Advertisement

Neurophysiology of Rett syndrome

      Abstract

      Neurophysiological studies on Rett syndrome (RTT) are reviewed, and pathophysiology of RTT is discussed. The electroencephalography (EEG), sensory evoked potentials (SEP), sleep–wake rhythm study and polysomnography (PSG) study showed age-dependent characteristics. PSG revealed the brainstem and midbrain monoaminergic systems are deranged from early developmental stage, that is serotonin and noradrenaline systems seem to be hypoactive and dopaminergic system is also hypoactive associated with receptor supersensitivity. These monoaminergic systems are known to influence the maturation of the higher neuronal systems at specific areas and at specific ages. Particularly the synaptogenesis of the cerebral cortex is modulated by region or layer specifically from an early stage of the development. The observations made in EEG and SEP studies also suggested specific subcortical and cortical involvements taking place during the development. The age-dependent appearance of characteristic clinical features of RTT, and the variation of the clinical severities, e.g. classical, variant, form fruste, etc., can also be explained by the specific features of these monoaminergic systems. Furthermore, analysis of the components of rapid eye movement sleep suggested the onset of RTT lies between 36 gestational weeks to 3–4 months postnatally. The discovery of the mutations of methyl-CpG-binding protein 2 (MECP2) gene as the causative gene of RTT is an epoch helping not only to understand the pathophysiology of RTT but also various neurodevelopmental disorders.

      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

        • Verma N.P.
        • Chheda R.L.
        • Nigro M.A.
        • Hart Z.H.
        Electroencephalographic findings in Rett syndrome.
        Electroencephalogr Clin Neurophysiol. 1986; 64: 394-401
        • Garofalo E.A.
        • Drury I.
        • Goldstein G.W.
        EEG abnormalities aid diagnosis of Rett syndrome.
        Pediatr Neurol. 1988; 4: 350-353
        • Ishizaki A.
        • Inoue Y.
        • Sasaki H.
        • Fukuyama Y.
        Longitudinal observation of electroencephalograms in the Rett syndrome.
        Brain Dev. 1989; 11: 407-412
        • Cooper R.A.
        • Kerr A.M.
        • Amos P.M.
        Rett syndrome: critical examination of clinical features, serial EEG and video-monitoring in understanding and management.
        Eur J Paediatr Neurol. 1998; 2: 127-135
        • Robertson R.
        • Langill L.
        • Wong P.K.
        • Ho H.H.
        Rett syndrome: EEG presentation.
        Electroencephalogr Clin Neurophysiol. 1988; 70: 388-395
        • Niedermeyer E.
        • Rett A.
        • Renner H.
        • Murphy M.
        • Naidu S.
        Rett syndrome and the electroencephalogram.
        Am J Med Genet Suppl. 1986; 1: 195-199
        • Niedermeyer E.
        • Naidu S.B.
        • Plate C.
        Unusual EEG theta rhythms over central region in Rett syndrome: considerations of the underlying dysfunction.
        Clin Electroencephalogr. 1997; 28: 36-43
        • Trauner D.A.
        • Haas R.H.
        Electroencephalographic abnormalities in Rett syndrome.
        Pediatr Neurol. 1987; 3: 331-334
        • Niedermeyer E.
        • Naidu S.
        Further EEG observations in children with the Rett syndrome.
        Brain Dev. 1990; 12: 53-54
        • Laan L.A.
        • Brouwer O.F.
        • Begeer C.H.
        • Zwinderman A.H.
        • Gert van Dijk J.
        The diagnostic value of the EEG in Angelman and Rett syndrome at a young age.
        Electroencephalogr Clin Neurophysiol. 1998; 106: 404-408
        • Ho H.H.
        • Wong P.K.
        • Robertson R.
        Rett syndrome: clinical profile and EEG abnormalities.
        Clin Invest Med. 1988; 11: 234-241
        • Hagne I.
        • Witt-Engerstrom I.
        • Hagberg B.
        EEG development in Rett syndrome. A study of 30 cases.
        Electroencephalogr Clin Neurophysiol. 1989; 72: 1-6
        • Takeuchi T.
        • Matsumoto A.
        • Kumagai T.
        • Miyazaki S.
        • Watanabe K.
        Long-term evolution of EEG features in Rett syndrome.
        Brain Dysfunct. 1989; 2: 34-44
        • Robb S.A.
        • Harden A.
        • Boyd S.G.
        Rett syndrome: an EEG study in 52 girls.
        Neuropediatrics. 1989; 20: 192-195
        • Bashina V.M.
        • Simashkova N.V.
        • Gorbachevskaia N.L.
        • Kozhushko L.F.
        • Iakupova L.P.
        The clinical and neurophysiological aspects of Rett’s syndrome (in Russian).
        Zh Nevropatol Psikhiatr Im SS Korsakova. 1993; 93: 52-55
        • Espinar-Sierra J.
        • Toledano M.A.
        • Franco C.
        • Campos-Castello J.
        • Gonzalez-Hidalgo M.
        • Oliete F.
        • et al.
        Rett’s syndrome: a neurophysiological study.
        Neurophysiol Clin. 1990; 20: 35-42
        • Kerr A.
        • Southall D.
        • Amos P.
        • Cooper R.
        • Samuels M.
        • Mitchell J.
        • et al.
        Correlation of electroencephalogram, respiration and movement in the Rett syndrome.
        Brain Dev. 1990; 12: 61-68
        • Elian M.
        • Rudolf N.D.
        EEG and respiration in Rett syndrome.
        Acta Neurol Scand. 1991; 83: 123-128
        • Ishizaki A.
        Electroencephalographical study of the Rett syndrome with special reference to the monorhythmic theta activities in adult patients.
        Brain Dev. 1992; 14: S31-S36
        • Niedermeyer E.
        • Naidu S.B.
        Rett syndrome, EEG and the motor cortex as a model for better understanding of attention deficit hyperactivity disorder (ADHD).
        Eur Child Adolesc Psychiatry. 1998; 7: 69-72
        • Lappalainen R.
        • Liewendahl K.
        • Sainio K.
        • Nikkinen P.
        • Riikonen R.S.
        Brain perfusion SPECT and EEG findings in Rett syndrome.
        Acta Neurol Scand. 1997; 95: 44-50
        • Pelson R.O.
        • Budden S.S.
        Auditory brainstem response findings in Rett syndrome.
        Brain Dev. 1987; 9: 514-516
        • Stach B.A.
        • Stoner W.R.
        • Smith S.L.
        • Jerger J.F.
        Auditory evoked potentials in Rett syndrome.
        J Am Acad Audiol. 1994; 5: 226-230
        • Pillion J.P.
        • Rawool V.W.
        • Naidu S.
        Auditory brainstem responses in Rett syndrome: effects of hyperventilation, seizures, and tympanometric variables.
        Audiology. 2000; 39: 80-87
        • Kalmanchey R.
        Evoked potentials in the Rett syndrome.
        Brain Dev. 1990; 12: 73-76
        • Bader G.G.
        • Witt-Engerstrom I.
        • Hagberg B.
        Neurophysiological findings in the Rett syndrome. II: Visual and auditory brainstem, middle and late evoked responses.
        Brain Dev. 1989; 11: 110-114
        • Verma N.P.
        • Nigro M.A.
        • Hart Z.H.
        Rett syndrome – a gray matter disease? Electrophysiologic evidence.
        Electroencephalogr Clin Neurophysiol. 1987; 67: 327-329
        • Gorke W.
        Normal latencies of cortical somatosensory evoked potentials – an additional v criterion for the diagnosis or Rett syndrome (in German).
        Klin Padiatr. 1989; 201: 93-97
        • Bader G.G.
        • Witt-Engerstrom I.
        • Hagberg B.
        Brain stem and spinal cord impairment in Rett syndrome: somatosensory and auditory evoked responses investigation.
        Brain Dev. 1987; 8: 517-522
        • Bader G.G.
        • Witt-Engerstrom 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
        • Yoshikawa H.
        • Kaga M.
        • Suzuki H.
        • Sakuragawa N.
        • Arima M.
        Giant somatosensory evoked potentials in the Rett syndrome.
        Brain Dev. 1991; 13: 36-39
        • Kimura K.
        • Nomura Y.
        • Segawa M.
        Middle and short latency somatosensory evoked potentials (SEPm, SEPs) in the Rett syndrome: chronological changes of cortical and subcortical involvements.
        Brain Dev. 1992; 14: S37-S42
        • Kimura K.
        • Sonoo M.
        • Nomura Y.
        • Tanaka R.
        • Segawa M.
        Somatosensory evoked potentials (SEP) in Rett syndrome – evaluating cortical involvement using onset latency.
        in: Hashimoto I. Kakigi R. Recent advances in human neurophysiology. Elsevier Science, Amsterdam1998: 189-193
        • Nomura Y.
        • Segawa M.
        • Higurashi M.
        Rett syndrome – an early catecholamine and indolamine deficient disorder?.
        Brain Dev. 1985; 7: 334-341
        • Nomura Y.
        • Honda K.
        • Segawa M.
        Pathophysiology of Rett syndrome.
        Brain Dev. 1987; 9: 506-513
        • McArthur A.
        • Budden S.S.
        Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment.
        Dev Med Child Neurol. 1998; 40: 186-192
        • Nomura Y.
        • Segawa M.
        The monoamine hypothesis in Rett syndrome.
        in: Kerr A. Witt-Engerstrom I. Rett disorder and the developing brain. Oxford University Press, Oxford, UK2001: 205-225
        • Nomura Y.
        • Segawa M.
        Anatomy of Rett syndrome.
        Am J Med Genet Suppl. 1986; 1: 289-303
        • Segawa M.
        • Nomura Y.
        The pathophysiology of the Rett syndrome from the standpoint of polysomnography.
        Brain Dev. 1990; 12: 55-60
        • Segawa M.
        • Nomura Y.
        Polysomnography in Rett syndrome.
        Brain Dev. 1992; 14: S46-S54
        • Eyre J.A.
        • Kerr A.M.
        • Miller S.
        • O'Sullivan M.C.
        • Ramesh V.
        Neurophysiological observations on corticospinal projections to the upper limb in subjects with Rett syndrome.
        J Neurol Neurosurg Psychiatry. 1990; 53: 874-879
        • Heinen F.
        • Peterson H.
        • Fietzek U.
        • Mall V.
        • Shulte-Monting J.
        • Korinthenberg R.
        Transcranial magnetic stimulation in patients with Rett syndrome: preliminary results.
        Eur Child Adolesc Psychiatry. 1997; 6: 61-63
        • Nezu A.
        • Kimura S.
        • Takeshita S.
        • Tanaka M.
        Characteristic response to transcranial magnetic stimulation in Rett syndrome.
        Electroencephalogr Clin Neurophysiol. 1998; 109: 100-103
        • Nomura Y.
        • Kimura K.
        • Arai H.
        • Segawa M.
        Involvement of the autonomic nervous system in the pathophysiology of Rett syndrome.
        Eur Child Adolesec Psychiatry. 1997; 6: 42-46
        • Boltshauser E.
        • Lange B.
        • Dumermuth G.
        Differential diagnosis of syndromes with abnormal respiration (tachypnea-apnea).
        Brain Dev. 1987; 9: 462-465
        • Cirignotta F.
        • Lugaresi E.
        • Montagna P.
        Breathing impairment in Rett syndrome.
        Am J Med Genet Suppl. 1986; 1: 167-173
        • Cirignotta F.
        • Mondini S.
        • Zucconi M.
        • Sforza E.
        • Gerardi R.
        • Petronelli R.
        Breathing impairment in central alveolar hypoventilation and Rett syndrome.
        Funct Neurol. 1987; 2: 487-492
        • Marcus C.L.
        • Carroll J.L.
        • McColley S.A.
        • Loughlin G.M.
        • Curtis S.
        • Pyzik P.
        • et al.
        Polysomnographic characteristics of patients with Rett syndrome.
        J Pediatr. 1994; 125: 218-224
        • Woodyatt G.C.
        • Murdoch B.E.
        The effect of the presentation of visual and auditory stimuli on the breathing patterns of two girls with Rett syndrome.
        J Intellect Disabil Res. 1996; 40: 252-259
        • Southall D.P.
        • Kerr A.M.
        • Tirosh E.
        • Amos P.
        • Lang M.H.
        • Stephenson J.B.
        Hyperventilation in the awake state: potentially treatable component or Rett syndrome.
        Arch Dis Child. 1998; 63: 1039-1048
        • Schluter B.
        • Aguigah G.
        • Buschatz D.
        • Trowitzsch E.
        • Aksu F.
        Polysomnographic recordings of respiratory disturbances in Rett syndrome.
        J Sleep Res. 1995; 4: 203-207
        • Morton R.E.
        • Pinnington L.
        • Ellis R.E.
        Air swallowing in Rett syndrome.
        Dev Med Child Neurol. 2000; 42: 271-275
        • 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
        • Julu P.O.
        The central autonomic disturbance in Rett syndrome.
        in: Kerr A. Witt-Engerstrom I. Rett disorder and the developing brain. Oxford University Press, Oxford, UK2001: 131-181
        • Nomura Y.
        • Segawa M.
        • Hasegawa M.
        Rett syndrome-clinical studies and pathophysiological consideration.
        Brain Dev. 1984; 6: 475-486
        • Segawa M.
        Pathophysiology of Rett syndrome from the standpoint of early catecholamine disturbance.
        Eur Child Adolesc Psychiatry. 1997; 6: 56-60
        • McCarley R.W.
        • Hobson J.A.
        Single unit activity in cat gigantocellular tegmental field: selectivity of discharge in desynchronized sleep.
        Science. 1971; 174: 1250-1252
        • Hobson J.A.
        • McCarley R.W.
        • Pivic R.T.
        • Freedman R.
        Selective firing by cat pontine brain stem neurons in desynchronized sleep.
        J Neurophysiol. 1974; 37: 497-511
        • Hobson J.A.
        • McCarley R.W.
        • Wyzinzki R.W.
        Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups.
        Science. 1975; 189: 55-58
        • Sakai K.
        Central mechanisms of paradoxical sleep.
        in: Borbély A. Valatx J.L. Sleep mechanisms. Springer, Berlin1984: 3-18
        • Swaab D.F.
        • Flier E.
        • Partiman T.S.
        Suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia.
        Brain Res. 1985; 342: 37-44
        • Takahashi K.
        • Shimoda K.
        • Yamada N.
        • Sasaki Y.
        • Hayashi S.
        Effect of dorsal midbrain lesion in infant rats on development of circadian rhythm.
        Brain Dev. 1986; 8: 373-381
        • Parmelee Jr, A.H.
        • Stern E.
        Sleep and the maturing nervous system.
        in: Clemente C.D. Purpura D.P. Mayer F.E. Academic Press, New York1972: 199-215
        • Segawa M.
        Ontogenesis of REM sleep.
        in: Mellick B.N. Inoué I. Rapid eye movement sleep. Narosa Publishing House, New Delhi1999: 39-50
        • Hobson J.A.
        Sleep: order and disorder. Behavioral biology in medicine. A monograph series. 1983: 1-36
        • Kohyama J.
        • Iwakawa Y.
        Interrelationships between rapid eye and body movements during sleep: polysomnographic examinations of infants including premature neonates.
        Electroencephalogr Clin Neurophysiol. 1991; 79: 277-280
        • Kohyama J.
        • Shinohira M.
        • Hasegawa T.
        • Kouji T.
        • Iwakawa Y.
        Phasic motor activity reduction occurring with horizontal rapid eye movements during sleep in humans.
        Exp Brain Res. 1995; 107: 137-144
        • Segawa M.
        • Nomura Y.
        • Hakamada S.
        • Nagata E.
        • Sakamoto M.
        • Oka N.
        Polysomnography – functional topographical examination of the basal ganglia.
        Brain Dev. 1986; 8: 475-481
        • Segawa M.
        • Nomura Y.
        • Hikosaka O.
        • Soda M.
        • Usui S.
        • Kase M.
        Roles of the basal ganglia and related structures in symptoms of dystonia.
        in: Carpenter M.B. Jayaraman A. Structure and function. Basal ganglia. Plenum Press, New York1989: 489-504
        • Segawa M.
        • Nomura Y.
        Rapid eye movements during stage REM are modulated by nigrostriatal dopamine (NS-DA) neurons?.
        in: Bermardi G. Basal ganglia. Plenum Press, New York1991: 663-671
        • Fukumoto M.
        • Mochizuki N.
        • Takeishi M.
        • Nomura Y.
        • Segawa M.
        Studies of body movements during night sleep in infancy.
        Brain Dev. 1981; 3: 37-43
        • Mirmiran M.
        The role of the central monoaminergic system and rapid eye movement sleep in development.
        Brain Dev. 1986; 8: 382-389
        • Brenner E.
        • Mirmiran M.
        • Uylings H.B.M.
        • Van Der Gugten J.
        Impaired growth of the cerebral cortex of rats treated neonatally with 6-hydroxydopamine under different environmental conditions.
        Neurosci Lett. 1983; 42: 13-17
        • Jürgens U.
        • Pratt R.
        Role of the periaqueductal grey in vocal expression of emotion.
        Brain Res. 1979; 167: 367-378
        • Jürgens U.
        The squirrel monkey as an experimental model in the study of cerebral organization of emotional vocal utterances.
        Eur Arch Psychiatry Neurol Sci. 1986; 236: 40-43
        • Harting J.K.
        • Van Lieshout P.V.
        • Feig S.
        Connectional studies of the primate lateral geniculate nucleus: distribution of axons arising from the thalamic reticular nucleus of Galago crassicaudatus.
        J Comp Neurol. 1991; 310: 411-427
        • Jayaraman A.
        • Batton R.R.
        • Carpenter M.B.
        Nigrotectal projections in the monkey: an autoradiographic study.
        Brain Res. 1977; 135: 147-152
        • Armstrong D.D.
        The neuropathology of Rett syndrome – overview 1994.
        Neuropediatrics. 1995; 26: 100-104
        • Armstrong D.
        • Dunn J.K.
        • Antalffy B.
        • Trivedi R.
        Selective dendritic alterations in the cortex of Rett syndrome.
        J Neuropathol Exp Neurol. 1995; 54: 195-201
        • Levitt P.
        • Harvey J.A.
        • Friedam E.
        • Simansky K.
        • Murphy E.H.
        Monoamines in neural differentiation. New evidence for neurotransmitter influences on brain development.
        Trends Neurosci. 1997; 20: 269-274
        • Mirmiran M.
        The function of fetal/neonatal rapid eye movement sleep.
        Behav Brain Res. 1995; 69: 13-22
        • Marks G.A.
        • Shaffery J.P.
        • Oksenberg A.
        • Speciale S.G.
        • Roffwarg H.P.
        A functional role for REM sleep in brain maturation.
        Behav Brain Res. 1995; 69: 1-11
        • Koh T.
        • Kakazawa M.
        • Kani K.
        • Maeda T.
        Investigation of origin of serotonergic projection to developing rat visual cortex: a combined retrograde tracing and immunohistochemical study.
        Brain Res Bull. 1991; 27: 675-684
        • Tate P.
        • Skarnes W.
        • Bird A.
        The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse.
        Nat Genet. 1996; 12: 205-208
        • 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