Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Down syndrome (DS) is associated with mental retardation, immune disorders and congenital heart diseases. Although it is usually caused by the presence of an extra chromosome 21, a subset of the diagnostic phenotypic features may be caused by the presence of the band 21q22, called the "Down syndrome region". Many proteins important for the immune and nervous systems as CuZn-superoxide dismutase (SOD-1), CD18-beta chain of LFA-1, interferon receptor, APP-amyloid precursor protein, protein S-100 beta are coded by chromosome 21. Overexpression of these molecules may contribute to the thymic derangement that results in anomalous maturation leading to functionally impaired T cells. Many factors have been shown to contribute to the immune deficiency which results in high susceptibility to infections, high rate of malignancies, and autoimmune phenomena in persons with DS. The main disorders in the immune system include thymus abnormalities, changes in cell-mediated immunity, phagocytosis, antibodies-mediated immunity and a high prevalence of autoantibodies in persons with DS. Furthermore, the duplication of chromosome 21 genes may generate most of the pathological changes in the central nervous system. There is an increased prevalence of seizure disorders. Such widespread alterations in the cortical areas seem to account for specific impairments observed in short-term and long-term memory, language skills, and cognitive and learning processes. If all principles of optimal health care and adequate education were followed without exception for persons with DS, then the quality of their life could be improved significantly and they would be able to become productive citizens in the society. (Tab. 5, Fig. 3, Ref. 42.)
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PMID:[Down's syndrome--effect of increased gene expression in chromosome 21 on the function of the immune and nervous system]. 926 31

Secreted forms of the beta-amyloid precursor protein (beta-APP) have neuroprotective properties in vitro and may be involved in the containment of neuronal excitation. To test whether loss of secreted forms of beta-APP (sAPPs) may enhance excitotoxic responses, we injected mice homozygous for a targeted mutation of the beta-APP gene (beta-APPDelta/Delta) intraperitoneally with kainic acid. We found that in these mice, kainic acid induced seizures initiated earlier, and acute mortality was enhanced compared to isogenic wild-type mice independently from the callosal agenesis phenotype observed to occur at increased frequency in APP mutant mice. Expression of c-fos in cortex and cingulate gyrus was enhanced in beta-APPDelta/Delta mice, although the amount of structural damage and apoptosis in the hippocampal pyramidal cell layer and cortex was similar to that of controls. When cerebellar granule cell cultures and cortical neuronal cultures were challenged with glutamate receptor agonists, the rates of cell death and apoptosis of beta-APPDelta/Delta mice were indistinguishable from those of controls. Therefore, deficiency of sAPPs causes facilitation of seizure activity in the absence of enhanced cell death. Since enhanced seizures were observed also in mice homozygous for a deletion of the entire beta-APP gene, this phenotype results from a loss of APP rather than from a dominant effect of APPDelta.
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PMID:Hypersensitivity to seizures in beta-amyloid precursor protein deficient mice. 1020 85

A mutant amyloid precursor protein (APP/RK) designed to interfere with processing by alpha-secretase caused a severe phenotype in transgenic mice, including behavioural abnormalities, i.e. neophobia, aggression, hypersensitivity to kainic acid, hyposensitivity to N-methyl-D-aspartate, and premature death [Moechars D. et al. (1996) Eur. molec. Biol. Org. J. 15, 1265-1274]. We now demonstrated that the APP/RK transgene did not disturb the expression of several other genes, i.e. endogenous amyloid precursor protein and amyloid precursor protein-like proteins, members of the low density lipoprotein receptor lipoprotein receptor family and several of their ligands, including apolipoprotein E, but expression of alpha-2-macroglobulin was never detected. Neither amyloid deposits nor neurofibrillary tangles were detected in the brain of APP/RK transgenic mice, even when 15-months-old. The tendency for seizures and hyposensitivity for N-methyl-D-aspartate was not due to or reflected in the distribution of the three major types of glutamate receptors. The major and consistent finding in transgenic APP/RK mice that died prematurely was extensive neurodegeneration and apoptosis, mainly in hippocampus and cortex, and accompanied by astrocytosis throughout the brain. Reduced synaptic density and dendritic damage was only observed in three transgenic mice that were killed shortly after positive observation of seizures. In addition, the distribution of cathepsin D and ubiquitin was abnormal in these mice.
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PMID:Premature death in transgenic mice that overexpress a mutant amyloid precursor protein is preceded by severe neurodegeneration and apoptosis. 1039 65

Typical (TPP) and atypical (APP) perfusion patterns (PP) may be seen in ictal SPECT of patients with temporal lobe epilepsy (TLE). APP may pose problem in the lateralization of the epileptogenic zone (EZ). We aimed to investigate predictive variables for the occurrence of TPP and APP. Fifty-one TLE patients were submitted to successful anterior-mesial temporal lobectomy. Univariate (UVA) and multivariate (MVA) analysis were performed upon clinical data, distribution of interictal spikes, and ictal chronology of seizures. From MVA, a final predictive model (FPM) was determined to better predict TPP and APP. Forty patients showed TPP (78.5%) and 11 patients APP (21.5%). Accuracy of ictal SPECT was higher in the unilateral (UIS) than in the bilateral (BIS) interictal spikes group (P = 0.05). FPM showed that patients exhibiting BIS, with shorter proportion of the electrographic seizure occurring after completion of tracer injection, and longer clinical than EEG seizure duration had more APP (P = 0.003). Generalized tonic-clonic seizures did not result in more APP. We concluded that analysis of ictal SPECT in TLE requires the knowledge of TPP and APP, the distribution of interictal spikes on temporal lobes and the ictal chronology of seizures. BIS showed that beyond a more complex epileptogenicity and seizure propagation, they may also lead to APP.
Seizure 2004 Jul
PMID:Ictal chronology and interictal spikes predict perfusion patterns in temporal lobe epilepsy: a multivariate study. 1515 7

The occurrence of an APP T174I mutation is described in a large American family of African descent with Alzheimer disease. The clinical characteristics were an unusually early onset of disease (early 30s), similar to a previously reported age at onset of this mutation in an Austrian family. Distinct from that family, seizures and myoclonus were prominent features of the disease in this kindred.
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PMID:An African American family with early-onset Alzheimer disease and an APP (T714I) mutation. 1566 48

Different duplications of the APP locus have been identified in five families with autosomal dominant early onset Alzheimer's disease (ADEOAD) and Abeta-related cerebral amyloid angiopathy (CAA). This study describes the phenotype of this new entity. Clinical, neuropsychological, imagery and neuropathological data were reviewed. The phenotype was not dependent on the size of the duplication and there was no clinical feature of Down's syndrome. Dementia was observed in all cases; intracerebral haemorrhage (ICH) was reported in 6 (26%) and seizures occurred in 12 (57%) of 21 patients. Age of onset of dementia ranged from 42 to 59 years, ICH from 53 to 64 years and age at death from 46 to 75 years. The neuropathological findings in five cases demonstrated Alzheimer's disease and severe CAA lesions that were reminiscent from those reported in brains of Down's syndrome patients. A striking feature consisted in intraneuronal Abetax-40 accumulation located in the granular cell layer of the dentate gyrus and in the pyramidal cell layer of the Ammon's horn.
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PMID:Phenotype associated with APP duplication in five families. 1695 15

Accumulation of cerebral amyloid-beta (Abeta) has been implicated as a putative causal factor in the development of Alzheimer's disease (AD). Transgenic mice like the PDAPP line overexpress human mutant Amyloid Precursor Protein (hAPP) and recapitulate many features of AD, including amyloid neuropathology and cognitive deficits. Inhibition of the beta-site aspartyl cleaving enzyme (BACE1) enzyme responsible for the first proteolytic cleavage that ultimately generates Abeta has been proposed as a strategy for AD therapy. To assess the theoretical repercussions of beta-secretase activity reduction in an in vivo model of AD, BACE1(-/-) mice bred to the PDAPP line were examined in a series of behavioral tasks. Although BACE1 gene ablation abolished hAbeta accumulation, BACE1(-/-) mice had unexpected sensorimotor impairments, spatial memory deficits, and displayed seizures, phenotypes which were severe on the PDAPP background. These results suggest that while excess Abeta is functionally pathological, BACE1-mediated processing of APP and other substrates play a role in "normal" learning, memory and sensorimotor processes.
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PMID:BACE1 gene deletion: impact on behavioral function in a model of Alzheimer's disease. 1733 21

Gliosis is a pathological hallmark of posttraumatic epileptic foci, but little is known about these reactive astrocytes beyond their high glial fibrillary acidic protein (GFAP) expression. Using diolistic labeling, we show that cortical astrocytes lost their nonoverlapping domain organization in three mouse models of epilepsy: posttraumatic injury, genetic susceptibility, and systemic kainate exposure. Neighboring astrocytes in epileptic mice showed a 10-fold increase in overlap of processes. Concurrently, spine density was increased on dendrites of excitatory neurons. Suppression of seizures by the common antiepileptic, valproate, reduced the overlap of astrocytic processes. Astrocytic domain organization was also preserved in APP transgenic mice expressing a mutant variant of human amyloid precursor protein despite a marked upregulation of GFAP. Our data suggest that loss of astrocytic domains was not universally associated with gliosis, but restricted to seizure pathologies. Reorganization of astrocytes may, in concert with dendritic sprouting and new synapse formation, form the structural basis for recurrent excitation in the epileptic brain.
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PMID:Loss of astrocytic domain organization in the epileptic brain. 1969 29

There are two types of dementia with early onset: (i) presenile dementias; and (ii) senile dementias with early onset. Most patients who develop dementia before 65 years of age have Alzheimer's disease (AD). The remainder are likely to have vascular dementia (VaD), frontotemporal dementia, head injury, alcohol intoxication, or metabolic disorder. Presenile dementias, caused by frontotemporal lobar degeneration, progressive supranuclear palsy, and corticobasal degeneration, usually occur in patients of presenile and are rarely seen in patients of senile age. Although the factors responsible for the accelerated onset of the illness are not fully known, genetic abnormalities appear to be important in some types of presenile dementia, such as frontotemporal dementia with parkinsonism linked to chromosome 17. Conversely, senile dementias such as sporadic AD and VaD commonly occur in patients of senile age. These disorders may also occur in patients of presenile age, although less frequently. Alzheimer's disease was originally classified as a 'presenile dementia'. Since the 1980s, 'senile dementia of Alzheimer type' (SDAT) and 'Alzheimer's disease' have been considered to belong to the same pathological entity and both are now known as 'dementia of Alzheimer's type (DAT)' or merely 'Alzheimer's disease'. Rapid progression of cognitive impairment with neuropsychological syndromes and neurological symptoms has been considered a characteristic of early onset AD. However, recently, neurological symptoms such as spastic paraparesis, seizures, and myoclonic convulsions have been reported to occur infrequently in early onset AD, although language problems and visuospatial dysfunctions are common. There are at least three dominant genes that have been identified in cases of familial Alzheimer's disease with early onset, namely the amyloid precursor gene (APP), and the genes encoding presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Therefore, genetic abnormalities are important factors contributing to the earlier onset of the illness. It is also important to investigate the pathophysiological mechanism in relation to genetic abnormalities, environmental factors, physical illnesses, and metabolic disturbances to understand the processes underlying the development of dementia with early onset.
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PMID:What is 'early onset dementia'? 1960 28

Diffusible oligomeric assemblies of the amyloid beta-protein (Abeta) could be the primary factor in the pathogenic pathway leading to Alzheimer's disease (AD). Converging lines of evidence support the notion that AD begins with subtle alterations in synaptic efficacy, prior to the occurrence of extensive neuronal degeneration. Recently, however, a shared or overlapping pathogenesis for AD and epileptic seizures occurred as aberrant neuronal hyperexcitability, as well as nonconvulsive seizure activity were found in several different APP transgenic mouse lines. This generated a renewed attention to the well-known comorbidity of AD and epilepsy and interest in how Abeta oligomers influence neuronal excitability. In this study therefore, we investigated the effect of various in vitro-aged Abeta(1-42) oligomer solutions on the perforant pathway-evoked field potentials in the ventral hippocampal dentate gyrus in vivo. Firstly, Abeta oligomer solutions (1 microl, 200 microM) which had been aggregated in vitro for 0, 24 or 72h were injected into the hippocampus of urethane-anesthetized rats, in parallel with in vitro physico-chemical characterization of Abeta oligomerization (atomic force microscopy, thioflavin-T fluorescence). We found a marked increase of hippocampal population spike (pSpike) after injection of the 24-h Abeta oligomer solution and a decrease of the pSpike amplitude after injection of the 72-h Abeta oligomer. Since urethane anesthesia affects the properties of hippocampal evoked potentials, we repeated the injection of these two Abeta oligomer solutions in awake, freely moving animals. Evoked responses to perforant pathway stimulation revealed a 70% increase of pSpike amplitude 50 min after the 24-h Abeta oligomer injection and a 55% decrease after the 72-h Abeta oligomer injection. Field potentials, that reflect synaptic potentials, were not affected by the Abeta injection. These results demonstrate that oligomeric Abeta aggregates elicit opposite electrophysiological effects on neuronal excitability which depend on their degree of oligomerization.
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PMID:Different electrophysiological actions of 24- and 72-hour aggregated amyloid-beta oligomers on hippocampal field population spike in both anesthetized and awake rats. 2065 35


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