Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many individuals with mental retardation exhibit chronic aberrant behaviors (CABs) that includes hyperactive, stereotyped, aggressive, and self-injurious behaviors. Brain imaging studies have found that several of these individuals have abnormalities in their dopaminergic neurotransmitter systems that are thought to be responsible in part, for the development of these behaviors. The present study evaluated the effects of a selective dopamine re-uptake blocker, GBR-12909 in three animal models of varying striatal dopamine concentrations. The three animal models included the neonatal 6-hydroxydopamine (6-OHDA)-lesioned rat, a model of dopamine neuronal depletion, the prenatal methylazoxymethanol (MAM)-exposed rat, a model of hyper-dopaminergic innervation and control rats, a model of normal dopaminergic function. The animals were given five daily injections of GBR-12909 and videotaped observations were conducted immediately following the injections and 6h later. The results of the study indicate that the MAM-treated rats exhibited more hyperactive behaviors than either the 6-OHDA or the control animals in response to the GBR-12909 injections. However, the 6-OHDA and control rats exhibited more self-injurious behaviors than the MAM rats. Interestingly, the topography of the self-injurious behavior exhibited differed from that we have previously observed in 6-OHDA lesioned rats following dopamine agonists and resembles the mouthing behaviors seen in some individuals with mental retardation, in particular those with Rett syndrome. These findings indicate the models of varying dopaminergic function interact differently with a dopamine re-uptake blocker than dopamine agonists and that the partially dopamine depleted model may model the behaviors seen in individuals with Rett syndrome.
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PMID:Dopamine re-uptake inhibitor GBR-12909 induction of aberrant behaviors in animal models of dopamine dysfunction. 1217 69

All systematic searches for uniparental disomy (UPD) so far published and comprising clinically defined populations (Silver-Russell syndrome/primordial growth retardation (SRS/PGR) (n = 14), multiple malformations (n = 2), or rare syndromes (n = 12)) or situations at risk (confined placental mosaicism (CPM) (n = 13), spontaneous abortions (n = 6), additional marker chromosomes (n = 15), balanced non-Robertsonian translocations (n = 3), or balanced Robertsonian translocations (n = 15)) were reviewed. In many studies clinical and/or cytogenetic information on fluorescent in situ hybridization (FISH) results was very scarce. Meta-analysis concerning an adequate number of cases was possible for SRS/PGR, CPM, additional marker chromosomes, and balanced Robertsonian translocations only. As expected, the highest risk for UPD was found in cases with translocations between homologous acrocentric chromosomes (11 cases with UPD of 15 investigated) and in CPM due to a meiotic error (25 of 51 cases). In prenatal investigations or in cases with a normal phenotype, translocations between nonhomologous acrocentric chromosomes implied a risk for UPD of less than 0.5%. The risks for maternal UPD 7 in cases with SRS/PGR, for UPD 15 in cases with an additional inv dup(15) marker chromosome, and for UPD of any chromosome in cases with multiple malformation/mental retardation were approximately 5.5%, and approximately 1.3%, respectively. Searches for UPD in well-defined syndromes (Brachmann-De Lange syndrome, Sotos syndrome, Rett syndrome, Weaver syndrome, or XX true hermaphroditism) were disappointing. Not a single case was found.
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PMID:Review and meta-analysis of systematic searches for uniparental disomy (UPD) other than UPD 15. 1221 Feb 94

Rett syndrome is a progressive neurologic disorder affecting girls in early childhood with loss of achieved psychomotor abilities and mental retardation. Six sedated female patients (4 to 15 years of age) with a diagnosis of Rett syndrome were studied with [(18)F]fluorodeoxyglucose (FDG) and underwent positron emission tomography scanning of the brain. Relative tracer concentrations between different areas of the brain were assessed, and results were compared with 18 age-matched control subjects. Patients were divided into two age groups: 3 to 8 years of age and 9 to 15 years of age. A relative decrease in [(18)F]FDG uptake in the lateral occipital areas in relation with the whole brain and a relative increase in the cerebellum was evident in both age groups (P < 0.001, unpaired Student t test). A relative increase in frontal tracer uptake was observed in the younger group. Sensorimotor areas and relations between cortical and subcortical structures were preserved in all patients. Changes in glucose cerebral metabolism resemble the regional distribution of normal children less than 1 year of age, likely reflecting a maturational arrest. Changes in frontal areas parallel those in postmortem N-methyl-D-aspartate receptor densities and could correlate with different clinical stages of the disease. This pattern differs from those described in Down syndrome, autism, and Alzheimer's disease.
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PMID:Brain glucose metabolism in Rett Syndrome. 1221 12

Mutations in the methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome, a severe neurodevelopmental disorder occurring predominantly in females. Male patients with Rett syndrome are extremely rare, as the Rett-causing mutations in the MECP2 gene are usually lethal in hemizygous males. However, different mutations in the same gene were reported to cause mental retardation, both in sporadic non-syndromic males as well as in syndromic families with disease manifestation in carrier females. The majority of the reported MECP2 mutations in mentally retarded patients cause amino acid substitutions and, especially in isolated cases, discrimination between a disease-causing mutation and a rare polymorphism is not obvious and the significance of each individual variation should be verified. We mapped a new non-syndromic X-linked family (MRX79) to the chromosomal region Xq27.3-Xq28 and identified an A140V mutation in the MEPC2 gene in all patients with the disease haplotype. In addition to data published by others, this suggests that A140V is a recurrent mutation (and not a polymorphism) found in patients with X-linked mental retardation.
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PMID:Identification of a family with nonspecific mental retardation (MRX79) with the A140V mutation in the MECP2 gene: is there a need for routine screening? 1232 19

Mutations in the coding region of the methyl-CpG-binding protein 2 ( MECP2) gene cause Rett syndrome and have also been reported in a number of X-linked mental retardation syndromes. Furthermore, such mutations have recently been described in a few autistic patients. In this study, a large sample of individuals with autism was screened in order to elucidate systematically whether specific mutations in MECP2 play a role in autism. The mutation analysis of the coding sequence of the gene was performed by denaturing high-pressure liquid chromatography and direct sequencing. Taken together, 14 sequence variants were identified in 152 autistic patients from 134 German families and 50 unrelated patients from the International Molecular Genetic Study of Autism Consortium affected relative-pair sample. Eleven of these variants were excluded for having an aetiological role as they were either silent mutations, did not cosegregate with autism in the pedigrees of the patients or represented known polymorphisms. The relevance of the three remaining mutations towards the aetiology of autism could not be ruled out, although they were not localised within functional domains of MeCP2 and may be rare polymorphisms. Taking into account the large size of our sample, we conclude that mutations in the coding region of MECP2 do not play a major role in autism susceptibility. Therefore, infantile autism and Rett syndrome probably represent two distinct entities at the molecular genetic level.
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PMID:Mutation analysis of the coding sequence of the MECP2 gene in infantile autism. 1238 70

Methyl-CpG-binding protein 2 is a characteristic member of the methyl-CpG-binding protein family of transcription regulators. In conjunction with Sin3, MeCP2 recruits class I histone deacetylases to methyl-CpG regions to suppress transcription. Rett syndrome, a disorder characterized by mental retardation and autistic features, is associated in a majority of cases with mutations within the coding region of the MeCP2 gene. 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. Methyl-CpG-binding protein 2 immunoreactivity is present mainly in neurons; while the few immunostained glia show label confined to nuclei, many neurons also show slight perikaryal staining. Using well-characterized tissue fractions, we found that methyl-CpG-binding protein 2 but not Sin3 is found in both nuclear and postsynaptic compartments. This novel extranuclear localization is not unique to methyl-CpG-binding protein 2, since it has been previously reported for other transcription regulators such as c-Fos. These findings support the concept that methyl-CpG-binding protein 2 may link synaptic activity and transcriptional regulation in neurons.
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PMID:Methyl-CpG-binding protein 2 is localized in the postsynaptic compartment: an immunochemical study of subcellular fractions. 1253 40

The methyl-CpG binding protein 2 (MeCP2) gene has recently been identified as the gene responsible for Rett syndrome (RS), a pervasive developmental disorder considered by many to be one of the autism spectrum disorders. Most female patients with MeCP2 mutations exhibit the classic features of RS, including autistic behaviors. Most male patients with MeCP2 mutations exhibit moderate to severe developmental delay/mental retardation. Ninety nine patients from the South Carolina autism project (SCAP) were screened for MeCP2 mutations, including all 41 female patients from whom DNA samples were available plus the 58 male patients with the lowest scores on standard IQ tests and/or the Vineland Adaptive Behavior Scale. No pathogenic mutations were observed in these patients. One patient had the C582T variant, previously reported in the unaffected father of an RS patient. Two other patients had single nucleotide polymorphisms in the 3' UTR of the gene, G1470A and C1516G. These variants were seen in 12/82 and 1/178 phenotypically normal male controls, respectively. The findings from this and other studies suggest that mutations in the coding sequence of the MeCP2 gene are not a significant etiological factor in autism.
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PMID:Absence of MeCP2 mutations in patients from the South Carolina autism project. 1255 43

Cognitive disorders in children have traditionally been described in terms of clinical phenotypes or syndromes, chromosomal lesions, metabolic disorders, or neuropathology. Relatively little is known about how these disorders affect the chemical reactions involved in learning and memory. Experiments in fruit flies, snails, and mice have revealed some highly conserved pathways that are involved in learning, memory, and synaptic plasticity, which is the primary substrate for memory storage. These can be divided into short-term memory storage through local changes in synapses, and long-term storage mediated by activation of transcription to translate new proteins that modify synaptic function. This review summarizes evidence that disruptions in these pathways are involved in human cognitive disorders, including neurofibromatosis type I, Coffin-Lowry syndrome, Rubinstein-Taybi syndrome, Rett syndrome, tuberous sclerosis-2, Down syndrome, X-linked alpha-thalassemia/mental retardation, cretinism, Huntington disease, and lead poisoning.
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PMID:Learning, memory, and transcription factors. 1259 82

Mutations in the MECP2 (methyl-CpG-binding protein 2) gene are known to cause Rett syndrome, a well-known and clinically defined neurodevelopmental disorder. Rett syndrome occurs almost exclusively in females and for a long time was thought to be an X-linked dominant condition lethal in hemizygous males. Since the discovery of the MECP2 gene as the cause of Rett syndrome in 1999, MECP2 mutations have, however, also been reported in males. These males phenotypically have classical Rett syndrome when the mutation arises as somatic mosaicism or when they have an extra X chromosome. In all other cases, males with MECP2 mutations show diverse phenotypes different from classical Rett syndrome. The spectrum ranges from severe congenital encephalopathy, mental retardation with various neurological symptoms, occasionally in association with psychiatric illness, to mild mental retardation only. We present a 21-year-old male with severe mental retardation, spastic tetraplegia, dystonia, apraxia and neurogenic scoliosis. A history of early hypotonia evolving into severe spasticity, slowing of head growth, breathing irregularities and good visual interactive behaviour were highly suggestive of Rett syndrome. He has a de novo missense mutation in exon 3 of the MECP2 gene (P225L). The clinical spectrum and molecular findings in males with MECP2 mutations are reviewed.
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PMID:Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). 1261 69

RS, the most common cause of profound cognitive impairment in girls and women, is composed of characteristic clinical features, including communication dysfunction, stereotypic movements, and pervasive growth failure. Neuropathologic findings indicate a failure of neuronal maturation with too small neurons and too few dendritic arbors and no evidence of a progressive neurodegenerative process. The combination of clinical and neuropathologic characteristics presents the profile of a neurodevelopmental disorder. Mutations in the gene MECP2, which encodes MeCP2, have been identified in 80% to 85% of girls and women with RS. Furthermore, the panorama of phenotypes with MECP2 mutations now extends far beyond RS to include normal girls and women, mild learning disability, autistic spectrum disorders, and X-linked mental retardation. These rapid advances in our understanding of RS over the past three decades have opened new avenues of study in developmental neurobiology.
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PMID:Rett syndrome. Current status and new vistas. 1261 84


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