Defective exercise-related expiratory muscle recruitment in patients with PHOX2B mutations: A clue to neural determinants of the congenital central hypoventilation syndrome.

Introduction and objectives: The human congenital central hypoventilation syndrome (CCHS) is caused by mutations in the PHOX2B (paired-like homeobox 2B) gene. Genetically engineered PHOX2B rodents exhibit defective development of the brainstem retrotrapezoid nucleus (RTN), a carbon dioxide sensitive structure that critically controls expiratory muscle recruitment. This has been linked to a blunted exercise ventilatory response. Whether this can be extrapolated to human CCHS is unknown and represents the objective of this study.

Materials and methods: Thirteen adult CCHS patients and 13 healthy participants performed an incremental symptom-limited cycle cardiopulmonary exercise test. Responses were analyzed using guideline approaches (ventilation V'_E, tidal volume V_T, breathing frequency, oxygen consumption, carbon dioxide production) complemented by a breathing pattern analysis (i.e. expiratory and inspiratory reserve volume, ERV and IRV).

Results: A ventilatory response occurred in both study groups, as follows: V'_E and V_T increased in CCHS patients until 40 W and then decreased, which was not observed in the healthy participants (p<0.001). In the latter, exercise-related ERV and IRV decreases attested to concomitant expiratory and inspiratory recruitment. In the CCHS patients, inspiratory recruitment occurred but there was no evidence of expiratory recruitment (absence of any ERV decrease, p<0.001).

Conclusions: Assuming a similar organization of respiratory rhythmogenesis in humans and rodents, the lack of exercise-related expiratory recruitment observed in our CCHS patients is compatible with a PHOX2B-related defect of a neural structure that would be analogous to the rodents' RTN. Provided corroboration, ERV recruitment could serve as a physiological outcome in studies aiming at correcting breathing control in CCHS.