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

• Type of Material: Article
• Authors: Daniel Tarquinio, Emory University; Wei Hou, Stony Brook University; Jeffrey L. Neul, Vanderbilt University; Gamze Kilic Berkmen, Emory University; Jana Drummond, Emory University; Elizabeth Aronoff, Emory University; Jennifer Harris, Center for Rare Neurological Diseases; Jane B. Lane, University of Alabama Birmingham; Walter E. Kaufmann, Emory University; Kathleen J. Motil, Baylor College of Medicine; Daniel G. Glaze, Baylor College of Medicine; Steven A. Skinner, Greenwood Genetic Center; Alan K. Percy, University of Alabama Birmingham
• Language: English
• Date: 2018-08-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 The Japanese Society of Child Neurology
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.braindev.2018.03.010
• Title of Journal or Parent Work: Brain and Development
• ISSN: 0387-7604
• Volume: 40
• Issue: 7
• Start Page: 515
• End Page: 529
• Grant/Funding Information: Support is provided by grants from the International Rett Syndrome Foundation and from the NIH (RR019478), including the Angelman, Rett, Prader-Willi syndrome consortium (U54HD61222) a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS) and the Eunice Kennedy Shriver Child Health and Human Development Institute.
• Keywords: DISORDERS; MICE; Periodic breathing; DYSFUNCTION; Neurosciences & Neurology; YOUNG GIRLS; Natural History Study; NEUROTROPHIC FACTOR EXPRESSION; CPG-BINDING PROTEIN-2; DYSREGULATION; MOUSE MODEL; RESPIRATORY-FUNCTION; MECP2; Dysautonomia; Science & Technology; Rett syndrome; NATURAL-HISTORY; Life Sciences & Biomedicine; Clinical Neurology
• Research Categories: Biology, Neuroscience

Abstract

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.