Rett syndrome (RTT) has experienced remarkable progress over the past three decades since emerging as a disorder of worldwide proportions, particularly with discovery of the linkage of RTT to MECP2 mutations. The advances in clinical research and the increasing pace of basic science investigations have accelerated the pattern of discovery and understanding. Clinical trials are ongoing and others are planned. A review of these events and the prospects for continued success are highlighted below. The girls and women encountered today with RTT are, overall, in better general, neurologic, and behavioral health than those encountered earlier. This represents important progress worldwide from the concerted efforts of a broadly based and diverse clinical and basic research consortium as well as the efforts of parents, family, and friends. 1. Introduction: Early History of Rett Syndrome Rett syndrome (RTT; Online Mendelian Inheritance in Man #312750; http://www.ncbi.nlm.nih.gov/omim/) was first recognized by Andreas Rett, a neurodevelopmental pediatrician in Vienna, more than fifty years ago when he observed two girls in his clinic simultaneously engaged in hand stereotypies [1, 2]. His attempts to raise awareness of this observation among physicians in Europe met with little success in creating interest in expanding understanding of this unique neurodevelopmental disorder. As it happened, most of his written efforts were in German and were not widely circulated beyond Austria. Bengt Hagberg, a Swedish child neurologist, had also identified young girls with virtually identical features, but unlike Rett, he did not report these observations or extend his information beyond Sweden. Rett’s single major English publication appeared in the Handbook of Clinical Neurology in 1977 [3]. However, a series of extensive metabolic tests on blood and urine in his participants with this disorder had identified hyperammonemia, the subject of this Handbook volume. Fortunately, this finding turned out to be spurious. At a gathering of child neurologists in Europe near the end of the 1970s, Hagberg became aware of this change in the association of these clinical features and hyperammonemia, realized that they were observing the same disorder, and planned together with Jean Aicardi, Karin Dias, and Ovidio Ramos to publish their own combined experiences. Shortly thereafter in 1981, Hagberg had a chance meeting with Rett in Toronto and following this discussion elected to name the disorder Rett syndrome. At the time, RTT was scarcely known outside of Europe, but with the 1983
References
[1]
A. Rett, “Uber ein eigenartiges hirnatrophisches Syndrom bei Hyperammonamie im Kindesalter,” Wiener Medizinische Wochenschrift, vol. 116, pp. 723–726, 1966.
[2]
A. Rett, Uber ein cerebral-atrophisches Syndrom bei Hyperammonaemie, Bruder Hollinek, Wien, Germany, 1966.
[3]
A. Rett, “Cerebral atrophy associated with hyperammonemia,” in Handbook of Clinical Neurology, P. J. Vincken and G. W. Bruyn, Eds., pp. 305–329, North-Holland Publishing, Amsterdam, The Netherlands, 1977.
[4]
B. Hagberg, J. Aicardi, K. Dias, and O. Ramos, “A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome. Report of 35 cases,” Annals of Neurology, vol. 14, no. 4, pp. 471–479, 1983.
[5]
A. Rett, “Rett syndrome: history and general overview,” American Journal of Medical Genetics, vol. 24, no. 1, pp. 21–25, 1986.
[6]
A. K. Percy, H. Zoghbi, and V. M. Riccardi, “Rett syndrome: initial experience with an emerging clinical entity,” Brain and Development, vol. 7, no. 3, pp. 300–304, 1985.
[7]
B. Hagberg, F. Goutieres, and F. Hanefeld, “Rett syndrome: criteria for inclusion and exclusion,” Brain and Development, vol. 7, no. 3, pp. 372–373, 1985.
[8]
H. Y. Zoghbi, A. K. Percy, and D. G. Glaze, “Reduction of biogenic amine levels in the Rett syndrome,” The New England Journal of Medicine, vol. 313, no. 15, pp. 921–924, 1985.
[9]
A. Lekman, I. Witt-Engerstrom, J. Gottfries, B. A. Hagberg, A. K. Percy, and L. Svennerholm, “Rett syndrome: biogenic amines and metabolites in postmortem brain,” Pediatric Neurology, vol. 5, no. 6, pp. 357–362, 1989.
[10]
C. A. Kozinetz, M. L. Skender, N. MacNaughton et al., “Epidemiology of Rett syndrome: a population-based registry,” Pediatrics, vol. 91, no. 2, pp. 445–450, 1993.
[11]
D. F. Wong, J. C. Harris, S. Naidu et al., “Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 11, pp. 5539–5543, 1996.
[12]
R. J. Schultz, D. G. Glaze, K. J. Motil et al., “The pattern of growth failure in Rett syndrome,” American Journal of Diseases of Children, vol. 147, no. 6, pp. 633–637, 1993.
[13]
R. Schultz, D. Glaze, K. Motil, D. Hebert, and A. Percy, “Hand and foot growth failure in Rett syndrome,” Journal of Child Neurology, vol. 13, no. 2, pp. 71–74, 1998.
[14]
D. G. Glaze, J. D. Frost Jr., H. Y. Zoghbi, and A. K. Percy, “Rett's syndrome. Correlation of electroencephalographic characteristics with clinical staging,” Archives of Neurology, vol. 44, no. 10, pp. 1053–1056, 1987.
[15]
D. G. Glaze, R. J. Schultz, and J. D. Frost, “Rett syndrome: characterization of seizures versus non-seizures,” Electroencephalography and Clinical Neurophysiology, vol. 106, no. 1, pp. 79–83, 1998.
[16]
I. Hagne, I. Witt-Engerstrom, and B. Hagberg, “EEG development in Rett syndrome. A study of 30 cases,” Electroencephalography and Clinical Neurophysiology, vol. 72, no. 1, pp. 1–6, 1989.
[17]
E. Niedermeyer and S. Naidu, “Further EEG observations in children with the Rett syndrome,” Brain and Development, vol. 12, no. 1, pp. 53–54, 1990.
[18]
E. Niedermeyer, A. Rett, and H. Renner, “Rett syndrome and the electroencephalogram,” American Journal of Medical Genetics, vol. 24, supplement 1, pp. 195–199, 1986.
[19]
E. Lugaresi, F. Cirignotta, and P. Montagna, “Abnormal breathing in the Rett syndrome,” Brain and Development, vol. 7, no. 3, pp. 329–333, 1985.
[20]
D. Glaze, J. Frost, R. Schultz, and A. Percy, “Effect of naloxone on breathing, hand movements, electroencephalogram during wakefulness in patients in rett syndrome,” Annals of Neurology, vol. 26, article 486, 1989.
[21]
D. G. Glaze, J. D. Frost, H. Y. Zoghbi, and A. K. Percy, “Rett's syndrome: characterization of respiratory patterns and sleep,” Annals of Neurology, vol. 21, no. 4, pp. 377–382, 1987.
[22]
C. L. Laurvick, N. de Klerk, C. Bower et al., “Rett syndrome in Australia: a review of the epidemiology,” Journal of Pediatrics, vol. 148, no. 3, pp. 347–352, 2006.
[23]
B. Hagberg and P. Rasmussen, “‘Forme fruste’ of Rett syndrome. A case report,” American Journal of Medical Genetics, vol. 24, supplement 1, pp. 175–181, 1986.
[24]
B. A. Hagberg and O. H. Skjeldal, “Rett variants: a suggested model for inclusion criteria,” Pediatric Neurology, vol. 11, no. 1, pp. 5–11, 1994.
[25]
M. Zappella, “The Rett girls with preserved speech,” Brain and Development, vol. 14, no. 2, pp. 98–101, 1992.
[26]
O. H. Skjeldal, S. von Tetzchner, K. Jacobsen, L. Smith, and A. Heiberg, “Rett syndrome—distribution of phenotypes with special attention to the preserved speech variant,” Neuropediatrics, vol. 26, no. 2, p. 87, 1995.
[27]
F. Hanefeld, B. Hagberg, and A. Percy, “Molecular and neurobiology aspects of Rett syndrome,” Neuropediatrics, vol. 26, no. 2, pp. 60–61, 1995.
[28]
H. Y. Zoghbi, A. K. Percy, R. J. Schultz, and C. Fill, “Patterns of X chromosome inactivation in the Rett syndrome,” Brain and Development, vol. 12, no. 1, pp. 131–135, 1990.
[29]
H. Y. Zoghbi, D. H. Ledbetter, R. Schultz, A. K. Percy, and D. G. Glaze, “A de novo X;3 translocation in Rett syndrome,” American Journal of Medical Genetics, vol. 35, no. 1, pp. 148–151, 1990.
[30]
N. C. Schanen, E. J. R. Dahle, F. Capozzoli, V. A. Holm, H. Y. Zoghbi, and U. Francke, “A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map,” American Journal of Human Genetics, vol. 61, no. 3, pp. 634–641, 1997.
[31]
C. Schanen, “A severely affected male born into a Rett syndrome kindred supports X-linked inheritance and allows extension of the exclusion map,” American Journal of Human Genetics, vol. 63, no. 1, pp. 267–269, 1998.
[32]
N. C. Schanen, “Molecular approaches to the Rett syndrome gene,” Journal of Child Neurology, vol. 14, no. 12, pp. 806–814, 1999.
[33]
N. Sirianni, S. Naidu, J. Pereira, R. F. Pillotto, and E. P. Hoffman, “Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28,” American Journal of Human Genetics, vol. 63, no. 5, pp. 1552–1558, 1998.
[34]
K. A. Ellison, C. P. Fill, J. Terwilliger et al., “Examination of X chromosome markers in Rett syndrome: exclusion mapping with a novel variation on multilocus linkage analysis,” American Journal of Human Genetics, vol. 50, no. 2, pp. 278–287, 1992.
[35]
K. A. Ellison, E. J. Roth, E. R. B. McCabe, A. C. Chinault, and H. Y. Zoghbi, “Isolation of a yeast artificial chromosome contig spanning the X chromosomal translocation breakpoint in a patient with Rett syndrome,” American Journal of Medical Genetics, vol. 47, no. 7, pp. 1124–1134, 1993.
[36]
R. E. Amir, I. B. van den Veyver, M. Wan, C. Q. Tran, U. Francke, and H. Y. Zoghbi, “Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2,” Nature Genetics, vol. 23, no. 2, pp. 185–188, 1999.
[37]
B. R. Migeon, M. A. Dunn, G. Thomas, B. J. Schmeckpeper, and S. Naidu, “Studies of X inactivation and isodisomy in twins provide further evidence that the X chromosome is not involved in Rett syndrome,” American Journal of Human Genetics, vol. 56, no. 3, pp. 647–653, 1995.
[38]
N. Sirianni, S. Naidu, J. Pereira, R. F. Pillotto, and E. P. Hoffman, “Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28,” American Journal of Human Genetics, vol. 63, no. 5, pp. 1552–1558, 1998.
[39]
B. Hendrich and A. Bird, “Identification and characterization of a family of mammalian methyl-CpG binding proteins,” Molecular and Cellular Biology, vol. 18, no. 11, pp. 6538–6547, 1998.
[40]
J. Christodoulou, A. Grimm, T. Maher, and B. Bennetts, “RettBASE: the IRSA MECP2 variation database—a new mutation database in evolution,” Human Mutation, vol. 21, no. 5, pp. 466–472, 2003.
[41]
M. J. Friez, J. R. Jones, K. Clarkson et al., “Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28,” Pediatrics, vol. 118, no. 6, pp. e1687–e1695, 2006.
[42]
A. K. Percy, “Rett syndrome: recent research progress,” Journal of Child Neurology, vol. 23, no. 5, pp. 543–549, 2008.
[43]
A. K. Percy, “Rett syndrome: from recognition to diagnosis to intervention,” Expert Review of Endocrinology and Metabolism, vol. 3, no. 3, pp. 327–336, 2008.
[44]
E. Trevathan and H. W. Moser, “Diagnostic criteria for Rett syndrome,” Annals of Neurology, vol. 23, no. 4, pp. 425–428, 1988.
[45]
B. Hagberg, F. Hanefeld, A. Percy, and O. Skjeldal, “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,” European Journal of Paediatric Neurology, vol. 6, no. 5, pp. 293–297, 2002.
[46]
J. L. Neul, W. E. Kaufmann, D. G. Glaze et al., “Rett syndrome: revised diagnostic criteria and nomenclature,” Annals of Neurology, vol. 68, no. 6, pp. 944–950, 2010.
[47]
A. K. Percy, J. L. Neul, D. G. Glaze et al., “Rett syndrome diagnostic criteria: lessons from the Natural History study,” Annals of Neurology, vol. 68, no. 6, pp. 951–955, 2010.
[48]
G. Hagberg, Y. Stenbom, and I. Witt Engerstr？m, “Head growth in Rett syndrome,” Acta Paediatrica, International Journal of Paediatrics, vol. 89, no. 2, pp. 198–202, 2000.
[49]
D. C. Tarquinio, K. J. Motil, W. Hou, et al., “Growth failure and outcome in Rett syndrome: specific growth references,” Neurology, vol. 79, no. 16, pp. 1653–1661, 2012.
[50]
C. Philippe, L. Villard, N. de Roux et al., “Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update,” European Journal of Medical Genetics, vol. 49, no. 1, pp. 9–18, 2006.
[51]
A. Quenard, S. Yilmaz, H. Fontaine et al., “eleterious mutations in exon 1 of MECP2 in Rett syndrome,” European Journal of Medical Genetics, vol. 49, no. 4, pp. 313–322, 2006.
[52]
I. Kim, Y. Kim, B. Son et al., “Diagnostic mutational analysis of MECP2 in Korean patients with Rett syndrome,” Experimental and Molecular Medicine, vol. 38, no. 2, pp. 119–125, 2006.
[53]
D. Zahorakova, R. Rosipal, J. Hadac et al., “Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms,” Journal of Human Genetics, vol. 52, no. 4, pp. 342–348, 2007.
[54]
K. Sampieri, I. Meloni, E. Scala et al., “Italian Rett database and biobank,” Human Mutation, vol. 28, no. 4, pp. 329–335, 2007.
[55]
L. Abuhatzira, K. Makedonski, Y. P. Galil et al., “Splicing mutation associated with Rett syndrome and an experimental approach for genetic diagnosis,” Human Genetics, vol. 118, no. 1, pp. 91–98, 2005.
[56]
R. Khajuria, S. Sapra, M. Ghosh et al., “Rapid detection of deletions in hotspot C-terminal segment region of MECP2 by routine PCR method: report of two classical Rett syndrome patients of Indian origin,” Genetic Testing and Molecular Biomarkers, vol. 13, no. 2, pp. 277–280, 2009.
[57]
M. Li, H. Pan, X. Bao, Y. Zhang, and X. Wu, “MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome,” Journal of Human Genetics, vol. 52, no. 1, pp. 38–47, 2007.
[58]
K. A. Percy, B. J. Lane, J. Childers et al., “Rett syndrome: North American database,” Journal of Child Neurology, vol. 22, no. 12, pp. 1338–1341, 2007.
[59]
T. Bienvenu, L. Villard, N. de Roux et al., “Spectrum of MECP2 mutations in Rett syndrome,” Genetic Testing, vol. 6, no. 1, pp. 1–6, 2002.
[60]
I. M. Buyse, P. Fang, K. T. Hoon, R. E. Amir, H. Y. Zoghbi, and B. B. Roa, “Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms,” American Journal of Human Genetics, vol. 67, no. 6, pp. 1428–1436, 2000.
[61]
V. Bourdon, C. Philippe, O. Labrune, D. Amsallem, C. Arnould, and P. Jonveaux, “A detailed analysis of the MECP2 gene: prevalence of recurrent mutations and gross DNA rearrangements in Rett syndrome patients,” Human Genetics, vol. 108, no. 1, pp. 43–50, 2001.
[62]
R. C. Samaco, R. P. Nagarajan, D. Braunschweig, and J. M. LaSalle, “Multiple pathways regulate MECP2 expression in normal brain development and exhibit defects in autism-spectrum disorders,” Human Molecular Genetics, vol. 13, no. 6, pp. 629–639, 2004.
[63]
A. Shibayama, E. H. Cook Jr., J. Feng et al., “MECP2 structural and 3′-UTR variants in schizophrenia autism and other psychiatric diseases: a possible association with autism,” American Journal of Medical Genetics B: Neuropsychiatric Genetics, vol. 128, no. 1, pp. 50–53, 2004.
[64]
K. Augenstein, J. B. Lane, A. Horton, C. Schanen, and A. K. Percy, “Variable phenotypic expression of a MECP2 mutation in a family,” Journal of Neurodevelopmental Disorders, vol. 1, no. 4, article 313, 2009.
[65]
J. S. Schwartzman, A. Bernardino, A. Nishimura, R. R. Gomes, and M. Zatz, “Rett syndrome in a boy with a 47,XXY karyotype confirmed by a rare mutation in the MECP2 gene,” Neuropediatrics, vol. 32, no. 3, pp. 162–164, 2001.
[66]
J. S. Schwartzman, M. Zatz, L. dos Reis Vasquez et al., “Rett syndrome in a boy with a 47,XXY karyotype,” American Journal of Human Genetics, vol. 64, no. 6, pp. 1781–1785, 1999.
[67]
S. G. Vorsanova, Y. B. Yurov, V. Y. Ulas et al., “Cytogenetic and molecular-cytogenetic studies of Rett syndrome (RTT): a retrospective analysis of a Russian cohort of RTT patients (the investigation of 57 girls and three boys),” Brain and Development, vol. 23, supplement 1, pp. S196–S201, 2001.
[68]
J. Clayton-Smith, P. Watson, S. Ramsden, and G. C. M. Black, “Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males,” The Lancet, vol. 356, no. 9232, pp. 830–832, 2000.
[69]
L. Villard, “MECP2 mutations in males,” Journal of Medical Genetics, vol. 44, no. 7, pp. 417–423, 2007.
[70]
P. Kankirawatana, H. Leonard, C. Ellaway et al., “Early progressive encephalopathy in boys and MECP2 mutations,” Neurology, vol. 67, no. 1, pp. 164–166, 2006.
[71]
T. Ylisaukko-Oja, K. Rehnstr？m, R. Vanhala et al., “MECP2 mutation analysis in patients with mental retardation,” American Journal of Medical Genetics, vol. 132, no. 2, pp. 121–124, 2005.
[72]
D. Lugtenberg, A. P. M. de Brouwer, T. Kleefstra et al., “Chromosomal copy number changes in patients with non-syndromic X linked mental retardation detected by array CGH,” Journal of Medical Genetics, vol. 43, no. 4, pp. 362–370, 2006.
[73]
D. Lugtenberg, T. Kleefstra, A. R. Oudakker et al., “Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy,” European Journal of Human Genetics, vol. 17, no. 4, pp. 444–453, 2009.
[74]
H. van Esch, M. Bauters, J. Ignatius et al., “Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males,” American Journal of Human Genetics, vol. 77, no. 3, pp. 442–453, 2005.
[75]
M. B. Ramocki, S. U. Peters, Y. J. Tavyev et al., “Autism and other neuropsychiatric symptoms are prevalent in individuals with MECP2 duplication syndrome,” Annals of Neurology, vol. 66, no. 6, pp. 771–782, 2009.
[76]
M. B. Ramocki, Y. J. Tavyev, and S. U. Peters, “The MECP2 duplication syndrome,” American Journal of Medical Genetics A, vol. 152, no. 5, pp. 1079–1088, 2010.
[77]
S. U. Peters, R. J. Hundley, A. K. Wilson, et al., “The behavioral phenotype in MECP2 duplication syndrome: a comparison with idiopathic autism,” Autism Research, vol. 6, no. 1, pp. 42–50, 2013.
[78]
B. Hagberg and I. Witt-Engerstrom, “Rett syndrome: a suggested staging system for describing impairment profile with increasing age towards adolescence,” American Journal of Medical Genetics, vol. 24, supplement 1, pp. 47–59, 1986.
[79]
C. A. Chapleau, J. Lane, J. Larrimore, W. Li, L. Pozzo-Miller, and A. Percy, “Recent progress in Rett syndrome and MECP2 dysfunction: assessment of potwntial treatment options,” Future Neurology, vol. 8, pp. 21–28, 2013.
[80]
P. M. Baptista, M. T. Mercadante, E. C. Macedo, and J. S. Schwartzman, “Cognitive performance in Rett syndrome girls: a pilot study using eyetracking technology,” Journal of Intellectual Disability Research, vol. 50, part 9, pp. 662–666, 2006.
[81]
A. Djukic and M. V. McDermott, “Social preferences in Rett syndrome,” Pediatric Neurology, vol. 46, no. 4, pp. 240–242, 2012.
[82]
A. Djukic, M. V. McDermott, K. Mavrommatis, and C. L. Martins, “Rett syndrome: basic features of visual processing: a pilot study of eye-tracking,” Pediatric Neurology, vol. 47, no. 1, pp. 25–29, 2012.
[83]
D. G. Glaze, “Neurophysiology of Rett syndrome,” Mental Retardation and Developmental Disabilities Research Reviews, vol. 8, no. 2, pp. 66–71, 2002.
[84]
D. G. Glaze, “Neurophysiology of Rett syndrome,” Journal of Child Neurology, vol. 20, no. 9, pp. 740–746, 2005.
[85]
D. G. Glaze, A. K. Percy, S. Skinner et al., “Epilepsy and the natural history of Rett syndrome,” Neurology, vol. 74, no. 11, pp. 909–912, 2010.
[86]
E. E. J. Smeets, P. O. O. Julu, D. van Waardenburg et al., “Management of a severe forceful breather with Rett Syndrome using carbogen,” Brain and Development, vol. 28, no. 10, pp. 625–632, 2006.
[87]
A. K. Percy, “Clinical trials and treatment prospects,” Mental Retardation and Developmental Disabilities Research Reviews, vol. 8, no. 2, pp. 106–111, 2002.
[88]
A. K. Percy, D. G. Glaze, R. J. Schultz et al., “Rett syndrome: controlled study of an oral opiate antagonist, naltrexone,” Annals of Neurology, vol. 35, no. 4, pp. 464–470, 1994.
[89]
E. E. Hagebeuk, R. P. Bijlmer, J. H. Koelman, and B. T. Poll-The, “Respiratory disturbances in rett syndrome: don't forget to evaluate upper airway obstruction,” Journal of Child Neurology, vol. 27, no. 7, pp. 888–892, 2012.
[90]
K. J. Motil, R. J. Schultz, W. W. Wang, and D. G. Glaze, “Increased energy expenditure associated with repetitive involuntary movement does not contribute to growth failure in girls with Rett syndrome,” Journal of Pediatrics, vol. 132, no. 2, pp. 228–233, 1998.
[91]
K. J. Motil, R. Schultz, B. Brown, D. G. Glaze, and A. K. Percy, “Altered energy balance may account for growth failure in Rett syndrome,” Journal of Child Neurology, vol. 9, no. 3, pp. 315–319, 1994.
[92]
K. J. Motil, R. J. Schultz, K. Browning, L. Trautwein, and D. G. Glaze, “Oropharyngeal dysfunction and gastroesophageal dysmotility are present in girls and women with Rett syndrome,” Journal of Pediatric Gastroenterology and Nutrition, vol. 29, no. 1, pp. 31–37, 1999.
[93]
K. J. Motil, E. Caeg, J. O. Barrish et al., “Gastrointestinal and nutritional problems occur frequently throughout life in girls and women with rett syndrome,” Journal of Pediatric Gastroenterology and Nutrition, vol. 55, no. 3, pp. 292–298, 2012.
[94]
K. J. Motil, M. Morrissey, E. Caeg, J. O. Barrish, and D. G. Glaze, “Gastrostomy placement improves height and weight gain in girls with rett syndrome,” Journal of Pediatric Gastroenterology and Nutrition, vol. 49, no. 2, pp. 237–242, 2009.
[95]
G. S. Bassett and V. T. Tolo, “The incidence and natural history of scoliosis in Rett syndrome,” Developmental Medicine and Child Neurology, vol. 32, no. 11, pp. 963–966, 1990.
[96]
S. Ager, S. Fyfe, J. Christodoulou, P. Jacoby, L. Schmitt, and H. Leonard, “Predictors of scoliosis in Rett syndrome,” Journal of Child Neurology, vol. 21, no. 9, pp. 809–813, 2006.
[97]
E. Stokland, J. Lidstrom, and B. Hagberg, “Scoliosis in Rett Syndrome,” in Rett Syndrome—Clinical & Biological Aspects, B. Hagberg, Ed., pp. 61–71, Mac Keith Press, London, UK, 1993.
[98]
J. Lidstrom, E. Stokland, and B. Hagberg, “Scoliosis in Rett syndrome: clinical and biological aspects,” Spine, vol. 19, no. 14, pp. 1632–1635, 1994.
[99]
A. M. Kerr, P. Webb, R. J. Prescott, and Y. Milne, “Results of surgery for scoliosis in Rett syndrome,” Journal of Child Neurology, vol. 18, no. 10, pp. 703–708, 2003.
[100]
D. J. Harrison and P. J. Webb, “Scoliosis in the Rett syndrome: natural history and treatment,” Brain and Development, vol. 12, no. 1, pp. 154–156, 1990.
[101]
V. A. Holm and H. A. King, “Scoliosis in the Rett syndrome,” Brain and Development, vol. 12, no. 1, pp. 151–153, 1990.
[102]
A. K. Percy, H. Lee, J. L. Neul et al., “Profiling scoliosis in rett syndrome,” Pediatric Research, vol. 67, no. 4, pp. 435–439, 2010.
[103]
J. Downs, A. Bergman, P. Carter et al., “Guidelines for management of scoliosis in rett syndrome patients based on expert consensus and clinical evidence,” Spine, vol. 34, no. 17, pp. E607–E617, 2009.
[104]
J. B. Lane, H.-S. Lee, L. W. Smith et al., “Clinical severity and quality of life in children and adolescents with Rett syndrome,” Neurology, vol. 77, no. 20, pp. 1812–1818, 2011.
[105]
M. Freilinger, A. Bebbington, I. Lanator et al., “Survival with Rett syndrome: comparing Rett's original sample with data from the Australian Rett Syndrome Database,” Developmental Medicine and Child Neurology, vol. 52, no. 10, pp. 962–965, 2010.
[106]
R. S. Kirby, J. B. Lane, J. Childers et al., “Longevity in Rett Syndrome: analysis of the North American database,” Journal of Pediatrics, vol. 156, no. 1, pp. 135–138, 2010.
[107]
M. D. McCauley, T. Wang, E. Mike et al., “Rett syndrome: pathogenesis of lethal cardiac arrhythmias in MECP2 mutant mice: implication for therapy in Rett syndrome,” Science Translational Medicine, vol. 3, no. 113, Article ID 113ra125, 2011.
[108]
E. A. Sekul, J. P. Moak, R. J. Schultz, D. G. Glaze, and A. K. Percy, “Electrocardiographic findings in Rett syndrome: an explanation for sudden death?” Journal of Pediatrics, vol. 125, no. 1, pp. 80–82, 1994.
[109]
D. D. Armstrong, “Review of Rett syndrome,” Journal of Neuropathology and Experimental Neurology, vol. 56, no. 8, pp. 843–849, 1997.
[110]
D. Armstrong, “Recent developments in neuropathology—electron microscopy—brain pathology,” European Child and Adolescent Psychiatry, vol. 6, supplement 1, pp. 69–70, 1997.
[111]
D. Armstrong, J. K. Dunn, B. Antalffy, and R. Trivedi, “Selective dendritic alterations in the cortex of Rett syndrome,” Journal of Neuropathology and Experimental Neurology, vol. 54, no. 2, pp. 195–201, 1995.
[112]
D. D. Armstrong, “The neuropathology of the Rett syndrome,” Brain and Development, vol. 14, supplement, pp. S89–S98, 1992.
[113]
D. D. Armstrong, “The neuropathology of Rett syndrome—overview 1994,” Neuropediatrics, vol. 26, no. 2, pp. 100–104, 1995.
[114]
D. D. Armstrong, “Rett syndrome neuropathology review 2000,” Brain and Development, vol. 23, supplement 1, pp. S72–S76, 2000.
[115]
D. D. Armstrong, “Neuropathology of Rett syndrome,” Mental Retardation and Developmental Disabilities Research Reviews, vol. 8, no. 2, pp. 72–76, 2002.
[116]
D. D. Armstrong, “Neuropathology of Rett syndrome,” Journal of Child Neurology, vol. 20, no. 9, pp. 747–753, 2005.
[117]
D. D. Armstrong, K. Dunn, and B. Antalffy, “Decreased dendritic branching in frontal, motor and limbic cortex in Rett Syndrome compared with Trisomy 21,” Journal of Neuropathology and Experimental Neurology, vol. 57, no. 11, pp. 1013–1017, 1998.
[118]
K. Jellinger, D. Armstrong, H. Y. Zoghbi, and A. K. Percy, “Neuropathology of Rett syndrome,” Acta Neuropathologica, vol. 76, no. 2, pp. 142–158, 1988.
[119]
K. Jellinger and F. Seitelberger, “Neuropathology of Rett syndrome,” American Journal of Medical Genetics, vol. 24, supplement 1, pp. 259–288, 1986.
[120]
K. Jellinger, D. Armstrong, H. Zoghbi, and A. Percy, “The Rett Syndrome: an overview,” in Movement Disorders in Neurology and Neuropsychiatry, A. B. Joseph and R. Young, Eds., pp. 667–678, Blackwell Scientific Publications, 1992.
[121]
K. A. Jellinger, “Rett syndrome—an update: review,” Journal of Neural Transmission, vol. 110, no. 6, pp. 681–701, 2003.
[122]
A. L. Reiss, F. Faruque, S. Naidu et al., “Neuroanatomy of Rett syndrome: a volumetric imaging study,” Annals of Neurology, vol. 34, no. 2, pp. 227–234, 1993.
[123]
A. Percy, J. Dragich, and N. Schanen, “Rett Syndrome: clinical-molecular correlates,” in Genetics and Genomics of Neurobehavioral Disorders, G. Fisch, Ed., pp. 391–418, Humana Press, Totowa, NJ, USA, 2003.
[124]
J. C. Evans, H. L. Archer, S. D. Whatley, and A. Clarke, “Germline mosaicism for a MECP2 mutation in a man with two Rett daughters,” Clinical Genetics, vol. 70, no. 4, pp. 336–338, 2006.
[125]
J. Dragich, I. Houwink-Manville, and C. Schanen, “Rett syndrome: a surprising result of mutation in MECP2,” Human Molecular Genetics, vol. 9, no. 16, pp. 2365–2375, 2000.
[126]
C. Schanen, E. J. F. Houwink, N. Dorrani et al., “Phenotypic manifestations of MECP2 mutations in classical and atypical Rett Syndrome,” American Journal of Medical Genetics A, vol. 126, no. 2, pp. 129–140, 2004.
[127]
A. Bebbington, A. Anderson, D. Ravine et al., “Investigating genotype-phenotype relationships in Rett syndrome using an international data set,” Neurology, vol. 70, no. 11, pp. 868–875, 2008.
[128]
A. Bebbington, A. Percy, J. Christodoulou et al., “Updating the profile of C-terminal MECP2 deletions in Rett syndrome,” Journal of Medical Genetics, vol. 47, no. 4, pp. 242–248, 2010.
[129]
J. L. Neul, P. Fang, J. Barrish et al., “Specific mutations in Methyl-CpG-Binding Protein 2 confer different severity in Rett syndrome,” Neurology, vol. 70, no. 16, pp. 1313–1321, 2008.
[130]
G. Pini, S. Bigoni, I. Engerstr？m et al., “Variant of rett syndrome and CDKL5 gene: clinical and autonomic description of 10 cases,” Neuropediatrics, vol. 43, no. 1, pp. 37–43, 2012.
[131]
N. Rademacher, M. Hambrock, U. Fischer et al., “Identification of a novel CDKL5 exon and pathogenic mutations in patients with severe mental retardation, early-onset seizures and rett-like features,” Neurogenetics, vol. 12, no. 2, pp. 165–167, 2011.
[132]
F. Ariani, G. Hayek, D. Rondinella et al., “FOXG1 is responsible for the congenital variant of Rett Syndrome,” American Journal of Human Genetics, vol. 83, no. 1, pp. 89–93, 2008.
[133]
C. Philippe, D. Amsallem, C. Francannet et al., “Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females,” Journal of Medical Genetics, vol. 47, no. 1, pp. 59–65, 2010.
[134]
H. L. Archer, J. C. Evans, D. S. Millar et al., “NTNG1 mutations are a rare cause of Rett syndrome,” American Journal of Medical Genetics A, vol. 140, no. 7, pp. 691–694, 2006.
[135]
M. Chahrour, Y. J. Sung, C. Shaw et al., “MECP2, a key contributor to neurological disease, activates and represses transcription,” Science, vol. 320, no. 5880, pp. 1224–1229, 2008.
[136]
W. Li, G. Calfa, J. Larimore, and L. Pozzo-Miller, “Activity-dependent BDNF release and TRPC signaling is impaired in hippocampal neurons of MECP2 mutant mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 42, pp. 17087–17092, 2012.
[137]
B. E. McGill, S. F. Bundle, M. B. Yaylaoglu, J. P. Carson, C. Thaller, and H. Y. Zoghbi, “Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 48, pp. 18267–18272, 2006.
[138]
C. Garcia-Rudaz, V. Deng, V. Matagne et al., “FXYD1, a modulator of Na+, K+-ATPase activity, facilitates female sexual development by maintaining gonadotrophin-releasing hormone neuronal excitability,” Journal of Neuroendocrinology, vol. 21, no. 2, pp. 108–122, 2009.
[139]
J. Guy, B. Hendrich, M. Holmes, J. E. Martin, and A. Bird, “A mouse MECP2-null mutation causes neurological symptoms that mimic rett syndrome,” Nature Genetics, vol. 27, no. 3, pp. 322–326, 2001.
[140]
R. Z. Chen, S. Akbarian, M. Tudor, and R. Jaenisch, “Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice,” Nature Genetics, vol. 27, no. 3, pp. 327–331, 2001.
[141]
G. J. Pelka, C. M. Watson, T. Radziewic et al., “MECP2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice,” Brain, vol. 129, no. 4, pp. 887–898, 2006.
[142]
R. C. Samaco, C. Mandel-Brehm, H. Chao et al., “Loss of MECP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 51, pp. 21966–21971, 2009.
[143]
H. Chao, H. Chen, R. C. Samaco et al., “Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes,” Nature, vol. 468, no. 7321, pp. 263–269, 2010.
[144]
D. T. Lioy, S. K. Garg, C. E. Monaghan et al., “A role for glia in the progression of Rett-syndrome,” Nature, vol. 475, no. 7357, pp. 497–500, 2011.
[145]
M. D. Shahbazian, J. I. Young, L. A. Yuva-Paylor et al., “Mice with truncated MECP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3,” Neuron, vol. 35, no. 2, pp. 243–254, 2002.
[146]
A. Lawson-Yuen, D. Liu, L. Han et al., “Ube3a mRNA and protein expression are not decreased in MECP2R168X mutant mice,” Brain Research, vol. 1180, no. 1, pp. 1–6, 2007.
[147]
G. M. Jentarra, S. L. Olfers, S. G. Rice et al., “Abnormalities of cell packing density and dendritic complexity in the MECP2 A140V mouse model of Rett syndrome/X-linked mental retardation,” BMC Neuroscience, vol. 11, article 19, 2010.
[148]
C. Brendel, V. Belakhov, H. Werner et al., “Readthrough of nonsense mutations in Rett syndrome: evaluation of novel aminoglycosides and generation of a new mouse model,” Journal of Molecular Medicine, vol. 89, no. 4, pp. 389–398, 2011.
[149]
D. Goffin, M. Allen, L. Zhang et al., “Rett syndrome mutation MECP2 T158A disrupts DNA binding, protein stability and ERP responses,” Nature Neuroscience, vol. 15, no. 2, pp. 274–283, 2012.
[150]
D. M. Katz, J. E. Berger-Sweeney, J. H. Eubanks, et al., “Preclinical research in Rett syndrome: setting the foundation for translational success,” Disease Models and Mechanisms, vol. 5, no. 6, pp. 733–745, 2012.
[151]
W. Li and L. Pozzo-Miller, “Beyond widespread MECP2 deletions to model Rett syndrome: conditional spatio-temporal knockout, single-point mutations and transgenic rescue mice,” Autism, supplement 1, pp. 1–10, 2012.
[152]
S. L. Fyffe, J. L. Neul, R. C. Samaco et al., “Deletion of MECP2 in Sim1-expressing neurons reveals a critical role for MECP2 in feeding behavior, aggression, and the response to stress,” Neuron, vol. 59, no. 6, pp. 947–958, 2008.
[153]
R. C. Samaco, C. M. McGraw, C. S. Ward, Y. Sun, J. L. Neul, and H. Y. Zoghbi, “Female MECP2(+/-) mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies,” Human Molecular Genetics, vol. 22, no. 1, pp. 96–109, 2013.
[154]
M. A. Toward, A. P. Abdala, S. J. Knopp, J. F. Paton, and J. M. Bissonnette, “Increasing brain serotonin corrects CO2 chemosensitivity in methyl-CpG-binding protein 2 (MECP2)-deficient mice,” Experimental Physiology, vol. 98, no. 3, pp. 842–849, 2013.
[155]
C. M. Buchovecky, S. D. Turley, H. M. Brown, et al., “A suppressor screen in MECP2 mutant mice implicates cholesterol metabolism in Rett syndrome,” Nature Genetics, vol. 45, pp. 1013–1020, 2013.
[156]
J. Guy, J. Gan, J. Selfridge, S. Cobb, and A. Bird, “Reversal of neurological defects in a mouse model of Rett syndrome,” Science, vol. 315, no. 5815, pp. 1143–1147, 2007.
[157]
J. M. LaSalle, J. Goldstine, D. Balmer, and C. M. Greco, “Quantitative localization of heterogeneous methyl-CpG-binding protein 2 (MECP2) expression phenotypes in normal and Rett syndrome brain by laser scanning cytometry,” Human Molecular Genetics, vol. 10, no. 17, pp. 1729–1740, 2001.
[158]
N. Ballas, D. T. Lioy, C. Grunseich, and G. Mandel, “Non-cell autonomous influence of MECP2-deficient glia on neuronal dendritic morphology,” Nature Neuroscience, vol. 12, no. 3, pp. 311–317, 2009.
[159]
J. W. Pan, J. B. Lane, H. Hetherington, and A. K. Percy, “Rett syndrome: 1H spectroscopic imaging at 4.1 Tesla,” Journal of Child Neurology, vol. 14, no. 8, pp. 524–528, 1999.
[160]
M. E. Blue, W. E. Kaufmann, J. Bressler et al., “Temporal and regional alterations in NMDA receptor expression in MECP2-null mice,” Anatomical Record, vol. 294, no. 10, pp. 1624–1634, 2011.
[161]
M. V. Johnston, O. Jeon, J. Pevsner, M. E. Blue, and S. Naidu, “Neurobiology of Rett syndrome: a genetic disorder of synapse development,” Brain and Development, vol. 23, supplement 1, pp. S206–S213, 2001.
[162]
G. Calfa, J. J. Hablitz, and L. Pozzo-Miller, “Network hyperexcitability in hippocampal slices from MECP2 mutant mice revealed by voltage-sensitive dye imaging,” Journal of Neurophysiology, vol. 105, no. 4, pp. 1768–1784, 2011.
[163]
G. Calfa, A. K. Percy, and L. Pozzo-Miller, “Experimental models of rett syndrome based on MECP2 dysfunction,” Experimental Biology and Medicine, vol. 236, no. 1, pp. 3–19, 2011.
[164]
S.-M. Weng, F. McLeod, M. E. S. Bailey, and S. R. Cobb, “Synaptic plasticity deficits in an experimental model of rett syndrome: long-term potentiation saturation and its pharmacological reversal,” Neuroscience, vol. 180, pp. 314–321, 2011.
[165]
W. Li and L. Pozzo-Miller, “BDNF deregulation in Rett syndrome,” Neuropharmacology, vol. 76, pp. 737–746, 2014.
[166]
J. L. Larimore, C. A. Chapleau, S. Kudo, A. Theibert, A. K. Percy, and L. Pozzo-Miller, “Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations,” Neurobiology of Disease, vol. 34, no. 2, pp. 199–211, 2009.
[167]
H. Wang, S. Chan, M. Ogier et al., “Dysregulation of brain-derived neurotrophic factor expression and neurosecretory function in MECP2 null mice,” The Journal of Neuroscience, vol. 26, no. 42, pp. 10911–10915, 2006.
[168]
M. Ogier, H. Wang, E. Hong, Q. Wang, M. E. Greenberg, and D. M. Katz, “Brain-derived neurotrophic factor expression and respiratory function improve after ampakine treatment in a mouse model of Rett syndrome,” The Journal of Neuroscience, vol. 27, no. 40, pp. 10912–10917, 2007.
[169]
D. D. Kline, M. Ogier, D. L. Kunze, and D. M. Katz, “Exogenous brain-derived neurotrophic factor rescues synaptic dysfunction in MECP2-null mice,” The Journal of Neuroscience, vol. 30, no. 15, pp. 5303–5310, 2010.
[170]
D. A. Schmid, T. Yang, M. Ogier et al., “A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of rett syndrome,” The Journal of Neuroscience, vol. 32, no. 5, pp. 1803–1810, 2012.
[171]
R. A. Johnson, M. Lam, A. M. Punzo et al., “7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome,” Journal of Applied Physiology, vol. 112, no. 5, pp. 704–710, 2012.
[172]
D. Tropea, E. Giacometti, N. R. Wilson et al., “Partial reversal of Rett Syndrome-like symptoms in MECP2 mutant mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 6, pp. 2029–2034, 2009.
[173]
M. C. N. Marchetto, C. Carromeu, A. Acab et al., “A model for neural development and treatment of rett syndrome using human induced pluripotent stem cells,” Cell, vol. 143, no. 4, pp. 527–539, 2010.
[174]
C. Brendel, E. Klahold, J. G？rtner, and P. Huppke, “Suppression of nonsense mutations in Rett syndrome by aminoglycoside antibiotics,” Pediatric Research, vol. 65, no. 5, pp. 520–523, 2009.
[175]
A. C. Popescu, E. Sidorova, G. Zhang, and J. H. Eubanks, “Aminoglycoside-mediated partial suppression of MECP2 nonsense mutations responsible for Rett syndrome in vitro,” The Journal of Neuroscience Research, vol. 88, no. 11, pp. 2316–2324, 2010.
[176]
N. C. Derecki, J. C. Cronk, Z. Lu et al., “Wild-type microglia arrest pathology in a mouse model of Rett syndrome,” Nature, vol. 484, no. 7392, pp. 105–109, 2012.
[177]
N. C. Derecki, J. C. Cronk, and J. Kipnis, “The role of microglia in brain maintenance: implications for Rett syndrome,” Trends in Immunology, vol. 34, no. 3, pp. 144–150, 2013.
[178]
S. K. Garg, D. T. Lioy, H. Cheval, et al., “Systemic delivery of MECP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome,” The Journal of Neuroscience, vol. 33, no. 34, pp. 13612–13620, 2013.
