Systemic oxidative stress in the Congenital Central Hypoventilation Syndrome

The Congenital Central Hypoventilation Syndrome (CCHS), also known as Ondine's curse, is a rare disorder characterised by severe hypoventilation during sleep and autonomic dysregulation [1, 2]. The incidence of CCHS is about 1/200 000 live births. In more than 90% of cases, polyalanine repeat expansion (PolyALA) mutations are present in the paired-like homeobox PHOX-2B gene, although a frameshift variant (FS) may also be found [3]. The PHOX-2B gene encodes a highly conserved homeobox domain transcription factor which plays a regulatory role in the differentiation of the motor neuron and the serotonergic neuronal fate in the development of the central nervous system [4]. The hallmark of CCHS is the “forgotten breathing”, which implies the need for life-long mechanical ventilation during sleep. However, in more severe cases characterised by global hypoventilation, mechanical ventilation must also be extended during wakefulness. Ventilatory support may be provided by tracheostomy and assisted ventilation, non-invasive ventilation, or diaphragm pacemakers. Severe respiratory depression typically arises at birth, but in milder cases, CCHS may be diagnosed later on in childhood or adulthood (later-onset CCHS) [1, 2]. The clue to the respiratory defect is a reduced response to hypercapnia and hypoxemia depending on the malfunctioning of brainstem areas such as the retrotrapezoid nucleus, the parafacial respiratory group and the pre-Bötzinger complex which are involved in the chemosensory drive to breathe [5–7].