Congenital central hypoventilation syndrome and the PHOX2B gene: A model of respiratory and autonomic dysregulation

Abstract

The paired-like homeobox 2B gene (PHOX2B) is the disease-defining gene for congenital central hypoventilation syndrome (CCHS). Individuals with CCHS typically present in the newborn period with alveolar hypoventilation during sleep and often during wakefulness, altered respiratory control including reduced or absent ventilatory responses to hypercarbia and hypoxemia, and autonomic nervous system (ANS) dysregulation; however, a subset of individuals present well into adulthood. Thermoregulation is altered and perception of shortness of breath is absent, but voluntary breathing is retained. Structural and functional magnetic resonance imaging (MRI) and limited post-mortem studies in subjects with CCHS reveal abnormalities in both forebrain and brainstem. MRI changes appear in the hypothalamus (responsible for thermal drive to breathing), posterior thalamus and midbrain (mediating O 2 and oscillatory motor patterns), caudal raphé and locus coeruleus (regulating serotonergic and noradrenergic systems), the lateral medulla, parabrachial pons, and cerebellum (coordinating chemoreceptor and somatic afferent activity with

Pupillometry in congenital central hypoventilation syndrome (CCHS): quantitative evidence of autonomic nervous system dysregulation

“…The evidence for both sympathetic and parasympathetic dysregulation in CCHS follows logically from a basic understanding of the PHOX2B gene role in embryologic development of the sympathetic, parasympathetic, and enteric pathways of the ANS (5,22). We postulate that the demonstrated functional differences in pupillary measures are specific to the ANS efferent pathways.…”

“…This is based on the absence of afferent defects as observed from a review of the records and demonstration that refractive variance (as demonstrated by the need or a lack of it for glasses) was not associated with differences in pupil measurements. PHOX2B expression patterns in mouse knockout models indicate a lack of PHOX2B expression at the level of the midbrain (Edinger-Westphal nucleus, pretectal nucleus) and hypothalamus (22). Consequently, we propose that pupillometry measures obtained in genetically confirmed CCHS can be used to elucidate efferent ophthalmologic ANS dysfunction and may have applicability in the evaluation of efferent pathways of other autonomic disorders.…”

Respiratory and autonomic dysfunction in congenital central hypoventilation syndrome

“…In addition, pathological evidence obtained from polyalanine repeat mutation (PARM) CCHS animal models supports the notion that central respiratory chemosensitivity relies on relatively few specialized neurons, such as the chemoreceptor neurons of the RTN (Dubreuil et al 2008;Ramanantsoa et al 2011). In this genetic disease, central chemosensitivity is essentially absent; severe hypoventilation occurs during sleep but relatively adequate breathing persists during waking, and some degree of exercise-induced hyperventilation remains, at least in the milder cases (Amiel et al 2003(Amiel et al , 2009Carroll et al 2010;Gozal, 1998;Shea et al 1993). The severity of the symptoms increases according to the number of extra alanine residues in the mutated polyalanine track of PHOX2B (Carroll et al 2010).…”

“…In this genetic disease, central chemosensitivity is essentially absent; severe hypoventilation occurs during sleep but relatively adequate breathing persists during waking, and some degree of exercise-induced hyperventilation remains, at least in the milder cases (Amiel et al 2003(Amiel et al , 2009Carroll et al 2010;Gozal, 1998;Shea et al 1993). The severity of the symptoms increases according to the number of extra alanine residues in the mutated polyalanine track of PHOX2B (Carroll et al 2010). The respiratory symptoms of the disease suggest that the central respiratory controller located in the pre-Bötz-inger complex of CCHS patients is largely intact but that the brain of these individuals lacks neurons that are either uniquely specialized in detecting CO 2 or are specialized in funneling the excitatory influence of CO 2 to the respiratory controller.…”

“…CCHS was first described by modern medicine in 1970 (Mellins et al 1970) and is classically characterized as a genetically inherited disorder with alveolar hypoventilation and monotonous respiratory rates despite abnormal Pa CO 2 and pH concentrations, especially during nonrapid eye movement (NREM) sleep (Patwari et al 2010). CCHS patients fail to arouse from sleep despite progressive hypercapnia or hypoxemia.…”