Impaired neural structure and function contributing to autonomic symptoms in congenital central hypoventilation syndrome

Abstract

Congenital central hypoventilation syndrome (CCHS) patients show major autonomic alterations in addition to their better-known breathing deficiencies. The processes underlying CCHS, mutations in the PHOX2B gene, target autonomic neuronal development, with frame shift extent contributing to symptom severity. Many autonomic characteristics, such as impaired pupillary constriction and poor temperature regulation, reflect parasympathetic alterations, and can include disturbed alimentary processes, with malabsorption and intestinal motility dyscontrol. The sympathetic nervous system changes can exert life-threatening outcomes, with dysregulation of sympathetic outflow leading to high blood pressure, time-altered and dampened heart rate and breathing responses to challenges, cardiac arrhythmia, profuse sweating, and poor fluid regulation. The central mechanisms contributing to failed autonomic processes are readily apparent from structural and functional magnetic resonance imaging studies, which reveal substantial cortical thinning, tissue injury, and disrupted functional responses in hypothalamic, hippocampal, posterior thalamic, and basal ganglia sites and their descending projections, as well as insular, cingulate, and medial frontal cortices, which influence subcortical autonomic structures. Midbrain structures are also compromised, including the raphe system and its projections to cerebellar and medullary sites, the locus coeruleus, and medullary reflex integrating sites, including the dorsal and ventrolateral medullary nuclei. The damage to rostral autonomic sites overlaps metabolic, affective and cognitive regulatory regions, leading to hormonal disruption, anxiety, depression, behavioral control, and sudden death concerns. The injuries suggest that interventions for mitigating hypoxic exposure and nutrient loss may provide cellular protection, in the same fashion as interventions in other conditions with similar malabsorption, fluid turnover, or hypoxic exposure.

Congenital central hypoventilation syndrome: Broader cognitive deficits revealed by parent controls

“…Our findings suggest that the adverse neurocognitive impact of CCHS may be even broader than previous studies have suggested, emphasizing the importance of early identification and conservative management. Our data also complement a rapidly growing body of brain imaging research in CCHS providing clear evidence of structural and functional abnormalities of brain systems involved in autonomic regulation . Our findings urge caution in the design and interpretation of research on neurocognitive functioning in rare disease clinical populations such as CCHS relative to general population norms, and emphasize the importance of controls matched as nearly as possible on socioeconomic, situational, and other non‐disease‐related heritable factors in studies of pediatric neurocognitive outcome.…”

“…Neuropathology evaluation of young infants with CCHS indicates anatomic alterations that may translate to reduced neurological outcomes . Neuroimaging studies of adolescents with CCHS have provided clear evidence of structural and functional abnormalities of brain systems involved in autonomic regulation that might result in altered neurological outcomes . A report of Japanese infants with CCHS who had delayed diagnosis and management with supplemental oxygen rather than tracheostomy/artificial ventilation in the newborn period indicates the impact of postnatal physiologic compromise on neurocognitive outcome especially when compared with our report in preschool children with CCHS…”

Molecular insights into the role of the polyalanine region in mediating PHOX2B aggregation

“…It is worth noting that the role of PHOX2B in adulthood has not been investigated, although in mice Phox2b expression persists in most brainstem structures after birth . Together with the findings that brain imaging and functional magnetic resonance imaging (fMRI) studies of CCHS patients suggest that other damages occur progressively, in addition to the developmental defects induced by PHOX2B mutations , we cannot exclude a role for fibrils in CCHS ‘progression’. This evidence could pave the way for an innovative rational design of therapeutic drugs.…”

Sudden unexpected death in epilepsy: The neuro-cardio-respiratory connection

“…The posterior thalamus plays a significant role in oxygen sensing [28] and in relaying afferent activity essential for breathing [12]. A disruption of the thalamic-brain stem link in high-risk SUDEP patients is particularly worrisome due to its involvement with respiratory failure in SUDEP.…”