{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:20:01Z","timestamp":1760145601820,"version":"build-2065373602"},"reference-count":91,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T00:00:00Z","timestamp":1722556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Reverse Rett","award":["RE16403"],"award-info":[{"award-number":["RE16403"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Rett syndrome (RTT) is a paediatric neurodevelopmental disorder spanning four developmental stages. This multi-system disorder offers a unique window to explore genotype\u2013phenotype relationships in a disease model. However, genetic prognosticators of RTT have limited clinical value due to the disorder\u2019s heterogeneity on multiple levels. This case report used a precision medicine approach to better understand the clinical phenotype of RTT twins with an identical pathogenic MECP2 mutation and discordant neurodevelopmental profiles. Targeted genotyping, objective physiological monitoring of heart rate variability (HRV) parameters, and clinical severity were assessed in a RTT twin pair (5 years 7 months old) with an identical pathogenic MECP2 mutation. Longitudinal assessment of autonomic HRV parameters was conducted using the Empatica E4 wristband device, and clinical severity was assessed using the RTT-anchored Clinical Global Impression Scale (RTT-CGI) and the Multi-System Profile of Symptoms Scale (MPSS). Genotype data revealed impaired BDNF function for twin A when compared to twin B. Twin A also had poorer autonomic health than twin B, as indicated by lower autonomic metrics (autonomic inflexibility). Hospitalisation, RTT-CGI-S, and MPSS subscale scores were used as measures of clinical severity, and these were worse in twin A. Treatment using buspirone shifted twin A from an inflexible to a flexible autonomic profile. This was mirrored in the MPSS scores, which showed a reduction in autonomic and cardiac symptoms following buspirone treatment. Our findings showed that a combination of a co-occurring rs6265 BDNF polymorphism, and worse autonomic and clinical profiles led to a poorer prognosis for twin A compared to twin B. Buspirone was able to shift a rigid autonomic profile to a more flexible one for twin A and thereby prevent cardiac and autonomic symptoms from worsening. The clinical profile for twin A represents a departure from the disorder trajectory typically observed in RTT and underscores the importance of wider genotype profiling and longitudinal objective physiological monitoring alongside measures of clinical symptoms and severity when assessing genotype\u2013phenotype relationships in RTT patients with identical pathogenic mutations. A precision medicine approach that assesses genetic and physiological risk factors can be extended to other neurodevelopmental disorders to monitor risk when genotype\u2013phenotype relationships are not so obvious.<\/jats:p>","DOI":"10.3390\/cimb46080497","type":"journal-article","created":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T15:24:16Z","timestamp":1722957856000},"page":"8424-8440","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Using Precision Medicine to Disentangle Genotype\u2013Phenotype Relationships in Twins with Rett Syndrome: A Case Report"],"prefix":"10.3390","volume":"46","author":[{"given":"Jatinder","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0884-8494","authenticated-orcid":false,"given":"Georgina","family":"Wilkins","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ella","family":"Goodman-Vincent","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samiya","family":"Chishti","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0907-6530","authenticated-orcid":false,"given":"Ruben","family":"Bonilla Guerrero","sequence":"additional","affiliation":[{"name":"Genetica Consulting Services, Laguna Niguel, CA 92677, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Fiori","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shashidhar","family":"Ameenpur","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leighton","family":"McFadden","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zvi","family":"Zahavi","sequence":"additional","affiliation":[{"name":"Myogenes Limited, Borehamwood WD6 4PJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4830-5893","authenticated-orcid":false,"given":"Paramala","family":"Santosh","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK"},{"name":"Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London, London SE5 8AF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/mrdd.10020","article-title":"Clinical manifestations and stages of Rett syndrome","volume":"8","author":"Hagberg","year":"2002","journal-title":"Ment. Retard. Dev. Disabil. Res. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1002\/humu.10194","article-title":"RettBASE: The IRSA MECP2 variation database\u2014A new mutation database in evolution","volume":"21","author":"Christodoulou","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_3","first-page":"6956934","article-title":"Analysis of the Phenotypes in the Rett Networked Database","volume":"2019","author":"Frullanti","year":"2019","journal-title":"Int. J. Genom."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1136\/jmedgenet-2013-102113","article-title":"Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome","volume":"51","author":"Cuddapah","year":"2014","journal-title":"J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e000717","DOI":"10.1136\/bmjpo-2020-000717","article-title":"Consensus guidelines on managing Rett syndrome across the lifespan","volume":"4","author":"Fu","year":"2020","journal-title":"BMJ Paediatr. Open"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/ana.22124","article-title":"RettSearch Consortium. Rett syndrome: Revised diagnostic criteria and nomenclature","volume":"68","author":"Neul","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1007\/s10803-013-1902-z","article-title":"Brief report: MECP2 mutations in people without Rett syndrome","volume":"44","author":"Suter","year":"2014","journal-title":"J. Autism Dev. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41597-020-00794-7","article-title":"A catalogue of 863 Rett-syndrome-causing MECP2 mutations and lessons learned from data integration","volume":"8","author":"Ehrhart","year":"2021","journal-title":"Sci. Data"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/s41398-022-02259-4","article-title":"Low levels of Methyl-CpG binding protein 2 are accompanied by an increased vulnerability to the negative outcomes of stress exposure during childhood in healthy women","volume":"12","author":"Cosentino","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/S2213-8587(23)00131-6","article-title":"Rare variants in the MECP2 gene in girls with central precocious puberty: A translational cohort study","volume":"11","author":"Canton","year":"2023","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Vidal, S., Xiol, C., Pascual-Alonso, A., O\u2019Callaghan, M., Pineda, M., and Armstrong, J. (2019). Genetic Landscape of Rett Syndrome Spectrum: Improvements and Challenges. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20163925"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e1917","DOI":"10.1002\/mgg3.1917","article-title":"Analysis of X-inactivation status in a Rett syndrome natural history study cohort","volume":"10","author":"Fang","year":"2022","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Merritt, J.K., Fang, X., Caylor, R.C., Skinner, S.A., Friez, M.J., Percy, A.K., and Neul, J.L. (2024). Normalized Clinical Severity Scores Reveal a Correlation between X Chromosome Inactivation and Disease Severity in Rett Syndrome. Genes, 15.","DOI":"10.20944\/preprints202403.1844.v1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1002\/ajmg.a.34418","article-title":"Genotype-phenotype relationships as prognosticators in Rett syndrome should be handled with care in clinical practice","volume":"158A","author":"Halbach","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1111\/dmcn.15289","article-title":"Delivering paediatric precision medicine: Genomic and environmental considerations along the causal pathway of childhood neurodevelopmental disorders","volume":"64","author":"Woolfenden","year":"2022","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e12048","DOI":"10.1002\/jcv2.12048","article-title":"A national harmonised data collection network for neurodevelopmental disorders: A transdiagnostic assessment protocol for neurodevelopment, mental health, functioning and well-being","volume":"1","author":"Boulton","year":"2021","journal-title":"JCPP Adv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"20552076231191622","DOI":"10.1177\/20552076231191622","article-title":"Feasibility of wearable devices and machine learning for sleep classification in children with Rett syndrome: A pilot study","volume":"9","author":"Migovich","year":"2023","journal-title":"Digit. Health"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Suresha, P.B., O\u2019Leary, H., Tarquinio, D.C., Von Hehn, J., and Clifford, G.D. (2023). Rett syndrome severity estimation with the BioStamp nPoint using interactions between heart rate variability and body movement. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0266351"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Singh, J., Ameenpur, S., Ahmed, R., Basheer, S., Chishti, S., Lawrence, R., Fiori, F., and Santosh, P. (2022). An Observational Study of Heart Rate Variability Using Wearable Sensors Provides a Target for Therapeutic Monitoring of Autonomic Dysregulation in Patients with Rett Syndrome. Biomedicines, 10.","DOI":"10.3390\/biomedicines10071684"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.jpsychires.2021.03.052","article-title":"Emotional Behavioural and Autonomic Dysregulation (EBAD) in Rett Syndrome\u2014EDA and HRV monitoring using wearable sensor technology","volume":"138","author":"Gualniera","year":"2021","journal-title":"J. Psychiatr. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/jir.13010","article-title":"Preliminary assessment of the reliability and validity of infrared skin temperature measurements in Rett syndrome","volume":"67","author":"Byiers","year":"2023","journal-title":"J. Intellect. Disabil. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.cmpb.2010.05.012","article-title":"An open source tool for heart rate variability spectral analysis","volume":"103","author":"Lado","year":"2011","journal-title":"Comput. Methods Programs Biomed."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1136\/jmedgenet-2019-106601","article-title":"Diurnal variation in autonomic regulation among patients with genotyped Rett syndrome","volume":"57","author":"Carroll","year":"2020","journal-title":"J. Med. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1002\/ppul.20866","article-title":"Autonomic dysregulation in young girls with Rett Syndrome during nighttime in-home recordings","volume":"43","author":"Lieske","year":"2008","journal-title":"Pediatr. Pulmonol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1203\/01.pdr.0000238302.84552.d0","article-title":"Autonomic nervous system dysregulation: Breathing and heart rate perturbation during wakefulness in young girls with Rett syndrome","volume":"60","author":"Lieske","year":"2006","journal-title":"Pediatr. Res."},{"key":"ref_26","unstructured":"(2024, May 03). Validation of Innovative Biosensors for Rett Autonomic Symptom Tracking (VIBRANT), Available online: https:\/\/clinicaltrials.gov\/study\/NCT06338267."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"114564","DOI":"10.1016\/j.addr.2022.114564","article-title":"Challenges and opportunities for precision medicine in neurodevelopmental disorders","volume":"191","author":"Chen","year":"2022","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1097\/WCO.0b013e32835f19c3","article-title":"What have we learned from recent twin studies about the etiology of neurodevelopmental disorders?","volume":"26","author":"Posthuma","year":"2013","journal-title":"Curr. Opin. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s10882-013-9351-3","article-title":"Monozygotic twins with Rett syndrome: Phenotyping the first two years of life","volume":"26","author":"Einspieler","year":"2014","journal-title":"J. Dev. Phys. Disabil."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5063","DOI":"10.1007\/s10803-019-04185-9","article-title":"Brief Report: Modest but Clinically Meaningful Effects of Early Behavioral Intervention in Twins with Rett Syndrome-A Case Study","volume":"49","author":"Titlestad","year":"2019","journal-title":"J. Autism Dev. Disord."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1002\/ajmg.a.32002","article-title":"MECP2 deletions and genotype-phenotype correlation in Rett syndrome","volume":"143A","author":"Scala","year":"2007","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1089\/cap.2015.0247","article-title":"Pediatric Antipsychotic Use and Outcomes Monitoring","volume":"27","author":"Santosh","year":"2017","journal-title":"J. Child Adolesc. Psychopharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1177\/0883073815579707","article-title":"Improving Treatment Trial Outcomes for Rett Syndrome: The Development of Rett-specific Anchors for the Clinical Global Impression Scale","volume":"30","author":"Neul","year":"2015","journal-title":"J Child Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Singh, J., Fiori, F., Law, M.L., Ahmed, R., Ameenpur, S., Basheer, S., Chishti, S., Lawrence, R., Mastroianni, M., and Mosaddegh, A. (2022). Development and Psychometric Properties of the Multi-System Profile of Symptoms Scale in Patients with Rett Syndrome. J. Clin. Med., 11.","DOI":"10.3390\/jcm11175094"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Agorastos, A., Mansueto, A.C., Hager, T., Pappi, E., Gardikioti, A., and Stiedl, O. (2023). Heart Rate Variability as a Translational Dynamic Biomarker of Altered Autonomic Function in Health and Psychiatric Disease. Biomedicines, 11.","DOI":"10.3390\/biomedicines11061591"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/S0735-1097(97)00554-8","article-title":"Twenty-four hour time domain heart rate variability and heart rate: Relations to age and gender over nine decades","volume":"31","author":"Umetani","year":"1998","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_37","unstructured":"Empatica (2019, July 18). Session Start-Time Format and Synchronization. Available online: https:\/\/support.empatica.com\/hc\/en-us\/articles\/202800715-Session-start-time-format-and-synchronization."},{"key":"ref_38","unstructured":"R Core Team (2024). A Language and Environment for Statistical Computing, R Foundation for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_39","unstructured":"de Looff, P., Duursma, R., Koldijk, S., de Schepper, K., Noordzij, M., Jaques, N., and Taylor, S. (2019, July 18). Package \u2018Wearables\u201912 October 2022. Available online: https:\/\/cran.r-project.org\/web\/packages\/wearables\/wearables.pdf."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.21105\/joss.01686","article-title":"Welcome to the tidyverse","volume":"4","author":"Wickham","year":"2019","journal-title":"J. Open Source Softw."},{"key":"ref_41","unstructured":"Van Hees, V., Migueles, J., Sabia, S., Patterson, M.R., Fang, Z., Heywood, J., Pujol, J.C., Kushleyeva, L., Chen, M., and Yerramalla, M. (2019, July 18). GGIR: Raw Accelerometer Data Analysis. R Package Version 3.1-1. Available online: https:\/\/CRAN.R-project.org\/package=GGIR."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"055016","DOI":"10.1088\/1361-6579\/ad450d","article-title":"Facilitating ambulatory heart rate variability analysis using accelerometry-based classifications of body position and self-reported sleep","volume":"45","author":"Rietz","year":"2024","journal-title":"Physiol. Meas."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.sleep.2024.04.036","article-title":"Predominant cardiac sympathetic modulation during wake and sleep in patients with Rett syndrome","volume":"119","author":"Rodrigues","year":"2024","journal-title":"Sleep Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1080\/02643290701290146","article-title":"Comparison of a single case to a control or normative sample in neuropsychology: Development of a Bayesian approach","volume":"24","author":"Crawford","year":"2007","journal-title":"Cogn. Neuropsychol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Shkundin, A., and Halaris, A. (2023). Associations of BDNF\/BDNF-AS SNPs with Depression, Schizophrenia, and Bipolar Disorder. J. Pers. Med., 13.","DOI":"10.3390\/jpm13091395"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"252","DOI":"10.26502\/jppd.2572-519X0025","article-title":"The Role of Brain-Derived Neurotrophic Factor in the Pathophysiology of Psychiatric and Neurological Disorders","volume":"1","author":"Anneken","year":"2017","journal-title":"J. Psychiatry Psychiatr. Disord."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Percy, A.K., Neul, J.L., Benke, T.A., Berry-Kravis, E.M., Glaze, D.G., Marsh, E.D., An, D., Bishop, K.M., and Youakim, J.M. (2024). Trofinetide for the treatment of Rett syndrome: Results from the open-label extension LILAC study. Med, In press.","DOI":"10.1016\/j.medj.2024.05.018"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1038\/s41591-023-02398-1","article-title":"Trofinetide for the treatment of Rett syndrome: A randomized phase 3 study","volume":"29","author":"Neul","year":"2023","journal-title":"Nat. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e1912","DOI":"10.1212\/WNL.0000000000007316","article-title":"Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome","volume":"92","author":"Glaze","year":"2019","journal-title":"Neurology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s13023-022-02240-w","article-title":"Improving clinical trial readiness to accelerate development of new therapeutics for Rett syndrome","volume":"17","author":"Leonard","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.yebeh.2010.06.011","article-title":"RMSSD, a measure of vagus-mediated heart rate variability, is associated with risk factors for SUDEP: The SUDEP-7 Inventory","volume":"19","author":"DeGiorgio","year":"2010","journal-title":"Epilepsy Behav."},{"key":"ref_53","unstructured":"Task Force of the European Society of Cardiology the North American Society of Pacing Electrophysiology (1996). Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Eur. Heart J., 17, 354\u2013381."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Shaffer, F., and Ginsberg, J.P. (2017). An Overview of Heart Rate Variability Metrics and Norms. Front. Public Health, 5.","DOI":"10.3389\/fpubh.2017.00258"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Singh, J., Lanzarini, E., and Santosh, P. (2021). Autonomic Characteristics of Sudden Unexpected Death in Epilepsy in Children-A Systematic Review of Studies and Their Relevance to the Management of Epilepsy in Rett Syndrome. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.632510"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.neubiorev.2020.08.007","article-title":"Heart rate variability in individuals with autism spectrum disorders: A meta-analysis","volume":"118","author":"Cheng","year":"2020","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Bradshaw, J., O\u2019reilly, C., Everhart, K.C., Dixon, E., Vinyard, A., Tavakoli, A., and Dail, R.B. (2024). Neonatal autonomic regulation as a predictor of autism symptoms in very preterm infants. J. Perinatol.","DOI":"10.1038\/s41372-024-01942-2"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/0166-2236(88)90011-2","article-title":"5-Hydroxytryptamine receptor subtypes: Molecular, biochemical and physiological characterization","volume":"11","author":"Peroutka","year":"1988","journal-title":"Trends Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.brainres.2012.04.032","article-title":"Buspirone: What is it all about?","volume":"1461","author":"Loane","year":"2012","journal-title":"Brain Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"279","DOI":"10.3233\/NRE-2005-20405","article-title":"Treatment of agitation following traumatic brain injury: A review of the literature","volume":"20","author":"Levy","year":"2005","journal-title":"NeuroRehabilitation"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1002\/ejhf.1854","article-title":"Benefit of buspirone on chemoreflex and central apnoeas in heart failure: A randomized controlled crossover trial","volume":"23","author":"Giannoni","year":"2021","journal-title":"Eur. J. Heart Fail."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0022-3476(97)70315-9","article-title":"Treatment of apneustic respiratory disturbance with a serotonin-receptor agonist","volume":"130","author":"Wilken","year":"1997","journal-title":"J. Pediatr."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"S38","DOI":"10.1016\/S0387-7604(01)00335-7","article-title":"Importance of Rett syndrome in child neurology","volume":"23","author":"Dunn","year":"2001","journal-title":"Brain Dev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.braindev.2004.09.011","article-title":"Buspirone in Rett syndrome respiratory dysfunction","volume":"27","author":"Andaku","year":"2005","journal-title":"Brain Dev."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.pediatrneurol.2011.12.003","article-title":"Use of buspirone and fluoxetine for breathing problems in Rett syndrome","volume":"46","year":"2012","journal-title":"Pediatr. Neurol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.pediatrneurol.2016.03.016","article-title":"Effect of Serotonin 1A Agonists and Selective Serotonin Reuptake Inhibitors on Behavioral and Nighttime Respiratory Symptoms in Rett Syndrome","volume":"60","author":"Ohno","year":"2016","journal-title":"Pediatr. Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s11689-017-9196-7","article-title":"Autonomic breathing abnormalities in Rett syndrome: Caregiver perspectives in an international database study","volume":"9","author":"Mackay","year":"2017","journal-title":"J. Neurodev. Disord."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s40263-023-01014-7","article-title":"The Serotonin 1A (5-HT1A) Receptor as a Pharmacological Target in Depression","volume":"37","author":"Smith","year":"2023","journal-title":"CNS Drugs"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"448","DOI":"10.4088\/JCP.v62n0608","article-title":"Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: Results from a placebo-controlled, randomized, double-blind, placebo wash-in study","volume":"62","author":"Appelberg","year":"2001","journal-title":"J. Clin. Psychiatry"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s11689-022-09432-2","article-title":"Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study","volume":"14","author":"Buchanan","year":"2022","journal-title":"J. Neurodev. Disord."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"217","DOI":"10.4236\/jbbs.2013.32023","article-title":"Treatment Response in Behaviour Disorders in Rett Syndrome","volume":"3","author":"Turon","year":"2013","journal-title":"J. Behav. Brain Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.resp.2009.04.017","article-title":"Breathing disorders in Rett syndrome: Progressive neurochemical dysfunction in the respiratory network after birth","volume":"168","author":"Katz","year":"2009","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1503\/jpn.190033","article-title":"Autonomic dysfunction and sudden death in patients with Rett syndrome: A systematic review","volume":"45","author":"Singh","year":"2020","journal-title":"J. Psychiatry Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.resp.2008.05.014","article-title":"Contributions of 5-HT neurons to respiratory control: Neuromodulatory and trophic effects","volume":"164","author":"Hodges","year":"2008","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Abdala, A.P., Bissonnette, J.M., and Newman-Tancredi, A. (2014). Pinpointing brainstem mechanisms responsible for autonomic dysfunction in Rett syndrome: Therapeutic perspectives for 5-HT1A agonists. Front. Physiol., 5.","DOI":"10.3389\/fphys.2014.00205"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1006\/mcne.2000.0841","article-title":"Sequential activation of the 5-HT1(A) serotonin receptor and TrkB induces the serotonergic neuronal phenotype","volume":"15","author":"Galter","year":"2000","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Lavezzi, A.M., Corna, M.F., and Matturri, L. (2014). Disruption of the brain-derived neurotrophic factor (BDNF) immunoreactivity in the human K\u00f6lliker-Fuse nucleus in victims of unexplained fetal and infant death. Front. Hum. Neurosci., 8.","DOI":"10.3389\/fnhum.2014.00648"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S0092-8674(03)00035-7","article-title":"The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function","volume":"112","author":"Egan","year":"2003","journal-title":"Cell"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Camuso, S., La Rosa, P., Fiorenza, M.T., and Canterini, S. (2022). Pleiotropic effects of BDNF on the cerebellum and hippocampus: Implications for neurodevelopmental disorders. Neurobiol. Dis., 163.","DOI":"10.1016\/j.nbd.2021.105606"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.neuropharm.2013.03.024","article-title":"BDNF deregulation in Rett syndrome","volume":"76","author":"Li","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Pejhan, S., Del Bigio, M.R., and Rastegar, M. (2020). The MeCP2E1\/E2-BDNF-miR132 Homeostasis Regulatory Network Is Region-Dependent in the Human Brain and Is Impaired in Rett Syndrome Patients. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00763"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1111\/nan.12619","article-title":"Differential brain region-specific expression of MeCP2 and BDNF in Rett Syndrome patients: A distinct grey-white matter variation","volume":"46","author":"Pejhan","year":"2020","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1126\/science.1086446","article-title":"Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2","volume":"302","author":"Chen","year":"2003","journal-title":"Science"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13023-017-0752-8","article-title":"Environmental enrichment intervention for Rett syndrome: An individually randomised stepped wedge trial","volume":"13","author":"Downs","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1212\/01.wnl.0000345664.72220.6a","article-title":"The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome","volume":"72","author":"Zeev","year":"2009","journal-title":"Neurology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1212\/01.wnl.0000304086.75913.b2","article-title":"The p.Val66Met polymorphism in the BDNF gene protects against early seizures in Rett syndrome","volume":"70","author":"Nectoux","year":"2008","journal-title":"Neurology"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Haase, F., Singh, R., Gloss, B., Tam, P., and Gold, W. (2022). Meta-Analysis Identifies BDNF and Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome. Int. J. Mol. Sci., 23.","DOI":"10.20944\/preprints202207.0030.v1"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Ball, N.J., Mercado, E., and Ordu\u00f1a, I. (2019). Enriched Environments as a Potential Treatment for Developmental Disorders: A Critical Assessment. Front. Psychol., 10.","DOI":"10.3389\/fpsyg.2019.00466"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.neubiorev.2020.08.012","article-title":"Organic features of autonomic dysregulation in paediatric brain injury\u2014Clinical and research implications for the management of patients with Rett syndrome","volume":"118","author":"Singh","year":"2020","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1111\/cts.12895","article-title":"Retrospective Review of Pharmacogenetic Testing at an Academic Children\u2019s Hospital","volume":"14","author":"Roberts","year":"2021","journal-title":"Clin. Transl. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Jameson, A., Fylan, B., Bristow, G.C., Sagoo, G.S., Dalton, C., Cardno, A., Sohal, J., and McLean, S.L. (2021). What Are the Barriers and Enablers to the Implementation of Pharmacogenetic Testing in Mental Health Care Settings?. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.740216"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/46\/8\/497\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:28:48Z","timestamp":1760110128000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/46\/8\/497"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,2]]},"references-count":91,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["cimb46080497"],"URL":"https:\/\/doi.org\/10.3390\/cimb46080497","relation":{},"ISSN":["1467-3045"],"issn-type":[{"type":"electronic","value":"1467-3045"}],"subject":[],"published":{"date-parts":[[2024,8,2]]}}}