Central Hypoventilation Syndrome Research Articles

An insight into understanding ancient perspectives of respiratory health

This article explores the historical evolution of respiratory diseases highlighting its references in early Vedic texts such as the Rigveda, Yajurveda, Atharvaveda & Upanishads, offering insights into ancient understandings of respiratory diseases. It also delves into Ayurvedic treatments and practices detailed in classical texts like Veerasimhavalokana in relation to respiratory disease . Additionally, it covers traditional healing practices including Vedic mantras and their impact on human health. The narrative extends to folklore with the story of Ondine’s Curse, which inspired the term for central hypoventilation syndrome. By synthesizing these historical sources and practices, it underscores the depth of ancient knowledge in managing respiratory health and its influence on contemporary respiratory therapy.

Central hypoventilation syndrome with hyperinsulinism in infancy - management challenges

Central hypoventilation syndrome with hyperinsulinism in infancy - management challenges

Identification of a histone deacetylase inhibitor as a therapeutic candidate for congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome (CCHS), a rare genetic disease caused by heterozygous PHOX2B mutations, ischaracterized by life-threatening breathing deficiencies. PHOX2B is a transcription factor required for the specification of the autonomic nervous system, which contains, in particular, brainstem respiratory centers. In CCHS, PHOX2B mutations lead to cytoplasmic PHOX2B protein aggregations, thus compromising its transcriptional capability. Currently, the only available treatment for CCHS is assisted mechanical ventilation. Therefore, identifying molecules with alleviating effects on CCHS-related breathing impairments is of primary importance. A transcriptomic analysis of cells transfected with different PHOX2B constructs was used to identify compounds of interest with the CMap tool. Using fluorescence microscopy and luciferase assay, the selected molecules were further tested invitro for their ability to restore the nuclear location and function of PHOX2B. Finally, an electrophysiological approach was used to investigate exvivo the effects ofthe most promising molecule on respiratory activities of PHOX2B-mutant mouse isolated brainstem. The histone deacetylase inhibitor SAHA was found to have low toxicity invitro, to restore the proper location and function of PHOX2B protein, and to improve respiratory rhythm-relatedparameters exvivo. Thus, our results identify SAHA as a promising agent to treat CCHS-associated breathing deficiencies.

A new nonsense pathogenic variant in exon 1 of PHOX2B leads to the diagnosis of congenital central hypoventilation syndrome with intra-familial variability

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of the autonomic nervous system resulting in decreased brain sensitivity to hypercapnia and hypoxia characterized by a genetic abnormality in the pair-like homeobox 2B (PHOX2B) gene. Most patients have a heterozygous expansion of the polyalanine repeat in exon 3 (PARM), while 10 % of patients have non-PARM (NPARM) mutations that can span the entire gene. The majority of pathogenic variants are de novo, but variants with incomplete penetrance can be identified in the heterozygous state. In the present report, CCHS was diagnosed in a symptomatic 3-month-old infant with neonatal respiratory distress. Genetic analysis revealed a new mutation in exon 1 of the PHOX2B gene – p.Ser28* (c.83C>G) – which was further identified in two family members, one minimally symptomatic and one asymptomatic. The identification of this new mutation supports the importance of sequencing the entire gene even when the classic PARM mutation is not found and highlights the phenotypic variability of CCHS.

Autism spectrum disorder in young patients with congenital central hypoventilation syndrome: role of the autonomic nervous system dysfunction

BackgroundCongenital central hypoventilation syndrome (CCHS) is a rare condition characterized by alveolar hypoventilation and autonomic nervous system (ANS) dysfunction requiring long-term ventilation. CCHS could constitute a risk factor of autism spectrum disorder (ASD) due to birth injury related to respiratory failure, which remains to be determined. ANS dysfunction has also been described in ASD and there are indications for altered contribution of ANS-central nervous system interaction in processing of social information; thus, CCHS could be a risk factor for ASD based on pathophysiological background also. Our study aimed to determine the prevalence of ASD among CCHS patients, identify risk factors, and explore the relationship between the ANS, evaluated by heart rate variability indices, and adaptative functioning.ResultsOur retrospective study, based on the analysis of records of a French national center of patients with CCHS under 20 years of age, determined that the prevalence of ASD (diagnosed by a psychiatrist, following the criteria of DSM-4 or DSM-5) was 6/69 patients, 8.7% (95% confidence interval: 3.3–18.0%). In a case (CCHS with ASD, n = 6) – control (CCHS without ASD, n = 12) study with matching on sex, longer neonatal hospitalization stay and glycemic dysfunction were associated with ASD. Adaptative functioning was assessed using Vineland Adaptative behavioral scales (VABS) and heart rate variability indices (including daytime RMSSD as an index of parasympathetic modulation) were obtained from ECG Holter performed the same day. In 19 young subjects with CCHS who had both ECG Holter and VABS, significant positive correlations were observed between RMSSD and three of four sub-domains of the VABS (communication: R = 0.50, p = 0.028; daily living skills: R = 0.60, p = 0.006; socialization: R = 0.52, p = 0.021).ConclusionOur study suggests a high prevalence of ASD in patients with CCHS. Glycemic dysfunction and longer initial hospitalization stays were associated with ASD development. A defect in parasympathetic modulation was associated with worse adaptative functioning.

Tracheostomy and inpatient outcomes among children with congenital central hypoventilation syndrome: A kids' inpatient database study.

Congenital central hypoventilation syndrome (CCHS) is a rare disease predisposing children to respiratory failure due to abnormal ventilatory drive. Variability in hypoventilation and respiratory support need have been reported. We aim to identify clinical variables associated with incident tracheostomy and common etiologies of hospitalization among children with CCHS. Hospital discharge records were obtained for children (<21 years) with CCHS hospitalized between 2006 and 2019 from the Kid's Inpatient Database. Primary diagnostic categories for hospitalizations with CCHS were summarized. Multivariable logistic regression models were used to explore risk factors associated with incident tracheostomy. Among 2404 hospitalizations with CCHS, 133 (5.5%) had incident tracheostomy, 1230 (51.2%) had established tracheostomy, and 1041 (43.3%) had no tracheostomy. Compared with children without tracheostomy, those with incident tracheostomy were younger, had a history of prematurity, congenital heart disease, laryngeal, glottic, and subglottic stenosis (LGSS), congenital airway anomalies, neuromuscular weakness, gastroesophageal reflux disease. Children without tracheostomy had higher mortality than those with tracheostomy status (2.19% vs. 0.66%). Multivariable-adjusted analyses showed that incident tracheostomy was associated with infancy (0-1 years), neuromuscular weakness, and congenital heart disease. Most common diagnostic categories include (1) diseases of the respiratory system (30.23%), (2) injury and poisoning (9.35%), and (3) diseases of the nervous system and sense organs (6.71%). Children with CCHS who received incident tracheostomy are more likely to be younger and with LGSS, neuromuscular weakness and congenital heart disease. Clinicians should be aware of these risk factors representing more severe CCHS with earlier manifestation needing tracheostomy. Higher mortality among nontracheostomy group highlights the need for considering tracheostomy in caring for children with CCHS.

Maxillary Hypoplasia and Non-Invasive Ventilation: Literature Review and Proposed New Treatment Protocol.

The impact of non-invasive ventilation (NIV) on pediatric maxillary growth is a subject of ongoing research considering its increased use in the pediatric population due to technological advancements and broader indications. This review examines the existing literature, encompassing original articles, case reports, and reviews, to evaluate the effects of NIV on maxillary development and explore potential treatment options. Although the majority of studies agree on the adverse effects of prolonged NIV on maxillary development, techniques for its correction remain understudied. Introducing a novel treatment protocol, we addressed the challenge of correcting severe midfacial hypoplasia in a child with congenital central hypoventilation syndrome (CCHS) undergoing NIV therapy, thus sidestepping the necessity for osteotomies. This proposed protocol holds promise in correcting the adverse impact of NIV on maxillary growth, emphasizing the need for further exploration into innovative treatment modalities.

Neuroblastoma Predisposition and Surveillance-An Update from the 2023 AACR Childhood Cancer Predisposition Workshop.

Genetic predisposition to neuroblastoma (NB) is relatively rare. Only 1% to 2% of patients have a family history of NB, 3% to 4% of cases present with bilateral or multifocal primary tumors, and occasional patients have syndromes that are associated with increased NB risk. Previously, a germline pathogenic variant (GPV) in PHOX2B was associated with Hirschsprung disease and congenital central hypoventilation syndrome. Recently, certain GPVs were shown to be responsible for congenital central hypoventilation syndrome and NB predisposition. Also, several groups determined that activating GPVs in ALK accounted for a substantial number of familial NB. Finally, there are additional genes and cancer predisposition syndromes in which NB occurs with greater frequency or that have been associated with NB based on genome-wide association studies. We review the evidence for all these genes and whether there is sufficient evidence to warrant surveillance. We review recommended surveillance for hereditary patients with NB, including minor updates to surveillance recommendations that were published previously in 2017.

Dyspnea in young subjects with congenital central hypoventilation syndrome

Dyspnea in young subjects with congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome in korea: 20 years of clinical observation and evaluation of the ventilation strategy in a single center

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by hypoventilation due to impaired breathing control by the central nervous system and other symptoms of autonomic dysfunction. Mutations in paired-like homeobox 2 B (PHOX2B) are responsible for most cases of CCHS. Patients with CCHS have various phenotypes and severities, making the diagnosis difficult. This study aimed to present a comprehensive single-center experience of patients with CCHS, including key clinical features, treatment strategies, and outcomes. A retrospective chart review was performed for patients diagnosed with CCHS between January 2001 and July 2023 at Seoul National University Children’s Hospital. Finally, we selected 24 patients and collected their demographic data, genotypes, ventilation methods, and clinical features related to autonomic dysfunction. The relationship between the clinical manifestations and genotypes was also examined. All patients used home ventilators, and tracheostomy was performed in 87.5% of patients. Fifteen (62.5%) patients had constipation and nine (37.5%) were diagnosed with Hirschsprung disease. Arrhythmia, endocrine dysfunction, and subclinical hypothyroidism were present in nine (37.5%), six patients (25.0%), and two patients (16.7%), respectively. A significant number of patients exhibited neurodevelopmental delays (19 patients, 79.2%). There was a correlation between the phenotype and genotype of PHOX2B in patients with CCHS. (r = 0.71, p < 0.001). Conclusion: There was a positive correlation between paired-like homeobox 2 B mutations (especially the number of GCN repeats in the polyalanine repeat mutations sequence) and clinical manifestations. This study also demonstrated how initial treatment for hypoventilation affects neurodevelopmental outcomes in patients with CCHS.What is Known:• Congenital central hypoventilation syndrome is a rare genetic disorder characterized by hypoventilation and dysfunction of autonomic nervous system.• The disease-defining gene of CCHS isPHOX2Bgene – most of the cases have heterozygous PARMs and the number of GCN triplets varies among the patients(20/24 – 20/33).What is New:• We have noted in the Korean patients with CCHS that there is a correlation between genotype (number of GCN repeats) and severity of phenotype.• National support for rare diseases allowed for a prompter diagnosis of patients with CCHS in Korean population.

Knockdown of PHOX2B in the retrotrapezoid nucleus reduces the central CO2 chemoreflex in rats

PHOX2B is a transcription factor essential for the development of different classes of neurons in the central and peripheral 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 CO2 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 naive 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 it was associated with reduced expression of both Task2 and Gpr4, two CO2/pH sensors in the RTN. We conclude that PHOX2B in the adult brain has an important role in CO2 chemoreception and reduced PHOX2B expression in CCHS beyond the developmental period may contribute to the impaired central chemoreflex function.

Knockdown of PHOX2B in the retrotrapezoid nucleus reduces the central CO2 chemoreflex in rats.

PHOX2B is a transcription factor essential for the development of different classes of neurons in the central and peripheral 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 CO2 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 naive 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 it was associated with reduced expression of both Task2 and Gpr4, two CO2/pH sensors in the RTN. We conclude that PHOX2B in the adult brain has an important role in CO2 chemoreception and reduced PHOX2B expression in CCHS beyond the developmental period may contribute to the impaired central chemoreflex function.

The progestinic drug, etonogestrel, rescues breathing in a rodent model of central chemoreflex impairment

The central CO2-chemoreflex is crucial in regulating breathing, providing stimulation at rest and during challenges to homeostasis. The retrotrapezoid nucleus (RTN), located in the ventral brainstem, is essential to this process. Impaired RTN function is linked to hypoventilation syndromes, including congenital central hypoventilation syndrome (CCHS) characterized by apnea and blunted responsiveness to inhaled CO2. Intriguingly, progestins stimulate breathing and CO2-chemoreflexes, and the high-affnity ligand etonogestrel (ETO) has been proposed as a treatment option in CCHS. Our objectives were to address two important gaps-in-knowledge: 1) assess ETO’s ability to “rescue” breathing in a rat model of central CO2-chemoreflex impairment, and 2) determine ETO’s site of action. We generated a model of CO2-chemoreflex impairment in adult female Sprague-Dawley rats using targeted injections of substance-P conjugated saporin toxin. Resulting RTN lesions were classified by the number of surviving chemosensitive neurons vs. non-surgical controls. We first administered systemic ETO (acute/vehicle:1h; or chronic/sham: 28 days) and measured resting ventilation and chemoreflexes (hypercapnia, 7.2% CO2; hypoxia, 10% O2) using whole-body plethysmography. In separate ongoing experiments, ETO was infused directly into target brain regions expressing progesterone receptors. We observed a positive relationship between lesion size and CO2-chemoreflex impairment (hypoxic response was intact). Twenty-one days of systemic ETO reversed CO2-impairment selectively in rats with moderate RTN lesions; large-lesion rats were refractory to ETO’s effects. These data suggest that ETO may enhance the CO2-chemoreflex by inducing neuroplasticity in brain structures with connectivity to surviving RTN chemosensitive neurons. Experiments are ongoing to parse out the site of ETO’s restorative action in the brain. T.A.J.:Canadian Lung Association BaO Fellowship, Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowships. S.C.: Canadian Lung Association BaO Fellowship. S.P.: Women and Children’s Health Research Institute Innovation Grant, CIHR Project scheme grant. Nexplanon was kindly donated by Merck through the Investigator-Initiated Study Program (IISP # 55869; SP). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Clinical and Genetic Correlation in Neurocristopathies: Bridging a Precision Medicine Gap.

Neurocristopathies (NCPs) encompass a spectrum of disorders arising from issues during the formation and migration of neural crest cells (NCCs). NCCs undergo epithelial-mesenchymal transition (EMT) and upon key developmental gene deregulation, fetuses and neonates are prone to exhibit diverse manifestations depending on the affected area. These conditions are generally rare and often have a genetic basis, with many following Mendelian inheritance patterns, thus making them perfect candidates for precision medicine. Examples include cranial NCPs, like Goldenhar syndrome and Axenfeld-Rieger syndrome; cardiac-vagal NCPs, such as DiGeorge syndrome; truncal NCPs, like congenital central hypoventilation syndrome and Waardenburg syndrome; and enteric NCPs, such as Hirschsprung disease. Additionally, NCCs' migratory and differentiating nature makes their derivatives prone to tumors, with various cancer types categorized based on their NCC origin. Representative examples include schwannomas and pheochromocytomas. This review summarizes current knowledge of diseases arising from defects in NCCs' specification and highlights the potential of precision medicine to remedy a clinical phenotype by targeting the genotype, particularly important given that those affected are primarily infants and young children.

The Influence of Neurotrophins on the Brain-Lung Axis: Conception, Pregnancy, and Neonatal Period.

Neurotrophins (NTs) are four small proteins produced by both neuronal and non-neuronal cells; they include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). NTs can exert their action through both genomic and non-genomic mechanisms by interacting with specific receptors. Initial studies on NTs have identified them only as functional molecules of the nervous system. However, recent research have shown that some tissues and organs (such as the lungs, skin, and skeletal and smooth muscle) as well as some structural cells can secrete and respond to NTs. In addition, NTs perform several roles in normal and pathological conditions at different anatomical sites, in both fetal and postnatal life. During pregnancy, NTs are produced by the mother, placenta, and fetus. They play a pivotal role in the pre-implantation process and in placental and embryonic development; they are also involved in the development of the brain and respiratory system. In the postnatal period, it appears that NTs are associated with some diseases, such as sudden infant death syndrome (SIDS), asthma, congenital central hypoventilation syndrome (CCHS), and bronchopulmonary dysplasia (BPD).

Recurrence of CCHS-associated PHOX2B Poly-Alanine expansion variant due to paternal mosaicism

BackgroundPaired-like Homeobox 2B (PHOX2B) is considered the causative gene of Congenital Central Hypoventilation Syndrome (CCHS), a dominant genetic disorder characterized by impaired central respiratory control and subsequent hypoventilation during sleep. MethodsHerein, we present a family with recurrent severe CCHS. The potential causative genetic variant was confirmed through Whole-Exome Sequencing (WES), Sanger sequencing, and droplet digital PCR (ddPCR). Furthermore, prenatal diagnosis was performed on the proband's mother at 20 weeks of her fourth pregnancy upon request. ResultsThe proband and her brother were both carriers of the PHOX2B polyalanine expansion variant: c.744_758dupCGCGGCAGCGGCGGCGGCGGC. Sanger sequencing revealed that the proband's father had a small variant peak in the gene position, implying potential somatic mosaicism. In addition, ddPCR results showed that the proband's father had germline mosaicism, with a mosaicism proportion of 14.3%. Notably, the detect p.(Ala241[26]) variant was not detected in the fetus. ConclusionsThese findings have important implications for improving genetic counseling of CCHS families as they suggest that even parents without CCHS symptoms may have somatic chimerism, necessitating careful genetic counseling and consideration of prenatal testing for subsequent pregnancies.

Congenital central hypoventilation syndrome: A rare disorder in a neonate

No abstract available

Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions

Abnormal trinucleotide repeat expansions alter protein conformation causing malfunction and contribute to a significant number of incurable human diseases. Scarce structural insights available on disease-related homorepeat expansions hinder the design of effective therapeutics. Here, we present the dynamic structure of human PHOX2B C-terminal fragment, which contains the longest polyalanine segment known in mammals. The major α-helical conformation of the polyalanine tract is solely extended by polyalanine expansions in PHOX2B, which are responsible for most congenital central hypoventilation syndrome cases. However, polyalanine expansions in PHOX2B additionally promote nascent homorepeat conformations that trigger length-dependent phase transitions into solid condensates that capture wild-type PHOX2B. Remarkably, HSP70 and HSP90 chaperones specifically seize PHOX2B alternative conformations preventing phase transitions. The precise observation of emerging polymorphs in expanded PHOX2B postulates unbalanced phase transitions as distinct pathophysiological mechanisms in homorepeat expansion diseases, paving the way towards the search of therapeutics modulating biomolecular condensates in central hypoventilation syndrome.

Delineation of ADPRHL2 Variants: Report of Two New Patients with Review of the Literature.

ADPRHL2 is involved in posttranslational modification and is known to have a role in physiological functions such as cell signaling, DNA repair, gene control, cell death, and response to stress. Recently, a group of neurological disorders due to ADPRHL2 variants is described, characterized by childhood-onset, stress-induced variable movement disorders, neuropathy, seizures, and neurodegenerative course. We present the diagnostic pathway of two pediatric patients with episodic dystonia and ataxia, who later had a neurodegenerative course complicated by central hypoventilation syndrome due to the same homozygous ADPRHL2 variant. We conducted a systematic literature search and data extraction procedure following the Preferred Reporting Items for Systematic Review and Meta-Analysis 2020 statement in terms of patients with ADPRHL2 variants, from 2018 up to 3 February, 2023. In total, 12 articles describing 47 patients were included in the final analysis. Median age at symptom onset was 2 (0.7-25) years, with the most common presenting symptoms being gait problems (n = 19, 40.4%), seizures (n = 16, 34%), ataxia (n = 13, 27.6%), and weakness (n = 10, 21.2%). Triggering factors (28/47; 59.5%) and regression (28/43; 60.4%), axonal polyneuropathy (9/23; 39.1%), and cerebral and cerebellar atrophy with white matter changes (28/36; 77.7%) were the other clues. The fatality rate and median age of death were 44.6% (n = 21) and 7 (2-34) years, respectively. ADPRHL2 variants should be considered in the context of episodic, stress-induced pediatric and adult-onset movement disorders and seizures.

Monitoring of physiologic features and treatment aspects of children on home invasive mechanical ventilation.

Pediatric home invasive mechanical ventilation patients are a small but resource-intensive cohort, requiring close monitoring and multidisciplinary care. Patients are often dependent on their ventilator for life support, with any significant complications such as equipment failure, tracheostomy blockage, or accidental decannulation becoming potentially life-threatening if not identified quickly. This review discusses the indications and variations in practice worldwide, in terms of models of care, including home care provision, choice of equipment, and monitoring. With advances in technology, optimal monitoring strategies for home, continue to be debated: In-built ventilator alarms are often inadequately sensitive for pediatric patients, necessitating additional external monitoring devices to minimize risk. Pulse oximetry has been the preferred monitoring modality at home, though in some special circumstances such as congenital central hypoventilation syndrome, home carbon dioxide monitoring may be important to consider. Children should be under regular follow-up at specialist respiratory centers where clinical evaluation, nocturnal oximetry, and capnography monitoring and/or poly(somno)graphy and analysis of ventilator download data can be performed regularly to monitor progress. Recent exciting advances in technology, particularly in telemonitoring, which have potential to hugely benefit this complex group of patients are also discussed.