Using wearables to investigate and understand breathing irregularities in Rett syndrome in Australian population-based and Italian clinic samples

Background: Individuals with Rett syndrome (RTT) commonly experience breathing irregularities, but previous studies have been limited by small sample sizes and clinic-based assessments. We examined respiratory dysfunction using objective measurements within a large, representative international cohort. Methods: We recruited 64 individuals with genetically confirmed RTT from Australia (n=54) and Italy (n=10), with a mean age of 17.3 years (SD 9.8). Respiratory inductive plethysmography using BioRadio™ monitored breathing patterns continuously for an average of 5.6 hours in home settings. We algorithmically identified hyperventilation and apnoea episodes, categorised severity, and examined associations with genotype and phenotypic characteristics. Results: Normal breathing occurred 84% of recorded time, hyperventilation 13%, and apnoea 4%. All participants exhibited hyperventilation; 75% demonstrated apnoea. Parent-reported prevalence underestimated objectively measured abnormalities (hyperventilation 40% vs 100%; breath-holding 42% vs 75%). Hyperventilation severity increased with age (P<0.001) and was associated with walking ability (P=0.010). Apnoea severity correlated somewhat with p.Arg294* and p.Arg133Cys variants, parent-reported breath-holding frequency (P=0.003), and poor seizure control (P=0.014). Conclusions: Objective monitoring reveals universal breathing dysfunction in RTT, substantially exceeding caregiver-reported prevalence, supporting its potential as an outcome measure for autonomic dysregulation.