Congenital central hypoventilation syndrome: An update

Gozal, David

doi:10.1002/(sici)1099-0496(199810)26:4<273::aid-ppul7>3.3.co;2-3

Cited by 125 publications

(75 citation statements)

References 59 publications

(87 reference statements)

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“…Together, these data point to the possibility that Phox2b cells control aspects of respiratory rhythm generation, at least at birth. This is compatible with the lack of spontaneous breathing at birth in severe cases of CCHS (Gozal 1998). It could also explain the abnormalities of the respiratory rhythm in Phox2b 27Ala/þ newborns, which range from a slow rhythm to gasping (Dubreuil et al 2008).…”

Section: Mutations In Phox2b and The Drive To Breathesupporting

confidence: 68%

Breathing withPhox2b

Dubreuil

Barhanin

Goridis

et al. 2009

Phil. Trans. R. Soc. B

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In the last few years, elucidation of the architecture of breathing control centres has reached the cellular level. This has been facilitated by increasing knowledge of the molecular signatures of various classes of hindbrain neurons. Here, we review the advances achieved by studying the homeodomain factor Phox2b, a transcriptional determinant of neuronal identity in the central and peripheral nervous systems. Evidence from human genetics, neurophysiology and mouse reverse genetics converges to implicate a small population of Phox2b-dependent neurons, located in the retrotrapezoid nucleus, in the detection of CO 2 , which is a paramount source of the 'drive to breathe'. Moreover, the same and other studies suggest that an overlapping or identical neuronal population, the parafacial respiratory group, might contribute to the respiratory rhythm at least in some circumstances, such as for the initiation of breathing following birth. Together with the previously established Phox2b dependency of other respiratory neurons (which we review briefly here), our new data highlight a key role of this transcription factor in setting up the circuits for breathing automaticity.

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Section: Mutations In Phox2b and The Drive To Breathesupporting

confidence: 68%

Breathing withPhox2b

Dubreuil

Barhanin

Goridis

et al. 2009

Phil. Trans. R. Soc. B

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“…The extent to which brain regions in addition to the preBötC are also necessary for the normal pattern of breathing is yet to be determined. PreBötC NK1R neurons may contain the kernel for the genetically determined behavior of breathing in mammals, and delineating their properties may provide ways to understand and treat lifethreatening and poorly understood central failures of breathing such as central sleep apnea17 ,18 , congenital central hypoventilation syndrome (Ondine's curse) 19, 20, Joubert's Syndrome21 and Sudden Infant Death Syndrome22.…”

Section: Discussionmentioning

confidence: 99%

Normal breathing requires preBötzinger complex neurokinin-1 receptor-expressing neurons

et al. 2001

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The normal breathing rhythm in mammals is hypothesized to be generated by neurokinin-1 receptor (NK1R)-expressing neurons in the preBötzinger complex (preBötC), a medullary region proposed to contain the kernel of the circuits generating respiration. If this hypothesis is correct, then complete destruction of preBötC NK1R neurons should severely perturb and perhaps even fatally arrest breathing. Here we show that specific and near complete bilateral (but not unilateral) destruction of preBötC NK1R neurons results in both an ataxic breathing pattern with markedly altered blood gases and pH, and pathological responses to challenges such as hyperoxia, hypoxia and anesthesia. Thus, these ~600 neurons seem necessary for the generation of normal breathing in rats.Breathing is an exceptionally reliable and continuous mammalian behavior that regulates blood gases and pH at rest and in response to diverse challenges such as exercise, sleep or altitude. The rhythm underlying breathing is postulated to depend critically on neurons in the preBötC1 , 2. Two recent developments allowed us to determine in awake adult rats whether this critical regulatory behavior would be affected by lesions in the preBötC. First, the extent of the preBötC can be anatomically defined by the sub-population of propriobulbar respiratory neurons within the ventrolateral respiratory column expressing NK1R3 -5 . Second, NK1R neurons can be specifically lesioned by substance P conjugated to saporin (SP-SAP) 6 , an effect that takes several days, allowing for complete recovery from surgery6. ResultsSP-SAP was effective in eliminating preBötC NK1R neurons in adult rats. Injections of 0.1-0.2 pmol of SP-SAP or 0.3 pmol each of unconjugated saporin and SP were made in the preBötC. Unilateral SP-SAP injection transiently produced sighs (large inspiratory efforts followed by prolonged expiration), consistent with the effects of injection of SP alone into the pre-BötC in vitro 7 and in vivo (P.A.G., D.R.M. and J.L.F., unpublished observations). All rats returned to normal behavior upon recovery from surgery. Two to eighteen days after injection, rats were perfused and their medullas were stained for NK1R immunoreactivity (n = 20 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript lesion extent was estimated by counting NK1R immunopositive neuronal soma in the rostral medulla inside a circle of 600-μm diameter approximating the preBötC (ventrolateral to the nucleus ambiguus) and in a rectangle (1600 × 1070 μm) outside this circle (Fig. 1, inset). Counts were estimated from four transverse sections beginning within 100 μm of the rostral border of the lateral reticular nucleus and spanning the preBötC 3,4 containing approximately 12-15% of the total preBötC volume. Uninjected controls (n = 4) had 35 ± 5.1 (mean ± s.e.m., per side) NK1R neurons within the preBötC (~600 preBötC NK1R neurons total, which we estimate represent less than 10% of all preBötC neurons) and 82 ± 9 NK1R neurons outside the preBötC. Most of the latter were i...

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“…Little is known regarding the bases of ventilatory control anomalies in CCHS. It has been speculated that the disease involves a defect in the integration by the nucleus of the solitary tract and interneurons of the inputs from the central CO 2 /pH-sensitive chemoreceptors (medulla oblongata) and the peripheral O 2 , CO 2 and pH-sensitive chemoreceptors in the carotid bodies 1 . Notably, several of these structures express Phox2b in mice 8,9 and humans (this study) and fail to form or degenerate in Phox2b -/-mouse mutants (refs.…”

mentioning

confidence: 99%