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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angelman Syndrome (AS), characterized by mental retardation, absence of speech, seizures and motor dysfunction, is caused by genetic defects leading to loss of expression of the maternal copy of the chromosome 15q11-13 imprinted region. Most cases are sporadic, being caused by de novo deletion of maternal chromosome 15q11-13 (75%) or by paternal uniparental disomy (3-4%). Familial cases can occur, due to mutations in the UBE3A gene or in the imprinting center. We describe the case of a pregnant woman having two nephews with AS caused by a UBE3A mutation; lack of communication within the family led the woman to be completely unaware of the risk of disease recurrence until 15 weeks of gestation. UBE3A genetic testing revealed she carried the familial mutation 892-893delCT. Prenatal diagnosis was performed on amniotic fluid and demonstrated that the fetus had inherited the mutation. The unexpected diagnosis and the subsequent termination of the pregnancy caused the woman to undergo acute psychological distress showing relevant psychopathological symptoms. Nevertheless, at 2-year follow-up, adverse consequences were minimized, and the couple was planning a new pregnancy. Factors affecting the psychological outcome of abortion and the role of psychological support in reducing the risk of long-term unfavorable consequences are discussed.
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PMID:Psychological consequences of prenatal diagnosis in a case of familial Angelman syndrome. 1700 41

Angelman syndrome (AS) is a profound disorder notable for mental retardation and severe language deficits that results from lack of function of the maternally inherited copy of the UBE3A gene. Chromosome deletions of 15q11q13, paternal uniparental disomy (UPD), UBE3A gene mutations, and imprinting center defects are all commonly recognized mechanisms that disrupt the function of the maternal copy of the UBE3A gene. We report here two patients with different atypical etiologies of AS. The first patient is a 3-year-old boy with global developmental delay, severe speech deficits, seizures, and very happy disposition. Southern blot analysis for the maternal and paternal chromosome 15 methylation products showed a mosaic methylation pattern, suggesting an imprinting center defect. The second patient is a 4(1/2)-year-old boy with global developmental delay, no expressive language, microcephaly, seizures, and ataxic gait. Array-based comparative genomic hybridization (CGH) demonstrated a loss in copy number for two overlapping clones encompassing the UBE3A gene, indicating a partial deletion within UBE3A. His mother, who was adopted, had an identical pattern, suggesting that her deletion was probably on her paternally imprinted allele. These patients illustrate the expanding spectrum of molecular findings in AS, reinforce the need to maintain suspicion when clinical features suggest AS but initial testing is normal, and show the power of CGH as a tool to uncover partial UBE3A deletions.
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PMID:Atypical cases of Angelman syndrome. 1703 11

MLPA analysis for a panel of syndromes with mental retardation (MRS-MLPA) was used for investigation of 258 mentally retarded and dysmorphic patients with normal conventional karyotypes (P064 probe set, MRC-Holland, for detection of (micro)deletions associated with 1p36-deletion, Sotos, Williams-Beuren, Prader-Willi, Angelman, Miller-Dieker, Smith-Magenis, and 22q11-deletion syndromes). Patients were initially referred for HR-CGH analysis and MRS-MLPA was performed retrospectively. MRS-MLPA analysis revealed imbalances in 15/258 patients (5.8%). Ten deletions were identified, including deletions of 1p36, 5q35 (Sotos syndrome), 7q11 (Williams-Beuren syndrome), 17p11 (Smith-Magenis syndrome), 15q11 (Angelman syndrome) and 22q11. Duplications were detected in 5q35, 7q11, 17p13, 17p11 and 22q11. We reviewed another 170 patients referred specifically for MRS-MLPA analysis. Eighty of these patients were referred with a clinical suspicion of a specific syndrome, which was confirmed in 17 patients (21.3%). The remaining 90 patients were referred because of mental retardation and dysmorphism but without suspicion of a specific syndrome. Seven imbalances, including four duplications, were detected in these 90 patients (7.8%). Clinical data regarding three patients investigated by MRS-MLPA are presented. The imbalances carried by these patients include a small interstitial 1p36 deletion, a small duplication of 5q35 (encompassing the NSD1 gene, which is deleted/mutated in Sotos syndrome) and a duplication of 7q11 (reciprocal of the Williams-Beuren syndrome deletion), respectively. MRS-MLPA allows testing for a number of micro-deletions/-duplications in a single experiment, thereby filling a gap between array techniques and single locus techniques. MRS-MLPA combined with Subtelomeric MLPA represents an attractive first test in a clinical algorithm for mental retardation.
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PMID:MLPA analysis for a panel of syndromes with mental retardation reveals imbalances in 5.8% of patients with mental retardation and dysmorphic features, including duplications of the Sotos syndrome and Williams-Beuren syndrome regions. 1709 Mar 94

This chapter explores some of the molecular events contributing to memory formation and how, when these events malfunction, disturbances in memory occur. After a brief discussion of signaling in the hippocampus, we will explore the topics of human mental retardation syndromes that involve disruption of these processes, including Angelman syndrome (AS), Neurofibromatosis 1 (NF1)-associated learning disorders, Coffin-Lowry syndrome (CLS), Rubinstein-Taybi syndrome (RTS), and Rett syndrome (RTT).
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PMID:Signal transduction mechanisms in memory disorders. 1716 2

Angelman syndrome (AS) is a severe neurological disorder characterized by mental retardation, motor dysfunction and epilepsy. We show that the molecular and cellular deficits of an AS mouse model can be rescued by introducing an additional mutation at the inhibitory phosphorylation site of alphaCaMKII. Moreover, these double mutants no longer show the behavioral deficits seen in AS mice, suggesting that these deficits are the direct result of increased inhibitory phosphorylation of alphaCaMKII.
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PMID:Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of alphaCaMKII inhibitory phosphorylation. 1725 80

Two common classes of deletions are described in the literature in individuals with Prader-Willi/Angelman syndrome (PWS/AS): one between breakpoint 1 (BP1) to BP3 and the other between BP2 to BP3 of the PWS/AS critical region on chromosome 15q11-->q13. We present here a novel observation of an approximately 253-kb deletion between BP1 and BP2 on 15q11.2, in a 3(1/2)-year-old boy, who was referred to us with a clinical suspicion of having Angelman syndrome and presenting with mental retardation, neurological disorder, developmental delay and speech impairment. Karyotype and FISH results were found to be normal. The microdeletion between BP1 and BP2 includes four genes - NIPA1, NIPA2, CYFIP1 and TUBGCP5 which was detected by a high-resolution oligonucleotide array-CGH that was further validated by a Multiplex Ligation-dependent Probe Amplification (MLPA) assay. The same deletion was observed in the father who presented with similar but relatively milder clinical features as compared to the affected son. Methylation studies by methylation-specific MLPA (MS-MLPA) of the SNRPN imprinting center (IC) showed a normal imprinting pattern, both in the patient and the father. To our knowledge a microdeletion limited only to the BP1-BP2 region has not yet been reported. The familial genetic alteration together with the striking clinical presentation in this study are interesting, but from our single case study it is difficult to suggest if the deletion is causative of some of the abnormal features or if it is a normal variant. The study however further strengthens the fact that genome-wide analysis by array CGH in individuals with developmental delay and mental retardation is very useful in detecting such hidden interstitial chromosomal rearrangements.
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PMID:Detection of a novel familial deletion of four genes between BP1 and BP2 of the Prader-Willi/Angelman syndrome critical region by oligo-array CGH in a child with neurological disorder and speech impairment. 1726 93

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation, absent speech, ataxia, and a happy disposition. Deletions of the 15q11q13 region are found in approximately 70% of AS patients. The deletions are sub-classified into class I and class II based on their sizes of approximately 6.8 and approximately 6.0, respectively, with two different proximal breakpoints and a common distal breakpoint. Utilizing a chromosome 15-specific comparative genomic hybridization genomic microarray (array-CGH), we have identified, determined the deletion sizes, and mapped the breakpoints in a cohort of 44 cases, to relate those breakpoints to the genomic architecture and derive more precise genotype-phenotype correlations. Interestingly four patients of the 44 studied (9.1%) had novel and unusually large deletions, and are reported here. This is the first report of very large deletions of 15q11q13 resulting in AS; the largest deletion being >10.6 Mb. These novel deletions involve three different distal breakpoints, two of which have been earlier shown to be involved in the generation of isodicentric 15q chromosomes (idic15). Additionally, precise determination of the deletion breakpoints reveals the presence of directly oriented low-copy repeats (LCRs) flanking the recurrent and novel breakpoints. The LCRs are adequate in size, orientation, and homology to enable abnormal recombination events leading to deletions and duplications. This genomic organization provides evidence for a common mechanism for the generation of both common and rare deletion types. Larger deletions result in a loss of several genes outside the common Angelman syndrome-Prader-Willi syndrome (AS-PWS) critical interval, and a more severe phenotype.
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PMID:Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: molecular characterization and genotype-phenotype correlations. 1752 20

Rett syndrome (RS) is an X-linked neurodevelopmental disorder and the second most common cause of genetic mental retardation in females. Different mutations in MECP2 are found in up to 95% of typical cases of RS. This mainly neuronal expressed gene functions as a major transcription repressor. Extensive studies on girls who have RS and mouse models are aimed at finding main gene targets for MeCP2 protein and defining neuropathologic changes caused by its defects. Studies comparing autistic features in RS with idiopathic autism and mentally retarded patients are presented. Decreased dendritic arborization is common to RS and autism, leading to further research on similarities in pathogenesis, including MeCP2 protein levels in autistic brains and MeCP2 effects on genes connected to autism, like DLX5 and genes on 15q11-13 region. This area also is involved in Angelman syndrome, which has many similarities to RS. Despite these connections, MECP2 mutations in nonspecific autistic and mentally retarded populations are rare.
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PMID:Rett syndrome. 1756 89

Neural developmental disorders, such as autism, Rett Syndrome, Fragile X syndrome, and Angelman syndrome manifest during early postnatal neural development. Although the genes responsible for some of these disorders have been identified, how the mutations of these genes affect neural development is currently unclear. Emerging evidence suggest that these disorders share common underlying defects in neuronal morphology, synaptic connectivity and brain plasticity. In particular, alterations in dendritic branching and spine morphology play a central role in the pathophysiology of most mental retardation disorders, suggesting that common pathways regulating neuronal function may be affected. Epigenetic modulations, mediated by DNA methylation, RNA-associated silencing, and histone modification, can serve as an intermediate process that imprints dynamic environmental experiences on the "fixed" genome, resulting in stable alterations in phenotypes. Disturbance in epigenetic regulations can lead to inappropriate expression or silencing of genes, causing an array of multi-system disorders and neoplasias. Rett syndrome, the most common form of mental retardation in young girls, is due to l mutation of MECP2, encoding a methylated DNA binding protein that translates DNA methylation into gene repression. Angelman syndrome is due to faulty genomic imprinting or maternal mutations in UBE3A. Fragile X Syndrome, in most cases, results from the hypermethylation of FMR1 promoter, hence the loss of expression of functional FMRP protein. Autism, with its complex etiology, may have strong epigenetic link. Together, these observations strongly suggest that epigenetic mechanisms may play a critical role in brain development and etiology of related disorders. This report summarizes the scientific discussions and major conclusions from a recent conference that aimed to gain insight into the common molecular pathways affected among these disorders and discover potential therapeutic targets that have been missed by looking at one disorder at a time.
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PMID:Epigenetics and Neural developmental disorders: Washington DC, September 18 and 19, 2006. 1796 27

Two elderly brothers with severe intellectual disability were diagnosed with Angelman syndrome after a once-removed, 15-year-old cousin was found to have the syndrome due to a deletion of the imprinting center. For many years it was believed the brothers, who both have macrocephaly, were affected by nonsyndromic X-linked mental retardation. This was because, apart from absent speech and intellectual disability, the phenotype of the two men was not characteristic of Angelman syndrome. Conversely, the cousin, in addition to severe intellectual disability, language impairment, and ataxic gait, has microcephaly. None of the three have seizures, and so in the presence of the brothers' macrocephaly, Angelman syndrome was not considered until a diagnosis was made in the younger distant cousin. We report on a familial imprinting center deletion and the importance of considering the mild and atypical Angelman syndrome phenotypes within the differential diagnosis of intellectual handicap, particularly in clarifying the genetic risk to other family members.
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PMID:Atypical Angelman syndrome with macrocephaly due to a familial imprinting center deletion. 1797 3


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