Residual chemosensitivity to ventilatory challenges in genotyped congenital central hypoventilation syndrome

Abstract

Congenital central hypoventilation syndrome (CCHS) is a neurodevelopmental disorder characterized by life-threatening hypoventilation, possibly resulting from disruption of central chemosensory integration. However, animal models suggest the possibility of residual chemosensory function in the human disease. Cardioventilatory function in a large cohort with CCHS and verified paired-like homeobox 2B (PHOX2B) mutations was assessed to determine the extent and genotype dependence of any residual chemosensory function in these patients. As part of inpatient clinical care and evaluation, 64 distinct studies from 32 infants, children, and young adults with the disorder were evaluated for physiological response to three different inspired steady-state gas exposures of 3 min each: hyperoxia [100% oxygen (O2)]; hyperoxic hypercapnia [95% O2 and 5% carbon dioxide (CO2)]; and hypoxic hypercapnia [14% O2 and 7% CO2 balanced with nitrogen (N2)]. These were followed by a hypoxia challenge consisting of five or seven breaths of N2 (100% N2). In addition, a control group of 15 young adults was exposed to all but the hypoxic challenge. Comprehensive monitoring was used to derive breath-to-breath and beat-to-beat measures of ventilatory, cardiovascular, and cerebrovascular function. On average, patients showed a residual awake ventilatory response to chemosensory challenge, independent of the specific patient PHOX2B genotype. Graded dysfunction in cardiovascular regulation was found to associate with genotype, suggesting differential effects on different autonomic subsystems. In addition, differences between cases and controls in the cerebrovascular response to chemosensory challenge may indicate alterations in cerebral autoregulation. Thus residual cardiorespiratory responses suggest partial preservation of central nervous system networks that could provide a fulcrum for potential pharmacological interventions.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): Response to ventilatory challenges

“…Markers and vertical bars signify mean ± SE, with lightly shaded background lines representing average responses from unique individuals. Dashed lines are an averaged response of five healthy young adults under an identical protocol, as previously published . Square markers above each time bin indicate significant difference from baseline ( P < 0.05, adjusted for multiple comparisons within each subpanel dataset).…”

“…None of the patients used medications with known respiratory effects. The protocol used in this study is identical to that used for a similar study of chemosensory response in CCHS …”

“…The sensitivity of ventilatory measures to changes in inspired gases during the challenges was evaluated from breath‐to‐breath metrics taken during the two hypercapnic challenges and recovery epochs, following the same procedure as detailed in Carroll et al (2014) . As in that study, these data often showed a threshold effect at an intermediate end‐tidal CO 2 value, so a piecewise linear model was used, with a zero‐slope null response domain and a linear response domain.…”

Mutations inMYO1Hcause a recessive form of central hypoventilation with autonomic dysfunction

“…Patients with CCHS require lifelong artificial ventilation. The most salient aspect of this respiratory control disorder is the inability to adjust breathing in response to changing levels of blood gases, that is, hypercapnia (high levels of CO 2 ) and hypoxaemia (low levels of O 2 ) 2. The respiratory phenotype is characteristically associated with physiological manifestations of autonomic nervous system dysregulation3 4 as well as anatomical manifestations including Hirschsprung disease (a rare disorder that produces aganglionosis of the distal hindgut) and neural-crest tumours such as neuroblastomas, ganglioneuromas and ganglioneuroblastomas 5 6.…”

Neural Control of Respiration by the Retrotrapezoid Nucleus.

“…Human CCHS patients lose the ability to sense the rise in PaCO 2 and drop in pH that normally stimulates breathing (Amiel et al, 2003;Weese-Mayer et al, 2009;Carroll et al, 2014). In mice carrying the most common CCHS mutation, a polyalanine expansion that causes a frameshift mutation (Phox2b 27ala/+), the chemoreflex is almost completely absent and resting ventilation is reduced (Ramanantsoa et al, 2011 andDubreuil et al, 2009).…”