Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rett syndrome is a neurodevelopmental disorder that primarily affects girls, most of whom have mutations in the transcription regulatory gene MECP2. However, mutations in MECP2 also have been identified in normal carrier female individuals, female individuals with mild learning disabilities and features of Angelman syndrome, and male individuals with Klinefelter syndrome or Rett syndrome-like features, fatal neonatal encephalopathy, and familial X-linked mental retardation with or without motor abnormalities. Therefore, molecular testing should be considered for a wide spectrum of individuals. As such, Rett syndrome remains a clinical diagnosis. In this article, we also discuss three recent developments: (1) the recognition of significant gallbladder dysfunction, especially in those 20 years of age or younger; (2) a clinical trial of folate and betaine, which produced no objective improvement but did yield a subjective increase in attention and interaction; and (3) measurement of cerebrospinal fluid folate levels in a large cohort, which yielded normal values, indicating no need for supplementation.
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PMID:Rett syndrome: model of neurodevelopmental disorders. 1622 24

Rett syndrome is a leading cause of postnatal neurodevelopmental regression. Rett syndrome is caused by mutations in MECP2, the gene encoding methyl-CpG binding protein 2. In up to 96% of all classic cases, Rett syndrome cases are caused by mutations or deletions in MECP2. The phenotypic spectrum of MECP2 mutations is broad and includes mental retardation with or without seizures, Angelman syndrome-like phenotype, and autism. Mecp308/Y mice carry a truncating mutation and display many of the features seen in Rett syndrome. Social behavior abnormalities and impaired social interactions in Mecp308/Y mice suggest that MeCP2 plays a role in modulating the activity of genes and neurons important for social interactions. Mice that overexpress MeCP2 at twice the endogenous levels develop a progressive neurologic disorder, demonstrating that MeCP2 levels are tightly regulated and raising the possibility that duplications or gain-of-function mutations of MECP2 might underlie some cases of neurodevelopmental X-linked disorders.
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PMID:MeCP2 dysfunction in humans and mice. 1622 28

Rett syndrome is a neurodevelopmental disorder and an important cause of mental retardation and autistic behavior in girls and in a small group of boys. In 1999, mutation of the methyl-CpG binding protein 2 (MECP2) gene encoding a transcriptional repressor on the X chromosome was found to cause Rett syndrome. Since this discovery, significant research has focused on the elucidation of its specific role in the central nervous system. Recent studies revealed that MECP2 is expressed in more differentiated neurons rather than in less differentiated neuroblasts and that MECP2 is involved in the maturation and maintenance of neurons, including dendritic arborization and axonal projections, rather than in early cell fate decisions in the mammalian brain. In this review, we summarize recent findings regarding regional, temporal, and cell type-specific MECP2 expression in the central nervous system; neurobiologic abnormalities in MECP2 -mutant mice; and MECP2 target genes in the central nervous system.
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PMID:Dissecting MECP2 function in the central nervous system. 1622 31

Positron emission tomography (PET) is a technique that enables imaging of the distribution of radiolabeled tracers designed to track biochemical and molecular processes in the body after intravenous injection or inhalation. New strategies for the use of radiolabeled tracers hold potential for imaging gene expression in the brain during development and following interventions. In addition, PET may be key in identifying the physiological consequences of gene mutations associated with mental retardation. The development of high spatial resolution microPET scanners for imaging of rodents provides a means for longitudinal study of transgenic mouse models of genetic disorders associated with mental retardation. In this review, we describe PET methodology, illustrate how PET can be used to delineate biochemical changes during brain development, and provide examples of how PET has been applied to study brain glucose metabolism in Rett syndrome, serotonin synthesis in autism, and GABAA receptors in Angelman's syndrome and Prader-Willi syndrome. Future application of PET scanning in the study of mental retardation might include measurements of brain protein synthesis in fragile X syndrome and tuberous sclerosis complex, two common conditions associated with mental retardation in which cellular mechanisms involve dysregulation of protein synthesis. Mental retardation results in life-long disability, and application of new PET technologies holds promise for a better understanding of the biological underpinnings of mental retardation, with the potential to uncover new treatment options.
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PMID:Positron emission tomography methods with potential for increased understanding of mental retardation and developmental disabilities. 1624 Apr 13

Rett syndrome (RTT) is a postnatal neurodevelopmental disorder characterized by the loss of acquired motor and language skills, autistic features, and unusual stereotyped movements. RTT is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Mutations in MECP2 cause a variety of neurodevelopmental disorders including X-linked mental retardation, psychiatric disorders, and some cases of autism. Although MeCP2 was identified as a methylation-dependent transcriptional repressor, transcriptional profiling of RNAs from mice lacking MeCP2 did not reveal significant gene expression changes, suggesting that MeCP2 does not simply function as a global repressor. Changes in expression of a few genes have been observed, but these alterations do not explain the full spectrum of Rett-like phenotypes, raising the possibility that additional MeCP2 functions play a role in pathogenesis. In this study, we show that MeCP2 interacts with the RNA-binding protein Y box-binding protein 1 and regulates splicing of reporter minigenes. Importantly, we found aberrant alternative splicing patterns in a mouse model of RTT. Thus, we uncovered a previously uncharacterized function of MeCP2 that involves regulation of splicing, in addition to its role as a transcriptional repressor.
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PMID:Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. 1625 Dec 72

Autonomic dysfunction is prevalent in girls with Rett syndrome, an X-chromosome-linked disorder of mental retardation resulting from mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). This gene plays a role in regulating neuronal activity-dependent gene expression, including brain-derived neurotrophic factor (BDNF), which is a potent serotonergic (5-HT) neuronal growth factor. We analyzed selected parameters of the 5-HT system of the medulla in autopsied patients with Rett syndrome because of the role of BDNF in 5-HT cell development and because 5-HT plays a key role in modulating autonomic control. 5-HT neurons were identified by immunostaining for tryptophan hydroxylase, the biosynthetic enzyme for 5-HT. We quantitated the number of 5-HT cells in the medulla at 2 standardized levels in 11 Rett and 7 control cases. There was no significant difference in 5-HT cell number between the groups. We analyzed binding to the serotonin transporter (SERT) using the radioligand [(125)I]-RTI-55 with tissue autoradiography in 7 Rett and 5 controls in 9 cardiorespiratory-related nuclei. In the dorsal motor nucleus of the vagus (DMX) (preganglionic parasympathetic outflow), SERT binding for the control cases decreased significantly over time (p = 0.049) but did not change in the Rett cases (p = 0.513). Adjusting for age, binding between the Rett and control cases differed significantly in this nucleus (p = 0.022). There was a marginally significant age versus diagnosis interaction (p = 0.06). Thus, altered 5-HT innervation and/or uptake in the DMX may contribute to abnormal 5-HT modulation of this major autonomic nucleus in patients with Rett syndrome. These data suggest hypotheses concerning 5-HT modulation of vagal function for testing in MeCP2 knockout mice to understand mechanisms underlying autonomic dysfunction in patients with Rett syndrome.
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PMID:Serotonin transporter abnormality in the dorsal motor nucleus of the vagus in Rett syndrome: potential implications for clinical autonomic dysfunction. 1625 96

X-linked cyclin-dependent kinase-like 5 (CDKL5 or STK9) has recently been implicated in atypical Rett and X-linked West syndromes, severe neurological disorders associated with mental retardation, loss of communication and motor skills and infantile spasms and seizures in predominantly females. Besides CDKL5, these disease phenotypes are also linked to mutations in the MECP2 and ARX genes. Here, we have expressed and characterized CDKL5 and its mutant forms. CDKL5 is a 118 kDa protein that is widely distributed in all tissues, with highest levels in brain, thymus and testes. Whole mount embryo staining reveals CDKL5 to be ubiquitous. Within cells, CDKL5 is localized primarily in the nucleus. Removal of the C-terminal domain increases CDKL5 expression, enhances autophosphorylation activity and causes perinuclear localization, indicating that the C-terminus regulates CDKL5 function. Although we detect MeCP2 but not ARX binding to CDKL5, our results suggest that neither of these proteins are direct substrates of the CDKL5 kinase. Finally, the CDKL5 mutations associated with the disease phenotype cause loss of kinase activity as assessed by autophosphorylation. These results suggest that inactivation of the CDKL5 kinase can lead to severe neurodevelopmental disorders.
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PMID:CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders. 1633 Apr 82

Mutations in the methyl-CpG-binding protein 2 (MECP2) gene located on Xq28, cause Rett syndrome (RTT) in female patients. Meanwhile, nonmosaic MECP2 mutations unknown in girls have been found in an increasing number of male patients with a normal 46, XY karyotype. They can cause a broad spectrum of neurodevelopmental disorders which often show a combination of mental retardation (MR) with neurological symptoms. We present the results of MECP2 analysis in a group of 72 male patients with an unexplained combination of MR and neurological features, and review the mutational reports published on male patients since the discovery of the MECP2 gene. Analysis included sequencing of exon 1 which thus far was mostly omitted from DNA screening. One pathogenic mutation has been found in a patient with Rett variant, in addition to an unclassified variant and a series of nonpathogenic changes. No changes have been found in exon 1. Criteria for testing of male patients are classic RTT, severe neonatal encephalopathy, and RTT variant which may be clinically underrecognized. Testing can also be considered in males with a combination of unexplained MR and (progressive) neurological manifestations although the yield of MECP2 analysis is probably low in this situation. Based on the literature, MECP2 testing in males with MR only is debatable.
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PMID:MECP2 mutations are an infrequent cause of mental retardation associated with neurological problems in male patients. 1637 10

Loss-of-function mutations or abnormal expression of the X-linked gene encoding methyl CpG binding protein 2 (MeCP2) cause a spectrum of postnatal neurodevelopmental disorders including Rett syndrome (RTT), nonsyndromic mental retardation, learning disability, and autism. Mice expressing a truncated allele of Mecp2 (Mecp2(308)) reproduce the motor and social behavior abnormalities of RTT; however, it is not known whether learning deficits are present in these animals. We investigated learning and memory, neuronal morphology, and synaptic function in Mecp2(308) mice. Hippocampus-dependent spatial memory, contextual fear memory, and social memory were significantly impaired in Mecp2(308) mutant males (Mecp2(308/Y)). The morphology of dendritic arborizations, the biochemical composition of synaptosomes and postsynaptic densities, and brain-derived neurotrophic factor expression were not altered in these mice. However, reduced postsynaptic density cross-sectional length was identified in asymmetric synapses of area CA1 of the hippocampus. In the hippocampus of symptomatic Mecp2(308/Y) mice, Schaffer-collateral synapses exhibited enhanced basal synaptic transmission and decreased paired-pulse facilitation, suggesting that neurotransmitter release was enhanced. Schaffer-collateral long-term potentiation (LTP) was impaired. LTP was also reduced in the motor and sensory regions of the neocortex. Finally, very early symptomatic Mecp2(308/Y) mice had increased basal synaptic transmission and deficits in the induction of long-term depression. These data demonstrate a requirement for MeCP2 in learning and memory and suggest that functional and ultrastructural synaptic dysfunction is an early event in the pathogenesis of RTT.
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PMID:Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. 1639 2

Studies addressing etiologic yield in childhood developmental disabilities have mainly looked at individuals with developmental delay/mental retardation. The few studies addressing the question of etiologic yield in patients with pervasive developmental disorders (PDDs) had a major drawback, in that the enrolled subjects were diagnosed as having the autistic spectrum disorders based only on history and clinical examination, and/or on unspecified instruments. In addition, only some of these patients underwent a complete laboratory evaluation. To investigate the etiologic yield of PDDs, we undertook a large prospective study on subjects selected according to very strict criteria and diagnosed as having PDD based on the present "gold standard" (ADI-R and ADOS-G), and a clinical diagnosis made by a child psychiatrist. Eighty-five (85) patients with PDD and their first degree relatives participated in this study. These patients were selected from a sample of 236 subjects who had received a clinical diagnosis of PDD at the Stella Maris Institute between March 2002 and 2005. Selection criteria for entering the study were: (1) a diagnosis of PDD (with exclusion of the Rett syndrome) confirmed after the administration of the ADI-R (autism diagnostic interview-revised) and the ADOS-G (autism diagnostic observation schedule-generic). In addition, a clinical diagnosis was made by the child psychiatrist, on the basis of presence or absence of DSM-IV symptoms of autism; (2) chronological age between 4 and 18 years; (3) IQ>30; (4) availability of both biologic parents. Patients, 65/85 (76.5%), had autism, 18/85 (21.2%) had PDD-NOS, and the remaining 2/85 (2.3%) had Asperger syndrome. Ages varied between 4 years 2 months and 12 years 5 months (mean 7.6 years), and there was a marked male preponderance (68/85). All subjects underwent various laboratory studies and neuroimaging. With respect to possible etiologic determination, a detailed history and physical examination in this group of patients with PDD was informative in 10.5% (9/85). HRB karyotype was diagnostic in one, and molecular fragile X studies in one child. Brain MRI was informative in two children (2.3%) with relative macrocrania but no neurological features; and EEG was helpful in one child, identifying a Landau-Kleffner disorder. Audiometry and brainstem auditory evoked potentials (BAEPs) showed a bilateral sensorineural loss in another child. Metabolic evaluation gave normal results in all subjects. The results suggest an evaluation paradigm with reference to etiologic determination for individuals with PDDs that does not presently justify metabolic or neuroimaging on a screening basis. Recurrence risk, treatment implications, and significant and long-lasting emotional relief for the parents suggest that serious consideration be given to clinical genetic examination, genetic testing, EEG study (during wakefulness and sleep), and audiometry, despite a relatively low yield.
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PMID:Etiologic yield of autistic spectrum disorders: a prospective study. 1641 94


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