Research Advances on Therapeutic Approaches to Congenital Central Hypoventilation Syndrome (CCHS).

Simona Di Lascio,Roberta Benfante,Silvia Cardani,Diego Fornasari

doi:10.3389/fnins.2020.615666

Abstract

Congenital central hypoventilation syndrome (CCHS) is a genetic disorder of neurodevelopment, with an autosomal dominant transmission, caused by heterozygous mutations in the PHOX2B gene. CCHS is a rare disorder characterized by hypoventilation due to the failure of autonomic control of breathing. Until now no curative treatment has been found. PHOX2B is a transcription factor that plays a crucial role in the development (and maintenance) of the autonomic nervous system, and in particular the neuronal structures involved in respiratory reflexes. The underlying pathogenetic mechanism is still unclear, although studies in vivo and in CCHS patients indicate that some neuronal structures may be damaged. Moreover, in vitro experimental data suggest that transcriptional dysregulation and protein misfolding may be key pathogenic mechanisms. This review summarizes latest researches that improved the comprehension of the molecular pathogenetic mechanisms responsible for CCHS and discusses the search for therapeutic intervention in light of the current knowledge about PHOX2B function.

Highlights

Sudden infant death syndrome (SIDS), Rett syndrome (RTT), and congenital central hypoventilation syndrome (CCHS) are human diseases that share developmental defects in the neural circuits that control breathing (Box 1) (Ramirez et al, 2018, 2020; Trang et al, 2020)
A residual cardiorespiratory response has been reported in some younger CCHS patients, an observation that can be explained by the fact that the loss of retrotrapezoid nucleus (RTN) described in a mouse models with a + 7 alanine mutation is not complete, but limited to 70% of the cells (Dubreuil et al, 2008)
The knowledge acquired so far on paired-like homeobox 2B (PHOX2B) and its mutation, and its role in the etiogenesis of CCHS have strongly contributed to the improvement of the diagnosis and treatment of the patient, including the attempt to predict the severity of the disease by genotype-phenotype correlation analyses

Summary

Introduction

Sudden infant death syndrome (SIDS), Rett syndrome (RTT), and congenital central hypoventilation syndrome (CCHS) are human diseases that share developmental defects in the neural circuits that control breathing (Box 1) (Ramirez et al, 2018, 2020; Trang et al, 2020). Other neural structures are under the developmental control of PHOX2B, such as the locus coerules (LC), the catecholaminergic neurons of the nucleus of solitary tract (NTS) and of the Therapeutic Approaches to CCHS. Congenital central hypoventilation syndrome (CCHS or Ondine’s curse; MIM# 209880) is a rare neurological disorder characterized by the deficient autonomic control of breathing (Weese-Mayer et al, 2010; Trang et al, 2020). Some drugs have shown some effects in improving ventilation (Straus et al, 2010; Schirwani et al, 2017), CCHS remains a severe breathing disorder without any effective pharmacological treatment

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