{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:55:50Z","timestamp":1760234150096,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T00:00:00Z","timestamp":1618790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neuroprostanes, a family of non-enzymatic metabolites of the docosahexaenoic acid, have been suggested as potential biomarkers for neurological diseases. Objective biological markers are strongly needed in Rett syndrome (RTT), which is a progressive X-linked neurodevelopmental disorder that is mainly caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene with a predominant multisystemic phenotype. The aim of the study is to assess a possible association between MECP2 mutations or RTT disease progression and plasma levels of 4(RS)-4-F4t-neuroprostane (4-F4t-NeuroP) and 10(RS)-10-F4t-neuroprostane (10-F4t-NeuroP) in typical RTT patients with proven MECP2 gene mutation. Clinical severity and disease progression were assessed using the Rett clinical severity scale (RCSS) in n = 77 RTT patients. The 4-F4t-NeuroP and 10-F4t-NeuroP molecules were totally synthesized and used to identify the contents of the plasma of the patients. Neuroprostane levels were related to MECP2 mutation category (i.e., early truncating, gene deletion, late truncating, and missense), specific hotspot mutations (i.e., R106W, R133C, R168X, R255X, R270X, R294X, R306C, and T158M), and disease stage (II through IV). Circulating 4-F4t-NeuroP and 10-F4t-NeuroP were significantly related to (i) the type of MECP2 mutations where higher levels were associated to gene deletions (p \u2264 0.001); (ii) severity of common hotspot MECP2 mutation (large deletions, R168X, R255X, and R270X); (iii) disease stage, where higher concentrations were observed at stage II (p \u2264 0.002); and (iv) deficiency in walking (p \u2264 0.0003). This study indicates the biological significance of 4-F4t-NeuroP and 10-F4t-NeuroP as promising molecules to mark the disease progression and potentially gauge genotype\u2013phenotype associations in RTT.<\/jats:p>","DOI":"10.3390\/ijms22084240","type":"journal-article","created":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T11:21:38Z","timestamp":1618831298000},"page":"4240","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Circulating 4-F4t-Neuroprostane and 10-F4t-Neuroprostane Are Related to MECP2 Gene Mutation and Natural History in Rett Syndrome"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0006-9414","authenticated-orcid":false,"given":"Cinzia","family":"Signorini","sequence":"first","affiliation":[{"name":"Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy;<email>ciccolil@yahoo.it<\/email>"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7027-1207","authenticated-orcid":false,"given":"Silvia","family":"Leoncini","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy;<email>s.leoncini74@gmail.com<\/email>"},{"name":"Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy;<email>hayekjoussef@gmail.com<\/email>"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thierry","family":"Durand","sequence":"additional","affiliation":[{"name":"Institut des Biomol\u00e9cules Max Mousseron, (IBMM), UMR 5247, CNRS, Universit\u00e9 de Montpellier, ENSCM, CEDEX 5, 34093 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Marie","family":"Galano","sequence":"additional","affiliation":[{"name":"Institut des Biomol\u00e9cules Max Mousseron, (IBMM), UMR 5247, CNRS, Universit\u00e9 de Montpellier, ENSCM, CEDEX 5, 34093 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandre","family":"Guy","sequence":"additional","affiliation":[{"name":"Institut des Biomol\u00e9cules Max Mousseron, (IBMM), UMR 5247, CNRS, Universit\u00e9 de Montpellier, ENSCM, CEDEX 5, 34093 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Val\u00e9rie","family":"Bultel-Ponc\u00e9","sequence":"additional","affiliation":[{"name":"Institut des Biomol\u00e9cules Max Mousseron, (IBMM), UMR 5247, CNRS, Universit\u00e9 de Montpellier, ENSCM, CEDEX 5, 34093 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5177-5792","authenticated-orcid":false,"given":"Camille","family":"Oger","sequence":"additional","affiliation":[{"name":"Institut des Biomol\u00e9cules Max Mousseron, (IBMM), UMR 5247, CNRS, Universit\u00e9 de Montpellier, ENSCM, CEDEX 5, 34093 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8175-7069","authenticated-orcid":false,"given":"Jetty Chung-Yung","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, The University of Hong Kong, Hong Kong"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Ciccoli","sequence":"additional","affiliation":[{"name":"Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy;<email>ciccolil@yahoo.it<\/email>"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joussef","family":"Hayek","sequence":"additional","affiliation":[{"name":"Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy;<email>hayekjoussef@gmail.com<\/email>"},{"name":"Pediatric Speciality Center \u201cL\u2019Isola di Bau\u201d, 50052 Certaldo, Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"De Felice","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy;<email>s.leoncini74@gmail.com<\/email>"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1602\/neurorx.1.2.182","article-title":"Biomarkers: Potential uses and limitations","volume":"1","author":"Mayeux","year":"2004","journal-title":"NeuroRx"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S0065-2423(08)00405-8","article-title":"Biomarkers related to aging in human populations","volume":"46","author":"Crimmins","year":"2008","journal-title":"Adv. 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