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

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.

Multisystem comorbidities in classic Rett syndrome: a scoping review

“…The study designs were divided equally between prospective (9 of 18 articles) and cross-sectional assessments (9 of 18 articles). Most of the prospective studies (8 articles) involved in person assessments; 5 studies with multisite data collection [15][16][17][18][19] and 3 studies with single institution cohorts. [20][21][22] A single prospective study used a national patient registry capturing data Open access from caregiver completed questionnaires.…”

Detection of neurophysiological features in female R255X MeCP2 mutation mice

“…Sleep disturbance is very common in individuals with RTT, with over 80% of affected people having sleep abnormalities including irregular sleep/wake patterns, frequent arousal during sleep, increased day time napping and increased sleep onset latency ( Glaze et al, 1987 ; Nomura, 2005 ; Tarquinio et al, 2018 ; Young et al, 2007 ). The reported evaluations of sleep/wake patterns in mouse models lacking MeCP2 function varied depending on whether the studies were in heterozygous female or hemizygous male mice.…”

“…RTT is characterized by a distinctive pattern of disease, with apparently normal early development for the first ~6 months of age, developmental stagnation, and then a period of regression with loss of acquired volitional hand skills and spoken language, onset of repetitive hand movements, and gait problems ( Neul et al, 2010 ). Affected individuals often develop clinical features such as seizures ( Tarquinio et al, 2017 ), breathing irregularities ( Tarquinio et al, 2018 ) and autonomic dysfunction ( McCauley et al, 2011 ). Loss of function mutations in the X-linked gene Methyl-CpG-binding Protein 2 ( MECP2 ), which encodes the transcriptional regulator protein MeCP2, are the major cause of RTT ( Amir et al, 1999 ; Cuddapah et al, 2014 ).…”

Towards a better diagnosis and treatment of Rett syndrome: a model synaptic disorder

“…Although most clinical trials aim at testing drugs as early as possible in the evolution of Rett syndrome, safety and logistical considerations determine that some of them will only enrol older children, teens, or adults. Since severity of symptoms, including breath-holding, seizures, and motor dysfunction, is particularly high in late childhood and adolescence (Tarquinio et al, 2017(Tarquinio et al, , 2018, combination of drugs with nonpharmacological therapies or other interventions for overcoming decreased or aberrant plasticity seems to be compelling. The experience with the GABA B agonist arbaclofen in fragile-X syndrome suggests age-dependent efficacy with greater efficacy in childhood than at later ages (Berry-Kravis et al, 2017).…”