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Preclinical studies using genetic\u2010based treatment showed robust phenotype recovery for both MDS and RTT. However, there is a risk of converting MDS to RTT, or vice versa, if accurate MeCP2 levels are not achieved. The aim of this study was to identify biomarkers distinguishing RTT from MDS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>We prospectively enrolled 11 MDS and 6 male RTT like (MRL) individuals for a panel of clinical and neurophysiological assessments over two visits, 8\u201310\u2009months apart.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified numerous clinical and physiological features as promising biomarkers. MRL individuals exhibited large amplitude whole body tremor, midline stereotypies (vs. hand flapping at sides in MDS), earlier neuromotor regression, and earlier onset but less commonly refractory epilepsy. In the neurophysiological domain, we observed several marked differences in sleep physiology between MDS\/MRL and typically developing (TD) individuals including reduced sleeping time, increased delta power during rapid eye movement (REM) sleep, decreased occipital alpha and increased brain\u2010wide delta power during wakefulness, and reduced spindle density and duration. MRL individuals also had much lower delta power during NREM 2 and 3 stages than the TD group. We found differences in spindle duration in the temporal lobes and spindle amplitude in the frontal lobes between MDS and MRL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our study revealed distinct clinical features of MDS and MRL that can be monitored during a clinical trial and may serve as target engagement, disease progression, or safety biomarkers for interventional studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.52269","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T01:15:20Z","timestamp":1737508520000},"page":"433-447","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Comprehensive assessment reveals numerous clinical and neurophysiological differences between\n                    <scp>\n                      <i>MECP2<\/i>\n                    <\/scp>\n                    \u2010allelic disorders"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5788-0270","authenticated-orcid":false,"given":"Davut","family":"Pehlivan","sequence":"first","affiliation":[{"name":"Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics Baylor College of Medicine  Houston Texas 77030 USA"},{"name":"Blue Bird Circle Rett Center Texas Children's Hospital  Houston Texas 77030 USA"},{"name":"Texas Children's Hospital  Houston Texas 77030 USA"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital  Houston Texas 77030 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengjun","family":"Huang","sequence":"additional","affiliation":[{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital  Houston Texas 77030 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly 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