Neuropathology of Rett syndrome

Abstract

Rett Syndrome is unlike any other pediatric neurologic disease, and its clinical-pathologic correlation can not be defined with standard histology techniques. Based on hypotheses suggested by careful clinical observations, the nervous system of the Rett child has been explored utilizing morphometry, golgi preparations, computerized tomography, magnetic resonance imaging, chemistry, immunocytochemistry, autoradiography, and molecular biologic techniques. From these many perspectives we conclude that Rett syndrome is not a typical degenerative disorder, storage disorder, nor the result of gross malformation, infectious or neoplastic processes. There remain regions of the brain that have not been studied in detail but the available data suggest that the neuropathology of Rett syndrome can be summarized as follows: the Rett brain is small for the age and the height of the patient; it does not become progressively smaller over three to four decades; it has small dendritic trees in pyramidal neurons of layers III and V in selected lobes (frontal, motor, and temporal); it has small neurons with an increased neuronal packing density; it has an immature expression of microtubular protein-2 and cyclooxygenase; it exhibits a changing pattern of neurotransmitter receptors with an apparent reduction in many neurotransmitters, possibly contributing to some symptomatology. A mutation in Mecp2 causes this unique disorder of brain development. Neuronal mosaicism for normal and mutated Mecp2 produces a consistent phenotype in the classic female patient and a small brain with some preserved islands of function, but with an inability to support hand use and speech. This paper summarizes our current observations about neuropathology of Rett syndrome. MRDD Research Reviews 2002;8:72-76.

Forensic issues and possible mechanisms of sudden death in Rett syndrome

“…Specifically there may be small dendritic trees in pyramidal neurones of layers III and IV of the cortex of frontal and temporal lobes and immaturity of cardiorespiratory neurones in brain stem centres suggesting failure of growth of axonodendritic connections composing the neuropil. 3,18,19 Studies have also demonstrated reduced levels of neurotransmitters, including serotonin, noradrenaline, dopamine and choline acetyltransferase. 4 In the reported case there was microcephaly with essentially non-specific neurological findings that may have been secondary to seizure activity.…”

Biogenic Amines in Rett Syndrome: The Usual Suspects

“…The neuropathology of Rett syndrome has been extensively reviewed on several occasions (Jellinger and Seitelberger 1986;Armstrong 2001Armstrong , 2002. As far as bioaminergic systems are concerned, it is interesting to note that one of the first post-mortem reports described a marked reduction in dopamine, norepinephrine, serotonin and the 5-HIAA and HVA metabolites (Riederer et al 1986).…”

CDKL5 Expression Is Modulated during Neuronal Development and Its Subcellular Distribution Is Tightly Regulated by the C-terminal Tail

“…An inspection of the primary structure of CDKL5 revealed the presence of a stretch of amino acids from 836 to 845 (LKSLRKLLHL) sharing high homology with the consensus NES (LX (2,3) [LIVFM]X (2,3) …”

“…Rett syndrome (RTT, 3 OMIM 312750) is an X-linked neurodevelopmental disorder that occurs almost exclusively in girls with an incidence of 1:10,000 female births. Patients affected with classic RTT are usually born healthy and start manifesting symptoms after an apparently normal period of development lasting 6 -18 months (1,2).…”

“…Then a rapid regression causes the loss of speech and purposeful movements and the appearance of autistic traits, ataxia, seizures, scoliosis, respiratory crisis, and characteristic stereotypic hand movements. Furthermore, decelerated head growth is typically present, leading to microcephaly within the second year (3). Despite the reduced brain volume, no diminution in neuronal number has been observed, but rather a decrease in cell soma size and dendritic arborization.…”