Neonatal apneic phenotype in a murine congenital central hypoventilation syndrome model is induced through non‐cell autonomous developmental mechanisms
Diego Alzate‐CorreaJillian Mei‐ling LiuMikayla JonesTalita M. SilvaMichele Joana AlvesElizabeth BurkeJessica N. ZunigaBehiye KayaGiuliana ZazaMehmet AslanJessica BlackburnMarina Y. ShimadaSilvio A. Fernandes‐JuniorLisa A. BaerKristin I. StanfordAmber KemptonSakima A. SmithCaroline SzujewskiAbby SilbaughJean‐Charles ViemariAna C. TakakuraAlfredo J. GarciaThiago S. MoreiraCatherine CzeislerJosé Javier Otero
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Congenital central hypoventilation syndrome (CCHS) represents a rare genetic disorder usually caused by mutations in the homeodomain transcription factor PHOX2B. Some CCHS patients suffer mainly from deficiencies in CO2 and/or O2 respiratory chemoreflex, whereas other patients present with full apnea shortly after birth. Our goal was to identify the neuropathological mechanisms of apneic presentations in CCHS. In the developing murine neuroepithelium, Phox2b is expressed in three discrete progenitor domains across the dorsal-ventral axis, with different domains responsible for producing unique autonomic or visceral motor neurons. Restricting the expression of mutant Phox2b to the ventral visceral motor neuron domain induces marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, and preBötzinger complex dysfunction. This finding suggests that the observed apnea develops through non-cell autonomous developmental mechanisms. Mutant Phox2b expression in dorsal rhombencephalic neurons did not generate significant respiratory dysfunction, but did result in subtle metabolic thermoregulatory deficiencies. We confirm the expression of a novel murine Phox2b splice variant which shares exons 1 and 2 with the more widely studied Phox2b splice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutant Phox2b expression in the visceral motor neuron progenitor domain increases cell proliferation at the expense of visceral motor neuron development. We propose that visceral motor neurons may function as organizers of brainstem respiratory neuron development, and that disruptions in their development result in secondary/non-cell autonomous maldevelopment of key brainstem respiratory neurons.Keywords:
Forebrain
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Although rare, congenital hypoventilation syndromes profoundly impact affected patients and families. In some diseases, such as congenital central hypoventilation syndrome (CCHS), hypoventilation is a key presenting feature. Ventilatory abnormalities may not be immediately evident in other disease states. The clinical aspects of several pediatric hypoventilation syndromes, including CCHS, Chiari type II malformation, Prader-Willi syndrome, familial dysautonomia, and rapid onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation are presented.
Dysautonomia
Familial dysautonomia
Obesity hypoventilation syndrome
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Abstract Congenital central hypoventilation syndrome, which is related to abnormal autonomic control of breathing and typically manifests at birth, was recently associated with PHOX2B gene mutations. In contrast, central hypoventilation with later onset constitutes a poorly defined group of unknown etiology. Here, we report on the identification of a de novo heterozygous PHOX2B mutation in a patient with central hypoventilation manifesting in childhood. This finding suggests that some of these cases may be genetically determined and allelic to congenital central hypoventilation syndrome. Pediatr Pulmonol. 2004; 38:349–351. © 2004 Wiley‐Liss, Inc.
Etiology
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Hypercarbia
Hypoxia
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Congenital central hypoventilation syndrome is a disorder predisposed by a paired-like homebox PHOX2B gene. A mutation in the PHOX2B gene is a requisite when diagnosing congenital central hypoventilation syndrome. This mutation is identified in 93–100% of diagnosed patients. The mutation regarding this disorder affects the sensors, the central controller, and the integration of the signals within the central nervous system. This, inter alia, leads to insufficient ventilation and a decrease in PaO 2 , as well as an increase in PaCO 2 . Affected children are at risk during and after the neonatal period. They suffer from hypoventilation periods which may be present whilst sleeping only or in more severe cases when both asleep and awake. It is important for clinicians to perform an early diagnosis of congenital central hypoventilation in order to prevent the deleterious effects of hypoxaemia, hypercapnia, and acidosis on the neurocognitive and cardiovascular functions. Patients need long-term management and appropriate ventilatory support for improving the qualities of their lives. This paper provides a detailed review of congenital central hypoventilation syndrome, a congenital disorder that is genetic in origin. We describe the genetic basis, the wider clinical picture, and those challenges during the diagnosis and management of patients with this condition.
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The association of congenital central hypoventilation syndrome (also known as Ondine's curse) and Hirschsprung's disease is termed Haddad syndrome, which is an extremely rare disorder. Recent studies have described that the PHOX2B gene mutation was responsible for congenital central hypoventilation syndrome. We report a term newborn male infant with clinical manifestations of recurrent hypoventilation with hypercapnia and bowel obstructions. These clinical manifestations were compatible with congenital central hypoventilation syndrome and Hirschsprung's disease. PHOXB direct sequencing showed a heterozygous in-frame duplication of 21 bp leading to an expansion of +7 alanines within the 20 alanine stretch of the PHOX2B gene and confirmed our diagnosis. In addition to a high index of clinical suspicion, testing for PHOX2B mutation can assist iq the diagnosis of congenital central hypoventilation syndrome and in the prediction of disease progression. Infants presenting with congenital central hypoventilation syndrome should also be screened for Hirschsprung's disease.
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Congenital central hypoventilation syndrome most commonly presents in neonates with sleep related hypoventilation; late onset cases have occurred up to the age of 10 years. It is associated with mutations in the PHOX2B gene, encoding a transcription factor involved in autonomic nervous system development. The case history is described of an adult who presented with chronic respiratory failure due to PHOX2B mutation-associated central hypoventilation and an impaired response to hypercapnia.
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Congenital central hypoventilation syndrome is a rare genetic disorder in which autonomic control of breathing is disturbed, resulting in hypoventilaton, which is manifested with inability to maintain normal values of the partial pressure of carbon
dioxide. The syndrome is the result of gene mutations PHOX2B which are inherited in autosomal dominant way. The gene encodes a transcription factor that plays an important role in the regulation of neural crest migration and development of the
autonomic nervous system. The syndrome can be presented differently, often with early symptoms in the newborn period. The range of symptoms is different, but they all include acute or chronic hypoventilation with hypoxia and hypercarbia. In severe forms, there is a complete cessation of breathing in sleep, with severe hypoventilation in wakefulness. In addition to respiratory symptoms, cardiac disorders such as arrhythmias may occur. 5% of patients with CCHS will have tumors of neural crest cells. In 13-20% of all patients Hirschsprung's disease occurs, which has significantly more severe clinical pressentation in combination with CCHS. Genetic testing to PHOX2B gene mutations has the important role in the diagnosis. Mutations are found in 95% of patients. For the final diagnosis of hypoventilation it is necessary to observe the
physiology of breathing during wakefulness, REM and non-REM sleep. This is accomplished by polysomnography. Hypoventilation is confirmed with the pCO2 > 45 mmHg. In the treatment, is essential to provide adequate ventilation, with continuous monitoring. There are different forms of assisted ventilation, which should connect the best technology with the lifestyle and possibilities of parents. In Croatia, for now, CCHS is discovered and confirmed by genetic analysis in three patients. It is always necessary to think about the possibility of this disease. With early diagnosis and treatment, patients can grow and develop normally.
Periodic breathing
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