GCB Masthead
Rett Syndrome Rett syndrome is a clinically-defined neurologic disorder, typically seen in females, which is associated in most cases with sporadic mutations in the coding region of the transcriptional regulator MeCP2. Rett syndrome occurs in a variety of racial and ethnic groups worldwide with estimates between 1:10,000-1:23,000 female births; however, the incidence may be greater as genetic evidence accumulates and the clinical spectrum of the disorder is re-evaluated. The clinical manifestations of Rett syndrome are variable and dynamic; development appears normal until 6-18 months of age, followed by slowing of head growth, loss of acquired speech and hand skills, gait abnormalities, and development of stereotyped repetitive hand movements. The latter may change over time and consist of hand washing, hand wringing, hand tapping, hand clapping, and hand mouthing. Other frequent manifestations include breathing irregularities (hyperventilation and apnea), seizures, teeth grinding, and scoliosis. Depending on the clinical presentation, cases of Rett syndrome are labeled as classic or atypical (several types). The almost exclusive presentation of Rett syndrome in females has been attributed to the X-linked nature of the disorder that leads to lethality in male fetuses, while its phenotypical spectrum is associated with the variable inactivation of the X chromosome carrying the mutated allele. However, many questions remain in Rett syndrome since correlations between genotype and phenotype are limited. In as many as one-third of patients, no mutation in the coding region of MeCP2 is detected. Conversely, MeCP2 mutations are seen occasionally in patients with other neurologic manifestations. The impact of the type of mutation or location within the MeCP2 gene on the severity of Rett syndrome is still under active investigation.

Rett Syndrome Research The GCB includes two multidisciplinary projects within the Rett Syndrome Research Program, a NIH-funded Program Project Grant based at the Kennedy Krieger Institute. The first project intends to delineate the foundations of the phenotypical variability of the disorder, by characterizing the Rett syndrome molecular phenotype in postmortem brain samples and in peripheral cells from affected patients. Molecular parameters in peripheral cells are also correlated with neurologic and behavioral features. The second project focuses on the neurobiological correlates of MeCP2 deficiency by studying experimental models. Mouse models are employed to characterize neurobehavioral phenotypic characteristics that resemble features of Rett syndrome. The emphasis of these studies is on brain regions preferentially affected in the disorder, namely cerebral cortex, basal forebrain, and cerebellum. The in vitro component studies synaptic connections and MeCP2 replacement approaches. Involved in the projects are investigators at KKI and the Johns Hopkins University School of Public Health, Morgan Sate University, and Emory University School of Medicine. Additionally, the GCB is the coordinating center for RettSearch, an international consortium of Rett syndrome researchers. More information on RettSearch can be found on their website at http://www.rettsearch.org.

Current Research Projects

Molecular Pathology of Rett Syndrome

Mutations of the MeCP2 gene are detected in most patients with Rett syndrome; however, the proportion of Rett syndrome patients who do not have MeCP2 mutations is still relatively large (up to one third) despite advances in diagnostic techniques. This, along with the fact that the type of MeCP2 mutation does not predict well the severity of the disorder, suggests that other aspects of the molecular profile of each Rett patient need to be studied. Our research team uses different techniques to delineate these molecular profiles in blood samples from patients with different clinical presentations of Rett syndrome. We intend to see whether certain molecular types are correlated with particular symptoms or the severity of Rett syndrome.

Funded by National Institute of Child Health and Development, NIH

Neurobiology of Rett Syndrome

The project applies sophisticated morphologic, molecular, cell biological, and behavioral approaches to the characterization of experimental models of MeCP2 deficiency. We intend to determine whether mouse models exhibit phenotypic changes that resemble features of Rett syndrome, with emphasis on regions particularly affected in this disorder: cerebral cortex, basal forebrain, and cerebellum. In addition, in vitro models are used to study synaptic connections and MeCP2 replacement techniques.

Funded by National Institute of Child Health and Development, NIH

Faculty Involved

Robert M. Gray, Ph.D.
Michael V. Johnston, M.D.
Walter E. Kaufmann, M.D.
Lynn J. Speedie, Ph.D.
Elaine Tierney, M.D.


Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, Leonard H, Bailey ME, Schanen NC, Kerr AM, Renieri A, Huppke P, Percy AK, for the RettSearch Consortium (2010) Rett syndrome: Revised diagnostic criteria and nomenclature. Ann Neurol 68: 944-950.

Downs J, Bebbington A, Kaufmann WE, Leonard H (2010) Longitudinal hand function in Rett syndrome. J Child Neurol: Oct 4.
Level of purposeful hand function as a marker of clinical severity in Rett syndrome. Dev Med Child Neurol 52: 817-823.

Horská A, Farage, L, Bibat G, Nagae LM, Kaufmann WE, Barker PB, Naidu S (2009) Brain metabolism in Rett Syndrome: age, clinical, and genotype correlations. Ann Neurol 65:90-97.

Kaufmann WE, Capone GT, Clarke M, Budimirovic DB (2008) Autism in genetic intellectual disability: insights into idiopathic autism. In Zimmerman AW (Ed). Autism: Current Theories and Evidence. Totowa, NJ: The Humana Press Inc., pp. 81-108.

Downs JA, Bebbington A, Jacoby P, Msall M, McIlroy O, Fyfe S, Bahi- Buisson N, Kaufmann WE, Leonard H (2008) Gross motor profile in Rett syndrome as determined by video analysis. Neuropediatrics 39:205-210.

Carter JC, Lanham DC, Pham D, Bibat G, Naidu S, Kaufmann WE (2008) Selective cerebral volume reduction in Rett syndrome: a multiple approach MR study. AJNR Am J Neuroradiol 29:436-441.

Bebbington A, Anderson A, Ravine D, Fyfe S, Pineda M, de Klerk N, Ben-Zeev B, Yatawara N, Percy A, Kaufmann WE, Leonard H (2008). Investigating genotype-phenotype relationships in Rett syndrome using an international dataset. Neurology, 70: 868-75.

Carter JC, Lanham DC, Pham D, Bibat G, Naidu S, Kaufmann WE (2008). Selective cerebral volume reduction in Rett syndrome: a multiple-approach MR imaging study. American Journal of Neuroradiology, 29: 436-41.

Fyfe S, Downs J, McIlroy O, Burford B, Lister J, Reilly S, Laurvick CL, Philippe C, Msall M, Kaufmann WE, Ellaway C, Leonard H (2007). Development of a video-based evaluations tool in Rett syndrome. Journal of Autism and Developmental Disorders, 37: 1636-46.

Young DJ, Bebbington A, Anderson A, Ravine D, Ellaway C, Kulkarni A, de Klerk N, Kaufmann WE, Leonard H (2008). The diagnosis of autism in a female: could it be Rett syndrome? European Journal of Pediatrics, 167(6):661-9.

Kankirawatana P, Leonard H, Ellaway C, Scurlock J, Mansour A, Makris CM, Dure LS IV, Friez M, Lane J, Kiraly-Borri C, Fabian V, Davis M, Jackson J, Christodoulou J, Kaufmann WE, Ravine D, Percy AK (2006) Early progressive encephalopathy in boys and MECP2 mutations. Neurology 67: 164-166.

Kaufmann WE, Johnston MV, Blue ME (2005) MeCP2 expression and function during brain development: implications for Rett syndrome’s pathogenesis and clinical evolution. Brain Dev 27: S77-S87.

Kaufmann WE, Jarrar MH, Wang JS, Lee Y-JM, Reddy S, Bibat G, Naidu S (2005). Histone modifications in Rett syndrome lymphocytes: a preliminary evaluation. Brain & Development, 27:331-39.

Mullaney BC, Johnston MV, Blue ME (2004). Developmental expression of methyl-CpG binding protein 2 is dynamically regulated in the rodent brain. Neuroscience, 123: 939-49.

Aber KM, Nori P, MacDonald S, Bibat G, Jarrar MH, Kaufmann WE (2003). Methyl-CpG-binding protein 2 is localized in the postsynaptic compartment: an immunochemical study of subcellular fractions. Neuroscience, 116: 77-80.

Jarrar MH, Danko CG, Reddy S, Lee YJ, Bibat G, Kaufmann WE (2003). MeCP2 expression in human cerebral cortex and lymphoid cells: immunochemical characterization of a novel higher-molecular-weight form. Journal of Child Neurology, 18: 675-82.

Johnston MV, Mullaney BC, Blue ME (2003). Neurobiology of Rett syndrome. Journal of Child Neurology, 18: 688-92.

Naidu S, Bibat G, Kratz L, Kelley RI, Pevsner J, Hoffman E, Cuffari C, Rohde C, Blue ME, Johnston MV (2003). Clinical Variability in Rett syndrome. Journal of Child Neurology, 18: 662-68.

Villemagne PM, Naidu S, Villemagne VL, Yaster M, Wagner HN Jr, Harris JC, Moser HW, Johnston MV, Dannals RF, Wong DF (2002). Brain glucose metabolism in Rett Syndrome. Pediatric Neurology, 27: 117-22.

Colantuoni C, Jeon OH, Hyder K, Chenchik A, Khimani AH, Narayanan V, Hoffman EP, Kaufmann WE, Naidu S, Pevsner J (2001). Gene expression profiling in postmortem Rett syndrome brain: differential gene expression and patient classification. Neurobiology of Disease, 8: 847-65.

Johnston MV, Jeon OH, Pevsner J, Blue ME, Naidu S (2001). Neurobiology of Rett syndrome: a genetic disorder of synapse development. Brain & Development, 23 Suppl 1: S206-13.

Naidu S, Kaufmann WE, Abrams MT, Pearlson GD, Lanham DC, Fredericksen KA, Barker PB, Horska A, Golay X, Mori S, Wong DF, Yablonski M, Moser HW, Johnston MV (2001). Neuroimaging studies in Rett syndrome. Brain & Development, 23: S62-71.

Horská A, Naidu S, Herskovits EH, Wang PY, Kaufmann WE, Barker PB (2000). Quantitative proton MR spectroscopic imaging in early Rett syndrome. Neurology, 54: 715-22.

Kaufmann WE, MacDonald SM, Altamura CR (2000). Dendritic cytoskeletal protein expression in mental retardation: an immunohistochemical study of the neocortex in Rett syndrome. Cerebral Cortex, 10: 992-1004.

Kaufmann WE, Moser HW (2000). Dendritic anomalies in disorders associated with mental retardation. Cerebral Cortex, 10: 981-91.

Blue ME, Naidu S, Johnston MV (1999). Altered development of glutamate and GABA reeptors in the basal ganglia of girls with Rett syndrome. Experimental Neurology, 156: 345-52.

Blue ME, Naidu S, Johnston MV (1999). Development of amino acid receptors in frontal cortex from girls with Rett syndrome. Annals of Neurology, 45: 541-45.

Kates WR, Warsofsky IS, Patwardhan A, Abrams MT, Liu AM, Naidu S, Kaufmann WE, Reiss AL (1999). Automated Talairach atlas-based parcellation and measurement of cerebral lobes in children. Psychiatry Research, 91: 11-30.

Rett Syndrome Resources

See Family Resources: Rett Syndrome