Original article| Volume 23, SUPPLEMENT 1, S218-S223, December 2001

Discussant – pathophysiologies of Rett syndrome


      Studies on sleep parameters of Rett syndrome revealed hypoactivity of the noradrenaline (NA) and the serotonin (5HT) neuron in early infancy while preserving the function of the dopamine (DA) and the cholinergic neurons of the pons normally. The sleep–wake cycle remains in its development at the level of 4 months of age. Polysomnographies also showed a decrease of the function of the nigrostriatal (NS)-DA neuron in early childhood and suggested the development of receptor supersensitivity in late childhood. Neurohistochemical and neuroimaging (PET) studies revealed the hypofunction of the NS-DA neuron with receptor supersensitivity and of involvement of the cholinergic neurons to the cortical pathology, whereas no substantial pathological or histochemical abnormalities were observed in the NA and the 5HT neurons in the brainstem. The decrease of tyrosine hydroxylase without neurodegenerative changes observed in the substantia nigra of Rett syndrome had similarity to the pathology caused by excitotoxic lesion of the pedunculopontine nuclei (PPN) observed in an animal experiments. Clinically the grade of disability of locomotion was shown to correlate to the grade of the disabilities of language. These clinical manifestations were also correlated to the specific loci of the mutation in the methyl binding domain of the MECP2 gene. In rodents the axons of the brainstem 5HT neuron involved in the morphogenesis of the brain in the early developmental course disappear in neonates without apoptotic or degenerative changes in the neurons. This period corresponds to the first 1.5–2 years in humans. Thus, in Rett syndrome, the primary lesion appears in the brainstem NA and 5HT neurons which affects development of synaptogenesis of the cortex and also dysfunction of the PPN. The latter causes dysfunction of the DA neuron and the cholinergic neuron in the midbrain. The mutation of the MECP2 gene may cause early transcription of the genes which prune the axons of the aminergic neurons for the developmental morphogenesis of the central nervous system in early infancy.


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


        • Segawa M.
        Pathophysiology of Rett syndrome from the standpoint of clinical neurology.
        Brain Dev. 2001; (Suppl)
        • Ellaway C.
        • Peat J.
        • Leonard H.
        • Christodoulou J.
        Sleep dysfunction in Rett syndrome: lack of age related decrease in sleep duration.
        Brain Dev. 2001; (Suppl)
        • Parmelee Jr., A.H.
        • Stern E.
        Development of states in infants.
        in: Clement C.D. Purpura D.P. Mayer F.E. Sleep and the maturing nervous system. Academic Press, New York1972: 199-228
        • Shimada M.
        • Segawa M.
        • Higurashi M.
        • Akamatsu H.
        Development of the sleep and wakefulness rhythm in preterm infants discharged from a neonatal care unit.
        Pediatr Res. 1993; 33: 159-163
        • Segawa M.
        Sleep mechanisms and their development (in Japanese).
        Shoni Igaku. 1987; 20: 828-853
        • Kohyama J.
        • Ohinata J.
        • Hasegawa T.
        Disturbance of phasic chin muscle activity during REM sleep.
        Brain Dev. 2001; (Suppl)
        • Kohyama J.
        Sleep as a window on the developing brain.
        Curr Probl Pediatr. 1998; 28: 69-100
      1. Nagata E, Oka N, Sakamoto M, Fusejima Y, Wabanabe J, Yonezawa M, et al. Rapid eye movements and twitch movement during REM sleep. Presented at the 13th EEG, EMG Conference of Japan, 1983.

        • Segawa M.
        • Nomura Y.
        Polysomnography in the Rett syndrome.
        Brain Dev. 1992; 14: S46-S54
        • 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. The basal ganglia. Plenum, New York1987: 489-504
        • Hobson J.A.
        • McCarley R.W.
        • Wyzinski P.W.
        Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups.
        Science. 1975; 155: 170-174
        • Sakai K.
        Central mechanisms of paradoxical sleep.
        in: Borbely A. Valax J.L. Sleep mechanism. Springer-Verlag, Berlin1984: 3-18
        • Segawa M.
        Ontogenesis of REM sleep.
        in: Mallick B.N. Inoue S. Rapid eye movement sleep. Narosa, New Delhi1999: 39-50
        • Mori S.
        • Matsuyama K.
        • Kohyama J.
        • Kobayashi Y.
        • Takakushi K.
        Neuronal constituents of postural and locomotor control systems and their interaction in cats.
        Brain Dev. 1992; 14: S109-S120
        • Nomura Y.
        • Kimura K.
        • Arai H.
        • Segawa M.
        Involvement of the autonomic nervous system in the pathophysiology of Rett syndrome.
        Eur Child Adoles Psychiatry. 1997; 6: S42-S46
        • Segawa M.
        Sudden infantile death syndrome (in Japanese).
        Shinkei Kenkyu no Shinpo. 1992; 36: 1029-1040
        • Deguchi K.
        • Reyes C.
        • Chakraborty S.
        • Antalffy B.
        • Glaza D.
        • Armstrong D.
        Substance P immunoreactivity in the enteric nervous system in Rett syndrome.
        Brain Dev. 2001; (Suppl)
        • Armstrong D.
        Rett syndrome neuropathology review 2000.
        Brain Dev. 2001; (Suppl)
        • Gerfen C.R.
        Molecular effects of dopamine on striatal projection pathways.
        Trends Neurosci. 2000; 23: S64-S70
        • Rakic P.
        A small step for the cell, a giant leap for mankind: a hypothesis of neocortical expansion during evolution.
        Trends Neurosci. 1995; 18: 383-388
        • Azmitia C.E.
        Neuronal instability: implications for Rett's syndrome.
        Brain Dev. 2001; (Suppl)
        • Johnston M.
        • Jeon O.H.
        • Pevsner J.
        • Blue M.E.
        • Naidu S.
        Neurobiology of Rett syndrome: a genetic disorder of synapse development.
        Brain Dev. 2001; (Suppl)
        • Saito Y.
        • Ito M.
        • Ozawa Y.
        • Matsuishi T.
        • Hamano K.
        • Takashima S.
        Reduced expression of neuropeptides can be related to respiratory disturbances in Rett syndrome.
        Brain Dev. 2001; (Suppl)
        • Segawa M.
        Development of the nigrostriatal dopamine neuron and the pathways in the basal ganglia.
        Brain Dev. 2000; 22: S1-S4
        • Kojima J.
        • Yamaji Y.
        • Matsumura M.
        • Nambu A.
        • Inase M.
        • Tokuno H.
        • et al.
        Excitotoxic lesions of the pedunculopontine tegmental nucleus produce contralateral hemiparkinsonism in the monkey.
        Neurosci Lett. 1997; 226: 111-114
        • Kobayashi Y.
        • Saito Y.
        • Isa T.
        Facilitation of saccade initiation brainstem cholinergic system.
        Brain Dev. 2001; (Suppl)
        • Calabresi P.
        • Cotonze D.
        • Guballin P.
        • Pisani A.
        • Bernardi G.
        Acetylcholine-mediated modulation of striatal function.
        Trends Neurosi. 2000; 23: 120-126
        • Chase T.N.
        • Oh J.D.
        Striatal dopamine- and glutamate-mediated dysregulation in experimental parkinsonism.
        Trends Neurosci. 2000; 23: S86-S91
        • Dunn H.
        The importance of Rett syndrome in child neurology.
        Brain Dev. 2001; (Suppl)
        • Nomoto M.
        • Iwata S.
        • Kaseda S.
        • Fukada T.
        • Nakagawa S.
        Increased dopamine turnover in the putamen after MPTP treatment in common marmosets.
        Brain Res. 1997; 767: 235-238
        • Levitt P.
        • Harvey J.A.
        • Friedman E.
        • Simansky K.
        • Murphy H.
        New evidence for neurotransmitter influences on brain development.
        Trends Neurosci. 1997; 20: 269-274
        • Brenner E.
        • Mirmiran M.
        • Uylings H.B.
        • 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
        • Marks G.A.
        • Shaffery J.P.
        • Oksenberg A.
        • Speciale S.G.
        • Robbwarg H.P.
        A functional role for REM sleep in brain maturation.
        Behav Brain Res. 1995; 69: 1-11
        • Segawa M.
        Neurological model of infantile autism (in Japanese).
        No No Kagaku (Tokyo). 1998; 20: 169-175
        • Segawa M.
        • Nomura Y.
        Pathophysiology of human locomotion – studies as clinical cases.
        in: Shimomura M. Grillner S. Edgerton V.R. Neurobiological basis of human locomotion. Japan Scientific Societies Press, Tokyo1991: 317-328
        • Segawa M.
        • Takano M.
        • Shimohira M.
        • Tanaka R.
        • Hachimori K.
        • Nomura Y.
        Locomotion in late infancy and development of higher cortical function at later ages.
        in: Perat M.V. New developments in child neurology. 8th International Child Neurology Congress, Ljubliana, Slovenia, 1998. Monduzzi Editore, Bologna1998: 27-30
        • Koh T.
        • Nakazawa 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
        • Amano K.
        • Nomura Y.
        • Segawa M.
        • Yamakawa K.
        Mutational analysis of the MECP2 gene in Japanese patients with Rett syndrome.
        J Hum Genet. 2000; 45: 231-236
        • Uchino J.
        Development of language in Rett syndrome.
        Brain Dev. 2001; (Suppl)