Ondine's curse

Ondine's curse
Classification and external resources
ICD-10	G47.3
ICD-9	348.8
OMIM	209880
DiseasesDB	32976
MedlinePlus	000078
eMedicine	ped/1645
MeSH	D020182

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).^[1]

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.^[1]

Symptoms

Ondine's curse is associated with respiratory arrests during sleep and, with incomplete penetrance,^{[clarification needed]} neuroblastoma (tumors of the sympathetic ganglia), Hirschsprung disease (partial agenesis of the enteric nervous system), dysphagia (difficulty swallowing) and anomalies of the pupilla.

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, stroke, or as a complication of neurosurgery). Long and Allen ^[2] 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.^[3][4][5][6] This homeobox gene is important for the normal development of the autonomic nervous system.

The disease used to be classified as a "neurocristopathy",^[7][8] 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.

Diagnosis

Children with Congenital Central Hypoventilation Syndrome develop life-threatening episodes of apnea with cyanosis, 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.^[9]

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.

Treatment and prognosis

Patients generally require tracheotomies 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.^[10]

Although rare, cases of long-term untreated CCHS have been reported.^[11]

History and etymology

It was first described in 1962 by Severinghaus and Mitchell in three patients following surgery to the upper cervical spinal cord and brainstem.^[12]

Its name is a reference to the myth of Ondine,^[13] 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.

References

1. ^ ^{a b} Chin, Terry. "Congentil Central Hypoventilation Syndrome." EMedicine. 27 Nov. 2006. 17 Sept. 2008 <http://www.emedicine.com/ped/topic1645.htm>.
2. ^ Long, KJ, Allen, N: "Abnormal Brainstem Auditory Evoked Potentials Following Ondine's Curse." Arch. Neurol. 1984; 41(10):1109-1110.
3. ^ Gaultier C, Amiel J, Dauger S, et al. (2004). "Genetics and early disturbances of breathing control". Pediatr. Res. 55 (5): 729–33. doi:10.1203/01.PDR.0000115677.78759.C5. PMID 14739359. 
4. ^ Gaultier C, Trang H, Dauger S, Gallego J (2005). "Pediatric disorders with autonomic dysfunction: what role for PHOX2B?". Pediatr. Res. 58 (1): 1–6. doi:10.1203/01.PDR.0000166755.29277.C4. PMID 15901893. 
5. ^ Todd ES, Weinberg SM, Berry-Kravis EM, et al. (2006). "Facial phenotype in children and young adults with PHOX2B-determined congenital central hypoventilation syndrome: quantitative pattern of dysmorphology". Pediatr. Res. 59 (1): 39–45. doi:10.1203/01.pdr.0000191814.73340.1d. PMID 16327002. 
6. ^ "Gene secret of 'mythical curse'" at BBC News, 5 May 2003 (The article misspells PHOX2B as "Thox2b".)
7. ^ Kincaid PK, Dietrich RB, Pais MJ (1994). "Pediatric case of the day. Neurocristopathy (Ondine-Hirschsprung syndrome)". Radiographics : a review publication of the Radiological Society of North America, Inc 14 (5): 1139–43. PMID 7991820. 
8. ^ Poceta JS, Strandjord TP, Badura RJ, Milstein JM (1987). "Undine curse and neurocristopathy". Pediatr. Neurol. 3 (6): 370–2. doi:10.1016/0887-8994(87)90011-7. PMID 3508086. 
9. ^ Trang H, Dehan M, Beaufils F, Zaccaria I, Amiel J, Gaultier C (2005). "The French Congenital Central Hypoventilation Syndrome Registry: general data, phenotype, and genotype". Chest 127 (1): 72–9. doi:10.1378/chest.127.1.72. PMID 15653965. 
10. ^ Takeda S, Fujii Y, Kawahara H, Nakahara K, Matsuda H (1996). "Central alveolar hypoventilation syndrome (Undine's curse) with gastroesophageal reflux". Chest 110 (3): 850–2. doi:10.1378/chest.110.3.850. PMID 8797441. 
11. ^ Windisch W, Hennings E, Storre J, Matthys H, Sorichter S (2004). "Long-term survival of a patient with congenital central hypoventilation syndrome despite the lack of continuous ventilatory support". Respiration 71 (2): 195–8. doi:10.1159/000076685. PMID 15031579. 
12. ^ Severinghaus JW, Mitchell RA. Undine's curse - failure of respiratory center automaticity while awake. Clin Res 1962;10:122.
13. ^ Nannapaneni R, Behari S, Todd NV, Mendelow AD (2005). "Retracing "Undine's curse"". Neurosurgery 57 (2): 354–63; discussion 354–63. doi:10.1227/01.NEU.0000166684.69422.49. PMID 16094167. 

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.