{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T16:55:33Z","timestamp":1789059333625,"version":"build-2803163510"},"reference-count":90,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2019,8,12]],"date-time":"2019-08-12T00:00:00Z","timestamp":1565568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI15\/01159"],"award-info":[{"award-number":["PI15\/01159"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Spanish Ministry of Health  (Fundacion Espanola para la Ciencia y la Tecnolog\u00eda)","award":["Precipita"],"award-info":[{"award-number":["Precipita"]}]},{"name":"Catalan Association for Rett Syndrome","award":["PFNR0004"],"award-info":[{"award-number":["PFNR0004"]}]},{"name":"Fondobiorett","award":["FPNR0004"],"award-info":[{"award-number":["FPNR0004"]}]},{"name":"Mi Princesa Rett","award":["PFNR0004"],"award-info":[{"award-number":["PFNR0004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that primarily affects females, resulting in severe cognitive and physical disabilities, and is one of the most prevalent causes of intellectual disability in females. More than fifty years after the first publication on Rett syndrome, and almost two decades since the first report linking RTT to the MECP2 gene, the research community\u2019s effort is focused on obtaining a better understanding of the genetics and the complex biology of RTT and Rett-like phenotypes without MECP2 mutations. Herein, we review the current molecular genetic studies, which investigate the genetic causes of RTT or Rett-like phenotypes which overlap with other genetic disorders and document the swift evolution of the techniques and methodologies employed. This review also underlines the clinical and genetic heterogeneity of the Rett syndrome spectrum and provides an overview of the RTT-related genes described to date, many of which are involved in epigenetic gene regulation, neurotransmitter action or RNA transcription\/translation. Finally, it discusses the importance of including both phenotypic and genetic diagnosis to provide proper genetic counselling from a patient\u2019s perspective and the appropriate treatment.<\/jats:p>","DOI":"10.3390\/ijms20163925","type":"journal-article","created":{"date-parts":[[2019,8,13]],"date-time":"2019-08-13T04:31:21Z","timestamp":1565670681000},"page":"3925","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Genetic Landscape of Rett Syndrome Spectrum: Improvements and Challenges"],"prefix":"10.3390","volume":"20","author":[{"given":"Silvia","family":"Vidal","sequence":"first","affiliation":[{"name":"Sant Joan de D\u00e9u Research Foundation, 08950 Barcelona, Spain"},{"name":"Institut de Recerca Pedi\u00e0trica Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Xiol","sequence":"additional","affiliation":[{"name":"Sant Joan de D\u00e9u Research Foundation, 08950 Barcelona, Spain"},{"name":"Institut de Recerca Pedi\u00e0trica Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainhoa","family":"Pascual-Alonso","sequence":"additional","affiliation":[{"name":"Sant Joan de D\u00e9u Research Foundation, 08950 Barcelona, Spain"},{"name":"Institut de Recerca Pedi\u00e0trica Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"O\u2019Callaghan","sequence":"additional","affiliation":[{"name":"Institut de Recerca Pedi\u00e0trica Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"},{"name":"Neurology Service, Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"},{"name":"CIBER-ER (Biomedical Network Research Center for Rare Diseases), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merc\u00e8","family":"Pineda","sequence":"additional","affiliation":[{"name":"Sant Joan de D\u00e9u Research Foundation, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0588-9307","authenticated-orcid":false,"given":"Judith","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Institut de Recerca Pedi\u00e0trica Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"},{"name":"CIBER-ER (Biomedical Network Research Center for Rare Diseases), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain"},{"name":"Molecular and Genetics Medicine Section, Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,12]]},"reference":[{"key":"ref_1","first-page":"723","article-title":"On a unusual brain atrophy syndrome in hyperammonemia in childhood","volume":"116","author":"Rett","year":"1966","journal-title":"Wien. Med. Wochenschr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/13810","article-title":"Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2","volume":"23","author":"Amir","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1093\/nar\/gkh349","article-title":"The major form of MeCP2 has a novel N-terminus generated by alternative splicing","volume":"32","author":"Kriaucionis","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/ng1327","article-title":"A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome","volume":"36","author":"Mnatzakanian","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2447","DOI":"10.1093\/hmg\/ddt640","article-title":"Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome","volume":"23","author":"Yasui","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1002\/humu.10194","article-title":"RettBASE: The IRSA MECP2 variation database-a new mutation database in evolution","volume":"21","author":"Christodoulou","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1212\/01.wnl.0000291011.54508.aa","article-title":"Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome","volume":"70","author":"Neul","year":"2008","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/ng1264","article-title":"Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation","volume":"35","author":"Kalscheuer","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.ajhg.2008.05.015","article-title":"FOXG1 is responsible for the congenital variant of Rett syndrome","volume":"83","author":"Ariani","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Srivastava, S., Love-Nichols, J.A., Dies, K.A., Ledbetter, D.H., Martin, C.L., Chung, W.K., Firth, H.V., Frazier, T., Hansen, R.L., and Prock, L. (2019). Meta-analysis and multidisciplinary consensus statement: Exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet. Med.","DOI":"10.1038\/s41436-019-0554-6"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1053\/ejpn.2002.0612","article-title":"An update on clinically applicable diagnostic criteria in Rett syndrome. Comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001","volume":"6","author":"Hagberg","year":"2002","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/ana.22124","article-title":"Rett syndrome: Revised diagnostic criteria and nomenclature","volume":"68","author":"Neul","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cell.2013.09.006","article-title":"The next-generation sequencing revolution and its impact on genomics","volume":"155","author":"Koboldt","year":"2013","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wang, J., Zhang, Q., Chen, Y., Yu, S., Wu, X., Bao, X., and Wen, Y. (2018). Novel MEF2C point mutations in Chinese patients with Rett (-like) syndrome or non-syndromic intellectual disability: Insights into genotype-phenotype correlation. BMC Med. Genet., 19.","DOI":"10.1186\/s12881-018-0699-1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12288","DOI":"10.1038\/s41598-017-11620-3","article-title":"The utility of Next Generation Sequencing for molecular diagnostics in Rett syndrome","volume":"7","author":"Vidal","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/cge.13153","article-title":"Clinician\u2019s guide to genes associated with Rett-like phenotypes-Investigation of a Danish cohort and review of the literature","volume":"95","author":"Bisgaard","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_17","first-page":"4","article-title":"Next-generation sequencing approach for the diagnosis of human diseases: Open challenges and new opportunities","volume":"29","author":"Galbiati","year":"2018","journal-title":"EJIFCC"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s10048-017-0535-3","article-title":"Monogenic disorders that mimic the phenotype of Rett syndrome","volume":"19","author":"Srivastava","year":"2018","journal-title":"Neurogenetics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1007\/s00439-016-1721-3","article-title":"Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype","volume":"135","author":"Lucariello","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41525-018-0056-5","article-title":"Exome sequencing for paediatric-onset diseases: Impact of the extensive involvement of medical geneticists in the diagnostic odyssey","volume":"3","author":"Mak","year":"2018","journal-title":"NPJ Genom. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s00439-016-1658-6","article-title":"Novel bioinformatic developments for exome sequencing","volume":"135","author":"Lelieveld","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1056\/NEJMoa0908094","article-title":"Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy","volume":"362","author":"Lupski","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/nature13394","article-title":"Genome sequencing identifies major causes of severe intellectual disability","volume":"511","author":"Gilissen","year":"2014","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1038\/gim.2015.155","article-title":"Mosaic mutations in early-onset genetic diseases","volume":"18","author":"Halvorsen","year":"2016","journal-title":"Genet. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1136\/jmedgenet-2018-105672","article-title":"Assessment of parental mosaicism in SCN1A-related epilepsy by single-molecule molecular inversion probes and next-generation sequencing","volume":"56","author":"Koudijs","year":"2019","journal-title":"J. Med. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e199","DOI":"10.1212\/NXG.0000000000000199","article-title":"Germline and somatic mutations in STXBP1 with diverse neurodevelopmental phenotypes","volume":"3","author":"Uddin","year":"2017","journal-title":"Neurol. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1038\/s41593-018-0257-3","article-title":"Somatic mosaicism and neurodevelopmental disease","volume":"21","author":"Walsh","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1111\/epi.14021","article-title":"Mosaicism of de novo pathogenic SCN1A variants in epilepsy is a frequent phenomenon that correlates with variable phenotypes","volume":"59","author":"Koudijs","year":"2018","journal-title":"Epilepsia"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e25","DOI":"10.1111\/epi.12554","article-title":"Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities","volume":"55","author":"Baasch","year":"2014","journal-title":"Epilepsia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/jhg.2014.71","article-title":"A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation","volume":"59","author":"Saitsu","year":"2014","journal-title":"J. Hum. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1111\/cge.12492","article-title":"Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders","volume":"88","author":"Okamoto","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1002\/ajmg.a.36775","article-title":"De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient","volume":"167","author":"Hara","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1002\/ajmg.a.37132","article-title":"Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome","volume":"167A","author":"Olson","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.mcp.2016.01.003","article-title":"WDR45 mutations in Rett (-like) syndrome and developmental delay: Case report and an appraisal of the literature","volume":"30","author":"Hoffjan","year":"2016","journal-title":"Mol. Cell Probes"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1111\/cge.12698","article-title":"SATB2-associated syndrome presenting with Rett-like phenotypes","volume":"89","author":"Lee","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/gim.2015.100","article-title":"Mutations in JMJD1C are involved in Rett syndrome and intellectual disability","volume":"18","author":"Saez","year":"2016","journal-title":"Genet. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.ejmg.2016.05.017","article-title":"MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and review","volume":"59","author":"Rocha","year":"2016","journal-title":"Eur. J. Med. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1136\/jmedgenet-2015-103568","article-title":"Identification of novel genetic causes of Rett syndrome-like phenotypes","volume":"53","author":"Lopes","year":"2016","journal-title":"J. Med. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/gim.2016.42","article-title":"Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2","volume":"19","author":"Sajan","year":"2017","journal-title":"Genet. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1111\/cge.12784","article-title":"Rett-like phenotypes: Expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease","volume":"91","author":"Allou","year":"2017","journal-title":"Clin. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1002\/ana.25032","article-title":"GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy","volume":"82","author":"Yoo","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1002\/ana.25155","article-title":"A novel mutation in the transmembrane 6 domain of GABBR2 leads to a Rett-like phenotype","volume":"83","author":"Vuillaume","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1002\/ajmg.a.38279","article-title":"Phenotypes and genotypes in individuals with SMC1A variants","volume":"173","author":"Huisman","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_44","first-page":"49","article-title":"When Rett syndrome is due to genes other than MECP2","volume":"3","author":"Percy","year":"2018","journal-title":"Transl. Sci. Rare Dis."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Iwama, K., Mizuguchi, T., Takeshita, E., Nakagawa, E., Okazaki, T., Nomura, Y., Iijima, Y., Kajiura, I., Sugai, K., and Saito, T. (2019). Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing. J. Med. Genet.","DOI":"10.1136\/jmedgenet-2018-105775"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Vidal, S., Brandi, N., Pacheco, P., Maynou, J., Fernandez, G., Xiol, C., Pascual-Alonso, A., Pineda, M., Rett Working, G., and Armstrong, J. (2019). The most recurrent monogenic disorders that overlap with the phenotype of Rett syndrome. Eur. J. Paediatr. Neurol.","DOI":"10.1016\/j.ejpn.2019.04.006"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1006\/geno.1997.5202","article-title":"Identification and characterization of the human ortholog of rat STXBP1, a protein implicated in vesicle trafficking and neurotransmitter release","volume":"48","author":"Swanson","year":"1998","journal-title":"Genomics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"18332","DOI":"10.1073\/pnas.0608507103","article-title":"Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size","volume":"103","author":"Toonen","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1152\/jn.00826.2007","article-title":"Early defects of GABAergic synapses in the brain stem of a MeCP2 mouse model of Rett syndrome","volume":"99","author":"Medrihan","year":"2008","journal-title":"J. Neurophysiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1093\/hmg\/dds112","article-title":"Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects","volume":"21","author":"Sepp","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s13023-016-0422-2","article-title":"Phenotype and natural history in 101 individuals with Pitt-Hopkins syndrome through an internet questionnaire system","volume":"11","author":"Baas","year":"2016","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.tins.2018.03.011","article-title":"Progress in Understanding and Treating SCN2A-Mediated Disorders","volume":"41","author":"Sanders","year":"2018","journal-title":"Trends Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9314","DOI":"10.1038\/sj.onc.1208331","article-title":"WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy","volume":"23","author":"Waddell","year":"2004","journal-title":"Oncogene"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1016\/j.ajhg.2012.10.019","article-title":"Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA","volume":"91","author":"Haack","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/jhg.2014.18","article-title":"De novo WDR45 mutation in a patient showing clinically Rett syndrome with childhood iron deposition in brain","volume":"59","author":"Ohba","year":"2014","journal-title":"J. Hum. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1002\/humu.21253","article-title":"Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression","volume":"31","author":"Zweier","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s10048-012-0344-7","article-title":"Refining the phenotype associated with MEF2C point mutations","volume":"14","author":"Bienvenu","year":"2013","journal-title":"Neurogenetics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/85899","article-title":"A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome","volume":"27","author":"Guy","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.nbd.2009.05.001","article-title":"Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations","volume":"35","author":"Chapleau","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1126\/science.1138389","article-title":"Reversal of neurological defects in a mouse model of Rett syndrome","volume":"315","author":"Guy","year":"2007","journal-title":"Science"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1523\/JNEUROSCI.2623-05.2006","article-title":"Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome","volume":"26","author":"Moretti","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"21966","DOI":"10.1073\/pnas.0912257106","article-title":"Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities","volume":"106","author":"Samaco","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Harrington, A.J., Raissi, A., Rajkovich, K., Berto, S., Kumar, J., Molinaro, G., Raduazzo, J., Guo, Y., Loerwald, K., and Konopka, G. (2016). MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders. Elife, 5.","DOI":"10.7554\/eLife.20059"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41467-017-00688-0","article-title":"Oligodendroglial excitability mediated by glutamatergic inputs and Nav1.2 activation","volume":"8","author":"Berret","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3389\/fnmol.2019.00145","article-title":"Scn2a Haploinsufficiency in Mice Suppresses Hippocampal Neuronal Excitability, Excitatory Synaptic Drive, and Long-Term Potentiation, and Spatial Learning and Memory","volume":"12","author":"Shin","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4525","DOI":"10.1523\/JNEUROSCI.3352-16.2017","article-title":"Early Golgi Abnormalities and Neurodegeneration upon Loss of Presynaptic Proteins Munc18-1, Syntaxin-1, or SNAP-25","volume":"37","author":"Santos","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1038\/s41380-019-0353-0","article-title":"Disruption of TCF4 regulatory networks leads to abnormal cortical development and mental disabilities","volume":"24","author":"Li","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Wan, H., Wang, Q., Chen, X., Zeng, Q., Shao, Y., Fang, H., Liao, X., Li, H.S., Liu, M.G., and Xu, T.L. (2019). WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death. Autophagy.","DOI":"10.1101\/282210"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s13023-016-0545-5","article-title":"Rett syndrome - biological pathways leading from MECP2 to disorder phenotypes","volume":"11","author":"Ehrhart","year":"2016","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Ehrhart, F., Coort, S.L., Eijssen, L., Cirillo, E., Smeets, E.E., Bahram Sangani, N., Evelo, C.T., and Curfs, L.M.G. (2019). Integrated analysis of human transcriptome data for Rett syndrome finds a network of involved genes. World J. Biol. Psychiatry.","DOI":"10.1101\/274258"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/0887-8994(91)90082-V","article-title":"Membrane cerebral lipids in Rett syndrome","volume":"7","author":"Lekman","year":"1991","journal-title":"Pediatr. Neurol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"10520","DOI":"10.1038\/ncomms10520","article-title":"Reduction of aberrant NF-kappaB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice","volume":"7","author":"Kishi","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.yfrne.2013.03.001","article-title":"Neurosteroid and neurotransmitter alterations in Parkinson\u2019s disease","volume":"34","author":"Luchetti","year":"2013","journal-title":"Front. Neuroendocrinol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1038\/nn.3710","article-title":"Cellular origins of auditory event-related potential deficits in Rett syndrome","volume":"17","author":"Goffin","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/nature09582","article-title":"Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes","volume":"468","author":"Chao","year":"2010","journal-title":"Nature"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"E7287","DOI":"10.1073\/pnas.1615330113","article-title":"Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome","volume":"113","author":"Banerjee","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1073\/pnas.1524013113","article-title":"KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome","volume":"113","author":"Tang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Cosentino, L., Vigli, D., Franchi, F., Laviola, G., and De Filippis, B. (2019). Rett syndrome before regression: A time window of overlooked opportunities for diagnosis and intervention. Neurosci. Biobehav. Rev.","DOI":"10.1016\/j.neubiorev.2019.05.013"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1093\/cercor\/bhv078","article-title":"Defects During Mecp2 Null Embryonic Cortex Development Precede the Onset of Overt Neurological Symptoms","volume":"26","author":"Bedogni","year":"2016","journal-title":"Cereb Cortex"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1212\/WNL.0000000000004515","article-title":"Randomized open-label trial of dextromethorphan in Rett syndrome","volume":"89","author":"Gupta","year":"2017","journal-title":"Neurology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1002\/acn3.468","article-title":"Effect of desipramine on patients with breathing disorders in RETT syndrome","volume":"5","author":"Mancini","year":"2018","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/acn3.533","article-title":"Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome","volume":"5","author":"Kaufmann","year":"2018","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1080\/14728222.2017.1386175","article-title":"STXBP1 as a therapeutic target for epileptic encephalopathy","volume":"21","author":"Stamberger","year":"2017","journal-title":"Expert. Opin. Ther. Targets"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1126\/science.1163174","article-title":"Conformational switch of syntaxin-1 controls synaptic vesicle fusion","volume":"321","author":"Gerber","year":"2008","journal-title":"Science"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.biopsych.2008.10.036","article-title":"Rett syndrome and the impact of MeCP2 associated transcriptional mechanisms on neurotransmission","volume":"65","author":"Monteggia","year":"2009","journal-title":"Biol. Psychiatry"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"11263","DOI":"10.1523\/JNEUROSCI.1019-09.2009","article-title":"Intact long-term potentiation but reduced connectivity between neocortical layer 5 pyramidal neurons in a mouse model of Rett syndrome","volume":"29","author":"Dani","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3389\/fncel.2012.00005","article-title":"Role of the neuronal K-Cl co-transporter KCC2 in inhibitory and excitatory neurotransmission","volume":"6","author":"Chamma","year":"2012","journal-title":"Front. Cell Neurosci."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Duarte, S.T., Armstrong, J., Roche, A., Ortez, C., Perez, A., O\u2019Callaghan Mdel, M., Pereira, A., Sanmarti, F., Ormazabal, A., and Artuch, R. (2013). Abnormal expression of cerebrospinal fluid cation chloride cotransporters in patients with Rett syndrome. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0068851"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"9276","DOI":"10.1038\/s41598-019-45635-9","article-title":"Early alterations in a mouse model of Rett syndrome: The GABA developmental shift is abolished at birth","volume":"9","author":"Lozovaya","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"eaau0164","DOI":"10.1126\/scitranslmed.aau0164","article-title":"Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice","volume":"11","author":"Tang","year":"2019","journal-title":"Sci. Transl. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/16\/3925\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:10:37Z","timestamp":1760188237000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/16\/3925"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,12]]},"references-count":90,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2019,8]]}},"alternative-id":["ijms20163925"],"URL":"https:\/\/doi.org\/10.3390\/ijms20163925","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,12]]}}}