RARE DISEASE
Congenital central hypoventilation syndrome
Congenital central hypoventilation syndrome
Congenital central hypoventilation syndrome
Synonyms: CCHS, Congenital central alveolar hypoventilation syndrome, Ondine curse, Ondine syndrome
Synonyms: CCHS, Congenital central alveolar hypoventilation syndrome, Ondine curse, Ondine syndrome
Synonyms: CCHS, Congenital central alveolar hypoventilation syndrome, Ondine curse, Ondine syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic disorder caused by PHOX2B gene mutations, impairing autonomic control of breathing. Characterized by hypoventilation (worsening during sleep), blunted chemoreceptor response to hypercapnia/hypoxia, and autonomic dysfunction. Up to 20% of cases coexist with Hirschsprung disease (Haddad syndrome). Diagnosis requires genetic confirmation. Management relies on lifelong ventilatory support and multidisciplinary care for associated neurocristopathies (e.g., neuroblastomas) and ANS dysregulation [1][2][6][17].
Categories: rare genetic diseases, rare neurological diseases, rare respiratory diseases
Research Papers
290 drug discovery papers about Congenital central hypoventilation syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
290 drug discovery papers about Congenital central hypoventilation syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-15 | Redefining PHOX2B-Related Neurodevelopmental Disorders as Circuitopathies: A New Paradigm in Autonomic Network Medicine.
The paired-like homeobox transcription factor 2B (PHOX2B) is a master regulator whose mutations cause a spectrum of severe neurological and neurodevelopmental disorders, including Congenital central hypoventilation syndrome (CCHS), Hirschsprung disease, and neuroblastoma. For decades, a central paradox has challenged the field: how can PHOX2B's seemingly restricted expression in the brainstem account for the broad, multi-system clinical phenotypes observed in patients? Here, we elucidate how this paradox has been resolved by recent methodological advances. We synthesize evidence from multiple complementary methodologies, including single-cell transcriptomics, spatial transcriptomics, and viral circuit tracing, which have revealed a vastly expanded PHOX2B anatomical landscape. These advances uncover previously unrecognized expression in caudal midbrain and higher brainstem regions, supportive glial populations, and peripheral components, extending far beyond classical autonomic nuclei. Furthermore, while mapping evidence predominantly derives from murine models, insights from human disease models, such as pluripotent stem cell-derived brainstem organoids, suggest that PHOX2B orchestrates integrated neuro-glial networks rather than isolated functions. Consequently, we propose reconceptualizing CCHS and related conditions as a class of multi-system network disorders termed PHOX2B circuitopathies. This circuitopathy framework critically differentiates primary circuit disruptions from secondary systemic cascades (such as hypoxia-induced cognitive deficits), providing a cohesive mechanistic basis for the constellation of cardiovascular, metabolic, and neurobehavioral symptoms. Crucially, it advances the field beyond the reactive, symptomatic management predominantly outlined in current clinical guidelines. By shifting the focus toward proactive, precision drug discovery and circuit-targeted strategies, this paradigm establishes a roadmap for developing network-based biomarkers and exploring novel disease-modifying interventions beyond conventional ventilatory support.
2026-05-18 | PHOX2B defects alter protein folding, cell-cycle, and mitochondrial pathways in an in vitro model of CCHS
Abstract Background Congenital Central Hypoventilation Syndrome (CCHS) is a rare autosomal dominant disorder caused by heterozygous mutations in the PHOX2B gene, leading to impaired ventilatory responses to hypoxia and hypercapnia. No pharmacological therapy exists, and patients rely on ventilatory support, tracheostomy, or diaphragmatic pacing. Most mutations are polyalanine expansions in exon 3, which mislocalize PHOX2B to the cytoplasm, disrupting the regulation of its transcriptional targets. Previous studies showed that geldanamycin and its derivative 17-AAG can partially rescue both the localization and the function of polyalanine expansion mutant PHOX2B. Nonetheless, downstream molecular effects of these mutations remain poorly understood. Methods The transcriptomic approach was applied to cells transiently expressing wild-type PHOX2B or the mutant carrying the most severe polyalanine expansion, to investigate the cellular consequences of whole transcripts deregulation caused by the PHOX2B mutation with or without 17-AAG treatments. Results Bioinformatic analysis allowed us to confirm the involvement of pathways already observed in polyalanine pathogenesis, such as protein folding and transcriptional repression, and to identify oxidative stress, mitochondrial dysfunction, and altered cell-cycle regulation as novel components of the PHOX2B+13Ala pathogenesis. Conclusions The RNA-sequencing approach recapitulates the molecular pathogenesis of PHOX2B polyalanine expansion mutations in CCHS and in vitro functional validations, thus confirming the suitability of this cellular model to study the molecular pathogenesis of the disease.
2026-03-13 | Sex Differences in the Effects of Etonogestrel on Respiratory Recovery in an In Vivo Rat Model of Central Chemoreflex Impairment.
Rhythmic breathing movements driven by the brainstem rely on chemosensory inputs to homeostatically adjust motor output to the prevailing metabolic demand. The central CO2 chemoreflex is a critical component of this neural circuitry, as defects in these sensors cause hypoventilation syndromes, which are typically difficult to manage pharmacologically. Progesterone has long been known to stimulate breathing in both sexes, and remarkably the progestinic metabolite, etonogestrel (ETO), enhances CO2 chemosensitivity in animal models and female patients affected by congenital central hypoventilation syndrome. However, ETO's mechanisms and sites of action remain unknown, and the experimental use of synthetic progestins has been met with mixed respiratory outcomes. In our recent work, we demonstrated that chronic ETO treatment improved the CO2 chemoreflex in female rats in which < 80% of chemoreceptor neurons comprising the retrotrapezoid nucleus (RTN) were eliminated. Since the progesterone receptor is widely expressed in both the male and female brain, we investigated whether ETO-induced CO2 chemoreflex recovery can be replicated in male rats in which RTN neurons are partially eliminated by the use of substance P-saporin toxin. Our results confirm dose-dependent impairment of the CO2 chemoreflex in both sexes following chemoreceptor lesion and corroborate the findings that ETO treatment restores ventilation in female rats with moderate-sized lesions. Interestingly, female respiratory recovery was associated with increased expression of the pH-sensing genes Gpr4 and Task2 in the RTN. In contrast, male rats failed to show significant recovery with ETO treatment, suggesting a sex-specific mechanism through which ETO promotes CO2 chemoreflex recovery.
2025-09-20 | Cesarean delivery with low-dose combined spinal epidural in a patient with congenital central hypoventilation syndrome: a case report.
Congenital central hypoventilation syndrome (CCHS), also known as Ondine's Curse, is an autonomic disorder resulting in an inadequate respiratory response to hypercapnia and hypoxia, especially during periods of decreased wakefulness. Patientswith CCHS are particularly sensitive to the effects of anesthetic medications, with increased risk for intraoperative events including hypotension, bradycardia, and hypoxemia. The current literature on the anesthetic management for patients with CCHS mainly described the use of general anesthesia, with few case reports describing neuraxial anesthesia. To our knowledge,this is the first case describing the anesthetic care for cesarean delivery of a patient with CCHS,with low-dose combined spinal epidural anesthesia. The patient had two previous cesarean deliveries with spinal anesthesia, complicated by hypotension and syncope secondary to autonomic dysfunction and/or neural-mediated syncope. This case highlights low-dose combined spinal epidural as a possible anesthetic approach in patients with CCHS, reducing the risk of hypotension and respiratory depression.
2025-05-01 | International CCHS Secure Health-hub Advancing Research Efforts (SHARE) Registry: Analysis of Patient-Reported Symptoms by PHOX2B Genotype in Congenital Central Hypoventilation Syndrome (CCHS)
Abstract RATIONALE: CCHS is a rare genetic disorder caused by variants of the PHOX2B gene. While the hallmark of CCHS is profound respiratory dysfunction requiring life-long artificial ventilatory support, PHOX2B variants also cause widespread, but less studied, autonomic nervous system (ANS) dysfunction. Most (∼90%) CCHS is caused by heterozygous in-frame expansion of the 20-alanine repeat region (PARM) of PHOX2B to between 24-33 repeats. The remaining CCHS cases are caused by a variety of other PHOX2B variants called non-PARMs (NPARMs), including missense, nonsense, and frameshift mutations. Both PARM and NPARM variants cause variable protein dysfunction, and a genotype-phenotype relationship has been reported for some primary symptoms of CCHS. The objective of this study was to assess symptoms and the relationship between PHOX2B genotypes and patient-reported dysfunction in all systems served by the ANS. Advancing understanding of symptom presentation and genotype-phenotype relationship for different organ systems is essential for developing targeted therapeutics and improving anticipatory management. METHODS: The CCHS SHARE Registry collects longitudinal data from individuals with PHOX2B mutation-confirmed CCHS, including information on 7 systems served by the ANS (cardiovascular, gastrointestinal, neurological, ophthalmologic, renal/urinary, respiratory, and sudomotor), totaling 64 possible ANS symptoms. 156 initial surveys were recorded. 19 were excluded due to incomplete surveys (137 analyzed). Participants were divided into moderate and severe PHOX2B genotype/variant groups based on established molecular data. Welch's test was utilized to compare between groupings for each organ system. Moderate genotypes were categorized as short PARMs (24-26 alanines) and NPARMs consisting of point mutations or frameshifts causing protein contraction. Severe genotypes were categorized as long PARMs (27-33 alanines) and NPARMs consisting of frameshifts causing expanded protein. RESULTS: Amongst all systems, 69% of individuals reported symptoms in the cardiovascular system, 63% in gastrointestinal, 65% in neurological, 66% in ophthalmologic, 15% in renal, 96% in respiratory, and 57% in sudomotor (Figure 1). Individuals with moderate PHOX2B genotypes reported less gastrointestinal, neurological, ophthalmologic, and respiratory symptoms than severe genotypes (p<0.05). No significant differences by PHOX2B group were observed in cardiovascular, renal, and sudomotor categories. CONCLUSION: The patient-reported impact of CCHS and specific PHOX2B genotype/variant varies by organ system. In addition to the typical focus on cardiorespiratory dysfunction in CCHS, these findings highlight additional systems/symptoms for future treatment, therapeutic development, and trial design. To improve our understanding of development, progression, and impact of autonomic symptoms in CCHS, longitudinal surveys should be captured and analyzed moving forward.
cell therapies
2023-11-13 | Carotid Body Dysfunction and Mechanisms of Disease.
Emerging evidence shows that the carotid body (CB) dysfunction is implicated in various physiological and pathophysiological conditions. It has been revealed that the CB structure and neurochemical profile alter in certain human sympathetic-related and cardiometabolic diseases. Specifically, a tiny CB with a decrease of glomus cells and their dense-cored vesicles has been seen in subjects with sleep disordered breathing such as sudden infant death syndrome and obstructive sleep apnea patients and people with congenital central hypoventilation syndrome. Moreover, the CB degranulation is accompanied by significantly elevated levels of catecholamines and proinflammatory cytokines in such patients. The intermittent hypoxia stimulates the CB, eliciting augmented chemoreflex drive and enhanced cardiorespiratory and sympathetic responses. High CB excitability due to blood flow restrictions, oxidative stress, alterations in neurotransmitter gases and disruptions of local mediators is also observed in congestive heart failure conditions. On the other hand, the morpho-chemical changes in hypertension include an increase in the CB volume due to vasodilation, altered transmitter phenotype of chemoreceptor cells and elevated production of neurotrophic factors. Accordingly, in both humans and animal models CB denervation prevents the breathing instability and lowers blood pressure. Knowledge of the morphofunctional aspects of the CB, a better understanding of its role in disease and recent advances in human CB translational research would contribute to the development of new therapeutic strategies.
2019-07-22 | Carotid Body Ablation: a New Target to Address Central Autonomic Dysfunction.
An abnormal heightened carotid body (CB) chemoreflex, which produces autonomic dysfunction and sympathetic overactivation, is the common hallmark of obstructive sleep apnea (OSA), resistant hypertension, systolic heart failure (HF), and cardiometabolic diseases. Accordingly, it has been proposed that the elimination of the CB chemosensory input to the brainstem may reduce the autonomic and cardiorespiratory alterations in sympathetic-associated diseases in humans. A growing body of evidence obtained in preclinical animal models support that an enhanced CB discharge produces sympathetic hyperactivity, baroreflex sensitivity and heart rate variability impairment, breathing instability, hypertension, and insulin resistance. The elimination CB chemosensory input reduces the sympathetic hyperactivity, the elevated arterial blood pressure in OSA and hypertensive models, abolishes breathing instability and improves animal survival in HF models, and restores insulin tolerance in metabolic models. These results highlight the role played by the enhanced CB drive in the progression of sympathetic-related diseases and support the proposal that the surgical ablation of the CB is useful to restore the autonomic balance and normal cardiorespiratory function in humans. Accordingly, the CB ablation has been used in pilot human studies as a therapeutic treatment for resistant hypertension and HF-induced sympathetic hyperactivity. In this review, I will discuss the supporting evidence for a crucial contribution of the CB in the central autonomic dysfunction and the pros and cons of the CB ablation as a therapy to revert autonomic overactivation. The CB ablation could be a useful method to reverse the enhanced chemoreflex in HF and severe hypertension, but caution is required before extensive use of bilateral CB ablation, which abolished ventilatory responses to hypoxia and may impair baroreceptor function.
2015-09-04 | Phrenic Nerve Stimulation: Technology and Clinical Applications
Phrenic nerve stimulation is a technique used to reanimate the diaphragm of patients with central nervous system etiologies of respiratory insufficiency. Current clinical indications include congenital central hypoventilation syndrome, spinal cord injury above C4, brain stem injury, and idiopathic severe sleep apnea. Presurgical evaluation ensures proper patient selection by validating the intact circuit from the phrenic nerve through alveolar oxygenation. The procedure involves placing leads around the phrenic nerves bilaterally and attaching these leads to radio receivers in a subcutaneous pocket. The rate and amplitude of the current is adjusted via an external radio transmitter. After implantation, each patient progresses through a conditioning phase that strengthens the diaphragm and progressively provides independence from the mechanical ventilator. Studies indicate that patients and families experience an improved quality of life and are satisfied with the results. Phrenic nerve stimulation provides a safe and effective means for reanimating the diaphragm for certain patients with respiratory insufficiency, providing independence from mechanical ventilation.
2003-06-20 | Carotid body denervation eliminates apnea in response to transient hypocapnia.
We determined the effects on breathing of transient ventilatory overshoots and concomitant hypocapnia, as produced by pressure support mechanical ventilation (PSV), in intact and carotid body chemoreceptor denervated (CBX) sleeping dogs. In the intact dog, PSV-induced transient increases in tidal volume and hypocapnia caused apnea within 10-11 s, followed by repetitive two-breath clusters separated by apneas, i.e., periodic breathing (PB). After CBX, significant expiratory time prolongation did not occur until after 30 s of PSV-induced hypocapnia, and PB never occurred. Average apneas of 8.4 +/- 1-s duration after a ventilatory overshoot required a decrease below eupnea of end-tidal Pco(2) 5.1 +/- 0.4 Torr below eupnea in the intact animal and 10.1 +/- 2 Torr in the CBX dog, where the former reflected peripheral and the latter central dynamic CO(2) chemoresponsiveness, as tested in the absence of peripheral chemoreceptor input. Hyperoxia when the dogs were intact shortened PSV-induced apneas and reduced PB but did not mimic the effects of CBX. We conclude that, during non-rapid eye movement sleep, carotid chemoreceptors are required to produce apneas that normally occur after a transient ventilatory overshoot and for PB.
gene therapies
2023-12-14 | Knockdown of PHOX2B in the retrotrapezoid nucleus reduces the central CO2chemoreflex in rats
ABSTRACT PHOX2B is a transcription factor essential for the development of the autonomic nervous system. Heterozygous mutations in the PHOX2B coding region are responsible for the occurrence of Congenital Central Hypoventilation Syndrome (CCHS), a rare neurological disorder characterised by inadequate chemosensitivity and life-threatening sleep-related hypoventilation. Animal studies suggest that chemoreflex defects are caused in part by the improper development or function of PHOX2B expressing neurons in the retrotrapezoid nucleus (RTN), a central hub for CO 2 chemosensitivity. Although the function of PHOX2B in rodents during development is well established, its role in the adult respiratory network remains unknown. In this study, we investigated whether reduction in PHOX2B expression in chemosensitive neuromedin-B (NMB) expressing neurons in the RTN altered respiratory function. Four weeks following local RTN injection of a lentiviral vector expressing the short hairpin RNA (shRNA) targeting Phox2b mRNA, a reduction of PHOX2B expression was observed in Nmb neurons compared to both naïve rats and rats injected with the non-target shRNA. PHOX2B knockdown did not affect breathing in room air or under hypoxia, but ventilation was significantly impaired during hypercapnia. PHOX2B knockdown did not alter Nmb expression but reduced the expression of both Task2 and Gpr4 , two CO 2 sensors in the RTN. We conclude that PHOX2B in the adult brain has an important role in CO 2 chemoreception and reduced PHOX2B expression in CCHS beyond the developmental period may contribute to the impaired central chemoreflex function.
2015-12-09 | Novel Mutation-Deletion in the PHOX2B Gene of the Patient Diagnosed with Neuroblastoma, Hirschsprung’s Disease, and Congenital Central Hypoventilation Syndrome (NB-HSCR- CCHS) Cluster
Neuroblastoma (NB), Hirschsprung disease (HSCR), Congenital Central Hypoventilation Syndrome (CCHS), clinically referred as the NB-HSCR-CCHS cluster, are genetic disorders linked to mutations in the PHOX2B gene on chromosome 4p12.The specific aim of this project is to define the PHOX2B gene mutations as the genomic basis for the clinical manifestations of the NB-HSCR-CCHS cluster.A one day old male patient presented to the Jagiellonian University Medical College (JUMC), American Children Hospital, neonatal Intensive Care Unit (ICU) due to abdominal distention, vomiting, and severe apneic episodes. With the preliminary diagnosis of the NB-HSCR-CCHS, the blood and tissue samples were acquired from the child, as well as from the child's parents. All procedures were pursued in accordance with the Declaration of Helsinki, with the patient's Guardian Informed Consent and the approval from the Institutional Review Board.Karyotyping was analyzed based upon Giemsa banding. The patient's genomic DNA was extracted from peripheral blood and amplified by polymerase chain reaction. Direct microfluidic Sanger sequencing was performed on the genomic DNA amplicons. These procedures were pursued in addition to the routine clinical examinations and tests.G-banding showed the normal 46 XY karyotype. However, genomic sequencing revealed a novel, heterozygous deletion (8 nucleotides: c.699-706, del8) in exon 3 of the PHOX2B gene on chromosome 4. This led to the frame-shift mutation and malfunctioning gene expression product.Herein, we report a novel PHOX2B gene mutation in the patient diagnosed with the NB-HSCR-CCHS cluster. The resulting gene expression product may be a contributor to the clinical manifestations of these genetic disorders. It adds to the library of the mutations linked to this syndrome. Consequently, we suggest that screening for the PHOX2B mutations becomes an integral part of genetic counseling, genomic sequencing of fetal circulating nucleic acids and / or genomes of circulating fetal cells prenatally, while preparing supportive therapy upon delivery, as well as on neonates' genomes of intubated infants, when breathing difficulties occur upon extubation. Further, we hypothesize that PHOX2B may be considered as a potential target for gene therapy.
2008-09-10 | A novel missense mutation in the PHOX2B gene is associated with late onset central hypoventilation syndrome.
Abstract We report the case of a 15‐month‐old male suffering from Late Onset Congenital Central Hypoventilation Syndrome and recto‐sigmoid Hirschsprung's disease, an association that has not been reported thus far. Nevertheless, our patient showed a missense mutation of the PHOX2B gene already known in isolated late onset central hypoventilation, resulting in a substitution of the Ala140 residue with a Glu residue (p.A140E). The present association of LO‐CHS and HSCR in a patient harboring a rare and atypical PHOX2B mutation allows to refine the mutational spectrum of this disease and suggests individualized ventilatory care along with specific surgical and oncological approaches. Pediatr Pulmonol. 2008; 43:1036–1039. © 2008 Wiley‐Liss, Inc.
proteins
2025-09-25 | Homozygous DBX1 Nonsense Variant in a Case of Atypical Congenital Central Hypoventilation.
Congenital central hypoventilation syndrome (CCHS) is a rare breathing disorder, predominantly caused by deleterious alterations in the PHOX2B gene. This report describes a rare case with PHOX2B-negative CCHS. We conducted a 10-year follow-up, including a clinical evaluation, polysomnography, brain MRI, analyses of blood and CSF, electrodiagnostic testing, and comprehensive genetic analyses including trio-whole exome sequencing (trio-WES). In a female patient necessitating artificial ventilation immediately postnatally, trio-WES revealed a homozygous deleterious variant in the candidate gene DBX1 (p.Ala114HisfsTer133), likely resulting in a complete loss of DBX1. Additional symptoms included central hypotonia, global developmental delay, seizures, and marked autoaggressive behavior. Dbx1 (developing brain homeobox 1) has an established critical role for mammalian inspiration, dramatically illustrated by the rapid postnatal demise of Dbx1 null mice because of asphyxia. Here, we describe the first human patient with atypical CCHS harboring a deleterious variant in the DBX1 gene. Surprisingly, over time, our patient gradually achieved the capability of ventilator-independent respiration, although with an irregular rhythm and only during the wake state. These findings suggest that DBX1-deficient individuals are able to install alternative neuronal circuits that maintain inspiratory drive during the wake state.
2022-10-27 | Thyrotropin-releasing hormone analog as a stable upper airway-preferring respiratory stimulant with arousal properties.
Taltirelin is a stable, brain-penetrating thyrotropin-releasing hormone (TRH) analog with minimal endocrine activity and potential respiratory stimulant properties. Taltirelin's receptor target shows high differential expression at the hypoglossal motor nucleus, and local taltirelin microperfusion into the hypoglossal motor nucleus causes sustained tongue motor activation compared with the transient activating effects of TRH itself. Here, we performed a randomized, within-subject, repeated-measures design over six separate study days (separated by at least 72 h) in chronically instrumented male (n = 10) and female (n = 9) rats to identify effects on sleep and breathing. Vehicle controls or taltirelin (0.1 and 1 mg/kg) with and without trazodone (30 mg/kg) were administered by intraperitoneal injection. Trazodone was included due to clinical interest in the context of sleep apnea pharmacotherapy as it can suppress arousal without compromising pharyngeal muscle activity. Systemically administered taltirelin (1 but not 0.1 mg/kg) increased tonic and within-breath phasic tonic muscle activity compared with vehicle controls (P ≤ 0.007), with little or no changes in diaphragm amplitude or respiratory rate. Taltirelin also suppressed nonrapid eye movement (non-REM) sleep and increased wakefulness (P ≤ 0.037). Other indices of taltirelin-induced central nervous system arousal included increased trapezius muscle tone in non-REM sleep and decreased total electroencephalogram power and δ (0.5-4 Hz) power (P ≤ 0.046). These effects were especially apparent in non-REM sleep and not prevented by trazodone. These preclinical findings identify taltirelin as a stable upper airway-preferring respiratory stimulant with arousal properties, traits that have potential favorable relevance to some respiratory disorders but not others.NEW & NOTEWORTHY One of the major goals for translational sleep science and medicine is to identify viable and tractable pharmacological targets for obstructive sleep apnea and other respiratory disorders of sleep or sedation. In the present preclinical study in rats, we performed a randomized, within-subject, repeated-measures design over six intervention study days in chronically instrumented male and female rats with systemic peripheral administration of vehicle controls, the thyrotropin-releasing hormone analog taltirelin at two doses, all with and without coadministered trazodone. Trazodone was included due to clinical interest in the context of sleep apnea pharmacotherapy as it can suppress arousal without compromising pharyngeal muscle activity. These preclinical findings newly identify taltirelin as a stable upper airway-preferring respiratory stimulant with arousal properties. These traits have potential favorable relevance to some respiratory disorders but not others, as identified and discussed.
other
2025-05-01 | Reduced Sigh Breathing Frequency in Congenital Central Hypoventilation Syndrome: Identification of a Potential Biomarker and Therapeutic Target
Abstract Introduction: Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic disorder characterized by impaired chemosensitivity and autonomic regulation due to PHOX2B mutations, with resultant life-threatening hypercarbia and hypoxemia. Patients require lifelong artificial ventilatory life-support asleep (in more severe cases awake and asleep). Currently there are no known therapeutic targets for intervention to address their hypoventilation and impaired chemosensitivity. Anecdotal clinical observation suggests decreased sighing in CCHS. Sigh breaths are deep, long breaths occurring every ∼5 minutes in healthy adults, playing a critical role in maintaining alveolar patency. Sigh frequency increases during hypercarbia and hypoxia and is conserved across mammals. Most neurons in the retrotrapezoid nucleus that project to the sigh-producing preBötC, express PHOX2B (Li et al.). Consequently, we posit that CCHS-causing PHOX2B mutations disrupt the production of sighs, highlighting sighing as a potential biomarker and therapeutic target in CCHS. Like CCHS, Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) causes severe respiratory deficits requiring artificial ventilatory support. Unlike CCHS, ROHHAD is not linked to PHOX2B, and emerging evidence suggests an autoimmune mechanism. This study explored differences in sigh breathing between CCHS and ROHHAD to evaluate the impact of their distinct pathophysiology on sigh frequency. We hypothesized that sigh frequency would be diminished in CCHS but relatively normal in ROHHAD. Methods: Continuously recorded respiratory inductance plethysmography (RIP) and end-tidal CO₂ waveforms in awake spontaneously breathing, PHOX2B mutation-confirmed patients with CCHS and clinically-confirmed ROHHAD during clinical testing at Ann & Robert H. Lurie Children's Hospital, between January 2018 and December 2024, were included. A sigh breath was defined as a RIP sum channel amplitude ≥2× the 5 preceding stable tidal-breaths and followed by stable tidal-breathing or post-sigh apnea. Results: 116 hours of continuous recording from 10 CCHS (mean age 20.6yrs (range 9-35), 60% female) and 47 hours from 5 ROHHAD (mean age 16.5yrs (range 13-20), 40% female) patients were analyzed. Sigh frequency in CCHS was significantly reduced compared to ROHHAD patients (6.0 vs 12.4 sighs/hour; p<0.004). Conclusion: While sigh frequency appears to be conserved in ROHHAD, with frequency similar to published healthy controls (12/hour), CCHS patients have significantly diminished sigh frequency (6/hour). Findings of conserved sighing in ROHHAD and diminished sighing in CCHS support the role of PHOX2B-expressing retrotrapezoid nucleus neurons in sigh-generation and highlight their potential role in CCHS pathology. These findings underscore fundamental differences in respiratory control and provide insight into both potential biomarker and targeted therapeutic strategies.
2025-02-17 | PHOX2B -associated Congenital Central Hypoventilation Syndrome Revealed Upon Treatment With Dinutuximab-beta.
Alterations of PHOX2B function is associated with a wide range of diseases, including congenital central hypoventilation syndrome (CCHS) and neural crest-derived tumors, from low-grade (ganglioneuromas) to malignant forms (neuroblastomas). We report a case bearing a novel nonpolyalanine repeat PHOX2B pathogenic variant presenting both as high-risk neuroblastoma and late-onset CCHS. CCHS was revealed upon severe respiratory decompensation while the patient was administered the anti-GD2 antibody dinutuximab-beta, as part of neuroblastoma treatment. From this experience, we make propositions for the management of patients with high-risk neuroblastoma and a constitutional pathogenic variant of PHOX2B .
small molecules
2026-06-15 | Redefining PHOX2B-Related Neurodevelopmental Disorders as Circuitopathies: A New Paradigm in Autonomic Network Medicine.
The paired-like homeobox transcription factor 2B (PHOX2B) is a master regulator whose mutations cause a spectrum of severe neurological and neurodevelopmental disorders, including Congenital central hypoventilation syndrome (CCHS), Hirschsprung disease, and neuroblastoma. For decades, a central paradox has challenged the field: how can PHOX2B's seemingly restricted expression in the brainstem account for the broad, multi-system clinical phenotypes observed in patients? Here, we elucidate how this paradox has been resolved by recent methodological advances. We synthesize evidence from multiple complementary methodologies, including single-cell transcriptomics, spatial transcriptomics, and viral circuit tracing, which have revealed a vastly expanded PHOX2B anatomical landscape. These advances uncover previously unrecognized expression in caudal midbrain and higher brainstem regions, supportive glial populations, and peripheral components, extending far beyond classical autonomic nuclei. Furthermore, while mapping evidence predominantly derives from murine models, insights from human disease models, such as pluripotent stem cell-derived brainstem organoids, suggest that PHOX2B orchestrates integrated neuro-glial networks rather than isolated functions. Consequently, we propose reconceptualizing CCHS and related conditions as a class of multi-system network disorders termed PHOX2B circuitopathies. This circuitopathy framework critically differentiates primary circuit disruptions from secondary systemic cascades (such as hypoxia-induced cognitive deficits), providing a cohesive mechanistic basis for the constellation of cardiovascular, metabolic, and neurobehavioral symptoms. Crucially, it advances the field beyond the reactive, symptomatic management predominantly outlined in current clinical guidelines. By shifting the focus toward proactive, precision drug discovery and circuit-targeted strategies, this paradigm establishes a roadmap for developing network-based biomarkers and exploring novel disease-modifying interventions beyond conventional ventilatory support.
2026-05-18 | PHOX2B defects alter protein folding, cell-cycle, and mitochondrial pathways in an in vitro model of CCHS
Abstract Background Congenital Central Hypoventilation Syndrome (CCHS) is a rare autosomal dominant disorder caused by heterozygous mutations in the PHOX2B gene, leading to impaired ventilatory responses to hypoxia and hypercapnia. No pharmacological therapy exists, and patients rely on ventilatory support, tracheostomy, or diaphragmatic pacing. Most mutations are polyalanine expansions in exon 3, which mislocalize PHOX2B to the cytoplasm, disrupting the regulation of its transcriptional targets. Previous studies showed that geldanamycin and its derivative 17-AAG can partially rescue both the localization and the function of polyalanine expansion mutant PHOX2B. Nonetheless, downstream molecular effects of these mutations remain poorly understood. Methods The transcriptomic approach was applied to cells transiently expressing wild-type PHOX2B or the mutant carrying the most severe polyalanine expansion, to investigate the cellular consequences of whole transcripts deregulation caused by the PHOX2B mutation with or without 17-AAG treatments. Results Bioinformatic analysis allowed us to confirm the involvement of pathways already observed in polyalanine pathogenesis, such as protein folding and transcriptional repression, and to identify oxidative stress, mitochondrial dysfunction, and altered cell-cycle regulation as novel components of the PHOX2B+13Ala pathogenesis. Conclusions The RNA-sequencing approach recapitulates the molecular pathogenesis of PHOX2B polyalanine expansion mutations in CCHS and in vitro functional validations, thus confirming the suitability of this cellular model to study the molecular pathogenesis of the disease.
2026-03-13 | Sex Differences in the Effects of Etonogestrel on Respiratory Recovery in an In Vivo Rat Model of Central Chemoreflex Impairment.
Rhythmic breathing movements driven by the brainstem rely on chemosensory inputs to homeostatically adjust motor output to the prevailing metabolic demand. The central CO2 chemoreflex is a critical component of this neural circuitry, as defects in these sensors cause hypoventilation syndromes, which are typically difficult to manage pharmacologically. Progesterone has long been known to stimulate breathing in both sexes, and remarkably the progestinic metabolite, etonogestrel (ETO), enhances CO2 chemosensitivity in animal models and female patients affected by congenital central hypoventilation syndrome. However, ETO's mechanisms and sites of action remain unknown, and the experimental use of synthetic progestins has been met with mixed respiratory outcomes. In our recent work, we demonstrated that chronic ETO treatment improved the CO2 chemoreflex in female rats in which < 80% of chemoreceptor neurons comprising the retrotrapezoid nucleus (RTN) were eliminated. Since the progesterone receptor is widely expressed in both the male and female brain, we investigated whether ETO-induced CO2 chemoreflex recovery can be replicated in male rats in which RTN neurons are partially eliminated by the use of substance P-saporin toxin. Our results confirm dose-dependent impairment of the CO2 chemoreflex in both sexes following chemoreceptor lesion and corroborate the findings that ETO treatment restores ventilation in female rats with moderate-sized lesions. Interestingly, female respiratory recovery was associated with increased expression of the pH-sensing genes Gpr4 and Task2 in the RTN. In contrast, male rats failed to show significant recovery with ETO treatment, suggesting a sex-specific mechanism through which ETO promotes CO2 chemoreflex recovery.
2025-09-20 | Cesarean delivery with low-dose combined spinal epidural in a patient with congenital central hypoventilation syndrome: a case report.
Congenital central hypoventilation syndrome (CCHS), also known as Ondine's Curse, is an autonomic disorder resulting in an inadequate respiratory response to hypercapnia and hypoxia, especially during periods of decreased wakefulness. Patientswith CCHS are particularly sensitive to the effects of anesthetic medications, with increased risk for intraoperative events including hypotension, bradycardia, and hypoxemia. The current literature on the anesthetic management for patients with CCHS mainly described the use of general anesthesia, with few case reports describing neuraxial anesthesia. To our knowledge,this is the first case describing the anesthetic care for cesarean delivery of a patient with CCHS,with low-dose combined spinal epidural anesthesia. The patient had two previous cesarean deliveries with spinal anesthesia, complicated by hypotension and syncope secondary to autonomic dysfunction and/or neural-mediated syncope. This case highlights low-dose combined spinal epidural as a possible anesthetic approach in patients with CCHS, reducing the risk of hypotension and respiratory depression.
2025-05-01 | International CCHS Secure Health-hub Advancing Research Efforts (SHARE) Registry: Analysis of Patient-Reported Symptoms by PHOX2B Genotype in Congenital Central Hypoventilation Syndrome (CCHS)
Abstract RATIONALE: CCHS is a rare genetic disorder caused by variants of the PHOX2B gene. While the hallmark of CCHS is profound respiratory dysfunction requiring life-long artificial ventilatory support, PHOX2B variants also cause widespread, but less studied, autonomic nervous system (ANS) dysfunction. Most (∼90%) CCHS is caused by heterozygous in-frame expansion of the 20-alanine repeat region (PARM) of PHOX2B to between 24-33 repeats. The remaining CCHS cases are caused by a variety of other PHOX2B variants called non-PARMs (NPARMs), including missense, nonsense, and frameshift mutations. Both PARM and NPARM variants cause variable protein dysfunction, and a genotype-phenotype relationship has been reported for some primary symptoms of CCHS. The objective of this study was to assess symptoms and the relationship between PHOX2B genotypes and patient-reported dysfunction in all systems served by the ANS. Advancing understanding of symptom presentation and genotype-phenotype relationship for different organ systems is essential for developing targeted therapeutics and improving anticipatory management. METHODS: The CCHS SHARE Registry collects longitudinal data from individuals with PHOX2B mutation-confirmed CCHS, including information on 7 systems served by the ANS (cardiovascular, gastrointestinal, neurological, ophthalmologic, renal/urinary, respiratory, and sudomotor), totaling 64 possible ANS symptoms. 156 initial surveys were recorded. 19 were excluded due to incomplete surveys (137 analyzed). Participants were divided into moderate and severe PHOX2B genotype/variant groups based on established molecular data. Welch's test was utilized to compare between groupings for each organ system. Moderate genotypes were categorized as short PARMs (24-26 alanines) and NPARMs consisting of point mutations or frameshifts causing protein contraction. Severe genotypes were categorized as long PARMs (27-33 alanines) and NPARMs consisting of frameshifts causing expanded protein. RESULTS: Amongst all systems, 69% of individuals reported symptoms in the cardiovascular system, 63% in gastrointestinal, 65% in neurological, 66% in ophthalmologic, 15% in renal, 96% in respiratory, and 57% in sudomotor (Figure 1). Individuals with moderate PHOX2B genotypes reported less gastrointestinal, neurological, ophthalmologic, and respiratory symptoms than severe genotypes (p<0.05). No significant differences by PHOX2B group were observed in cardiovascular, renal, and sudomotor categories. CONCLUSION: The patient-reported impact of CCHS and specific PHOX2B genotype/variant varies by organ system. In addition to the typical focus on cardiorespiratory dysfunction in CCHS, these findings highlight additional systems/symptoms for future treatment, therapeutic development, and trial design. To improve our understanding of development, progression, and impact of autonomic symptoms in CCHS, longitudinal surveys should be captured and analyzed moving forward.
cell therapies
2023-11-13 | Carotid Body Dysfunction and Mechanisms of Disease.
Emerging evidence shows that the carotid body (CB) dysfunction is implicated in various physiological and pathophysiological conditions. It has been revealed that the CB structure and neurochemical profile alter in certain human sympathetic-related and cardiometabolic diseases. Specifically, a tiny CB with a decrease of glomus cells and their dense-cored vesicles has been seen in subjects with sleep disordered breathing such as sudden infant death syndrome and obstructive sleep apnea patients and people with congenital central hypoventilation syndrome. Moreover, the CB degranulation is accompanied by significantly elevated levels of catecholamines and proinflammatory cytokines in such patients. The intermittent hypoxia stimulates the CB, eliciting augmented chemoreflex drive and enhanced cardiorespiratory and sympathetic responses. High CB excitability due to blood flow restrictions, oxidative stress, alterations in neurotransmitter gases and disruptions of local mediators is also observed in congestive heart failure conditions. On the other hand, the morpho-chemical changes in hypertension include an increase in the CB volume due to vasodilation, altered transmitter phenotype of chemoreceptor cells and elevated production of neurotrophic factors. Accordingly, in both humans and animal models CB denervation prevents the breathing instability and lowers blood pressure. Knowledge of the morphofunctional aspects of the CB, a better understanding of its role in disease and recent advances in human CB translational research would contribute to the development of new therapeutic strategies.
2019-07-22 | Carotid Body Ablation: a New Target to Address Central Autonomic Dysfunction.
An abnormal heightened carotid body (CB) chemoreflex, which produces autonomic dysfunction and sympathetic overactivation, is the common hallmark of obstructive sleep apnea (OSA), resistant hypertension, systolic heart failure (HF), and cardiometabolic diseases. Accordingly, it has been proposed that the elimination of the CB chemosensory input to the brainstem may reduce the autonomic and cardiorespiratory alterations in sympathetic-associated diseases in humans. A growing body of evidence obtained in preclinical animal models support that an enhanced CB discharge produces sympathetic hyperactivity, baroreflex sensitivity and heart rate variability impairment, breathing instability, hypertension, and insulin resistance. The elimination CB chemosensory input reduces the sympathetic hyperactivity, the elevated arterial blood pressure in OSA and hypertensive models, abolishes breathing instability and improves animal survival in HF models, and restores insulin tolerance in metabolic models. These results highlight the role played by the enhanced CB drive in the progression of sympathetic-related diseases and support the proposal that the surgical ablation of the CB is useful to restore the autonomic balance and normal cardiorespiratory function in humans. Accordingly, the CB ablation has been used in pilot human studies as a therapeutic treatment for resistant hypertension and HF-induced sympathetic hyperactivity. In this review, I will discuss the supporting evidence for a crucial contribution of the CB in the central autonomic dysfunction and the pros and cons of the CB ablation as a therapy to revert autonomic overactivation. The CB ablation could be a useful method to reverse the enhanced chemoreflex in HF and severe hypertension, but caution is required before extensive use of bilateral CB ablation, which abolished ventilatory responses to hypoxia and may impair baroreceptor function.
2015-09-04 | Phrenic Nerve Stimulation: Technology and Clinical Applications
Phrenic nerve stimulation is a technique used to reanimate the diaphragm of patients with central nervous system etiologies of respiratory insufficiency. Current clinical indications include congenital central hypoventilation syndrome, spinal cord injury above C4, brain stem injury, and idiopathic severe sleep apnea. Presurgical evaluation ensures proper patient selection by validating the intact circuit from the phrenic nerve through alveolar oxygenation. The procedure involves placing leads around the phrenic nerves bilaterally and attaching these leads to radio receivers in a subcutaneous pocket. The rate and amplitude of the current is adjusted via an external radio transmitter. After implantation, each patient progresses through a conditioning phase that strengthens the diaphragm and progressively provides independence from the mechanical ventilator. Studies indicate that patients and families experience an improved quality of life and are satisfied with the results. Phrenic nerve stimulation provides a safe and effective means for reanimating the diaphragm for certain patients with respiratory insufficiency, providing independence from mechanical ventilation.
2003-06-20 | Carotid body denervation eliminates apnea in response to transient hypocapnia.
We determined the effects on breathing of transient ventilatory overshoots and concomitant hypocapnia, as produced by pressure support mechanical ventilation (PSV), in intact and carotid body chemoreceptor denervated (CBX) sleeping dogs. In the intact dog, PSV-induced transient increases in tidal volume and hypocapnia caused apnea within 10-11 s, followed by repetitive two-breath clusters separated by apneas, i.e., periodic breathing (PB). After CBX, significant expiratory time prolongation did not occur until after 30 s of PSV-induced hypocapnia, and PB never occurred. Average apneas of 8.4 +/- 1-s duration after a ventilatory overshoot required a decrease below eupnea of end-tidal Pco(2) 5.1 +/- 0.4 Torr below eupnea in the intact animal and 10.1 +/- 2 Torr in the CBX dog, where the former reflected peripheral and the latter central dynamic CO(2) chemoresponsiveness, as tested in the absence of peripheral chemoreceptor input. Hyperoxia when the dogs were intact shortened PSV-induced apneas and reduced PB but did not mimic the effects of CBX. We conclude that, during non-rapid eye movement sleep, carotid chemoreceptors are required to produce apneas that normally occur after a transient ventilatory overshoot and for PB.
gene therapies
2023-12-14 | Knockdown of PHOX2B in the retrotrapezoid nucleus reduces the central CO2chemoreflex in rats
ABSTRACT PHOX2B is a transcription factor essential for the development of the autonomic nervous system. Heterozygous mutations in the PHOX2B coding region are responsible for the occurrence of Congenital Central Hypoventilation Syndrome (CCHS), a rare neurological disorder characterised by inadequate chemosensitivity and life-threatening sleep-related hypoventilation. Animal studies suggest that chemoreflex defects are caused in part by the improper development or function of PHOX2B expressing neurons in the retrotrapezoid nucleus (RTN), a central hub for CO 2 chemosensitivity. Although the function of PHOX2B in rodents during development is well established, its role in the adult respiratory network remains unknown. In this study, we investigated whether reduction in PHOX2B expression in chemosensitive neuromedin-B (NMB) expressing neurons in the RTN altered respiratory function. Four weeks following local RTN injection of a lentiviral vector expressing the short hairpin RNA (shRNA) targeting Phox2b mRNA, a reduction of PHOX2B expression was observed in Nmb neurons compared to both naïve rats and rats injected with the non-target shRNA. PHOX2B knockdown did not affect breathing in room air or under hypoxia, but ventilation was significantly impaired during hypercapnia. PHOX2B knockdown did not alter Nmb expression but reduced the expression of both Task2 and Gpr4 , two CO 2 sensors in the RTN. We conclude that PHOX2B in the adult brain has an important role in CO 2 chemoreception and reduced PHOX2B expression in CCHS beyond the developmental period may contribute to the impaired central chemoreflex function.
2015-12-09 | Novel Mutation-Deletion in the PHOX2B Gene of the Patient Diagnosed with Neuroblastoma, Hirschsprung’s Disease, and Congenital Central Hypoventilation Syndrome (NB-HSCR- CCHS) Cluster
Neuroblastoma (NB), Hirschsprung disease (HSCR), Congenital Central Hypoventilation Syndrome (CCHS), clinically referred as the NB-HSCR-CCHS cluster, are genetic disorders linked to mutations in the PHOX2B gene on chromosome 4p12.The specific aim of this project is to define the PHOX2B gene mutations as the genomic basis for the clinical manifestations of the NB-HSCR-CCHS cluster.A one day old male patient presented to the Jagiellonian University Medical College (JUMC), American Children Hospital, neonatal Intensive Care Unit (ICU) due to abdominal distention, vomiting, and severe apneic episodes. With the preliminary diagnosis of the NB-HSCR-CCHS, the blood and tissue samples were acquired from the child, as well as from the child's parents. All procedures were pursued in accordance with the Declaration of Helsinki, with the patient's Guardian Informed Consent and the approval from the Institutional Review Board.Karyotyping was analyzed based upon Giemsa banding. The patient's genomic DNA was extracted from peripheral blood and amplified by polymerase chain reaction. Direct microfluidic Sanger sequencing was performed on the genomic DNA amplicons. These procedures were pursued in addition to the routine clinical examinations and tests.G-banding showed the normal 46 XY karyotype. However, genomic sequencing revealed a novel, heterozygous deletion (8 nucleotides: c.699-706, del8) in exon 3 of the PHOX2B gene on chromosome 4. This led to the frame-shift mutation and malfunctioning gene expression product.Herein, we report a novel PHOX2B gene mutation in the patient diagnosed with the NB-HSCR-CCHS cluster. The resulting gene expression product may be a contributor to the clinical manifestations of these genetic disorders. It adds to the library of the mutations linked to this syndrome. Consequently, we suggest that screening for the PHOX2B mutations becomes an integral part of genetic counseling, genomic sequencing of fetal circulating nucleic acids and / or genomes of circulating fetal cells prenatally, while preparing supportive therapy upon delivery, as well as on neonates' genomes of intubated infants, when breathing difficulties occur upon extubation. Further, we hypothesize that PHOX2B may be considered as a potential target for gene therapy.
2008-09-10 | A novel missense mutation in the PHOX2B gene is associated with late onset central hypoventilation syndrome.
Abstract We report the case of a 15‐month‐old male suffering from Late Onset Congenital Central Hypoventilation Syndrome and recto‐sigmoid Hirschsprung's disease, an association that has not been reported thus far. Nevertheless, our patient showed a missense mutation of the PHOX2B gene already known in isolated late onset central hypoventilation, resulting in a substitution of the Ala140 residue with a Glu residue (p.A140E). The present association of LO‐CHS and HSCR in a patient harboring a rare and atypical PHOX2B mutation allows to refine the mutational spectrum of this disease and suggests individualized ventilatory care along with specific surgical and oncological approaches. Pediatr Pulmonol. 2008; 43:1036–1039. © 2008 Wiley‐Liss, Inc.
proteins
2025-09-25 | Homozygous DBX1 Nonsense Variant in a Case of Atypical Congenital Central Hypoventilation.
Congenital central hypoventilation syndrome (CCHS) is a rare breathing disorder, predominantly caused by deleterious alterations in the PHOX2B gene. This report describes a rare case with PHOX2B-negative CCHS. We conducted a 10-year follow-up, including a clinical evaluation, polysomnography, brain MRI, analyses of blood and CSF, electrodiagnostic testing, and comprehensive genetic analyses including trio-whole exome sequencing (trio-WES). In a female patient necessitating artificial ventilation immediately postnatally, trio-WES revealed a homozygous deleterious variant in the candidate gene DBX1 (p.Ala114HisfsTer133), likely resulting in a complete loss of DBX1. Additional symptoms included central hypotonia, global developmental delay, seizures, and marked autoaggressive behavior. Dbx1 (developing brain homeobox 1) has an established critical role for mammalian inspiration, dramatically illustrated by the rapid postnatal demise of Dbx1 null mice because of asphyxia. Here, we describe the first human patient with atypical CCHS harboring a deleterious variant in the DBX1 gene. Surprisingly, over time, our patient gradually achieved the capability of ventilator-independent respiration, although with an irregular rhythm and only during the wake state. These findings suggest that DBX1-deficient individuals are able to install alternative neuronal circuits that maintain inspiratory drive during the wake state.
2022-10-27 | Thyrotropin-releasing hormone analog as a stable upper airway-preferring respiratory stimulant with arousal properties.
Taltirelin is a stable, brain-penetrating thyrotropin-releasing hormone (TRH) analog with minimal endocrine activity and potential respiratory stimulant properties. Taltirelin's receptor target shows high differential expression at the hypoglossal motor nucleus, and local taltirelin microperfusion into the hypoglossal motor nucleus causes sustained tongue motor activation compared with the transient activating effects of TRH itself. Here, we performed a randomized, within-subject, repeated-measures design over six separate study days (separated by at least 72 h) in chronically instrumented male (n = 10) and female (n = 9) rats to identify effects on sleep and breathing. Vehicle controls or taltirelin (0.1 and 1 mg/kg) with and without trazodone (30 mg/kg) were administered by intraperitoneal injection. Trazodone was included due to clinical interest in the context of sleep apnea pharmacotherapy as it can suppress arousal without compromising pharyngeal muscle activity. Systemically administered taltirelin (1 but not 0.1 mg/kg) increased tonic and within-breath phasic tonic muscle activity compared with vehicle controls (P ≤ 0.007), with little or no changes in diaphragm amplitude or respiratory rate. Taltirelin also suppressed nonrapid eye movement (non-REM) sleep and increased wakefulness (P ≤ 0.037). Other indices of taltirelin-induced central nervous system arousal included increased trapezius muscle tone in non-REM sleep and decreased total electroencephalogram power and δ (0.5-4 Hz) power (P ≤ 0.046). These effects were especially apparent in non-REM sleep and not prevented by trazodone. These preclinical findings identify taltirelin as a stable upper airway-preferring respiratory stimulant with arousal properties, traits that have potential favorable relevance to some respiratory disorders but not others.NEW & NOTEWORTHY One of the major goals for translational sleep science and medicine is to identify viable and tractable pharmacological targets for obstructive sleep apnea and other respiratory disorders of sleep or sedation. In the present preclinical study in rats, we performed a randomized, within-subject, repeated-measures design over six intervention study days in chronically instrumented male and female rats with systemic peripheral administration of vehicle controls, the thyrotropin-releasing hormone analog taltirelin at two doses, all with and without coadministered trazodone. Trazodone was included due to clinical interest in the context of sleep apnea pharmacotherapy as it can suppress arousal without compromising pharyngeal muscle activity. These preclinical findings newly identify taltirelin as a stable upper airway-preferring respiratory stimulant with arousal properties. These traits have potential favorable relevance to some respiratory disorders but not others, as identified and discussed.
other
2025-05-01 | Reduced Sigh Breathing Frequency in Congenital Central Hypoventilation Syndrome: Identification of a Potential Biomarker and Therapeutic Target
Abstract Introduction: Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic disorder characterized by impaired chemosensitivity and autonomic regulation due to PHOX2B mutations, with resultant life-threatening hypercarbia and hypoxemia. Patients require lifelong artificial ventilatory life-support asleep (in more severe cases awake and asleep). Currently there are no known therapeutic targets for intervention to address their hypoventilation and impaired chemosensitivity. Anecdotal clinical observation suggests decreased sighing in CCHS. Sigh breaths are deep, long breaths occurring every ∼5 minutes in healthy adults, playing a critical role in maintaining alveolar patency. Sigh frequency increases during hypercarbia and hypoxia and is conserved across mammals. Most neurons in the retrotrapezoid nucleus that project to the sigh-producing preBötC, express PHOX2B (Li et al.). Consequently, we posit that CCHS-causing PHOX2B mutations disrupt the production of sighs, highlighting sighing as a potential biomarker and therapeutic target in CCHS. Like CCHS, Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) causes severe respiratory deficits requiring artificial ventilatory support. Unlike CCHS, ROHHAD is not linked to PHOX2B, and emerging evidence suggests an autoimmune mechanism. This study explored differences in sigh breathing between CCHS and ROHHAD to evaluate the impact of their distinct pathophysiology on sigh frequency. We hypothesized that sigh frequency would be diminished in CCHS but relatively normal in ROHHAD. Methods: Continuously recorded respiratory inductance plethysmography (RIP) and end-tidal CO₂ waveforms in awake spontaneously breathing, PHOX2B mutation-confirmed patients with CCHS and clinically-confirmed ROHHAD during clinical testing at Ann & Robert H. Lurie Children's Hospital, between January 2018 and December 2024, were included. A sigh breath was defined as a RIP sum channel amplitude ≥2× the 5 preceding stable tidal-breaths and followed by stable tidal-breathing or post-sigh apnea. Results: 116 hours of continuous recording from 10 CCHS (mean age 20.6yrs (range 9-35), 60% female) and 47 hours from 5 ROHHAD (mean age 16.5yrs (range 13-20), 40% female) patients were analyzed. Sigh frequency in CCHS was significantly reduced compared to ROHHAD patients (6.0 vs 12.4 sighs/hour; p<0.004). Conclusion: While sigh frequency appears to be conserved in ROHHAD, with frequency similar to published healthy controls (12/hour), CCHS patients have significantly diminished sigh frequency (6/hour). Findings of conserved sighing in ROHHAD and diminished sighing in CCHS support the role of PHOX2B-expressing retrotrapezoid nucleus neurons in sigh-generation and highlight their potential role in CCHS pathology. These findings underscore fundamental differences in respiratory control and provide insight into both potential biomarker and targeted therapeutic strategies.
2025-02-17 | PHOX2B -associated Congenital Central Hypoventilation Syndrome Revealed Upon Treatment With Dinutuximab-beta.
Alterations of PHOX2B function is associated with a wide range of diseases, including congenital central hypoventilation syndrome (CCHS) and neural crest-derived tumors, from low-grade (ganglioneuromas) to malignant forms (neuroblastomas). We report a case bearing a novel nonpolyalanine repeat PHOX2B pathogenic variant presenting both as high-risk neuroblastoma and late-onset CCHS. CCHS was revealed upon severe respiratory decompensation while the patient was administered the anti-GD2 antibody dinutuximab-beta, as part of neuroblastoma treatment. From this experience, we make propositions for the management of patients with high-risk neuroblastoma and a constitutional pathogenic variant of PHOX2B .
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