Disease relevance of Rett Syndrome

• A mutation in the rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males [1].
• Respiratory depression in this mouse model of Rett Syndrome is seen in with ubiquitous deficiency in Mecp2 but not when it is confined to neurons [2].
• Progressive scoliosis, epilepsy and other minor handicaps, usually present in Rett syndrome, are rare in the preserved speech variant [3].
• Considering that defective MeCP2 has mainly been related to Rett syndrome and other neurologic manifestations, we examined methyl-CpG-binding protein 2 cellular and subcellular compartmentalization in normal brain by immunochemical methods [4].
• Preimplantation genetic diagnosis was performed in 122 embryos obtained by IVF from 11 patients carriers of haemophilia, Duchenne's muscular dystrophy, Barth's syndrome, cystic fibrosis, Pelizaeus-Merzbacher syndrome or Rett's syndrome [5].

Psychiatry related information on Rett Syndrome

• Consistent with this notion is the recent demonstration that MECP2 mutations cause Rett syndrome (RTT, MIM 312750), a childhood neurological disorder that represents one of the most common causes of mental retardation in females [6].
• Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), a neurodevelopmental disorder characterized by the loss of language and motor skills during early childhood [7].
• Screening for mutations in the MECP2 (Rett syndrome) gene in Gilles de la Tourette syndrome [8].
• In contrast to young and old lesioned rats and patients with Alzheimer's disease, cholinergic cells in the brains of patients with Rett syndrome do not compensate for the loss of cholinergic cells by increasing acetylcholine vesicular storage [9].
• Fifty-nine cases with infantile autism/autistic disorder were subclassified according to associated medical condition (fragile-X, tuberous sclerosis, neurofibromatosis, hypo-melanosis of Ito, Moebius syndrome, Rett syndrome, and a 'new' syndrome associated with a marker chromosome) [10].

High impact information on Rett Syndrome

• Mutations in MECP2 are associated with Rett syndrome, an X-linked neurodevelopmental disorder [11].
• Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome [11].
• Because Dlx5 regulates production of enzymes that synthesize gamma-aminobutyric acid (GABA), loss of imprinting of Dlx5 may alter GABAergic neuron activity in individuals with Rett syndrome [11].
• A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome [12].
• The same inheritance pattern has been proposed for Rett syndrome, Aicardi syndrome and microphthalmia with linear skin defects, but in these sporadic conditions, evidence of male lethality is lacking [13].

Chemical compound and disease context of Rett Syndrome

• The alteration in the cerebrospinal fluid level of PEA may reflect dopamine system impairment in Rett syndrome [14].
• Cerebrospinal fluid biogenic amines and biopterin in Rett syndrome [15].
• Decreased cerebrospinal fluid levels of beta-phenylethylamine in patients with Rett syndrome [14].
• Serotonin transporter abnormality in the dorsal motor nucleus of the vagus in Rett syndrome: potential implications for clinical autonomic dysfunction [16].
• OBJECTIVE: To determine cerebral regional concentrations of N-acetyl aspartate (NAA), total choline (Cho), and total creatine (Cr) in Rett syndrome (RS) using 1H magnetic resonance spectroscopic imaging (MRSI) [17].

Biological context of Rett Syndrome

• Additionally, we show that although the truncated MeCP2 protein in these mice localizes normally to heterochromatic domains in vivo, histone H3 is hyperacetylated, providing evidence that the chromatin architecture is abnormal and that gene expression may be misregulated in this model of Rett syndrome [7].
• Classic Rett syndrome in a boy as a result of somatic mosaicism for a MECP2 mutation [18].
• Association by guilt: identification of DLX5 as a target for MeCP2 provides a molecular link between genomic imprinting and Rett syndrome [19].
• MeCP2 mutations in children with and without the phenotype of Rett syndrome [20].
• Females with identical mutations in the methyl-CpG binding protein 2 gene can display varying severity of symptoms, suggesting that other factors such as X-chromosome inactivation affect phenotypic expression in Rett syndrome [21].

Anatomical context of Rett Syndrome

• Early studies on neuronal cytoskeleton in MR, which have shown a selective reduction in MAP-2 expression, have focused on Rett syndrome (RS) [22].
• Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice [23].
• Although it is evident that phenotypes of MECP2 mutant mice that resemble those of Rett syndrome are attributable to lack of the MECP2 gene in the central nervous system (CNS), there is little understanding of the neuropathological abnormalities in the CNS of MECP2-null mice [24].
• Altered development of glutamate and GABA receptors in the basal ganglia of girls with Rett syndrome [25].
• Lymphocytes from venous blood from 15 girls with Rett syndrome (RTS), 7 girls with RTS "forme fruste," and 46 unrelated control females were examined [26].

Gene context of Rett Syndrome

• CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome [27].
• MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression [28].
• Based on its established expression pattern and known function, GLRA2 was selected as a candidate gene for Rett syndrome [29].
• The knowledge of additional existing MBD proteins and their expression pattern is important in the context of Rett syndrome [30].
• Mutation analysis of the HDAC 1, 2, 8 and CDKL5 genes in Rett syndrome patients without mutations in MECP2 [31].

Analytical, diagnostic and therapeutic context of Rett Syndrome

• METHODS: Thirty-nine patients with classical Rett syndrome, one with preserved speech variant (PSV), and 12 patients with developmental delay and some features of Rett syndrome were recruited for sequence analysis of the MECP2 gene coding region [32].
• To determine whether reduced nerve growth factor (NGF) and/or its high affinity receptor, trkA, play a role in the pathophysiology of Rett syndrome (RS), we used immunohistochemistry in paraffin-embedded human autopsy brain tissue, to quantify NGF and trkA levels within the frontal cortex of 9 RS females and 10 female controls of similar age [33].
• In order to establish the medium-term effects of L-carnitine, an open label trial was performed in a cohort of 21 Rett syndrome females, with a control group of 62 Rett syndrome females of a similar age, for a 6-month period [34].
• Oral glucose tolerance tests were performed in 10 of the subjects with Rett syndrome [35].
• 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 [36].

References