CDKL5 deficiency entails sleep apneas in mice

Abstract

A recently discovered neurodevelopmental disorder caused by the mutation of the cyclin-dependent kinase-like 5 gene (CDKL5) entails complex autistic-like behaviours similar to Rett syndrome, but its impact upon physiological functions remains largely unexplored. Sleep-disordered breathing is common and potentially life-threatening in patients with Rett syndrome; however, evidence is limited in children with CDKL5 disorder, and is lacking altogether in adults. The aim of this study was to test whether the breathing pattern during sleep differs between adult Cdkl5 knockout (Cdkl5-KO) and wild-type (WT) mice. Using whole-body plethysmography, sleep and breathing were recorded non-invasively for 8 h during the light period. Sleep apneas occurred more frequently in Cdkl5-KO than in WT mice. A receiver operating characteristic (ROC) analysis discriminated Cdkl5-KO significantly from WT mice based on sleep apnea occurrence. These data demonstrate that sleep apneas are a core feature of CDKL5 disorder and a respiratory biomarker of CDKL5 deficiency in mice, and suggest that sleep-disordered breathing should be evaluated routinely in CDKL5 patients.

Heterozygous CDKL5 Knockout Female Mice Are a Valuable Animal Model for CDKL5 Disorder

“…Respiratory problems, including the presence and frequency of breathing irregularities (hyperventilation, apnea), are a reported feature in CDKL5 patients [ 46 , 47 ]. Moreover, disrupted respiratory function and an increased number of apneas during sleep have been recently described also in male Cdkl5 KO mice [ 40 , 48 ]. We observed a similar increase in apnea occurrence during NREM sleep and during the whole sleep time in heterozygous and homozygous Cdkl5 KO female mice, strengthening the statement that the sleep apnea occurrence rate can be a significant biomarker for validation of future therapies in CDKL5 disorder.…”

“…Hypnic and respiratory phenotypes of mice were assessed noninvasively with a validated technique based on whole-body plethysmography (WBP) [ 39 , 40 ]. Briefly, each mouse was placed inside a WBP chamber flushed with air at 1.5 l/h for the first 8 h of the light period.…”

Cyclin-Dependent Kinase-Like 5 (CDKL5): Possible Cellular Signalling Targets and Involvement in CDKL5 Deficiency Disorder

“…This phenotype has subsequently been reported by many groups analysing both, Cdkl5-knockout and conditional Cdkl5-knockout mice. Motor impairment and loss of learning and/or memory are most often reported, but behaviours similar to that seen in the attention deficit hyperactivity disorder and sleep apnoea syndrome have also been observed [37,[98][99][100][101][102][103][104][105]. Thus, many Figure 3: CDKL5 and phosphorylative signalling.…”

Sleep in neurological disorders, sleep apnea, sleep duration and body weight

“…They were able to show that central sleep apnea was associated significantly with elevated left ventricular mass/ volume ratio, which is interpreted by the authors as reflecting an adverse cardiac finding signifying concentric remodelling. Martire et al (2017) studied wild-type and knockout mice for cyclin-dependent kinase-like 5 gene (CDKL5), a mutation which entails complex autistic-like behaviours similar to Rett syndrome, which is also characterized by sleep-disordered breathing. In their study the authors described that the knockout mice for CDKL5 had sleep apneas more frequently than the wild-type mice, and it is suggested that sleep apneas are a core feature of CDKL5 disorder and a respiratory biomarker of CDKL5 deficiency in mice.…”