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)

Neural cell adhesion molecules of the immunoglobulin superfamily are multidomain proteins involved in important cellular events pertinent to development and adult neurological function. This review attempts to give a concise overview of the complex intracellular signaling pathways enabling neural cell adhesion molecules NCAM and L1 to regulate axon growth, guidance, and synaptic plasticity. Recent research findings suggest that these molecules signal in part through integrins leading to cytoskeletal rearrangements locally in the growth cone or cell leading edge, and to MAP kinase, which has the potential to cause gene expression changes in the nucleus. Abnormal expression of NCAM on human chromosome 11q23 has been linked to schizophrenia in humans, a multigenic disease believed to be of neurodevelopmental origin. L1 at Xq28 is the target for mutation in a complex mental retardation disorder termed the L1 syndrome (also sometimes referred to as CRASH syndrome). Thus a full understanding of the mechanism of NCAM and L1 function will contribute to understanding both normal brain development and pathologies associated with cognitive dysfunction in schizophrenia and mental retardation.
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PMID:Cellular signalling mechanisms of neural cell adhesion molecules. 1270 44

Type I lissencephaly is a cortical malformation disorder characterized by disorganized cortical layers and gyral abnormalities and associated with severe cognitive impairment and epilepsy. The exact pathophysiological mechanisms underlying the epilepsy and mental retardation in this and related disorders remain unknown. Two genes, LIS1 and doublecortin, have both been shown to be mutated in a large proportion of cases of type I lissencephaly and a milder allelic disorder, subcortical laminar heterotopia (SCLH). Studying the protein products of these genes and the biochemical pathways in which they belong is likely to yield important information concerning both normal and abnormal cortical development. The relationships between the LIS1 and Doublecortin proteins are not yet well defined, but both are believed to play a critical role in cortical neuronal migration. Lis1 is expressed from very early development in the mouse and in both proliferating cells and post-mitotic neurons of the cortex. This protein is likely to have multiple functions since it is a subunit of the enzyme platelet-activating factor acetylhydrolase, which degrades platelet activating factor, and has also been shown to be involved in microtubule dynamics, potentially influencing nuclear migration through its interaction with the dynein motor protein complex. Doublecortin on the other hand is exclusively expressed in post-mitotic neurons and is developmentally regulated. In young developing neurons Doublecortin has a specific subcellular localization at the ends of neuritic and leading processes. This localization, combined with our previous data showing that it is a microtubule-associated protein and that it interacts with adapter complexes involved in vesicle trafficking, suggests a role in the growth of neuronal processes, downstream of directional or guidance signals. The observations summarized here favor the suggestion that whereas LIS1 may play a role in nuclear migration, Doublecortin is instead restricted to functions at the leading edge of the cell.
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PMID:Doublecortin functions at the extremities of growing neuronal processes. 1276 37

Previously, human genetics-based approaches allowed us to show that mutations in the IL-1 receptor accessory protein-like gene (IL1RAPL) are responsible for a non-specific form of X-linked mental retardation. This gene encodes a predicted protein of 696 amino acids that belongs to a novel class of the IL-1/Toll receptor family. In addition to the extracellular portion consisting of three Ig-like domains and the intracellular TIR domain characteristic of the IL-1/Toll receptor family, IL1RAPL contains a specific 150 amino acid carboxy terminus that has no significant homology with any protein of known function. In order to begin to elucidate the function of this IL-1/Toll receptor-like protein, we have assessed the effect of recombinant IL1RAPL on the binding affinity of type I IL-1R for its ligands IL-1alpha and beta and searched for proteins interacting with the specific carboxy terminus domain of IL1RAPL. Our results show that IL1RAPL is not a protein receptor for IL-1. In addition we present here the identification of Neuronal Calcium Sensor-1 (NCS-1) as an IL1RAPL interactor. Remarkably, although NCS-1 and its non-mammalian homologue, frequenin, are members of a highly conserved EF-hand Ca(2+) binding protein family, our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.
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PMID:IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. 1278 49

Recently, a frequent prion protein gene (PRNP) polymorphism consisting of a methionine (M) for valine (V) substitution at codon 129 has been associated with cognitive impairment in elderly individuals. Down syndrome (DS) is associated with mental retardation and development of Alzheimer-like brain abnormalities. In the present study, we investigated the role of the PRNP polymorphism in 122 relatively young Italian DS patients. Allele frequencies of DS subjects did not differ from those in the general population. However, we found a significantly faster rate of decline in intellectual ability in the subgroup of DS patients carrying at least one V allele compared with the M/M DS subjects. An additive deleterious effect of apolipoprotein E epsilon 4 allele was detected after stratifying by APOE gene status. Our findings provide evidence that variability of the PRNP gene at codon 129 might contribute to accelerating the rate of earlier cognitive decline in DS subjects.
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PMID:The 129 codon polymorphism of the prion protein gene influences earlier cognitive performance in Down syndrome subjects. 1525 99

Mice carrying a truncated form of cAMP-responsive element binding protein (CREB)-binding protein (CBP) show several developmental abnormalities similar to patients with Rubinstein-Taybi syndrome (RTS). RTS patients suffer from mental retardation, whereas long-term memory formation is defective in mutant CBP mice. A critical role for cAMP signaling during CREB-dependent long-term memory formation appears to be evolutionarily conserved. From this observation, we reasoned that drugs that modulate CREB function by enhancing cAMP signaling might yield an effective treatment for the memory defect(s) of CBP+/- mice. To this end, we designed a cell-based drug screen and discovered inhibitors of phosphodiesterase 4 (PDE4) to be particularly effective enhancers of CREB function. We extend previous behavioral observations by showing that CBP+/- mutants have impaired long-term memory but normal learning and short-term memory in an object recognition task. We demonstrate that the prototypical PDE4 inhibitor, rolipram, and a novel one (HT0712) abolish the long-term memory defect of CBP+/- mice. Importantly, the genetic lesion in CBP acts specifically to shift the dose sensitivity for HT0712 to enhance memory formation, which conveys molecular specificity on the drug's mechanism of action. Our results suggest that PDE4 inhibitors may be used to treat the cognitive dysfunction of RTS patients.
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PMID:A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4. 1293 Aug 88

The most common genetic cause of mental retardation is Down syndrome, trisomy of chromosome 21, which is accompanied by small stature, developmental delays, and mental retardation. In the Ts65Dn segmental trisomy mouse model of Down syndrome, the section of mouse chromosome 16 most homologous to human chromosome 21 is trisomic. This model exhibits aspects of Down syndrome including growth restriction, delay in achieving developmental milestones, and cognitive dysfunction. Recent data link vasoactive intestinal peptide malfunction with developmental delays and cognitive deficits. Blockage of vasoactive intestinal peptide during rodent development results in growth and developmental delays, neuronal dystrophy, and, in adults, cognitive dysfunction. Also, vasoactive intestinal peptide is elevated in the blood of newborn children with autism and Down syndrome. In the current experiments, vasoactive intestinal peptide binding sites were significantly increased in several brain areas of the segmental trisomy mouse, including the olfactory bulb, hippocampus, cortex, caudate/putamen, and cerebellum, compared with wild-type littermates. In situ hybridization for VIP mRNA revealed significantly more dense vasoactive intestinal peptide mRNA in the hippocampus, cortex, raphe nuclei, and vestibular nuclei in the segmental trisomy mouse compared with wild-type littermates. In the segmental trisomy mouse cortex and hippocampus, over three times as many vasoactive intestinal peptide-immunopositive cells were visible than in wild-type mouse cortex. These abnormalities in vasoactive intestinal peptide parameters in the segmental trisomy model of Down syndrome suggest that vasoactive intestinal peptide may have a role in the neuropathology of Down-like cognitive dysfunction.
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PMID:Vasoactive intestinal peptide in the brain of a mouse model for Down syndrome. 1295 88

OBJECTIVE: To discuss clinical and electroencephalographic aspects and the genetic mechanisms of three neurogenic syndromes that can be related to nosologic entities in the heterogenic pathological group presenting symptoms of mental retardation and autism. SOURCES: The authors carried out a bibliographic review on each syndrome involved, correlating and characterizing the neurological manifestations, as well as describing genetic mechanisms and identifying biological markers. SUMMARY OF THE FINDINGS: The authors were able to confirm that Rett Sydrome is a genetic disease resulting from the mutation of the MECP2 gene and clinical variations can be explained by different mutations in this gene. Angelman syndrome has four genetic mechanisms responsible for phenotypic variations and different risks of recurrence. In Fragile-X syndrome, the degree of cognitive impairment is related to the number of trinucleotide repeats. CONCLUSIONS: Different genetic mechanisms of the three syndromes are responsible for clinical variability. By identifying the biological markers, the diagnosis will be performed earlier and it will be possible to identify new subtle expressions of the disease.
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PMID:[Neurological manifestation and genetic diagnosis of Angelman, Rett and Fragile-X syndromes] 1467 69

Analyses of deletions in the dystrophin gene and of cognitive status were performed on patients with Duchenne (DMD) or Becker (BMD) muscular dystrophy in order to find a correlation between both features. Molecular study by multiplex and simplex PCR of dystrophin exons led to the identification of 51 deletions in 126 unrelated patients. Most of them were frameshift, in full agreement with severe clinical symptoms, three patients with a BMD-like phenotype had in-frame mutations. Deletions were localized with reference to the different dystrophin isoform sequences and were clustered in two main areas, 5' and central+ 3' end of the gene. Cognitive abilities were tested in 47 out of 51 patients with identified mutations, 23 of them being mentally impaired. Comparison of molecular and neuropsychological features showed that deletions localized in central and 3' parts of the gene (18 out of 23) are preferentially associated with mental impairment. Fourteen of them were found in the regulatory and coding sequences for the three CNS specific carboxy terminal isoforms. Therefore, though mutations with variable locations may lead to cognitive impairment, our results show that deletions in the distal portion of the gene are basically related to mental retardation.
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PMID:Dystrophin deletions and cognitive impairment in Duchenne/Becker muscular dystrophy. 1497 63

We report on a 50-year-old man with mental retardation and right-sided hemi-paresis. He seemed to be cured from epilepsy. In a short time a mental and physical deterioration developed which looked like a dementia, which was suggested by vascular risk factors. The EEG showed marked epileptic activity characterized by spikes appearing every 10 seconds over the left temporal lobe. After introduction of carbamazepine, a fast and long-term improvement of symptoms was noticed resulting in self sufficiency. The fast and marked effect of an antiepileptic drug being given to the patient with an non-typical reactivation of epilepsy in which the dementia-syndrome was caused by a transitory cognitive impairment due to sub-clinic electric seizures or non-convulsive status epilepticus.
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PMID:[Atypical epilepsy symptomatology as cause of a dementia like state in a mentally and physically retarded patient]. 1499 95

Clinical disorders of brain plasticity are common in the practice of child neurology. Children have an enhanced capacity for brain plasticity compared to adults as demonstrated by their superior ability to learn a second language or their capacity to recover from brain injuries or radical surgery such as hemispherectomy for epilepsy. Basic mechanisms that support plasticity during development include persistence of neurogenesis in some parts of the brain, elimination of neurons through apoptosis or programmed cell death, postnatal proliferation and pruning of synapses, and activity-dependent refinement of neuronal connections. Brain plasticity in children can be divided into four types: adaptive plasticity that enhances skill development or recovery from brain injury; impaired plasticity associated with cognitive impairment; excessive plasticity leading to maladaptive brain circuits; and plasticity that becomes the brain's 'Achilles' Heel' because makes it vulnerable to injury. A broad group of pediatric neurologic disorders can be understood in terms of their impact on fundamental mechanisms for brain plasticity. These include neurofibromatosis, tuberous sclerosis, Fragile X syndrome, other inherited forms of mental retardation, cretinism, Coffin-Lowry syndrome, lead poisoning, Rett syndrome, epilepsy, hypoxic-ischemic encephalopathy and cerebral palsy.
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PMID:Clinical disorders of brain plasticity. 1503 25


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