellerie des Universités de Paris, grant to C.D.); Fondation pour la recherche Médicale (FRM, grant to M.T.B.).