Ondine curse is an extremely rare genetic disease characterized by a violation of autonomous breathing as a result of an abnormal reaction of the body to hypercapnia during sleep. The main symptom of this condition is apnea during the deep sleep phase, which can lead to a fatal outcome, while any pathological changes from the respiratory, nervous and cardiovascular systems are morphologically absent. Diagnosis of Ondine syndrome is based on the results of an electroencephalogram, monitoring of the patient’s breathing and blood saturation during sleep, molecular genetic analyses and the study of hereditary history. There is no specific treatment for the disease, artificial ventilation of the lungs during sleep and implantation of a diaphragmatic nerve stimulator are used.
General information
Ondine curse (congenital central hypoventilation syndrome) is a very rare and relatively severe hereditary disease in which there is first a decrease (bradypnea), and then respiratory arrest during the deep sleep phase. The name of this pathology is associated with a legend from German folklore, in which a mermaid (undine) cursed her lover who betrayed her and doomed him to the fact that “the breath will leave you as soon as you fall asleep.” This is very similar to the main manifestation of Ondine syndrome, which boils down to stopping breathing during sleep. The occurrence of this condition has not been determined to date, about three hundred cases have been identified worldwide. The mechanism of inheritance of Ondine curse is autosomal dominant with incomplete penetrance, therefore, heterozygotes predominate among patients, but their parents may be phenotypically healthy. It has been established that in some cases spontaneous mutations are the cause of the disease.
Causes
Currently, despite the rarity of this disease, geneticists have managed to find out the molecular genetic basis of Ondine syndrome. In the vast majority of cases, mutations of the PHOX2B gene located on chromosome 4 are the cause of this pathology. The product of its expression is an extremely important transcription factor that regulates the embryogenesis of tissues of the medulla oblongata and other elements of the central nervous system. The essence of the genetic defect in Ondine curse is the development of a polyalanine site in one of the domains of the transcription factor, as a result of which its ability to attach to DNA and perform its function is impaired. A clear relationship was found between the severity of the manifestations of the disease and the size of the site of abnormal polyalanine repeats in exon 3 of the PHOX2B gene.
The above genetic anomalies lead to malformations of the autonomic nervous system at the molecular level, as a result of which the Ondine curse occurs. Evidence of such anomalies of development is the frequent detection of symptoms such as cardiac arrhythmias, instability of blood pressure, delayed reaction of pupils to light, sweating disorders in patients with congenital central hypoventilation syndrome. These processes are also controlled by the autonomic nervous system, so their presence in Ondine syndrome indicates the nature of the lesion. In rare cases, there are no changes in the PHOX2B gene in this disease, but there may be mutations of the RET, EDN3, GDNF and some others genes.
Ondine curse is often accompanied by neurocrystopathies – pathological conditions caused by embryonic malformations of neural crest structures. One of the conditions of this kind is Hirschsprung’s disease, manifested by the absence of cellular elements of the parasympathetic nervous system in the intestine. A similar disorder occurs in about 15-20% of patients with Ondine syndrome. Some researchers distinguish a combination of symptoms of Hirschsprung’s disease and congenital central hypoventilation into a separate nosological unit – Haddad syndrome, named after the doctor who in 1978 first described cases of such a combined lesion.
Symptoms
Manifestations of Ondine syndrome are often detected immediately after the patient is born. During the newborn period, various ventilation disorders may be detected in the waking state, which requires careful monitoring of the child and causes a high level of neonatal death in this disease. Subsequently, Ondine curse is characterized by normal breathing and adequate ventilation during daytime activity and a sharp drop in the depth of respiratory movements during sleep, which leads to insufficient blood oxygenation. Then bradypnea and respiratory arrest may occur during sleep, which without qualified medical care can cause the death of the patient.
Ondine curse is also often combined with other disorders of the autonomic nervous system – arrhythmias, blood pressure drops, possibly a decrease in peristalsis (including due to manifestations of Hirschsprung’s disease). In some cases, the progression of pathology symptoms may be detected – from reduced ventilation to apnea during the child’s sleep. In cases where the Ondine curse was identified in time and the necessary therapeutic measures were taken, symptoms of concomitant diseases due to the peculiarities of the treatment of such patients may join. These may be frequent cases of nosocomial infections due to the almost constant stay of patients in the hospital, as well as bronchitis and pneumonia caused by the use of a ventilator.
Diagnosis and treatment
Diagnosis of Ondine syndrome is made on the basis of data from a general examination of a sick child, an electroencephalogram, monitoring of respiratory function during sleep and wakefulness. A detailed study of the hereditary history can play an important role in determining the disease. As a rule, children with Ondine curse are phenotypically healthy at birth, prematurity and various pregnancy complications are occasionally observed. In severe forms of pathology, pronounced cyanosis of the skin and irregular breathing may occur almost in the first days or even hours after birth, which necessitates especially careful care of the child. Ondine curse can also be accompanied by arrhythmias and other disorders, which requires extensive and comprehensive medical examination.
On the electroencephalogram, in the presence of Ondine curse, reduced activity of bridge structures will be determined, especially during sleep. The study of the hereditary history can reveal similar respiratory disorders in the relatives of the patient – special attention should be paid to cases of sudden infant death. Individual laboratories determine Ondine syndrome using modern genetics methods – by identifying polyalanine sites in the PHOX2B gene. In this case, it is possible to establish not only the presence of a mutation, but also the extent of the pathological site, which makes it possible to predict the possible course of pathology, since the severity of the disease is directly related to the number of GCN repeats in the 3rd exon of the gene.
There is no specific treatment for Ondine curse today, the problem of preserving the life of such patients is a rather difficult question. Most often, even in childhood, they are given a tracheostomy to connect a ventilator during sleep. Since in some cases this requires a long stay of a patient with Ondine syndrome in a hospital, the risk of nosocomial infections and other complications increases significantly. Therefore, if possible, special equipment is installed in the home of a sick child, and parents are taught how to handle it.
To improve the quality of life, phrenic nerve stimulators can be implanted, which assess the frequency of respiratory movements and, if necessary, irritating the nerve, prevent the development of brady and apnea (similar to pacemakers). At the final stages of development, there are similar devices that assess the level of carbon dioxide in the blood and its total saturation and, if necessary, affect the central links of respiratory regulation in the brain.
Prognosis and prevention
It is believed that the prognosis of Ondine syndrome or congenital central hyperventilation is rather unfavorable – this disease is characterized by relatively high neonatal mortality, in the future the patient’s life depends on the ventilator. However, at present, many patients with this disease have already lived to adulthood, which indicates the absence of its direct effect on life expectancy or the development of concomitant disorders. Therefore, the development of more advanced respiratory movement stimulators in the future will allow people suffering from Ondine syndrome to provide an optimal level of quality of life. Prevention of the disease has not been developed to date due to the genetic nature and rarity of this condition.