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

Down syndrome, as a phenotypic result of trisomy 21, is a complex condition with a set of over 30 phenotypic features, which manifest themselves with varying frequencies among affected individuals. The importance for molecular medicine of understanding the molecular mechanisms underlying Down syndrome becomes fully appreciated when a striking feature of Down syndrome is taken into account: that the overdose of otherwise perfectly normal genes causes disorders of human health, indistinguishable from major public health problems of the general population, such as mandatory early onset Alzheimer s degeneration, increased risk of leukemia, and protection from cancer of solid tissues. The DNA sequence of human chromosome 21 is, at the moment, the most complete piece of DNA sequence known in the whole of human genome. The challenge for the future is an integrated, multidisciplinary approach to the molecular biology of chromosome 21 genes, in conjunction with the research into the variation in their genotype, expression, and function in the normal population, in Down syndrome individuals with well-characterized phenotypic traits, and in euploid patients suffering from diseases associated with phenotypic components of Down syndrome: mental retardation, developmental defects, hematological and solid tissue malignancies, and Alzheimer s disease.
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PMID:Functional genomics of the Down syndrome. 1147 Nov 93

A subset of aged individuals with Down syndrome (DS) exhibits the clinical features of Alzheimer's disease (AD) but our ability to detect dementia in this population is hampered by developmental differences as well as the sensitivity of existing test tools. Despite the apparent clinical heterogeneity in aged individuals with DS, age-associated neuropathology is a consistent feature. This is due to the fact that trisomy 21 leads to a dose-dependent increase in the production of the amyloid precursor protein and subsequently the production of the amyloidogenic fragments leading to early and predominant senile plaque formation. A review of the existing literature indicates that oxidative damage and neuroinflammation may interact to accelerate the disease process particularly in individuals with DS over the age of 40 years. By combining clinical information with measures of brain-region specific neuropathology we can "work backwards" and identify the earliest and most sensitive clinical change that may signal the onset of AD. For the past 50 years, investigators in the fields of mental retardation, developmental disabilities, and aging have been interested in the curious link between AD and DS. The morphologic and biochemical origins of AD are seen in the early years of the lifespan for individuals with DS. Study of the process by which AD evolves in DS affords an opportunity to understand an important link between development and aging. This review will focus on advances in the molecular and clinical basis of this association.
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PMID:Down syndrome and Alzheimer's disease: a link between development and aging. 1155 33

The availability of the recently published DNA sequence of human chromosome 21 (HSA21) is a landmark contribution that will have an immediate impact on the study of the role of specific genes to Down syndrome (DS). Trisomy 21 or DS is the only autosomal aneuploidy that is not lethal in the fetal or early postnatal period. DS phenotypes show variable penetrance, affecting many different organs, including brain (mental retardation, early onset of Alzheimer's disease, AD), muscle (hypotonia), skeleton, and blood. DS phenotypes may stem directly from the cumulative effect of overexpression of specific HSA21 gene products or indirectly through the interaction of these gene products with the whole genome, transcriptome, or proteome. Mouse genetic models have played an important role in the elucidation of the contribution of specific genes to the DS phenotype. To date, the strategies used for modeling DS in mice have been three: (1) to assess single-gene contributions to DS phenotype, using transgenic techniques to create models overexpressing single or combinations of genes, (2) to assess the effects of overexpressing large foreign DNA pieces, introduced on yeast artificial chromosomes (YACs) or bacterial artificial chromosomes (BACs) into transgenic mice, and (3) mouse trisomies that carry all or part of MMU16, which has regions of conserved homology with HSA21. Here we review the existing murine models and the relevance of their contribution to DS research.
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PMID:Murine models for Down syndrome. 1156 19

Apoptosis is the mechanism by which cells are programmed to die under a wide range of physiological and developmental stimuli. Accumulating evidence indicates that enhanced apoptosis (programmed cell death) in Down syndrome (DS) may play a role in mental retardation and precocious neurodegeneration of the Alzheimer-type. In this regard, alteration of several apoptosis related proteins have been reported in adult DS brain. Fetal DS neurons exhibited increased reactive oxygen species leading to early apoptosis, however, expression of apoptosis related proteins in fetal DS, has never been considered. To address this issue, we investigated the expression of proteins involved in apoptosis including Fas (CD95, APO-1), caspase-3, Bcl-2 and annexins in the cerebral cortex of control and DS fetal brain by western blot and two dimensional electrophoresis. Here, we report that no detectable changes were obtained in fetal DS brain in the expression of Fas, caspase-3, Bcl-2 and Annexins (I, II, V, and VI) compared to controls. In parallel experiment, we also examined the expression of neuron specific enolase (NSE), a neuronal marker found to be decreased in adult DS brain, to see if there is any neuronal loss and no difference was observed between the two groups. Protein expression did not correlate with age. The unchanged levels of Fas, Bcl-2 and annexins together with unaltered caspase-3 expression, a predominant caspase that executes apoptosis in the developing nervous system, suggest that enhanced apoptosis may not be apparent in fetal DS brain as demonstrated for adult DS brain.
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PMID:Unaltered expression of Fas (CD95/APO-1), caspase-3, Bcl-2 and annexins in brains of fetal Down syndrome: evidence against increased apoptosis. 1177 40

Down syndrome (trisomy 21) is a genetic disease with developmental brain abnormalities resulting in early mental retardation and precocious, age dependent Alzheimer-type neurodegeneration. We tried to discuss the role of neurodevelopmental abnormalities in connection with aberrant expression of genes on chromosome 21 including amyloid precursor protein (APP), CuZn superoxide dismutase (SOD1) and glial-derived S100 beta protein for neurodegeneration in DS. In this model, alterations in developmental pathways due to aberrant gene expression can impair cellular homeostasis and predispose to neurodegeneration of certain brain regions and types of nerve cells, involving cholinergic, serotonergic and catecholaminergic transmission, by shifting balance toward a pro-apoptotic state.
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PMID:The brain in Down syndrome. 1177 48

Enhancement of memory acquisition and recall represents an important pharmacological goal in the treatment of cognitive disorders. In addition to its involvement in pH regulation, HCO3- reabsorption and CO2 expiration, carbonic anhydrase plays a crucial role in signal processing, long-term synaptic transformation and attentional gating of memory storage. Carbonic anhydrase dysfunction impairs cognition and is associated with mental retardation, Alzheimer's disease and aging. The pharmacological profile of carbonic anhydrase has been refined and specific activators have been developed. In this article, an integrated view of the involvement of carbonic anhydrase activity in synaptic plasticity and cognition will be presented, with particular focus on attentional gating of spatial learning and memory.
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PMID:Carbonic anhydrase gating of attention: memory therapy and enhancement. 1183 Feb 65

Down syndrome (DS) is the most common chromosomal abnormality associated with early mental retardation and neurological abnormalities followed by precocious age dependent Alzheimer-type neurode generation later in life. Knowledge of the pathological mechanisms involved in DS is far from complete, but overexpression of genes residing in chromosome 21 was considered to be the central point for the DS phenotype. In this regard, beta amyloid precursor protein (APP), CuZn superoxide dismutase (SOD1) and S100beta have been implicated in causing apoptosis, a mechanism thought to be responsible for neuronal loss in DS, in one way or another. The gene dosage hypothesis has been challenged, however, and dysregulation of expression of genes located on other chromosomes has been described, which may well be secondary to chromosomal imbalance or a direct consequence of the disease process. The present review focuses on the protein expression profile in DS and we postulate that abnormalities in the coordinated expression, as well as interaction of proteins may be responsible for the neuropathology of DS. A series of candidate proteins are discussed that may be directly causing or reflecting the DS phenotype, in particular the brain abnormalities in DS.
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PMID:Protein expression in Down syndrome brain. 1185 95

Altered dendritic spines are characteristic of traumatized or diseased brain. Two general categories of spine pathology can be distinguished: pathologies of distribution and pathologies of ultrastructure. Pathologies of spine distribution affect many spines along the dendrites of a neuron and include altered spine numbers, distorted spine shapes, and abnormal loci of spine origin on the neuron. Pathologies of spine ultrastructure involve distortion of subcellular organelles within dendritic spines. Spine distributions are altered on mature neurons following traumatic lesions, and in progressive neurodegeneration involving substantial neuronal loss such as in Alzheimer's disease and in Creutzfeldt-Jakob disease. Similarly, spine distributions are altered in the developing brain following malnutrition, alcohol or toxin exposure, infection, and in a large number of genetic disorders that result in mental retardation, such as Down's and fragile-X syndromes. An important question is whether altered dendritic spines are the intrinsic cause of the accompanying neurological disturbances. The data suggest that many categories of spine pathology may result not from intrinsic pathologies of the spiny neurons, but from a compensatory response of these neurons to the loss of excitatory input to dendritic spines. More detailed studies are needed to determine the cause of spine pathology in most disorders and relationship between spine pathology and cognitive deficits.
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PMID:Dendritic spine pathology: cause or consequence of neurological disorders? 1208 7

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

Down's syndrome (trisomy 21) is the most common chromosomal aberration and is one of the major reasons for mental retardation. Down's syndrome has manifestations in many systems. The syndrome has many neurological complications, which include structural changes, mental retardation, young-onset Alzheimer's disease, strokes and basal ganglia damage. Epileptic seizures are more prevalent in Down's syndrome patients than in the general population. Cervical spinal cord instability, which is common in Down's syndrome, can cause neurological complications resulting from cervical spinal cord compression. The aim of this article is to review the neurological complications of Down's syndrome in order to increase awareness and assist doctors in diagnosis and counseling the patients' families.
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PMID:[Neurological complications in Down's Syndrome]. 1236 89


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