Advertisement

Importance of Rett syndrome in child neurology

  • Henry G. Dunn
    Correspondence
    Division of Neurology, Room A306, British Columbia's Children's Hospital, 4480 Oak Street, Vancouver, BC V6H 3V4, Canada. Tel.: +1-604-875-2121; fax: +1-604-875-2285
    Affiliations
    Department of Pediatrics, University of British Columbia, Vancouver, BC Canada
    Search for articles by this author

      Abstract

      The syndrome of brain atrophy in girls described by Andreas Rett in 1966 [Rett, Wien Klin Wochenschr, 1966;116:723–726] was brought to the attention of the English-speaking world by Hagberg et al. in 1983 [Hagberg et al., Ann Neurol, 1983;14:471–479]. Four clinical stages after the age of 6 months were described in classical cases of Rett syndrome (RS), namely early onset stagnation at 6 months to 11/2 years, the rapid destructive stage at 1–3 years, the pseudo-stationary stage from pre-school to school years, and the late motor deterioration stage at 15–30 or more years. The rapid destructive stage causes profound dementia with loss of speech and hand skills, stereotypic movements, ataxia, apraxia, irregular breathing with hyperventilation while awake, and frequently seizures. Most cases are isolated in their families, apart from identical twins. However, linkage studies in rare familial cases suggested a critical region at Xq28. In 1999 American investigators found several mutations in the X-linked gene MECP2 encoding Methyl-CpG-binding protein 2 in a proportion of Rett patients. The protein MeCP2 can bind methylated DNA and when mutated may interfere with transcriptional silencing of other genes and result in abnormal chromatin assembly. Many different mutations of the protein are being studied in humans and in mice. Neuropathological studies have shown decreased brain growth and decreased size of individual neurons, with thinned dendrites in some cortical layers, and abnormalities in substantia nigra, suggestive of deficient synaptogenic development, probably starting before birth. Electrophysiology demonstrates progressively abnormal electroencephalograms (EEG) in the first three stages of the syndrome, with some subsequent improvement and occurrence of pseudoseizures. Neurometabolic factors are discussed in detail, particularly reduced levels of dopamine, serotonin, noradrenaline and choline acetyltransferase (ChAT) in brain, also estimation of nerve growth factors, endorphin, substance P, glutamate and other amino acids and their receptor levels. Autonomic dysfunction is described, particularly reduced vagal and overactive sympathetic activity. Neuro-imaging may be required for further investigation, as shown in the differential diagnosis.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Brain and Development
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Rett A.
        Über ein eigenartiges hirnatrophisches Syndrom bei Hyperammonämie im Kindesalter.
        Wien Klin Wochenschr. 1966; 116: 723-726
        • 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. 1983; 14: 471-479
        • Hagberg B.
        • Witt-Engerström I.
        Rett syndrome: a suggested staging system for describing impairment profile with increasing age towards adolescence.
        Am J Med Genet ;24 Suppl. 1986; 1: 47-59
        • Leonard H.
        • Bower C.
        Is the girl with Rett syndrome normal at birth?.
        Dev Med Child Neurol. 1998; 40: 115-121
      1. Dunn, H.G., Stoessl, A.J., Ho, H.H., Poskitt, K.J., Doudet, D.J., Schulzer, M.J., etal. Studies of Rett syndrome: investigation of 9 patients after the age of 12 years, including Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET) and mutational analysis of the MECP2 gene. To be Published

        • Opitz J.
        • Lewin S.
        Rett syndrome: a review and discussion of syndrome delineation and syndrome definition.
        Brain Dev. 1987; 9: 445-450
        • Jellinger K.
        • Armstrong D.
        • Zoghbi H.Y.
        • Percy A.K.
        Neuropathology of Rett syndrome.
        Acta Neuropathol. 1988; 76: 142-158
        • Bauman M.L.
        • Kemper T.L.
        • Arin D.M.
        Microscopic observations of the brain in Rett syndrome.
        Neuropediatrics. 1995; 26: 105-108
        • Hagberg B.A.
        • Skjeldal O.H.
        Rett variants: a suggested model for inclusion criteria.
        Pediatr Neurol. 1994; 11: 5-11
        • Hagberg B.
        Rett's syndrome: prevalence and impact on progressive severe mental retardation in girls.
        Acta Paediatr Scand. 1985; 74: 405-408
        • Kerr A.M.
        • Stephenson J.B.P.
        Rett's syndrome in the West of Scotland.
        Br Med J. 1985; 291: 579-582
        • Witt-Engerström I.
        • Gillberg C.
        Rett syndrome in Sweden.
        J Autism Dev Disord. 1987; 17: 149-150
        • Akesson H.O.
        Rett syndrome: the Swedish Genealogic Research Project. New data and present position.
        Eur Child Adolesc Psychiatry. 1997; 6: 96-98
        • Akesson H.O.
        • Hagberg B.
        • Wahlstrom J.
        Rett syndrome, classical and atypical: genealogical support for common origin.
        J Med Genet. 1996; 33: 764-766
        • Pini G.
        • Milan M.
        • Zappella M.
        Rett syndrome in northern Tuscany: family tree studies.
        Clin Genet. 1996; 50: 486-490
        • Leonard H.
        • Bower C.
        • English D.
        The prevalence and incidence of Rett syndrome in Australia.
        Eur Child Adolesc Psychiatry ;6 Suppl. 1997; 1: 8-10
        • Hollody K.
        • Borvendeg K.
        • Kosztolanyi G.
        Pedigree analysis of Hungarian Rett syndrome girls.
        Eur Child Adolesc Psychiatry. 1997; 6: 99-100
        • Skjeldal O.H.
        • von Tetzchner S.
        • Aspelund F.
        • Herder G.A.
        • LofterMath Eqd B.
        Rett syndrome: geographic variation in prevalence in Norway.
        Brain Dev. 1997; 19: 258-261
        • Ellison K.A.
        • Fill C.P.
        • Terwilliger J.
        • De Gennaro L.J.
        • Martin-Gallarado A.
        • Anvret M.
        • et al.
        Examination of X chromosome markers in Rett syndrome: exclusion mapping with a novel variation on multilocus linkage analysis.
        Am J Hum Genet. 1992; 50: 278-287
        • 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. 1998; 63: 267-269
        • 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. 1998; 63: 1552-1558
        • Xiang F.
        • Zhang Z.
        • Clarke A.
        • Pereira J.
        • Naidu S.
        • Sarojini B.
        • et al.
        Chromosome mapping of Rett syndrome: a likely candidate region on the telomere of Xq.
        J Med Genet. 1998; 35: 297-300
        • Webb T.
        • Clarke A.
        • Hanefeld F.
        • Pereira J.L.
        • Rosenbloom L.
        • Woods C.G.
        Linkage analysis in Rett syndrome families suggests that there may be a critical region at Xq28.
        J Med Genet. 1998; 35: 997-1003
        • Schanen N.C.
        Molecular approaches to the Rett syndrome gene.
        J Child Neurol. 1999; 14: 806-814
        • Amir R.E.
        • Van den Veyver I.B.
        • Wan M.
        • Tran C.Q.
        • Francke U.
        • Zoghbi H.Y.
        Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.
        Nat Genet. 1999; 23: 185-188
        • Willard H.F.
        • Hendrich B.D.
        Breaking the silence in Rett syndrome.
        Nat Genet. 1999; 23: 127-128
        • Amir R.E.
        • Van den Veyver I.B.
        • Schultz R.
        • Malicki D.M.
        • Tran C.Q.
        • Dahle E.J.
        • et al.
        Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes.
        Ann Neurol. 2000; 47: 670-679
        • Huppke P.
        • Laccone F.
        • Krämer N.
        • Engel W.
        • Hanefeld F.
        Rett syndrome: analysis of MeCP2 and clinical characterization of 31 patients.
        Hum Mol Genet. 2000; 9: 1369-1375
        • Van den Veyver I.B.
        • Zoghbi H.Y.
        Methyl-CpG binding protein 2 mutations in Rett syndrome.
        Curr Opin Genet Dev. 2000; 10: 275-279
        • Cheadle J.P.
        • Gill H.
        • Fleming N.
        • Maynard J.
        • Kerr A.
        • Leonard H.
        • 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. 2000; 9: 1119-1129
        • Wan M.
        • Lee S.S.J.
        • Zhang X.
        • Houwink-Manville I.
        • Song H-R.
        • Amir R.E.
        • et al.
        Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CPG hotspots.
        Am J Hum Genet. 1999; 65: 1520-1529
        • Jellinger K.
        • Armstrong D.
        • Zoghbi H.Y.
        • Percy A.K.
        Neuropathology of Rett syndrome.
        Acta Neuropathol. 1988; 76: 142-158
        • Bauman M.L.
        • Kemper T.L.
        • Arin D.M.
        Microscopic observations of the brain in Rett syndrome.
        Neuropediatrics. 1995; 26: 105-108
        • Armstrong D.D.
        The neuropathology of Rett syndrome: overview 1994.
        Neuropediatrics. 1995; 26: 100-104
        • Kitt C.A.
        • Wilcox B.J.
        Preliminary evidence for neurodegenerative changes in the substantia nigra of Rett syndrome.
        Neuropediatrics. 1995; 26: 114-118
        • Belichenko P.V.
        • Hagberg B.
        • Dahlström A.
        Morphological study of neocortical areas in Rett syndrome.
        Acta Neuropathol. 1997; 93: 50-61
        • Glaze D.G.
        • Frost J.D.
        • Zoghbi H.Y.
        • Percy A.K.
        Rett syndrome: Correlation of electroencephalographic characteristics with clinical staging.
        Arch Neurol. 1987; 44: 1053-1056
        • Robertson R.
        • Langill L.
        • Wong P.K.H.
        • Ho H.H.
        Rett syndrome: EEG presentation.
        Electroencephalogr Clin Neurophysiol. 1988; 70: 388-395
        • Elian M.
        • Rudolf N.D.
        EEG and respiration in Rett syndrome.
        Acta Neurol Scand. 1991; 83: 123-128
        • Niedermeyer E.
        • Naidu S.B.
        • Plate C.
        • Unusual E.E.G.
        theta rhythms over central region in Rett syndrome: considerations of the underlying dysfunction.
        Clin Electroencephalogr. 1997; 28: 36-43
        • Glaze D.G.
        • Schultz R.J.
        • Frost J.D.
        Rett syndrome: characterization of seizures versus nonseizures.
        Electroencephalogr Clin Neurophysiol. 1998; 106: 79-83
        • Guerrini R.
        • Bonanni P.
        • Parmeggiani L.
        • Santucci M.
        • Parmeggiani A.
        • Santucci F.
        Cortical reflex myoclonus in Rett syndrome.
        Ann Neurol. 1998; 43: 472479
        • Haas R.H.
        • Love S.
        Peripheral nerve findings in Rett syndrome.
        J Child Neurol. 1988; 3: 525-530
        • Bader G.G.
        • Witt-Engerström I.
        • Hagberg B.
        Neurophysiological findings in the Rett syndrome. I:EMG, conduction velocity, EEG and somatosensory-evoked potential studies.
        Brain Dev. 1989; 11: 102-109
        • Nomura Y.
        • Segawa M.
        Anatomy of Rett syndrome.
        Am J Med Genet. 1986; 24: 289-303
        • Nomura Y.
        • Kimura K.
        • Arai H.
        • Segawa M.
        Involvement of the autonomic nervous system in the pathophysiology of Rett syndrome.
        Eur Child Adolesc Psychiatry. 1997; 6: 42-46
        • Julu P.O.
        • Kerr A.M.
        • Hansen S.
        • Apartopoulos F.
        • Jamal G.A.
        Functional evidence of brainstem immaturity in Rett syndrome.
        Eur Child Adolesc Psychiatry. 1997; 6: 47-54
        • Witt Engerström I.
        • Kerr A.
        Workshop on autonomic function in Rett syndrome. Swedish Rett Center, Frösön, Sweden, May 1998.
        Brain Dev. 1998; 20: 323-326
        • Budden S.S.
        Management of Rett syndrome: a ten-year experience.
        Neuropediatrics. 1995; 26: 75-77
        • Naidu S.
        Rett syndrome: a disorder affecting early brain growth.
        Ann Neurol. 1997; 42: 3-10
        • Chiron C.
        • Leboyer M.
        • Leon F.
        • Jambaqué I.
        • Nuttin C.
        • Syrota A.
        SPECT of the brain in childhood autism: Evidence for a lack of normal hemispheric asymmetry.
        Dev Med Child Neurol. 1995; 37: 849-860
        • Chugani D.C.
        • Muzik O.
        • Behen M.
        • Rothermel R.
        • Janisse J.J.
        • Lee J.
        • et al.
        Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children.
        Ann Neurol. 1999; 45: 287-295
        • Ellaway C.
        • Buchholz T.
        • Smith A.
        • Leonard H.
        • Christodoulou J.
        Rett syndrome: significant clinical overlap with Angelman syndrome but not with methylation status.
        J Child Neurol. 1998; 13: 448-451
        • Subramaniam B.
        • Naidu S.
        • Reiss A.L.
        Neuroanatomy in Rett syndrome: Cerebral cortex and posterior fossa.
        Neurology. 1997; 48: 399-407