AUTHOR=Leoncini Silvia , Signorini Cinzia , Boasiako Lidia , Scandurra Valeria , Hayek Joussef , Ciccoli Lucia , Rossi Marcello , Canitano Roberto , De Felice Claudio 

TITLE=Breathing Abnormalities During Sleep and Wakefulness in Rett Syndrome: Clinical Relevance and Paradoxical Relationship With Circulating Pro-oxidant Markers

JOURNAL=Frontiers in Neurology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2022.833239

DOI=10.3389/fneur.2022.833239

ISSN=1664-2295

ABSTRACT=<sec><title>Background</title><p>Breathing abnormalities are common in Rett syndrome (RTT), a pervasive neurodevelopmental disorder almost exclusively affecting females. RTT is linked to mutations in the methyl-CpG-binding protein 2 (<italic>MeCP2</italic>) gene. Our aim was to assess the clinical relevance of apneas during sleep-wakefulness cycle in a population with RTT and the possible impact of apneas on circulating oxidative stress markers.</p></sec><sec><title>Methods</title><p>Female patients with a clinical diagnosis of typical RTT (<italic>n</italic> = 66), <italic>MECP2</italic> gene mutation, and apneas were enrolled (mean age: 12.5 years). Baseline clinical severity, arterial blood gas analysis, and red blood cell count were assessed. Breathing was monitored during the wakefulness and sleep states (average recording time: 13 ± 0.5 h) with a portable polygraphic screening device. According to prevalence of breath holdings, the population was categorized into the wakefulness apnea (WA) and sleep apnea (SA) groups, and apnea-hypopnea index (AHI) was calculated. The impact of respiratory events on oxidative stress was assessed by plasma and intra-erythrocyte non-protein-bound iron (P-NPBI and IE-NPBI, respectively), and plasma F<sub>2</sub>-isoprostane (F<sub>2</sub>-IsoP) assays.</p></sec><sec><title>Results</title><p>Significant prevalence of obstructive apneas with values of AHI &gt; 15 was present in 69.7% of the population with RTT. The group with SA showed significantly increased AHI values &gt; 15 (<italic>p</italic> = 0.0032), total breath holding episodes (<italic>p</italic> = 0.007), and average SpO<sub>2</sub> (<italic>p</italic> = 0.0001) as well as lower nadir SpO<sub>2</sub> (<italic>p</italic> = 0.0004) compared with the patients with WAs. The subgroups of patients with WA and SA showed no significant differences in arterial blood gas analysis variables (<italic>p</italic> &gt; 0.089). Decreased mean cell hemoglobin (MCH) (<italic>p</italic> = 0.038) was observed in the group with WAs. P-NPBI levels were significantly higher in the group with WA than in that with SAs (<italic>p</italic> = 0.0001). Stepwise multiple linear regression models showed WA being related to nadir SpO<sub>2</sub>, average SpO<sub>2</sub>, and P-NPBI (adjusted <italic>R</italic><sup>2</sup> = 0.613, multiple correlation coefficient = 0.795 <italic>p</italic> &lt; 0.0001), and P-NPBI being related to average SpO<sub>2</sub>, blood PaCO<sub>2</sub>, red blood cell mean corpuscular volume (MCV), age, and topiramate treatment (adjusted <italic>R</italic><sup>2</sup> = 0.551, multiple correlation coefficient = 0.765, <italic>p</italic> &lt; 0.0001).</p></sec><sec><title>Conclusion</title><p>Our findings indicate that the impact of apneas in RTT is uneven according to the sleep-wakefulness cycle, and that plasma redox active iron represents a potential novel therapeutic target.</p></sec>