In the 50 years since its description by Andreas Rett, we have witnessed an explosion of knowledge about Rett syndrome (RTT) in relation to its genetic basis and clinical characteristics, and their interrelationships
Initially, the diagnosis of RTT was based solely on clinical criteria, but identification of its genetic cause has revolutionized this process, while presenting new challenges as we enter the era of next-generation sequencing
Mutations in the methyl-CpG-binding protein 2 (MECP2) gene were found to be causative of RTT, accounting for fundamentally altered neurobiological pathways, and providing the stimulus to identify pathways that can be manipulated therapeutically
The type of MECP2 mutation is associated with clinical severity, and influences many aspects of the phenotype, including functional abilities, onset of scoliosis, bone health, and sleep disturbances
Considerable progress has been made in understanding the natural history of RTT, leading to improvement in clinical management in selected areas, and changes in attitudes and allocation of health-care resources have increased life expectancy
The advancement in knowledge about RTT has been dependent on global efforts to study this disorder, including the establishment of database infrastructures, the input of advocacy groups, and the development of international collaborations
In the 50 years since Andreas Rett first described the syndrome that came to bear his name, and is now known to be caused by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, a compelling blend of astute clinical observations and clinical and laboratory research has substantially enhanced our understanding of this rare disorder. Here, we document the contributions of the early pioneers in Rett syndrome (RTT) research, and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation, and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, considering the lessons learned from both cell and animal models, and how they might inform future clinical trials. With a focus on the core criteria, we examine the relationships between genotype and clinical severity. We review current knowledge about the many comorbidities that occur in RTT, and how genotype may modify their presentation. We also acknowledge the important drivers that are accelerating this research programme, including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we highlight the major milestones since 1966, and what they mean for the day-to-day lives of individuals with RTT and their families.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Rett, A. On a unusual brain atrophy syndrome in hyperammonemia in childhood. Wien. Med. Wochenschr. 116, 723–726 (in German) (1966).
Hagberg, B., Aicardi, J., Dias, K. & Ramos, O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Ann. Neurol. 14, 471–479 (1983). The initial clinical description of 35 cases of Rett syndrome in the English-speaking literature.
Fehr, S., Downs, J., Bebbington, A. & Leonard, H. Atypical presentations and specific genotypes are associated with a delay in diagnosis in females with Rett syndrome. Am. J. Med. Genet. A 152A, 2535–2542 (2010).
Hagberg, B., Goutières, F., Hanefeld, F., Rett, A. & Wilson, J. Rett syndrome: criteria for inclusion and exclusion. Brain Dev. 7, 372–373 (1985).
[No authors listed.] Diagnostic criteria for Rett syndrome. The Rett Syndrome Diagnostic Criteria Work Group. Ann. Neurol. 23, 425–428 (1988).
Hagberg, B., Hanefeld, F., Percy, A. & Skjeldal, O. 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. Eur. J. Paediatr. Neurol. 6, 293–297 (2002).
Neul, J. L. et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann. Neurol. 68, 944–950 (2010).
Naidu, S., Murphy, M., Moser, H. W. & Rett, A. Rett syndrome — natural history in 70 cases. Am. J. Med. Genet. Suppl. 1, 61–72 (1986).
Kerr, A. M. & Stephenson, J. B. Rett's syndrome in the west of Scotland. Br. Med. J. (Clin. Res. Ed.) 291, 579–582 (1985).
Hagberg, B. & Witt-Engerström, I. Rett syndrome: a suggested staging system for describing impairment profile with increasing age towards adolescence. Am. J. Med. Genet. Suppl. 1, 47–59 (1986).
Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185–188 (1999). This study established that Rett syndrome is a genetic disorder caused by mutations in the MECP2 gene.
Schanen, C. & Francke, U. A severely affected male born into a Rett syndrome kindred supports X-linked inheritance and allows extension of the exclusion map. Am. J. Hum. Genet. 63, 267–269 (1998).
Sirianni, N., Naidu, S., Pereira, J., Pillotto, R. F. & Hoffman, E. P. Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28. Am. J. Hum. Genet. 63, 1552–1558 (1998).
Amir, R. E. et al. Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Ann. Neurol. 47, 670–679 (2000).
Bienvenu, T. et al. MECP2 mutations account for most cases of typical forms of Rett syndrome. Hum. Mol. Genet. 9, 1377–1384 (2000).
Hoffbuhr, K. et al. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology 56, 1486–1495 (2001).
Huppke, P., Held, M., Hanefeld, F., Engel, W. & Laccone, F. Influence of mutation type and location on phenotype in 123 patients with Rett syndrome. Neuropediatrics 33, 63–68 (2002).
Cheadle, J. P. et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum. Mol. Genet. 9, 1119–1129 (2000). One of the most important of the early genotype–phenotype studies, this joint UK–Australian collaboration identified MECP2 mutations in 80% of typical Rett syndrome cases. Each of the eight recurrent missense and nonsense mutations, which account for almost two-thirds of the mutations seen in Rett syndrome, were represented. Using a simple phenotype score, this study showed that missense mutations generally had milder effects than truncating mutations.
Dragich, J., Houwink-Manville, I. & Schanen, C. Rett syndrome: a surprising result of mutation in MECP2. Hum. Mol. Genet. 9, 2365–2375 (2000).
Cuddapah, V. A. et al. Methyl-CpG-binding protein 2, (MECP2) mutation type is associated with disease severity in Rett syndrome. J. Med. Genet. 51, 152–158 (2014).
Erlandson, A. et al. Multiplex ligation-dependent probe amplification (MLPA) detects large deletions in the MECP2 gene of Swedish Rett syndrome patients. Genet. Test. 7, 329–332 (2003).
Hardwick, S. A. et al. Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband. Eur. J. Hum. Genet. 15, 1218–1229 (2007).
Armstrong, D., Dunn, J. K., Antalffy, B. & Trivedi, R. Selective dendritic alterations in the cortex of Rett syndrome. J. Neuropathol. Exp. Neurol. 54, 195–201 (1995).
Marchetto, M. C. et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010).
Yazdani, M. et al. Disease modeling using embryonic stem cells: MeCP2 regulates nuclear size and RNA synthesis in neurons. Stem Cells 30, 2128–2139 (2012).
Livide, G. et al. GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells. Eur. J. Hum. Genet. 23, 195–201 (2015).
Williams, E. C. et al. Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons. Hum. Mol. Genet. 23, 2968–2980 (2014).
Cheung, A. Y., Horvath, L. M., Carrel, L. & Ellis, J. X-chromosome inactivation in Rett syndrome human induced pluripotent stem cells. Front. Psychiatry 3, 24 (2012).
Guy, J., Hendrich, B., Holmes, M., Martin, J. E. & Bird, A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 27, 322–326 (2001).
Chen, R. Z., Akbarian, S., Tudor, M. & Jaenisch, R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat. Genet. 27, 327–331 (2001). References 29 and 30 described neurological deficits in Mecp2 -knockout mice, establishing a model system for studying Rett syndrome.
Gemelli, T. et al. Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol. Psychiatry 59, 468–476 (2006).
Chao, H. T. et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468, 263–269 (2010).
Fyffe, S. L. 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 59, 947–958 (2008).
Wang, X., Lacza, Z., Sun, Y. E. & Han, W. Leptin resistance and obesity in mice with deletion of methyl-CpG-binding protein 2 (MeCP2) in hypothalamic pro-opiomelanocortin (POMC) neurons. Diabetologia 57, 236–245 (2014).
Samaco, R. C. et al. Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities. Proc. Natl Acad. Sci. USA 106, 21966–21971 (2009).
Goffin, D., Brodkin, E. S., Blendy, J. A., Siegel, S. J. & Zhou, Z. Cellular origins of auditory event-related potential deficits in Rett syndrome. Nat. Neurosci. 17, 804–806 (2014).
Zhang, W., Peterson, M., Beyer, B., Frankel, W. N. & Zhang, Z. W. Loss of MeCP2 from forebrain excitatory neurons leads to cortical hyperexcitation and seizures. J. Neurosci. 34, 2754–2763 (2014).
Ward, C. S. et al. MeCP2 is critical within HoxB1-derived tissues of mice for normal lifespan. J. Neurosci. 31, 10359–10370 (2011).
Lyst, M. J. & Bird, A. Rett syndrome: a complex disorder with simple roots. Nat. Rev. Genet. 16, 261–275 (2015).
Meng, X. et al. Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders. eLife 5, e14199 (2016).
Cheval, H. et al. Postnatal inactivation reveals enhanced requirement for MeCP2 at distinct age windows. Hum. Mol. Genet. 21, 3806–3814 (2012).
McGraw, C. M., Samaco, R. C. & Zoghbi, H. Y. Adult neural function requires MeCP2. Science 333, 186 (2011).
Guy, J., Gan, J., Selfridge, J., Cobb, S. & Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007). This study shows that overt neurological features seen in MeCP2-deficient mice can be substantially reversed by re-expression of the protein in adult mice.
Robinson, L. et al. Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome. Brain 135, 2699–2710 (2012).
Ure, K. et al. Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome. eLife 5, e14198 (2016).
Shahbazian, M. D., Antalffy, B., Armstrong, D. L. & Zoghbi, H. Y. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum. Mol. Genet. 11, 115–124 (2002).
Skene, P. J. et al. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457–468 (2010).
Lioy, D. T. et al. A role for glia in the progression of Rett's syndrome. Nature 475, 497–500 (2011).
Nguyen, M. V. et al. Oligodendrocyte lineage cells contribute unique features to Rett syndrome neuropathology. J. Neurosci. 33, 18764–18774 (2013).
Song, C. et al. DNA methylation reader MECP2: cell type- and differentiation stage-specific protein distribution. Epigenetics Chromatin 7, 17 (2014).
Ross, P. D. et al. Exclusive expression of MeCP2 in the nervous system distinguishes between brain and peripheral Rett syndrome-like phenotypes. Hum. Mol. Genet. http://dx.doi.org/10.1093/hmg/ddw269 (2016).
Ballas, N., Lioy, D. T., Grunseich, C. & Mandel, G. Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nat. Neurosci. 12, 311–317 (2009).
Luikenhuis, S., Giacometti, E., Beard, C. F. & Jaenisch, R. Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc. Natl Acad. Sci. USA 101, 6033–6038 (2004).
Kyle, S. M., Saha, P. K., Brown, H. M., Chan, L. C. & Justice, M. J. MeCP2 co-ordinates liver lipid metabolism with the NCoR1/HDAC3 corepressor complex. Hum. Mol. Genet. 25, 3029–3041 (2016).
De Felice, C. et al. Unrecognized lung disease in classic Rett syndrome: a physiologic and high-resolution CT imaging study. Chest 138, 386–392 (2010).
Panighini, A. et al. Vascular dysfunction in a mouse model of Rett syndrome and effects of curcumin treatment. PLoS ONE 8, e64863 (2013).
McCauley, M. D. et al. Pathogenesis of lethal cardiac arrhythmias in Mecp2 mutant mice: implication for therapy in Rett syndrome. Sci. Transl Med. 3, 113ra125 (2011).
O'Connor, R. D., Zayzafoon, M., Farach-Carson, M. C. & Schanen, N. C. Mecp2 deficiency decreases bone formation and reduces bone volume in a rodent model of Rett syndrome. Bone 45, 346–356 (2009).
Kamal, B. et al. Biomechanical properties of bone in a mouse model of Rett syndrome. Bone 71, 106–114 (2015).
Blue, M. E. et al. Osteoblast function and bone histomorphometry in a murine model of Rett syndrome. Bone 76, 23–30 (2015).
Conti, V. et al. MeCP2 affects skeletal muscle growth and morphology through non cell-autonomous mechanisms. PLoS ONE 10, e0130183 (2015).
Guy, J., Cheval, H., Selfridge, J. & Bird, A. The role of MeCP2 in the brain. Annu. Rev. Cell Dev. Biol. 27, 631–652 (2011).
Yasui, D. H. et al. Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome. Hum. Mol. Genet. 23, 2447–2458 (2014).
Kerr, B. et al. Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes. Eur. J. Hum. Genet. 20, 69–76 (2012).
Lewis, J. D. et al. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69, 905–914 (1992). This paper describes the original discovery of MeCP2 as a DNA-binding protein.
Nan, X., Meehan, R. R. & Bird, A. Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. Nucleic Acids Res. 21, 4886–4892 (1993).
Guo, W. et al. VPA alleviates neurological deficits and restores gene expression in a mouse model of Rett syndrome. PLoS ONE 9, e100215 (2014).
Mellen, M., Ayata, P., Dewell, S., Kriaucionis, S. & Heintz, N. MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 151, 1417–1430 (2012).
Spruijt, C. G. et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 152, 1146–1159 (2013).
Kriaucionis, S. & Heintz, N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929–930 (2009).
Lyst, M. J. et al. Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat. Neurosci. 16, 898–902 (2013). This paper describes the interaction of MeCP2 with NCOR–SMRT, and shows that this interaction is abolished by Rett syndrome-causing mutations in this region.
Baker, S. A. et al. An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders. Cell 152, 984–996 (2013).
Heckman, L. D., Chahrour, M. H. & Zoghbi, H. Y. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. eLife 3, e02676 (2014).
Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).
Chahrour, M. et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224–1229 (2008).
Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).
Jones, P. L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet. 19, 187–191 (1998).
Kokura, K. et al. The Ski protein family is required for MeCP2-mediated transcriptional repression. J. Biol. Chem. 276, 34115–34121 (2001).
Stancheva, I., Collins, A. L., Van den Veyver, I. B., Zoghbi, H. & Meehan, R. R. A mutant form of MeCP2 protein associated with human Rett syndrome cannot be displaced from methylated DNA by Notch in Xenopus embryos. Mol. Cell 12, 425–435 (2003).
Sugino, K. et al. Cell-type-specific repression by methyl-CpG-binding protein 2 is biased toward long genes. J. Neurosci. 34, 12877–12883 (2014).
Gabel, H. W. et al. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature 522, 89–93 (2015).
Brero, A. et al. Methyl CpG-binding proteins induce large-scale chromatin reorganization during terminal differentiation. J. Cell Biol. 169, 733–743 (2005).
Young, J. I. et al. Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc. Natl Acad. Sci. USA 102, 17551–17558 (2005).
Maunakea, A. K., Chepelev, I., Cui, K. & Zhao, K. Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell Res. 23, 1256–1269 (2013).
Cheng, T. L. et al. MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex. Dev. Cell 28, 547–560 (2014).
Klein, M. E. et al. Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat. Neurosci. 10, 1513–1514 (2007).
Han, K. et al. Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p. Genes Dev. 27, 485–490 (2013).
Tao, J. et al. Phosphorylation of MeCP2 at serine 80 regulates its chromatin association and neurological function. Proc. Natl Acad. Sci. USA 106, 4882–4887 (2009).
Ebert, D. H. et al. Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. Nature 499, 341–345 (2013).
Meins, M. et al. Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome. J. Med. Genet. 42, e12 (2005).
Van Esch, H. et al. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am. J. Hum. Genet. 77, 442–453 (2005).
Collins, A. L. et al. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum. Mol. Genet. 13, 2679–2689 (2004).
Lim, Z., Downs, J., Wong, K., Ellaway, C. & Leonard, H. Expanding the clinical picture of the MECP2 duplication syndrome. Clin. Genet. http://dx.doi.org/10.1111/cge.12814 (2016).
Sztainberg, Y. et al. Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides. Nature 528, 123–126 (2015).
Tudor, M., Akbarian, S., Chen, R. Z. & Jaenisch, R. Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain. Proc. Natl Acad. Sci. USA 99, 15536–15541 (2002).
Dani, V. S. et al. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 102, 12560–12565 (2005).
Nelson, E. D., Kavalali, E. T. & Monteggia, L. M. MeCP2-dependent transcriptional repression regulates excitatory neurotransmission. Curr. Biol. 16, 710–716 (2006).
Chao, H. T., Zoghbi, H. Y. & Rosenmund, C. MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56, 58–65 (2007).
Li, H., Zhong, X., Chau, K. F., Williams, E. C. & Chang, Q. Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory. Nat. Neurosci. 14, 1001–1008 (2011).
Weng, S. M., McLeod, F., Bailey, M. E. & Cobb, S. R. Synaptic plasticity deficits in an experimental model of Rett syndrome: long-term potentiation saturation and its pharmacological reversal. Neuroscience 180, 314–321 (2011).
Ricciardi, S. et al. Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum. Mol. Genet. 20, 1182–1196 (2011).
Kriaucionis, S. et al. Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome. Mol. Cell. Biol. 26, 5033–5042 (2006).
De Felice, C. et al. Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome. Neurobiol. Dis. 68, 66–77 (2014).
Trevathan, E. & Adams, M. J. The epidemiology and public health significance of Rett syndrome. J. Child Neurol. 3, S17–S20 (1988).
Trevathan, E. Rett syndrome. Pediatrics 83, 636–637 (1989).
Goutières, F. & Aicardi, J. Atypical forms of Rett syndrome. Am. J. Med. Genet. Suppl. 1, 183–194 (1986).
Zappella, M. The Rett girls with preserved speech. Brain Dev. 14, 98–101 (1992).
Hagberg, B. A. & Skjeldal, O. H. Rett variants: a suggested model for inclusion criteria. Pediatr. Neurol. 11, 5–11 (1994). This paper developed a model for the clinical delineation of atypical cases of Rett syndrome, based on the presence of combined clusters of at least three of six primary criteria and at least five of 11 supportive manifestations in children aged ≥10 years. Importantly, the paper acknowledged that many of the supportive criteria, such as epilepsy and scoliosis, are not present in children aged <5 years, but appear with age.
Leonard, H. & Bower, C. Is the girl with Rett syndrome normal at birth? Dev. Med. Child Neurol. 40, 115–121 (1998).
Hagberg, G., Stenbom, Y. & Engerstrom, I. W. Head growth in Rett syndrome. Brain Dev. 23, S227–S229 (2001).
Naidu, S. & Johnston, M. V. Neurodevelopmental disorders: clinical criteria for Rett syndrome. Nat. Rev. Neurol. 7, 312–314 (2011).
Beale, S., Sanderson, D., Sanniti, A., Dundar, Y. & Boland, A. A scoping study to explore the cost-effectiveness of next-generation sequencing compared with traditional genetic testing for the diagnosis of learning disabilities in children. Health Technol. Assess. 19, 1–90 (2015).
Fehr, S. et al. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur. J. Hum. Genet. 21, 266–273 (2013).
Ariani, F. et al. FOXG1 is responsible for the congenital variant of Rett syndrome. Am. J. Hum. Genet. 83, 89–93 (2008).
Urbanowicz, A., Downs, J., Girdler, S., Ciccone, N. & Leonard, H. Aspects of speech–language abilities are influenced by MECP2 mutation type in girls with Rett syndrome. Am. J. Med. Genet. A 167A, 354–362 (2015).
De Bona, C. et al. Preserved speech variant is allelic of classic Rett syndrome. Eur. J. Hum. Genet. 8, 325–330 (2000).
Hagberg, B. Clinical delineation of Rett syndrome variants. Neuropediatrics 26, 62 (1995).
Opitz, J. M. & Lewin, S. O. Rett syndrome — a review and discussion of syndrome delineation and syndrome definition. Brain Dev. 9, 445–450 (1987).
Erlandson, A. & Hagberg, B. MECP2 abnormality phenotypes: clinicopathologic area with broad variability. J. Child Neurol. 20, 727–732 (2005).
Bebbington, A. et al. Updating the profile of C-terminal MECP2 deletions in Rett syndrome. J. Med. Genet. 47, 242–248 (2010).
Suter, B., Treadwell-Deering, D., Zoghbi, H. Y., Glaze, D. G. & Neul, J. L. Brief report: MECP2 mutations in people without Rett syndrome. J. Autism Dev. Disord. 44, 703–711 (2014).
Kerr, A. M. et al. Guidelines for reporting clinical features in cases with MECP2 mutations. Brain Dev. 23, 208–211 (2001). An international group developed a simple scoring system to assess clinical severity and capture the variability in Rett syndrome, especially for the purpose of genotype–phenotype comparisons. 20 items were included, and 2 points were allocated for a severe abnormality, 1 point for a perceptible but not extreme abnormality, and 0 points for no abnormality.
Percy, A. K. Rett syndrome: clinical correlates of the newly discovered gene. Brain Dev. 23, S202–S205 (2001).
Monros, E. et al. Rett syndrome in Spain: mutation analysis and clinical correlations. Brain Dev. 23, S251–S253 (2001).
Colvin, L. et al. Describing the phenotype in Rett syndrome using a population database. Arch. Dis. Child. 88, 38–43 (2003).
Bebbington, A. et al. Investigating genotype–phenotype relationships in Rett syndrome using an international data set. Neurology 70, 868–875 (2008).
Neul, J. L. et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology 70, 1313–1321 (2008). References 126 and 127 described the first adequately sized samples to provide definitive information about genotype–phenotype relationships. The findings were broadly similar, with the most severe MECP2 mutations being Arg270X, Arg255X and Arg168X, whereas Arg133Cys and Arg294X had less-severe effects. Overall, individuals with severe mutations were less likely to walk, retain hand use, or use words.
Fehr, S. et al. Altered attainment of developmental milestones influences the age of diagnosis of Rett syndrome. J. Child Neurol. 26, 980–987 (2011).
Bebbington, A. et al. The phenotype associated with a large deletion on MECP2. Eur. J. Hum. Genet. 20, 921–927 (2012).
Archer, H. et al. Correlation between clinical severity in patients with Rett syndrome with a p. R168X or p. T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation. J. Med. Genet. 44, 148–152 (2007). One of the few papers to undertake a thorough examination of the effects of X-chromosome inactivation in individuals with the same mutation, namely, the two common MECP2 mutations Arg168X and Thr158Met. A statistically significant increase in clinical severity with increase in the proportion of active mutated allele was shown for both these mutations.
Zeev, B. B. et al. The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome. Neurology 72, 1242–1247 (2009). This study investigated the effect of a potential genetic modifier, the BDNF Val66Met polymorphism, on clinical severity. In individuals with the Arg168X mutation in MECP2 , heterozygosity for the Val66Met polymorphism was associated with an increase in Rett syndrome severity and earlier age of seizure onset in comparison with individuals homozygous for the wild-type BDNF allele.
Kondo, M. et al. Environmental enrichment ameliorates a motor coordination deficit in a mouse model of Rett syndrome — Mecp2 gene dosage effects and BDNF expression. Eur. J. Neurosci. 27, 3342–3350 (2008).
Lee, J. Y., Leonard, H., Piek, J. P. & Downs, J. Early development and regression in Rett syndrome. Clin. Genet. 84, 572–576 (2013).
Downs, J. et al. Level of purposeful hand function as a marker of clinical severity in Rett syndrome. Dev. Med. Child Neurol. 52, 817–823 (2010).
Downs, J. et al. Validating the Rett Syndrome Gross Motor Scale. PLoS ONE 11, e0147555 (2016).
Foley, K. R. et al. Change in gross motor abilities of girls and women with Rett syndrome over a 3- to 4-year period. J. Child Neurol. 26, 1237–1245 (2011).
Anderson, A., Wong, K., Jacoby, P., Downs, J. & Leonard, H. Twenty years of surveillance in Rett syndrome: what does this tell us? Orphanet J. Rare Dis. 9, 87 (2014).
Sigafoos, J. Communication intervention in Rett syndrome: a systematic review. Res. Autism Spectr. Disord. 3, 304 (2009).
Lotan, M., Schenker, R., Wine, J. & Downs, J. The conductive environment enhances gross motor function of girls with Rett syndrome. A pilot study. Dev. Neurorehabil. 15, 19–25 (2012).
Glaze, D. G., Frost, J. D. Jr, Zoghbi, H. Y. & Percy, A. K. Rett's syndrome. Correlation of electroencephalographic characteristics with clinical staging. Arch. Neurol. 44, 1053–1056 (1987).
Glaze, D. G., Schultz, R. J. & Frost, J. D. Rett syndrome: characterization of seizures versus non-seizures. Electroencephalogr. Clin. Neurophysiol. 106, 79–83 (1998).
Steffenburg, U., Hagberg, G. & Hagberg, B. Epilepsy in a representative series of Rett syndrome. Acta Paediatr. 90, 34–39 (2001).
Jian, L. et al. Predictors of seizure onset in Rett syndrome. J. Pediatr. 149, 542–547 (2006).
Jian, L. et al. Seizures in Rett syndrome: an overview from a one-year calendar study. Eur. J. Paediatr. Neurol. 11, 310–317 (2007).
Glaze, D. G. et al. Epilepsy and the natural history of Rett syndrome. Neurology 74, 909–912 (2010). This study used the Rare Disease Consortium Research Network for Rett syndrome to identify 602 cases who met the criteria for classic or atypical Rett syndrome. Just under half of the cohort had seizures according to physician assessment. Individuals with the MECP2 Thr158Met or Arg106Trp mutation were most likely to have epilepsy (74% and 78%, respectively), and those with the Arg255X or Arg306Cys mutation were least likely to have epilepsy (both 49%).
Bao, X., Downs, J., Wong, K., Williams, S. & Leonard, H. Using a large international sample to investigate epilepsy in Rett syndrome. Dev. Med. Child Neurol. 55, 553–558 (2013).
Nissenkorn, A. et al. Epilepsy in Rett syndrome — lessons from the Rett networked database. Epilepsia 56, 569–576 (2015).
Schultz, R., Glaze, D., Motil, K., Hebert, D. & Percy, A. Hand and foot growth failure in Rett syndrome. J. Child Neurol. 13, 71–74 (1998).
Motil, K. J., Schultz, R., Brown, B., Glaze, D. G. & Percy, A. K. Altered energy balance may account for growth failure in Rett syndrome. J. Child Neurol. 9, 315–319 (1994).
Oddy, W. H. et al. Feeding experiences and growth status in a Rett syndrome population. J. Pediatr. Gastroenterol. Nutr. 45, 582–590 (2007).
Platte, P., Jaschke, H., Herbert, C. & Korenke, G. C. Increased resting metabolic rate in girls with Rett syndrome compared to girls with developmental disabilities. Neuropediatrics 42, 179–182 (2011).
Tarquinio, D. C. et al. Growth failure and outcome in Rett syndrome: specific growth references. Neurology 79, 1653–1661 (2012). This study created growth charts for head circumference, weight, height and BMI on the basis of 9,749 observations of 816 females with Rett syndrome. Growth was decreased compared with a normative US population, and pubertal increases in height and weight were not observed.
Downs, J. et al. Experience of gastrostomy using a quality care framework: the example of Rett syndrome. Medicine (Baltimore) 93, e328 (2014).
Leonard, H. et al. Assessment and management of nutrition and growth in Rett syndrome. J. Pediatr. Gastroenterol. Nutr. 57, 451–460 (2013).
Julu, P. O. et al. Characterisation of breathing and associated central autonomic dysfunction in the Rett disorder. Arch. Dis. Child. 85, 29–37 (2001).
Weese-Mayer, D. E. et al. Autonomic nervous system dysregulation: breathing and heart rate perturbation during wakefulness in young girls with Rett syndrome. Pediatr. Res. 60, 443–449 (2006).
Baikie, G. et al. Gastrointestinal dysmotility in Rett syndrome. J. Pediatr. Gastroenterol. Nutr. 58, 237–244 (2014).
Lioy, D. T., Wu, W. W. & Bissonnette, J. M. Autonomic dysfunction with mutations in the gene that encodes methyl-CpG-binding protein 2: insights into Rett syndrome. Auton. Neurosci. 161, 55–62 (2011).
Hagberg, B. & Romell, M. Rett females: patterns of characteristic side-asymmetric neuroimpairments at long-term follow-up. Neuropediatrics 33, 324–326 (2002).
Downs, J. et al. The natural history of scoliosis in females with Rett syndrome. Spine (Phila. Pa 1976) 41, 856–863 (2016).
Percy, A. K. et al. Profiling scoliosis in Rett syndrome. Pediatr. Res. 67, 435–439 (2010).
Sponseller, P. D., Yazici, M., Demetracopoulos, C. & Emans, J. B. Evidence basis for management of spine and chest wall deformities in children. Spine (Phila. Pa 1976) 32, S81–S90 (2007).
Downs, J. et al. Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence. Spine (Phila. Pa 1976) 34, E607–E617 (2009).
Downs, J. et al. Surgical fusion of early onset severe scoliosis increases survival in Rett syndrome: a cohort study. Dev. Med. Child Neurol. 58, 632–638 (2016). Using the Australian population-based database, this study demonstrated the effects of spinal fusion to treat severe scoliosis in Rett syndrome. The findings indicated that survival was better in individuals who underwent surgery than in those who received conservative management, especially if scoliosis developed before 8 years of age.
Downs, J., Forbes, D., Johnson, M. & Leonard, H. How can clinical ethics guide the management of comorbidities in the child with Rett syndrome? J. Paediatr. Child Health 52, 809–813 (2016).
Ellaway, C., Peat, J., Leonard, H. & Christodoulou, J. Sleep dysfunction in Rett syndrome: lack of age related decrease in sleep duration. Brain Dev. 23, S101–S103 (2001).
Young, D. et al. Sleep problems in Rett syndrome. Brain Dev. 29, 609–616 (2007).
Wong, K., Leonard, H., Jacoby, P., Ellaway, C. & Downs, J. The trajectories of sleep disturbances in Rett syndrome. J. Sleep Res. 24, 223–233 (2015).
Boban, S. et al. Determinants of sleep disturbances in Rett syndrome: novel findings in relation to genotype. Am. J. Med. Genet. A 170, 2292–2300 (2016).
McArthur, A. J. & Budden, S. S. Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment. Dev. Med. Child Neurol. 40, 186–192 (1998).
Haas, R. H., Dixon, S. D., Sartoris, D. J. & Hennessy, M. J. Osteopenia in Rett syndrome. J. Pediatr. 131, 771–774 (1997).
Leonard, H. et al. A population-based approach to the investigation of osteopenia in Rett syndrome. Dev. Med. Child Neurol. 41, 323–328 (1999).
Downs, J. et al. Early determinants of fractures in Rett syndrome. Pediatrics 121, 540–546 (2008).
Roende, G. et al. DXA measurements in Rett syndrome reveal small bones with low bone mass. J. Bone Miner. Res. 26, 2280–2286 (2011).
Roende, G. et al. Patients with Rett syndrome sustain low-energy fractures. Pediatr. Res. 69, 359–364 (2011).
Motil, K. J., Ellis, K. J., Barrish, J. O., Caeg, E. & Glaze, D. G. Bone mineral content and bone mineral density are lower in older than in younger females with Rett syndrome. Pediatr. Res. 64, 435–439 (2008).
Shapiro, J. R. et al. Bone mass in Rett syndrome: association with clinical parameters and MECP2 mutations. Pediatr. Res. 68, 446–451 (2010).
Jefferson, A. L. et al. Bone mineral content and density in Rett syndrome and their contributing factors. Pediatr. Res. 69, 293–298 (2011).
Jefferson, A. et al. Longitudinal bone mineral content and density in Rett syndrome and their contributing factors. Bone 74, 191–198 (2015).
Motil, K. J. et al. Vitamin D deficiency is prevalent in girls and women with Rett syndrome. J. Pediatr. Gastroenterol. Nutr. 53, 569–574 (2011).
Leonard, H. et al. Valproate and risk of fracture in Rett syndrome. Arch. Dis. Child. 95, 444–448 (2010).
Roende, G. et al. Low bone turnover phenotype in Rett syndrome: results of biochemical bone marker analysis. Pediatr. Res. 75, 551–558 (2014).
Jefferson, A. et al. Clinical guidelines for management of bone health in Rett syndrome based on expert consensus and available evidence. PLoS ONE 11, e0146824 (2016).
Lotan, M., Reves-Siesel, R., Eliav-Shalev, R. S. & Merrick, J. Osteoporosis in Rett syndrome: a case study presenting a novel management intervention for severe osteoporosis. Osteoporos. Int. 24, 3059–3063 (2013).
Katz, D. M. et al. Rett syndrome: crossing the threshold to clinical translation. Trends Neurosci. 39, 100–113 (2016).
Gadalla, K. K., Bailey, M. E. & Cobb, S. R. MeCP2 and Rett syndrome: reversibility and potential avenues for therapy. Biochem. J. 439, 1–14 (2011).
Pozzo-Miller, L., Pati, S. & Percy, A. K. Rett syndrome: reaching for clinical trials. Neurotherapeutics 12, 631–640 (2015).
Ricceri, L., De Filippis, B. & Laviola, G. Rett syndrome treatment in mouse models: searching for effective targets and strategies. Neuropharmacology 68, 106–115 (2013).
Lang, M. et al. Rescue of behavioral and EEG deficits in male and female Mecp2-deficient mice by delayed Mecp2 gene reactivation. Hum. Mol. Genet. 23, 303–318 (2014).
Gadalla, K. K. et al. Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice. Mol. Ther. 21, 18–30 (2013).
Garg, S. K. et al. Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome. J. Neurosci. 33, 13612–13620 (2013).
Gadalla, K. E. et al. Gene therapy for Rett syndrome: prospects and challenges. Future Neurol. 10, 467–484 (2015).
Chao, H. T. & Zoghbi, H. Y. MeCP2: only 100% will do. Nat. Neurosci. 15, 176–177 (2012).
Bhatnagar, S. et al. Genetic and pharmacological reactivation of the mammalian inactive X chromosome. Proc. Natl Acad. Sci. USA 111, 12591–12598 (2014).
Vecsler, M. et al. Ex vivo treatment with a novel synthetic aminoglycoside NB54 in primary fibroblasts from Rett syndrome patients suppresses MECP2 nonsense mutations. PLoS ONE 6, e20733 (2011).
Brendel, C. et al. Readthrough of nonsense mutations in Rett syndrome: evaluation of novel aminoglycosides and generation of a new mouse model. J. Mol. Med. (Berl.) 89, 389–398 (2011).
Schanen, C. et al. Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome. Am. J. Med. Genet. A 126A, 129–140 (2004).
Khwaja, O. S. et al. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome. Proc. Natl Acad. Sci. USA 111, 4596–4601 (2014).
FitzGerald, P. M., Jankovic, J. & Percy, A. K. Rett syndrome and associated movement disorders. Mov. Disord. 5, 195–202 (1990).
Mount, R. H., Charman, T., Hastings, R. P., Reilly, S. & Cass, H. The Rett Syndrome Behaviour Questionnaire (RSBQ): refining the behavioural phenotype of Rett syndrome. J. Child Psychol. Psychiatry 43, 1099–1110 (2002).
Robertson, L. et al. The association between behavior and genotype in Rett syndrome using the Australian Rett Syndrome Database. Am. J. Med. Genet. B Neuropsychiatr. Genet. 141B, 177–183 (2006).
Barnes, K. V. et al. Anxiety-like behavior in Rett syndrome: characteristics and assessment by anxiety scales. J. Neurodev. Disord. 7, 30 (2015).
Neul, J. L. et al. Improving treatment trial outcomes for Rett syndrome: the development of Rett-specific anchors for the Clinical Global Impression Scale. J. Child Neurol. 30, 1743–1748 (2015).
Weese-Mayer, D. E. et al. Autonomic dysregulation in young girls with Rett syndrome during nighttime in-home recordings. Pediatr. Pulmonol. 43, 1045–1060 (2008).
Kozinetz, C. A. et al. Epidemiology of Rett syndrome: a population-based registry. Pediatrics 91, 445–450 (1993).
Leonard, H., Bower, C. & English, D. The prevalence and incidence of Rett syndrome in Australia. Eur. Child Adolesc. Psychiatry 6 (Suppl. 1), 8–10 (1997).
Fehr, S. et al. Trends in the diagnosis of Rett syndrome in Australia. Pediatr. Res. 70, 313–319 (2011).
Corbett, J. & Kerr, A. Rett syndrome: from gene to gesture. J. R. Soc. Med. 87, 562–566 (1994).
Young, D. et al. The relationship between MECP2 mutation type and health status and service use trajectories over time in a Rett syndrome population. Res. Autism Spectr. Disord. 5, 442–449 (2011).
Colvin, L. et al. Refining the phenotype of common mutations in Rett syndrome. J. Med. Genet. 41, 25–30 (2004).
Leonard, H. et al. Resourceful and creative methods are necessary to research rare disorders. Dev. Med. Child Neurol. 55, 870–871 (2013).
Percy, A. The American history of Rett syndrome. Pediatr. Neurol. 50, 1–3 (2014).
Louise, S. et al. InterRett, a model for international data collection in a rare genetic disorder. Res. Autism Spectr. Disord. 3, 639–659 (2009).
Christodoulou, J., Grimm, A., Maher, T. & Bennetts, B. RettBASE: the IRSA MECP2 variation database — a new mutation database in evolution. Hum. Mutat. 21, 466–472 (2003).
Hunter, K. Role of the International Rett Syndrome Association. J. Child Neurol. 3, S87–S88 (1988).
Hunter, K. Looking from the inside out: a parent's perspective. Ment. Retard. Dev. Disabil. Res. Rev. 8, 77–81 (2002).
Kerr, A. M., Webb, P., Prescott, R. J. & Milne, Y. Results of surgery for scoliosis in Rett syndrome. J. Child Neurol. 18, 703–708 (2003).
Downs, J. et al. Family satisfaction following spinal fusion in Rett syndrome. Dev. Neurorehabil. 19, 31–37 (2016).
Freilinger, M. et al. Survival with Rett syndrome: comparing Rett's original sample with data from the Australian Rett Syndrome Database. Dev. Med. Child Neurol. 52, 962–965 (2010). This study compared survival in Rett's original cohort with an Australian population-based cohort in 2009, and demonstrated that survival at 25 years had increased from 21% to 71%. These findings have major implications for the clinical care of individuals with Rett syndrome into adulthood.
Kirby, R. S. et al. Longevity in Rett syndrome: analysis of the North American Database. J. Pediatr. 156, 135–138.e1 (2010).
Tarquinio, D. C. et al. The changing face of survival in Rett syndrome and MECP2-related disorders. Pediatr. Neurol. 53, 402–411 (2015).
Leonard, H. et al. How can the Internet help parents of children with rare neurologic disorders? J. Child Neurol. 19, 902–907 (2004).
The authors declare no competing financial interests.
About this article
Cite this article
Leonard, H., Cobb, S. & Downs, J. Clinical and biological progress over 50 years in Rett syndrome. Nat Rev Neurol 13, 37–51 (2017). https://doi.org/10.1038/nrneurol.2016.186
Orphanet Journal of Rare Diseases (2022)
Orphanet Journal of Rare Diseases (2022)
Combined in Silico Prediction Methods, Molecular Dynamic Simulation, and Molecular Docking of FOXG1 Missense Mutations: Effect on FoxG1 Structure and Its Interactions with DNA and Bmi-1 Protein
Journal of Molecular Neuroscience (2022)
European Spine Journal (2022)
Nature Neuroscience (2021)