Advances in the molecular biology and pathogenesis of congenital central hypoventilation syndrome—implications for new therapeutic targets

Introduction: Congenital central hypoventilation syndrome (CCHS) is a rare life-long genetic disorder characterized by the failure of autonomic control of breathing. It is known to be caused by heterozygous mutations in the paired-like homeobox 2B (PHOX2B) transcription factor, although the underlying mechanism is still unclear, and no pharmacological treatment has yet proved to be effective in improving the disease-related respiratory defects. Areas covered: This review first describes the genetics, the clinical presentation, and management of CCHS, and then discusses recent advances in our understanding of the physiological role of PHOX2B during neuronal development and the molecular mechanisms underlying CCHS pathogenesis. Finally, it considers current therapeutic research strategies. Expert opinion: Studies of cell models of CCHS indicate that transcriptional dysregulation may be a key pathogenic mechanism, and that protein misfolding probably contributes to the transcriptional defects. Knowledge of the identity of the genes regulated by PHOX2B and its molecular interactors is very limited, and there is information about only a handful of genes. Extending this information is therefore extremely important as a first step toward the discovery of new druggable targets and the development of new therapeutic strategies.