Rett syndrome: Cerebellar pathology

Oldfors, Anders; Sourander, Patrick; Armstrong, Dawna L.; Percy, Alan K.; Witt‐Engerström, Ingegerd; Hagberg, B

doi:10.1016/0887-8994(90)90022-s

Cited by 79 publications

(38 citation statements)

References 19 publications

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“…Most structures that were reported to be abnormal in female RTT brains are not easily defined in mouse brain and were not the subject of our studies. Progressive atrophy of cerebellum was described in one MRI study (Murakami et al, 1992), and reduction of Purkinje neurons was reported twice (Oldfors et al, 1990;Bauman et al, 1995).…”

Section: Differences In Severity In Brain Morphology Of Mecp2b and Mementioning

confidence: 98%

Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome

Belichenko

et al. 2008

J of Comparative Neurology

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Rett syndrome (RTT) is caused by mutations in the X-linked gene MECP2. While patients with RTT show widespread changes in brain function, relatively few studies document changes in brain structure and none examine in detail whether mutations causing more severe clinical phenotypes are linked to more marked changes in brain structure. To study the influence of MeCP2-deficiency on the morphology of brain areas and axonal bundles, we carried out an extensive morphometric study of two Mecp2-mutant mouse models (Mecp2B and Mecp2J) of RTT. Compared to wildtype littermates, striking changes included reduced brain weight ( approximately 13% and approximately 9%) and the volumes of cortex ( approximately 11% and approximately 7%), hippocampus (both by approximately 8%), and cerebellum ( approximately 12% and 8%) in both mutant mice. At 3 weeks of age, most (24 of 47) morphological parameters were significantly altered in Mecp2B mice; fewer (18) were abnormal in Mecp2J mice. In Mecp2B mice, significantly lower values for cortical area were distributed along the rostrocaudal axis, and there was a reduced length of the olfactory bulb ( approximately 10%) and periaqueductal gray matter ( approximately 16%). In Mecp2J mice, while there was significant reduction in rostrocaudal length of cortex, this parameter was also abnormal in hippocampus ( approximately 10%), periaqueductal gray matter ( approximately 13%), fimbria ( approximately 18%), and anterior commissure ( approximately 10%). Our findings define patterns of Mecp2 mutation-induced changes in brain structure that are widespread and show that while some changes are present in both mutants, others are not. These observations provide the underpinning for studies to further define microarchitectural and physiological consequences of MECP2 deficiency.

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Section: Differences In Severity In Brain Morphology Of Mecp2b and Mementioning

confidence: 98%

Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome

Belichenko

et al. 2008

J of Comparative Neurology

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“…The cerebellum has been described as showing progressive atrophy by MRI [Murakami et al, 1992]. Oldfors et al [1990] observed a progressive loss of Purkinje neurons, loss of neurons in the dentate, and gliosis in the inferior medullary olives. Bauman reported a reduction of Purkinje neurons and a simplification of the olives in three cases of RTT [Bauman et al, 1995a;.…”

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confidence: 98%

Neuropathology of Rett syndrome

Armstrong

2002

Ment. Retard. Dev. Disabil. Res. Rev.

104

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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.

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“…This finding raises the possibility that the MeCP2 KO mouse shares some features with the robotic mouse, in particular those relevant to the function of AF4 in the cerebellum such as ataxia. Consistent with this postulate, PC loss occurs in the cerebellum of Rett patients (Oldfors et al, 1990) and IGF-1 treatment of MeCP2 mutant mice also partially rescues Rett syndrome symptoms including a marked improvement in locomotor activity (Tropea et al, 2009). Recently, a loss-of-function mutation in AF9 was described in a patient with neuromotor development delay, cerebellar ataxia, mental retardation, severe delay in language acquisition and communication skills, and epileptic seizures (Pramparo et al, 2005).…”

Section: Discussionmentioning

confidence: 55%

AF4 Is a Critical Regulator of the IGF-1 Signaling Pathway during Purkinje Cell Development

Bitoun¹,

Finelli²,

Oliver³

et al. 2009

J. Neurosci.

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Deregulation of the insulin-like growth factor 1 (IGF-1) signaling pathway is a recurrent finding in mouse models and human patients with cerebellar ataxia and thus represents a common pathological cascade in neuronal cell death that may be targeted for therapy. We have previously identified a point mutation in AF4, a transcription cofactor of RNA polymerase II elongation and chromatin remodeling, that causes progressive and highly specific Purkinje cell (PC) death in the ataxic mouse mutant robotic, leading to the accumulation of AF4 in PCs. Here we confirm that the spatiotemporal pattern of PC degeneration in the robotic cerebellum correlates with the specific profile of AF4 upregulation. To identify the underlying molecular pathways, we performed microarray gene expression analysis of PCs obtained by laser capture microdissection (LCM) at the onset of degeneration. Igf-1 was significantly downregulated in robotic PCs compared with wild-type controls before and throughout the degenerative process. Consistently, we observed a decrease in the activation of downstream signaling molecules including type 1 IGF receptor (IGF-1R) and the extracellular signal-regulated kinase (ERK) 1 and ERK2. Chromatin immunoprecipitation confirmed that Igf-1 is a direct and the first validated target of the AF4 transcriptional regulatory complex, and treatment of presymptomatic robotic mice with IGF-1 indeed markedly delayed the progression of PC death. This study demonstrates that small changes in the levels of a single transcriptional cofactor can deleteriously affect normal cerebellum function and opens new avenues of research for the manipulation of the IGF-1 pathway in the treatment of cerebellar ataxia in humans.

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Rett syndrome: Cerebellar pathology

Cited by 79 publications

References 19 publications

Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome

Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome

Neuropathology of Rett syndrome

AF4 Is a Critical Regulator of the IGF-1 Signaling Pathway during Purkinje Cell Development

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