The new england journal o f medicine n engl j med 373;6 August 6, 2015 573 Elizabeth G. Phimister, Ph.D., Editor Ondine Undone Eugene Nattie, M.D. Imagine having to remember to breathe, as in the myth of Ondine, who was cursed to think consciously of breathing even in sleep. The term “Ondine’s curse” has been applied to the congenital central hypoventilation syndrome (CCHS), a condition in which children hypoventilate and retain carbon dioxide (especially in sleep), have prominent apneas, and have a severely diminished carbon dioxide chemoreflex (the increase in breathing in response to elevated carbon dioxide levels). The cause of CCHS is a mutation in PHOX2B that affects a single amino acid in the PHOX2B protein. When this mutation is introduced into a mouse, much of the syndrome related to breathing is recapitulated. PHOX2B is expressed in the retrotrapezoid nucleus, a small cluster of neurons lying beneath the ventral surface of the medulla that does not develop properly in mice carrying mutated Phox2b. This nucleus of cells has been a focus of attention as an important central chemoreceptor site; disruption of its function by many approaches substantially reduces the carbon dioxide chemoreflex (Fig. 1). The ability to improve the chemosensory function of these neurons could provide a new therapy for persons with CCHS, who now undergo lifelong ventilator support during sleep. Recently, Kumar et al.1 asked whether a pHsensitive G-protein–coupled receptor (GPCR) was involved in the detection of carbon dioxide and pH in neurons of the retrotrapezoid nucleus. This GPCR is a member of a family of pH-sensitive receptors that detect carbon dioxide in insects and pH in mammalian kidney. Kumar et al. found that knockout of a GPCR protein, GPR4 (but not two other GPCR proteins), reduced the carbon dioxide chemoreflex in mice by more than 50% (Fig. 1), increased the number of apneas, and reduced the activation by carbon dioxide, in vitro, of chemosensitive neurons from the retrotrapezoid nucleus. They were then able to restore the carbon dioxide chemoreflex and reduce the frequency of apnea in these mice by restoring GPR4 activity in the neurons of the retrotrapezoid nucleus. They further elucidated the chemoreflex mechanism by knocking out the genes encoding GPR4 and TASK-2 (TASK-2 is a potassium channel previously shown to mediate the pH sensitivity of some of the neurons in the retrotrapezoid nucleus). The chemoreflex in mice with the double-knockout genotype was virtually abolished (Fig. 1), which strongly suggests that both genes are independently key to successful chemosensing. The active sensing site of GPR4 is made up of histidine residues (Fig. 1).2 This is of particular interest, given that the dissociation constant representing the dissociation of histidine protons varies with temperature, as do the pH of blood in cold-blooded animals in vivo and the pH of blood in humans in vitro. Thus, with changes in temperature, pH may change dramatically, but the fractional dissociation of histidine remains constant, as does the protein configuration and function. In contrast, at a constant temperature, changes in pH affect histidine dissociation, protein configuration, and in this case, breathing. Retrotrapezoid-nucleus chemosensing through histidines in GPR4 appears to be an evolutionarily old and conserved mechanism; histidine residues of GPR4 at the extracellular surface can be viewed as the pH-sensing amino acids. (TASK-2 channels sense pH through different amino acids.) Is there a therapeutic potential that might emerge from this work? It would have been of interest to examine breathing control in these mice during sleep, the time of greatest risk of apnea and death in patients with CCHS. Gene therapy to enhance retrotrapezoid-nucleus chemosensing and therefore GPR4 function is conceptually plausible and could be very helpful to The New England Journal of Medicine Downloaded from at UAB LISTER HILL LIBRARY on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. The new england journal o f medicine 574 n engl j med 373;6 August 6, 2015 BRAIN STEM CYTOPLASM EXTRACELLULAR SPACE PONS RETROTRAPEZOID NUCLEUS ↑CO2 and ↓pH H+ ↑CO2 and ↓pH ↑CO2 and ↓pH H+ H+ Histidine K+ K+ K+ K+ 4 2 0 0 5 K+ K+ K+ K+ Axon Dendrite Lateral hypothalamus VENTRAL MEDULLARY SURFACE VENTRAL MEDULLARY SURFACE VII Nucleus tractus solitarius Retrotrapezoid nucleus Facial-nerve nucleus Locus ceruleus VENTRAL MEDULLARY Normal retrotrapezoid neuron Retrotrapezoid neuron with GPR4 knockout Retrotrapezoid neuron with GPR4 knockout and TASK-2 knockout Lateral GPR4 GPR4 TASK-2 TASK-2 channel GPR4 TASK-2 channel GPR4 TASK-2 channel MEDULLA Normal retrotrapezoid neuron GPR4 TASK-2 CEREBRAL CORTEX THALAMUS MIDBRAIN SAGITTAL SECTION OF MAMMALIAN BRAIN CEREBELLUM CELL MEMBRANE A B C Inspired CO2 (%) Inspired CO2 (%) Inspired CO2 (%) VE (ml/min/g) 4 2 0 0 5 VE (ml/min/g) 4 2 0 0 5 VE (ml/min/g) Normal GPR4 knockout GPR4 and TASK-2 knockout Figure 1. The Drive to Breathe. The retrotrapezoid nucleus central chemoreceptor neurons detect pH and carbon dioxide (CO2) through histidine residues in GPR4 and TASK-2. Panel A shows a sagittal section of the mammalian hindbrain and highlights the location of some putative central chemoreceptor sites (in red), with emphasis on the retrotrapezoid nucleus. Panel B is a schematic drawing of a neuron of the retrotrapezoid nucleus with GPR4 receptors and TASK-2 channels, located on the cell membrane and identified in a study by Kumar et al.,1 as detectors of CO2 and pH. In Panel C, the cell membranes of a normal retrotrapezoid neuron, of a retrotrapezoid neuron with knockout of GPR4, and of a retrotrapezoid neuron with knockout of both GPR4 and TASK-2 are shown. In the normal ventilatory CO2 chemoreflex, increases in inspired CO2 lead to increases in ventilation (VE) through stimulation of chemoreceptors. In mice with knockout of GPR4 only, the CO2 chemoreflex is reduced by approximately 50%; in mice with knockout of both GPR4 and TASK-2, the CO2 chemoreflex is nearly absent. The New England Journal of Medicine Downloaded from at UAB LISTER HILL LIBRARY on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. Clinical Implications of Basic Research n engl j med 373;6 August 6, 2015 575 these patients, although there would be substantive technical challenges to realizing such an approach. Are these findings relevant to other disorders with altered central chemoreception, such as sleep apnea and chronic obstructive pulmonary disease? Here, the picture is a bit less clear. In addition to the retrotrapezoid nucleus, there are other sites of the central nervous system that participate in central chemoreception (Fig. 1). For example, acute chemogenetic silencing of medullary serotonergic neurons3 also reduces the carbon dioxide chemoreflex by approximately 50%. Furthermore, mice that are deficient in orexin4 have a reduced carbon dioxide chemoreflex during wakefulness. It remains unclear how the neural network involved in chemoreception is organized, what sensing mechanisms are in operation at other sites, and which sites participate in sleep when the carbon dioxide chemoreflex response is normally suppressed (and especially suppressed in patients with CCHS). Nevertheless, the firm identification of the protein and amino acid that detects carbon dioxide and pH in the neurons of the retrotrapezoid nucleus is an exciting finding that moves us one step closer to a potential therapy for disordered breathing in CCHS and may prove relevant to the modification of central chemoreception in other disease states. Disclosure forms provided by the author are available with the full text of this article at From the Geisel School of Medicine at Dartmouth College, Lebanon, NH. 1. Kumar NN, Velic A, Soliz J, et al. Regulation of breathing by CO2 requires the proton-activated receptor GPR4 in retrotrapezoid nucleus neurons. Science 2015;348:1255-60. 2. Ludwig MG, Vanek M, Guerini D, et al. Proton-sensing G-protein-coupled receptors. Nature 2003;425:93-8. 3. Ray RS, Corcoran AE, Brust RD, et al. Impaired respiratory and body temperature control upon acute serotonergic neuron inhibition. Science 2011;333:637-42. 4. Deng BS, Nakamura A, Zhang W, Yanagisawa M, Fukuda Y, Kuwaki T. Contribution of orexin in hypercapnic chemoreflex: evidence from genetic and pharmacological disruption and supplementation studies in mice. J Appl Physiol (1985) 2007;103: 1772-9. DOI: 10.1056/NEJMcibr1507734 Copyright © 2015 Massachusetts Medical Society. 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Hello, my name is Heather. I am a brain tumor survivor from the early‘80’s. I am also a stroke survivor with Spinocerebellar Ataxia, and a condition of disordered breathing referred to as Ondine’s Curse. “Cursed” is not how I choose to look at my life. The tumor and stroke took away abilities I had previously taken for granted, but I realize how fortunate I am to be alive. The type of “Brainstem Glioma” that I had would not have been operable 20 years earlier. I received great care at the University of Virginia Hospital and later at a children’s rehabilitation center in Charlottesville, Virginia. Respiratory failure had landed me in the surgical intensive care unit where I narrowly missed having a tenjoyed. My life had turned upside down, but I focused on the things I could still do. It hasn’t been easy because the “movement disorder” or ataxia I have is degenerative. After high school, I went on to college where I graduated Suma Cum Laude from Shenandoah University. I have a diploma in Nutritional Therapy and I have started a blog at Currently, I planning to write a book about growing up with disabilities.

Where There’s a Will, There’s a Way by Heather Y

September 25th is designated International Ataxia Awareness Day (IAAD). For those of you unfamiliar with the different types of the word Ataxia it is not a specific diagnosis, but rather a group of related symptoms (i.e. tremor, in coordination, etc.) characteristic of an underlying disorder whether hereditary (i.e. Freidrich’s Ataxia) or acquired as a symptom(s) of an underlying disorder. IAAD is an opportunity for the Ataxia community to spread awareness and I would like to share a personal experience. It was a crisp fall day, and I had decided to take the dog out before it rained. The sky was a bit overcast, but the weather forecast was for showers in the late afternoon. It was only 11:00 AM, but I donned my floppy purple hat and sunglasses, anyway. I opened the screen door and bounded out onto the porch, as the door slammed shut behind me. I never gave it a second thought, that is, until I discovered I was locked outside of the house. Oh, no! I pulled on the door handle, but it wouldn’t budge. My mind raced for a simple solution, but I had to admit that there was none. The dog made her usual rounds through the yard, and then she stopped and looked over at me. Even she knew that something was wrong. How am I going to get back in the house? I wondered. I needed to call for or help, but whom? There were some neighbors who might be home, but their house was on the other side of the fence. I have a severe balance problem, and I wasn’t about to attempt to climb the chain link. There are reports of people getting hung on wire fences, Still, I had to get back inside! The cats were in there, and one of them was very, very sick. My mind raced, again, as I glanced at the padlock on the gate. Could I get through it without letting the dog out? The animals were my responsibility and my biggest concern. It never occurred to me that I could get hurt, but there was another neighbor who might be able to help me. Carefully, I leaned on the gate and undid the padlock. Checking to make sure the dog was preoccupied on the other side of the yard, I eased open the gate door and slowly lowered myself until I was sitting on the top step. My joints are always locking up on me, but once I had scooted down those steps I stood erect without even giving my “tricky” equilibrium a second thought. I walked straight across the driveway, down the bank, across the next driveway, up over that embankment and down the uneven hill to the neighbor’s porch (All this without the usual staggering often confused as drunkenness).up the steps, and rang the doorbell. What a relief that someone was home! I asked to use the phone and was told that help would arrive within twenty minutes! That was a lesson to me to check the door latch before going outside.



1., “Congenital Central Hypoventilation Syndrome.” 2., “Central Alveolar Hypoventilan”


A Story about CCHS (Diaphragm Pacing) – Children’s Hospital Los Angeles

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Health: The little boy who forgets to breathe

THE sound of their child giggling would make most parents smile but it is one that Sarah Cross dreads. If her little boy Sam laughs for too long it can be life-threatening. Sam, aged six, is just one of around 60 people in Britain with congenital central hypoventilation syndrome (CCHS), which means he often stops breathing. It can happen if he’s upset, ill, playing with friends or just concentrating on his favourite TV programme. It always happens when he falls asleep.

BREATHING ISSUES: Sam is thriving despite his condition.
“He looks like a healthy, happy little boy but he has a deadly condition,” says Sarah, 38. “Even laughing can be dangerous if it goes on for too long, because he will either stop breathing or take very shallow breaths. If he’s not getting enough oxygen he will pass out. He needs someone to bring him round and if necessary get him breathing again.”Consultant paediatrician Martin Samuels, from the University Hospital of North Staffordshire, is a leading expert on the condition. He says CCHS or Ondine’s Curse, as it was formerly known, is a genetic condition of the central nervous system that affects the automatic control of breathing.The fault in the brain stem means those with the condition “forget” to breathe, especially during deep sleep. At other times they may under-breathe, resulting in a build-up of carbon dioxide – the waste gas we usually breathe out – and a fall in oxygen levels in the blood.
“When carbon dioxide levels rise patients can pass out, sometimes it can lead to brain damage or even death,” says Dr Samuels.He says people with CCHS need ventilation at night, with the severely affected needing 24-hour ventilation. In Sam’s case he’s attached to a ventilator via a tracheostomy at night, which kick-starts his breathing every time it stops. When he gets older he may choose to sleep with a mask on to aid breathing instead. Sam also has a trained carer watching over him while he sleeps in case the shoebox-sized ventilator breaks down. He has a carer when he’s at school, too.Sarah, who works in a bank, says Sam first stopped breathing 15 minutes after he was born. “He looked perfect when he was first given to me. He was so alert. But like all newborns he nodded off. It was the midwife who noticed he had turned blue.”
Often breathing problems are a sign of a heart defect but Sam was given the all clear, although he continued to stop breathing. Luckily the registrar overseeing his care had come across CCHS before and Sam was tested for the gene defect which is associated with the syndrome. The defect occurs in the first eight weeks of pregnancy, though no one understands why.“I was grateful to know he had been diagnosed but it sounded scary,” says Sarah, a single mum who lives with Sam in Pontprennau, Cardiff. “I was also told he might never eat or speak. I’m pleased to say they were wrong as he doesn’t stop doing either.”Sam spent the first nine months of his life in hospital. When he was allowed home, the first few years were very isolating as Sarah couldn’t drive Sam anywhere without another person in the back watching him in case he fell asleep. Because he has a tracheostomy, Sam is also more susceptible to infections, especially those related to the ears, nose and throat.
Now Sam is a little older, life is easier. Sarah can drive him short distances and he’s thriving at school, where he has lots of friends. Sarah is never far away from Sam when she’s his main carer. She also knows if he looks flushed, is clammy or sweaty, or has aching limbs, his carbon dioxide levels are building up.He has passed out a couple of times at school although fortunately he comes round quickly. If necessary he is attached to his ventilator but otherwise he is encouraged to take deep breaths. Sarah says: “People often say how healthy he looks and ask why I need so much support. But Sam stops breathing every day – he has a deadly but ‘unseen’ condition.”S arah adds: “Children like Sam used to live in hospitals. As a parent I’ve fought hard to get the support he needs so that he can be at home. Like every parent I think he is amazing. He’s a very bright little boy and he has achieved more than I would have ever expected.
“I’m really proud of him. I hope he does well at school and goes to university. Children with CCHS can achieve and be part of society – they just need a bit of support.
A toddler is preparing to go home for the first time in her life after spending almost three years at Great Ormond Street Hospital.
Ondine’s Curse: Girl With Ventilator Can Go Home
 Maisie Harris suffers from a rare condition called Ondine’s Curse, which means her brain does not tell her body to breathe, so she needs a ventilator to do it for her.Now, thanks to a smaller, more portable ventilator, Maisie will be able to leave hospital and head home to Gillingham in Kent.The new ventilator is intelligent enough to know when she is able to take her own breaths and when she is likely to have an episode and require ventilation.Her mother Rachel Bridger told the media: “It’s exciting, I’m nervous. It’s all new going home. It’ll be good to just be a normal family. You don’t feel normal being in hospital so long.”The last three years have been up and down, good and bad. You give up sometimes. I thought it might be the end of the road but she pulled through which is great news. I’m looking forward to taking her to the park and to her nan’s.”The new ventilator is the best thing she’s ever had.”

Maisie Harris has rare condition called Ondine's Curse
Maisie will leave hospital soon

Maisie, who turns three on October 23, has been at London’s Great Ormond Street so long that staff held a going-home party. Maisie will leave the hospital with her family on Monday.

Ward manager Kate Harkus said: “It means a lot to the staff that she’s going home. We feel very proud. We’ve nursed her through rocky times.

“There are very few machines in the world that will be able to support her at home. Technology is advancing so much that more companies are coming out with these ventilators that you can manage at home.”

Maisie’s parents have mostly been living in hospital accommodation ever since she was transferred to Great Ormond Street from Medway Maritime Hospital when she was three months old.

Her father Andrew Harris explained : “It’s been difficult. She was in intensive care going backwards and forwards.

Kate’s story

The Cobh toddler who has only spent a few nights at home since she was born almost two years ago is finally home with her delighted family.
Kate Flynn, who will be two next month, spent a number of nights at her Cobh home with her parents Mark and Lisa and brothers Adam and Alex in recent weeks.
And now to everyone’s joy she is at home full time, with support and care from a home nursing team set in place to cope with Kate’s needs.
Her thrilled father Mark said: “We are over the moon. We can scarcely believe its true. It will have a huge beneficial impact on all our lives, primarily that it will no longer revolve around a hospital setting but now a family home environment, the way it should be. Kate is so amazing and makes us so proud every day.”
Little Kate, who wasborn in June 2013 by emergency C-section at CUMH, needs a ventilator to survive and also has a tracheostomy. She spends between just two and three hours a day off the ventilator. She is fed through a peg because she has difficulty in swallowing. Kate was born in June 2013 by emergency C-section at Cork University Maternity Hospital.Within hours of her birth, she was transferred to Our Lady’s Hospital for Sick Children in Crumlin because she had immediate breathing problems. She has had dozens of episodes in her short life in which she has stopped breathing and needed resuscitation
Her parents, are now awaiting the results of tests to establish if she has a genetic condition.
Caption: Baby Kate with her brothers Alex and Adam and parents Mark and Lisa. Picture: Larry Cummins

Evening Echo's photo.

forwards. Now she’s ready to go home it’s all been worth it.

“I’m looking forward to seeing her go to school and growing up. We didn’t think she’d get to this stage.”