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Abstract
Background Rett syndrome is a severe neurological disorder with a range of disabling autonomic and respiratory symptoms and resulting predominantly from variants in the methyl-CpG binding protein 2 gene on the long arm of the X-chromosome. As basic research begins to suggest potential treatments, sensitive measures of the dynamic phenotype are needed to evaluate the results of these research efforts. Here we test the hypothesis that the physiological fingerprint of Rett syndrome in a naturalistic environment differs from that of controls, and differs among genotypes within Rett syndrome.
Methods A comprehensive array of heart rate variability, cardiorespiratory coupling and cardiac repolarisation measures were evaluated from an existing database of overnight and daytime inhome ambulatory recordings in 47 cases and matched controls.
Results Differences between girls with Rett syndrome and matched controls were apparent in a range of autonomic measures, and suggest a shift towards sympathetic activation and/or parasympathetic inactivation. Daily temporal trends analysed in the context of circadian rhythms reveal alterations in amplitude and phase of diurnal patterns of autonomic balance. Further analysis by genotype class confirms a graded presentation of the Rett syndrome phenotype such that patients with early truncating mutations were most different from controls, while late truncating and missense mutations were least different from controls.
Conclusions Comprehensive autonomic measures from extensive inhome physiological measurements can detect subtle variations in the phenotype of girls with Rett syndrome, suggesting these techniques are suitable for guiding novel therapies.
- rett syndrome
- autonomic regulation
- heart rate variability
- PHOX2B
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Footnotes
Contributors MSC led conception, design, software development, statistical analysis, interpretation, drafting and final revision of the manuscript for intellectual content. J-MR conceived and designed the original study from which the data are derived and revised the manuscript for intellectual content. DEW-M conceived and designed the original study, and revised the manuscript for intellectual content.
Funding This work was supported by the Rett Syndrome Research Trust under the project title “Outlining the Autonomic Signature of Rett Syndrome.”
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The original data were collected under approval from the Rush University Medical CenterCentre Institutional Review Board with written parental consent (Office of Human Research Protections Registration Numbers #00000482; study approval: 02042902). The supplemental analyses presented here were approved by the Institutional Review Board of Ann & Robert H. Lurie Children’s Hospital of Chicago (Office of Human Research Protections Registration Numbers #00000624 and #00009723; study approval: 2019–3120).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. Specific genotype information in this rare disease could allow reidentification of individuals who have not given explicit consent for data sharing. For this reason, data will be shared with any qualified researcher on request only to the extent that it is ethically and legally permissible.