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

ABSTRACT

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.

KEYWORDS:

• Autonomic dysregulation
• breathing disorder
• congenital central hypoventilation syndrome
• CCHS
• developmental disorder
• molecular pathogenesis
• PHOX2B
• polyalanine expansions
• protein aggregation
• transcription factor

Article highlights

• Congenital central hypoventilation syndrome (CCHS) is a rare life-long genetic disorder characterized by the failure of autonomic control over breathing. No pharmacological treatment has yet proved to be effective in improving the disease-related respiratory defects.

• The discovery of PHOX2B as the disease-defining gene in CCHS has greatly improved diagnosis and management, and studies of genotype–phenotype correlations help to predict the severity of the disease.

• CCHS is caused by heterozygous mutations in the PHOX2B gene, that encodes a key transcription factor in the development (and maintenance) of the autonomic nervous system. Data from mouse and cellular models of CCHS suggest that protein misfolding, transcriptional dysregulation, and dominant-negative effects of the mutant proteins on the functionality of the normal protein contribute to the pathogenesis of the disease.

• It is thought that the severity of the disease primarily depends on the number and importance of the dysregulated target genes, and that this depends on the type and severity of the PHOX2B mutations.

• Recent findings showing that some CCHS patients have residual cardiorespiratory responses, and the fortuitous observation that two female patients using the progestin drug desogestrel for contraceptive purposes experienced a partial recovery of chemosensitivity, have opened up new prospects for a pharmacological intervention that could at least improve respiratory symptoms.

• Further insights into the neurobiology and molecular pathophysiology of CCHS will provide a foundation upon which to develop novel pharmacological interventions that can restore PHOX2B function or by-pass PHOX2B mutations.

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Acknowledgments

The authors would like to thank Professor Kevin Smart for language editing assistance.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was supported by the Telethon Foundation [grant number: GGP13055] to D Fornasari, the Associazione Italiana per la Sindrome da Ipoventilazione Centrale Congenita (AISICC) and the CCHS Family Network [2017 Grant award to D Fornasari].