The course of awake breathing disturbances across the lifespan in Rett syndrome

Brain Dev. 2018 Aug;40(7):515-529. doi: 10.1016/j.braindev.2018.03.010. Epub 2018 Apr 12.


Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, is associated with a peculiar breathing disturbance exclusively during wakefulness that is distressing, and can even prompt emergency resuscitation. Through the RTT Natural History Study, we characterized cross sectional and longitudinal characteristics of awake breathing abnormalities in RTT and identified associated clinical features. Participants were recruited from 2006 to 2015, and cumulative lifetime prevalence of breathing dysfunction was determined using the Kaplan-Meier estimator. Risk factors were assessed using logistic regression. Of 1205 participants, 1185 had sufficient data for analysis, including 922 females with classic RTT, 778 of whom were followed longitudinally for up to 9.0 years, for a total of 3944 person-years. Participants with classic or atypical severe RTT were more likely to have breathing dysfunction (nearly 100% over the lifespan) compared to those with atypical mild RTT (60-70%). Remission was common, lasting 1 year on average, with 15% ending the study in terminal remission. Factors associated with higher odds of severe breathing dysfunction included poor gross and fine motor function, frequency of stereotypical hand movements, seizure frequency, prolonged corrected QT interval on EKG, and two quality of life metrics: caregiver concern about physical health and contracting illness. Factors associated with lower prevalence of severe breathing dysfunction included higher body mass index and head circumference Z-scores, advanced age, and severe scoliosis or contractures. Awake breathing dysfunction is common in RTT, more so than seizures, and is associated with function, quality of life and risk for cardiac dysrhythmia.

Keywords: Dysautonomia; MECP2; Natural History Study; Periodic breathing; Rett syndrome.

Publication types

  • Multicenter Study

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Body Mass Index
  • Child
  • Child, Preschool
  • Cross-Sectional Studies
  • Disease Progression
  • Female
  • Humans
  • Infant
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Prevalence
  • Quality of Life
  • Respiration Disorders / epidemiology
  • Respiration Disorders / etiology
  • Respiration Disorders / genetics
  • Respiration Disorders / physiopathology*
  • Rett Syndrome / complications
  • Rett Syndrome / epidemiology
  • Rett Syndrome / genetics
  • Rett Syndrome / physiopathology*
  • Risk Factors
  • Scoliosis / complications
  • Scoliosis / epidemiology
  • Scoliosis / genetics
  • Scoliosis / physiopathology
  • Seizures / complications
  • Seizures / epidemiology
  • Seizures / genetics
  • Seizures / physiopathology
  • Young Adult