Ondine's curse
Encyclopedia
Ondine's Curse, also called congenital central hypoventilation syndrome (CCHS) or primary alveolar hypoventilation, is a respiratory disorder that is fatal if untreated. Persons afflicted with Ondine's curse classically suffer from respiratory arrest
during sleep.
Persons who have CCHS have it at birth, or develop it due to severe neurological trauma/damage to the brainstem. The diagnosis may be delayed because of variations in the severity of the manifestations or lack of awareness in the medical community, particularly in milder cases. (Chin, 2006).
This very rare and serious form of central sleep apnea
involves an inborn failure of autonomic control
of breathing. About 1 in 200,000 live born children have the condition. In 2006, there were only about 200 known cases worldwide. In all cases, episodes of apnea
occur in sleep, but in a few patients, at the most severe end of the spectrum, apnea also occurs while awake.
A person’s gender or race is not a determining factor when dealing with susceptibility
to CCHS. Males and females are both affected equally and a person's ethnicity, as of this point, has not been considered a significant variable.
, neuroblastoma
(tumors of the sympathetic ganglia
), Hirschsprung disease (partial agenesis of the enteric nervous system
), dysphagia
(difficulty swallowing) and anomalies of the pupilla
.
, or as a complication of neurosurgery
). Long and Allen reported the abnormal brainstem auditory-evoked responses in an alcoholic woman who recovered from Ondine's curse. These investigators hypothesized that their patient's brainstem was poisoned, but not destroyed, by her chronic alcoholism.
Medical investigation of patients with this syndrome has led to a deeper understanding of how the body and brain regulate breathing on a molecular level. PHOX2B
can be associated with this condition. This homeobox gene is important for the normal development of the autonomic nervous system
.
The disease used to be classified as a "neurocristopathy
", or disease of the neural crest
because part of the autonomic nervous system
(such as sympathetic ganglia) derives from the neural crest. However, this denomination is no longer favored because essential neurons of the autonomic nervous system, including those that underlie the defining symptom of the disease (respiratory arrests), are derived from the neural tube
(the medulla
), not from the neural crest, although such mixed embryological origins are also true for most other neurocristopathies.
, usually in the first months of life. Medical evaluation excludes lesions of the brain, heart, and lungs but demonstrate impaired responses to build-up of carbon dioxide (hypercapnia
) and decreases of oxygen in the circulation (hypoxia
), the two strongest stimuli to increase breathing rate.
Polysomnography
shows that hypoventilation is most marked during slow-wave sleep
. In the most severe cases, hypoventilation
is present during other nonrapid eye movement sleep stages and even wakefulness. A subset of CCHS patients are at very high risk for developing malignant neural crest derived tumors, such as neuroblastoma
.
The sequence of PHOX2B
reveals mutations in 91% of the cases.
As in many disorders that are very rare, an infant with this unusual form of sleep apnea
suffers from the probability that their physician has most likely never seen another case and will not recognize the diagnosis. In some locations, such as France, optimal management of patients, once identified, has been aided by the creation of a national registry and the formation of a network of centers.
and lifetime mechanical ventilation on a ventilator in order to survive. However, it has now been shown that Biphasic Cuirass Ventilation
can effectively be used without the need for a tracheotomy.
Most people with congenital Ondine's curse do not survive infancy, unless they receive ventilatory assistance during sleep. An alternative to a mechanical ventilator is Phrenic Nerve Pacing
/diaphragm pacing.
Although rare, cases of long-term untreated CCHS have been reported.
and brainstem.
Its name is a reference to the myth
of Ondine
, a water nymph who had an unfaithful mortal lover. He swore to her that his "every waking breath would be a testimony of [his] love", and upon witnessing his adultery, she cursed that if he should fall asleep, he would forget to breathe. Eventually, he fell asleep from sheer exhaustion, and his breathing stopped.
Respiratory arrest
Respiratory arrest is the cessation of breathing. It is a medical emergency and it usually is related to or coincides with a cardiac arrest. Causes include opiate overdose, head injury, anaesthesia, tetanus, or drowning...
during sleep.
Persons who have CCHS have it at birth, or develop it due to severe neurological trauma/damage to the brainstem. The diagnosis may be delayed because of variations in the severity of the manifestations or lack of awareness in the medical community, particularly in milder cases. (Chin, 2006).
This very rare and serious form of central sleep apnea
Sleep apnea
Sleep apnea is a sleep disorder characterized by abnormal pauses in breathing or instances of abnormally low breathing, during sleep. Each pause in breathing, called an apnea, can last from a few seconds to minutes, and may occur 5 to 30 times or more an hour. Similarly, each abnormally low...
involves an inborn failure of autonomic control
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
of breathing. About 1 in 200,000 live born children have the condition. In 2006, there were only about 200 known cases worldwide. In all cases, episodes of apnea
Apnea
Apnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
occur in sleep, but in a few patients, at the most severe end of the spectrum, apnea also occurs while awake.
A person’s gender or race is not a determining factor when dealing with susceptibility
Susceptibility
*In physics, the susceptibility of a material or substance describes its response to an applied field. There are many kinds of susceptibilities, for example:These two susceptibilities are particular examples of a linear response function;...
to CCHS. Males and females are both affected equally and a person's ethnicity, as of this point, has not been considered a significant variable.
Symptoms
Ondine's curse is associated with respiratory arrests during sleep and, with incomplete penetrancePenetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
, neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
(tumors of the sympathetic ganglia
Sympathetic ganglia
Sympathetic ganglia are the ganglia of the sympathetic nervous system. They deliver information to the body about stress and impending danger, and are responsible for the familiar fight-or-flight response. They contain approximately 20000–30000 nerve cell bodies and are located close to and...
), Hirschsprung disease (partial agenesis of the enteric nervous system
Enteric nervous system
The enteric nervous system is a subdivision of the autonomic nervous system that directly controls the gastrointestinal system in vertebrates.It is derived from neural crest.-Function:...
), dysphagia
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
(difficulty swallowing) and anomalies of the pupilla
Pupilla
Pupilla is a genus of minute air-breathing land snails, terrestrial pulmonate gastropod mollusks or micromollusks in the family Pupillidae.The genus Pupilla is known from the Oligocene to the Recent period.-Species:...
.
Causes
Ondine's curse is exhibited typically as a congenital disorder, but in rare circumstances, can also result from severe brain or spinal trauma (such as after an automobile accident, strokeStroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, or as a complication of neurosurgery
Neurosurgery
Neurosurgery is the medical specialty concerned with the prevention, diagnosis, treatment, and rehabilitation of disorders which affect any portion of the nervous system including the brain, spine, spinal cord, peripheral nerves, and extra-cranial cerebrovascular system.-In the United States:In...
). Long and Allen reported the abnormal brainstem auditory-evoked responses in an alcoholic woman who recovered from Ondine's curse. These investigators hypothesized that their patient's brainstem was poisoned, but not destroyed, by her chronic alcoholism.
Medical investigation of patients with this syndrome has led to a deeper understanding of how the body and brain regulate breathing on a molecular level. PHOX2B
PHOX2B
Paired-like homeobox 2b , also known as neuroblastoma Phox , is a protein that in humans is encoded by the PHOX2B gene located on chromosome 4....
can be associated with this condition. This homeobox gene is important for the normal development of the autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
.
The disease used to be classified as a "neurocristopathy
Neurocristopathy
Neurocristopathy is a term coined by Robert P. Bolande in 1974, referring to a diverse class of pathologies that may arise from defects in the development of tissues containing cells commonly derived from the embryonic neural crest cell lineage....
", or disease of the neural crest
Neural crest
Neural crest cells are a transient, multipotent, migratory cell population unique to vertebrates that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia....
because part of the autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
(such as sympathetic ganglia) derives from the neural crest. However, this denomination is no longer favored because essential neurons of the autonomic nervous system, including those that underlie the defining symptom of the disease (respiratory arrests), are derived from the neural tube
Neural tube
In the developing vertebrate, the neural tube is the embryo's precursor to the central nervous system, which comprises the brain and spinal cord...
(the medulla
Medulla oblongata
The medulla oblongata is the lower half of the brainstem. In discussions of neurology and similar contexts where no ambiguity will result, it is often referred to as simply the medulla...
), not from the neural crest, although such mixed embryological origins are also true for most other neurocristopathies.
Diagnosis
Children with Congenital Central Hypoventilation Syndrome develop life-threatening episodes of apnea with cyanosisCyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...
, usually in the first months of life. Medical evaluation excludes lesions of the brain, heart, and lungs but demonstrate impaired responses to build-up of carbon dioxide (hypercapnia
Hypercapnia
Hypercapnia or hypercapnea , also known as hypercarbia, is a condition where there is too much carbon dioxide in the blood...
) and decreases of oxygen in the circulation (hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
), the two strongest stimuli to increase breathing rate.
Polysomnography
Polysomnography
Polysomnography , also known as a sleep study, is a multi-parametric test used in the study of sleep and as a diagnostic tool in sleep medicine. The test result is called a polysomnogram, also abbreviated PSG...
shows that hypoventilation is most marked during slow-wave sleep
Slow-wave sleep
Slow-wave sleep , often referred to as deep sleep, consists of stages 3 and 4 of non-rapid eye movement sleep, according to the Rechtschaffen & Kales standard of 1968. As of 2008, the American Academy of Sleep Medicine has discontinued the use of stage 4, such that the previous stages 3 and 4 now...
. In the most severe cases, hypoventilation
Hypoventilation
In medicine, hypoventilation occurs when ventilation is inadequate to perform needed gas exchange...
is present during other nonrapid eye movement sleep stages and even wakefulness. A subset of CCHS patients are at very high risk for developing malignant neural crest derived tumors, such as neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
.
The sequence of PHOX2B
PHOX2B
Paired-like homeobox 2b , also known as neuroblastoma Phox , is a protein that in humans is encoded by the PHOX2B gene located on chromosome 4....
reveals mutations in 91% of the cases.
As in many disorders that are very rare, an infant with this unusual form of sleep apnea
Sleep apnea
Sleep apnea is a sleep disorder characterized by abnormal pauses in breathing or instances of abnormally low breathing, during sleep. Each pause in breathing, called an apnea, can last from a few seconds to minutes, and may occur 5 to 30 times or more an hour. Similarly, each abnormally low...
suffers from the probability that their physician has most likely never seen another case and will not recognize the diagnosis. In some locations, such as France, optimal management of patients, once identified, has been aided by the creation of a national registry and the formation of a network of centers.
Treatment and prognosis
Patients generally require tracheotomiesTracheotomy
Among the oldest described surgical procedures, tracheotomy consists of making an incision on the anterior aspect of the neck and opening a direct airway through an incision in the trachea...
and lifetime mechanical ventilation on a ventilator in order to survive. However, it has now been shown that Biphasic Cuirass Ventilation
Biphasic Cuirass Ventilation
Biphasic cuirass ventilation is a method of ventilation which requires the patient to wear an upper body shell or cuirass, so named after the body armor worn by medieval soldiers. The ventilation is biphasic because the cuirass is attached to a pump which actively controls both the inspiratory and...
can effectively be used without the need for a tracheotomy.
Most people with congenital Ondine's curse do not survive infancy, unless they receive ventilatory assistance during sleep. An alternative to a mechanical ventilator is Phrenic Nerve Pacing
Phrenic Nerve Pacing
Phrenic Nerve Pacing or diaphragm pacing, is the rhythmic application of electrical impulses to the diaphragm, resulting in respiration for patients who would otherwise be dependent on a mechanical ventilator....
/diaphragm pacing.
Although rare, cases of long-term untreated CCHS have been reported.
History and etymology
It was first described in 1962 by Severinghaus and Mitchell in three patients following surgery to the upper cervical spinal cordSpinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
and brainstem.
Its name is a reference to the myth
Mythology
The term mythology can refer either to the study of myths, or to a body or collection of myths. As examples, comparative mythology is the study of connections between myths from different cultures, whereas Greek mythology is the body of myths from ancient Greece...
of Ondine
Ondine (mythology)
Undines , also called ondines, are elementals, enumerated as the water elementals in works of alchemy by Paracelsus. They also appear in European folklore as fairy-like creatures; the name may be used interchangeably with those of other water spirits. Undines are said to be able to gain a soul by...
, a water nymph who had an unfaithful mortal lover. He swore to her that his "every waking breath would be a testimony of [his] love", and upon witnessing his adultery, she cursed that if he should fall asleep, he would forget to breathe. Eventually, he fell asleep from sheer exhaustion, and his breathing stopped.
External links
- GeneReviews/NCBI/NIH/UW entry on Congenital Central Hypoventilation Syndrome
- http://www.cchsnetwork.org/ - Family, patient, and medical organization's website, advocating research and support for patients' and their families. In the past, this organization has arranged four US-based conferences offering research, lectures, & projects to support patients' families from around the world.