Abstract
This paper will review the study of the neuropathology of Rett syndrome as it has
evolved through several phases. In the 1986 the first descriptions of the Rett brain, by Seitelberger and Jellinger, identified
that the brains were small, and that there was quantitatively less melanin in the
pars compacta of the substantia nigra than in non-Rett brains. There were reports
of non- specific gliosis and cell loss in the spinal cords and in the cerebellum,
but with traditional neuropathology techniques there were no pathognomonic features
that defined a specific neuropathology for Rett syndrome. This apparent absence of
pathology was enigmatic in view of the profound clinical phenotype which involved
dysfunction of cortex, basal ganglia, the limbic. autonomic and peripheral nervous
systems. In the 1990’s evaluation of the accumulating and careful reports of the clinical,
functional, anatomic and chemical features of Rett syndrome suggested that the basis
of Rett syndrome could be an interruption of brain development. MRI and autopsy examinations
revealed that the brain in Rett syndrome was small, and that, unlike the brain in
a degenerative disease, it did not become progressively smaller over time. Moreover,
only the brain, and no other organ was small, emphasizing the susceptibility of the
nervous system in the Rett disorder. Using Golgi studies a selective alteration in
the size of dendrites of pyramidal neurons in the frontal, motor and temporal lobes
was defined. Regional decreases of dendritic spines were also observed and immunocytochemical
studies defined alterations in synaptic sites, early response gene activity and interneurons.
MAP-2 immunoreactivity was found to be altered in selected neuronal populations. Studies
of neurotransmitters using various techniques in various brain regions and CSF defined
alterations (increases or decreases) in most systems, with only, according to Wenk,
the studies of the cholinergic system being consistently decreased. The hypothesis
that there are decreased neurotransmitters in Rett syndrome remains attractive, for
it explains many of the functional deficits in Rett syndrome, and suggests a mechanism
for defective brain maturation. However, the measurement of neurotransmitters and
the interpretation of the results is problematic; the studies have included girls
and women at various stages of the Rett disorder, using numerous techniques and various
Rett tissues. In 2000 Rett families and researchers rejoiced at the long awaited identification of a mutated
gene in Rett syndrome. Now MeCP2 is the focus of research into the neuropathology
of Rett syndrome. An understanding of how this DNA methylating protein contributes
to normal brain development should allow us to understand the deficits in Rett syndrome.
Most importantly, it may allow us to devise strategies for therapy.
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 accessOne-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 DevelopmentAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl -CpG-binding protien 2.Nat Genet. 1999; 23: 185-188
- Growth and nutrition in 10 girls with Rett syndrome.Acta Paediatrica. 1992; 81: 868-890
- Organ growth in Rett syndrome, a post mortem examination analysis.Pediatr Neurol. 1999; 20: 125-129
- The pattern of growth failure in Rett children.Am J Dis Child. 1993; 147: 633-637
- Head growth in Rett syndrome.Acta Paediatr. 2000; 89: 198-202
- Neuroanatomy in Rett Syndrome.Neurology. 1997; 48: 399-407
- Pervasive neuroanatomic abnormalities of the brain in three cases of Rett syndrome.Neurology. 1995; 45: 1581-1586
- Selective dendritic alterations in the cortex of Rett syndrome.J Neuropath Exp Neurol. 1995; 54: 195-201
- Decreased dendritic branching in frontal, motor, limbic cortex in Rett syndrome compared with trisomy 21.J Neuropath Exp Neurol. 1998; 57: 1013-1017
- Studies on the 3 dimensional architecture of dendritic spines and vericosities in human cortex by confocal laser scanning microscopy and lucifer yellow microinjections.J Neurosci Methods. 1995; 57: 55-61
- Workshop on autonomic function in Rett syndrome. Swedish Rett Center Frosen Sweden May 1998.Brain Dev. 1998; 20: 323-326
- Abnormal expression of microtubule-associated protein 2 (MAP2) in the neocortex in Rett syndrome.Neuropediatrics. 1995; 26: 109-113
- Cyclooxygenase-2 expression during rat neocortical development and in Rett syndrome.Brain Dev. 1997; 19: 25-34
- Rett syndrome: pathophysiolgical consideration.Brain Dev. 1984; 6: 475-486
- Rett syndrome: neurobiological changes underlying specific symptoms.Prog Neurobiol. 1997; 51: 383-391
- Altered cholinergic function in the basal forebrain of girls with Rett syndrome.Neuropediatrics. 1999; 30: 125-129
- Acetylcholinasterase-rich pyramidal neurons in the human neocortex and hippocampus; absence at birth, development during the life span and dissolution in Alzheimer's disease.Ann Neurol. 1988; 24: 765-773
- Development of amino acid receptors in frontal cortex from girls with Rett syndrome.Ann Neruol. 1999; 45: 541-545
- Altered development of glutamate and GABA receptors in the basal ganglia of girls with Rett syndrome.Exp Neurol. 1999; 156: 345-352
- Decreased in benzodiazepine receptor binding in the brains of adult patients with Rett syndrome.J Neurol Sci. 1998; 154: 146-150
- Decreased cerebrospinal levels of substance P in patients with Rett syndrome.Ann Neurol. 1997; 42: 978-981
- Decreased cerebrospinal fluid level of beta phenylethylamine in patients with Rett syndrome.Ann Neurol. 2000; 47: 801-803
- Low levels of nerve growth factor in cerebrospinal fluid of children with Rett syndrome.J Child Neurol. 1996; 11: 296-300
- immunoreactivity in Rett syndrome.Pediatr Neurol. 2000; 22: 259-266
- The central nervous system, 2nd ed. Oxford University Press, New York1992: 598-599
- Morphological study of the entorhinal cortex, hippocampal formation and basal ganglia in Rett syndrome patients.Neurobiol Dis. 1999; 6: 77-91
- Some results of research into the development of the neuronal structure of the cortical ends of the analyzers in man.J Comp Neurol. 1961; 117: 197-217
- Neuropathology of Rett syndrome.Am J Med Genet. 1986; 24: 259-270
- Neuropathology of Rett syndrome.Acta Neuropath. 1988; 76: 142-158
- Breaking the silence in Rett Sydnrome Nat Genet. 1999; 23: 127-128
Article info
Identification
Copyright
© 2001 Elsevier Science B.V. Published by Elsevier Inc. All rights reserved.
