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)

Sixteen affected individuals are described from two families with early onset autosomal dominant familial Alzheimer's disease. A mutation at codon 139 in the presenilin 1 gene on chromosome 14 results in a methionine to valine substitution which cosegregates with the disease in these families. Onset of dementia was before the age of 50 years in all individuals. The ages at onset within each family were tightly clustered but were significantly different between the families; this difference could not be accounted for by apolipoprotein E status and suggests the existence of a further genetic factor that modifies age at disease onset. The pattern of cognitive decline was similar in both families: early memory loss (initially selective for verbal memory in some individuals) was followed soon after by loss of arithmetic skills while naming and object perception skills were relatively preserved. A speech production deficit was observed in three members of one family but not in the other. Seizures were common and usually predated by myoclonic jerks by a number of years. Serial MRIs showed progressive cortical atrophy with periventricular white matter change appearing 3-4 years into the disease. PET revealed parieto-temporal hypometabolism in all individuals scanned. The diagnosis of Alzheimer's disease was confirmed with typical histopathology in one individual from each family.
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PMID:Clinicopathological features of familial Alzheimer's disease associated with the M139V mutation in the presenilin 1 gene. Pedigree but not mutation specific age at onset provides evidence for a further genetic factor. 912 60

S-Methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO), a metabolite of the drug disulfiram, is a selective carbamoylating agent for sulfhydryl groups. Treatment of glutamate receptors isolated from mouse brain with DETC-MeSO blocks glutamate binding. In vivo, carbamoylated glutathione, administered directly to mice or formed by reaction of DETC-MeSO with glutathione in the blood, also blocks brain glutamate receptors. Carbamoyl groups appear to be delivered to brain glutamate receptors or to liver aldehyde dehydrogenase in vivo by a novel glutathione-mediated mechanism. Seizures caused by the glutamate analogs N-methyl-D-aspartate and methionine sulfoximine, or by hyperbaric oxygen, are prevented by DETC-MeSO, indicating that carbamoylation of glutamate receptors gives an antagonist effect. These observations offer an explanation for some of the previously reported neurological effects of disulfiram, such as its ability to prevent O2-induced seizures. Furthermore, some of the physiology of the disulfiram-ethanol reaction, that could not be accounted for based on the known inhibition of aldehyde dehydrogenase alone, may be explained by disulfiram's effect on glutamate receptors.
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PMID:Carbamoylation of brain glutamate receptors by a disulfiram metabolite. 930 77

Successful surgical management of a neoplastic or nonneoplastic seizure focus in close proximity to or within eloquent brain areas relies on precise delineation of the relationship between the lesion and functional brain areas. The aim of this series was to validate the usefulness and test the efficacy of noninvasive presurgical PET mapping of eloquent brain areas to predict surgical morbidity and outcome in children with seizures. To identify eloquent brain areas in 15 children (6 female and 9 male; mean age 11 years) with epileptogenic lesions PET images of regional cerebral blood flow were performed following the administration of [(15)O]water during motor, visual, articulation, and receptive language tasks. These images with coregistered magnetic resonance (MR) images were then used to delineate the anatomic relationship of a seizure focus to eloquent brain areas. Additional PET images using [18F]fluoro-2-deoxy-D-glucose (FDG) and [11C]methionine (CMET) were acquired to help localize the seizure focus, as well as characterize the lesion. Patient surgical management decisions were based on PET mapping in combination with coregistered MR images, PET-FDG findings, and the anatomic characteristics of the lesion. At follow-up 1-26 months after surgery, all patients that underwent temporal lobectomy (9 patients) and extratemporal resection (4 patients) for a neoplastic or nonneoplastic seizure focus are seizure-free with minimal postoperative morbidity. Of prime importance, no child sustained a postoperative speech or language deficit. PET imaging was also well tolerated without procedural complications. Based on PET mapping, a nonoperative approach was used for 2 children and a biopsy only was used in one child. When cortical injury involved prenatally determined eloquent cortex, PET demonstrated reorganization of language areas to new adjacent areas or even to the contralateral hemisphere. Integration of anatomical and functional data enhanced the surgical safety, defined optimal surgical approach, delineated the seizure focus from eloquent brain areas, facilitated maximum resection and optimized the timing of surgery, thereby minimizing surgical morbidity while maximizing surgical goals. PET measurements of FDG and CMET uptake were also helpful in localizing the seizure focus and grading the tumors. PET used for brain mapping in children provides the surgeon with strategic preoperative information not readily attainable with traditional invasive Wada testing or intraoperative cortical stimulation. PET mapping may also improve the outcome of extratemporal resections by allowing aggressive seizure focus resection. In addition, serial brain maps may optimize timing for surgical intervention by demonstrating reorganization of eloquent cortex often seen in younger children after cortical injury. Our results suggest that noninvasive presurgical brain mapping has the potential to reduce risk and improve neurologic outcome.
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PMID:Use of positron emission tomography for presurgical localization of eloquent brain areas in children with seizures. 941 31

Inbred animal strains provide an opportunity to study genetic factors in alcoholism in the absence of environmental factors. Although the concentration of methionine enkephalin (Met-enkephalin) in whole brain has been implicated in the consumption of ethanol, it has not been studied in the brains of alcohol withdrawal seizure-prone (WSP) and withdrawal seizure-resistant (WSR) mice. We compared these concentrations with the levels of preproenkephalin (PPE) mRNA and with the activity of peptide transport system-1 (PTS-1), a brain-to-blood transport system for Met-enkephalin that is affected by ethanol. The concentrations of Met-enkephalin were significantly greater in WSP mice than in WSR mice, whereas synthesis of Met-enkephalin, as reflected by PPE mRNA levels, and transport out of the brain by PTS-1 was not different. These results support a direct link between elevated concentrations of Met-enkephalin in whole brain and proneness to withdrawal-induced seizures. We suggest that the inverse relationship between the consumption of ethanol and proneness to seizures in inbred mice can be explained through their opposite relationships to Met-enkephalin.
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PMID:Enkephalin, PPE mRNA, and PTS-1 in alcohol withdrawal seizure-prone and -resistant mice. 942 34

Neuropeptide Y (NPY) gene expression is known to be modulated in the mossy fiber projection of hippocampal granule cells following seizure. We investigated NPY biosynthesis and metabolism in an attempt to characterize NPY biochemically as a neurotransmitter in the granule cell mossy fiber projection. NPY biosynthesis was compared in normal control animals and in animals that had experienced a single pentylenetetrazole-induced seizure. In situ hybridization analysis established the postseizure time course of preproNPY mRNA expression in the hippocampal formation, localizing the majority of increased preproNPY mRNA content to the hilus of the dentate gyrus. Radioimmunoassay analysis of the CA3/mossy fiber terminal subfield confirmed a subsequent increase in NPY peptide content. Biosynthesis of NPY peptide by granule cells and transport to the CA3/mossy fiber subfield was demonstrated by in vivo radiolabel infusion to the dentate gyrus/hilus followed by sequential HPLC purification of identified radiolabeled peptide from the CA3/mossy fiber terminal subfield. Additional in vivo radiolabeling studies revealed a postseizure increase in an unidentified NPY-like immunoreactive (NPY-LI) species. HPLC/radioimmunoassay analyses of CA3 subfield tissue extracts comparing normal control animals and pentylenetetrazole-treated animals confirmed the increased total NPY-LI, and demonstrated that the increased NPY-LI was comprised of a minor increase in native NPY and a major increase in the unknown NPY-LI. Data from subsequent and separate analyses incorporating immunoprecipitation with anti-C-terminal flanking peptide of NPY, further HPLC purification, and matrix-assisted laser desorption/ionization mass spectrometry support the conclusion that the unknown NPY-LI is methionine sulfoxide NPY. NPY and NPY-sulfoxide displayed differential calcium sensitivity for release from mossy fiber synaptosomes. Similar to NPY, NPY sulfoxide displayed high-affinity binding to each of the cloned Y1, Y2, Y4, and Y5 receptor subtypes. Postrelease inactivation of NPY was demonstrated in a mossy fiber synaptosomal preparation. Thus, the present study in combination with previously reported electrophysiological activity of NPY in the CA3 subfield demonstrates that NPY fulfills the classical criteria for a neurotransmitter in the hippocampal granule cell mossy fiber projection, and reveals the presence of two molecular forms of NPY that display differential mechanisms of release while maintaining similar receptor potencies.
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PMID:Biosynthesis and metabolism of native and oxidized neuropeptide Y in the hippocampal mossy fiber system. 957 79

Positron emission tomography (PET) with various tracers provides physiologic and biochemical information of living organs. Since radiologic examinations are usually avoided in pregnant women, mainly because of the radiation risk to the fetus, little is known about the effect of pregnancy on cerebral blood flow and metabolism. This paper reports findings of a 11C methionine PET scan of the pituitary gland in a woman after an abortion. The patient was a 31-year-old woman who suffered a seizure in the 9th week of her second pregnancy. On admission, computed tomography showed an abnormal mass lesion in the right frontal lobe, and a brain tumor was suspected. The patient and her family asked that that pregnancy be terminated. Seven days after a surgical abortion, methionine PET was performed. The scan showed high methionine uptake in the pituitary gland as well as in the right frontal lobe tumor. We suspected that another tumor was present in the pituitary gland. The right frontal tumor was partially resected, and pathologic examination of the resected specimen showed an astrocytoma (grade 2). After the operation, the patient received 50 Gy irradiation and chemotherapy. Two months after the operation, we performed a second methionine PET scan, which showed high uptake in the residual right frontal tumor but not in the pituitary gland. Results of other radiologic studies of the pituitary gland were normal. These findings suggest that the transport of 11C methionine into the pituitary gland may increase during pregnancy. Moreover, the pituitary gland of pregnancy should be a part of the differential diagnosis of pituitary adenomas in PET scanning. The change in physiologic uptake by the female pituitary gland should be taken into account in the diagnosis of pituitary adenoma with methionine PET.
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PMID:[High uptake on 11C methionine PET scan in the pituitary gland of a patient with cerebral glioma after surgical abortion]. 965 54

Fatal Familial Insomnia is a hereditary prion disease characterized by a mutation at codon 178 of the prion protein gene cosegregating with the methionine polymorphism at codon 129 of the mutated allele. It is characterized by disturbances of the wake-sleep cycle, dysautonomia and somatomotor manifestations (myoclonus, ataxia, dysarthria, spasticity). PET studies disclose severe thalamic and additionally cortical hypometabolism. Neuropathology shows marked neuronal loss and gliosis in the thalamus, especially the medio-dorsal and anterior-ventral nuclei, olivary hypertrophy and some spongiosis of the cerebral cortex. Detailed analysis of 14 cases from 5 unrelated families showed that patients ran either a short (9.1 +/- 1.1 months) or a prolonged (30.8 +/- 21.3 months) clinical course according to whether they were homozygote met/met or heterozygote met/val at codon 129. Moreover, homozygotes had more prominent oneiric episodes, insomnia and dysautonomia at onset, whereas heterozygotes showed ataxia and dysarthria at onset, earlier sphincter loss and epileptic Grand Mal seizures; they also displayed more extensive cortical involvement on PET and at postmortem examination. Our data suggest that the phenotype expression of Fatal Familial Insomnia is related, at least partly, to the polymorphism at codon 129 of the prion protein-gene.
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PMID:Clinical features of fatal familial insomnia: phenotypic variability in relation to a polymorphism at codon 129 of the prion protein gene. 966 7

Methionine synthase (MS) catalyses the methylation of homocysteine to methionine and requires the vitamin B12 derivative, methylcobalamin, as cofactor. We and others have recently cloned cDNAs for MS and described mutations associated with the cblG complementation group that correspond to MS deficiency. A subset of cblG, known as "cblG variant," shows no detectable MS activity and failure of [57Co]CN cobalamin to incorporate into MS in patient fibroblasts. We report the mutations responsible for three cblG-variant patients, two of them siblings, who presented with neonatal seizures, severe developmental delay, and elevated plasma homocysteine. Cell lines from all three patients were negative by northern blotting, though trace MS mRNA could be detected by means of phosphorimage analysis. Reverse transcriptase-PCR, SSCP, and nucleotide sequence analysis revealed four mutations. All were functionally null, creating either a frameshift with a downstream stop codon or an insert containing an internal stop codon. Of the two mutations found in the siblings, one of them, intervening sequence (IVS)-166A-->G, generates a cryptic donor splice site at position -166 of an intron beginning after Leu113, resulting in a 165-bp insertion of intronic sequence at junction 339/340. The second is a 2-bp deletion, 2112delTC. Mutations in the third patient include a G-->A substitution, well within the intron after Lys203, which results in intronic inserts of 128 or 78 bp in the mRNA. The second mutation is a 1-bp insertion, 3378insA. We conclude that the absence of MS protein in these cblG variants is due to mutations causing premature translation termination and consequent mRNA instability.
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PMID:Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency. 968 7

Regional brain protein synthesis was evaluated with positron emission tomography (PET) and L-(S-[11C]methyl)methionine ([11C]MET) in depressive patients, before and 3 h after an electroconvulsive shock (ECS), when energy supply is restored, and in healthy volunteers. Depressive patients presented apparent lower protein synthesis than normals, in agreement with known reduction of cerebral activity. In contrast, ECS resulted in a significant increase (56%, P < 0.05) in global cortical protein synthesis. This paradoxical hyperactivation of cellular protein metabolism in response to seizures and the fact that synaptic activity is further reduced after electroconvulsive therapy (ECT), may provide new insights for understanding the mechanism of action of ECT.
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PMID:Paradoxical metabolic response of the human brain to a single electroconvulsive shock. 978 87

Methylenetetrahydrofolate reductase deficiency is the most common inborn error of folate metabolism and should be suspected when homocystinuria is combined with hypomethioninemia. The main clinical findings are neurologic signs such as severe developmental delay, marked hypotonia, seizures, microcephaly, apnea, and coma. Most patients present in early life. The infantile form is severe, with rapid deterioration leading to death usually within 1 year. Treatment with betaine has been shown to be efficient in lowering homocysteine concentrations and returning methionine to normal, but the clinical response is variable. We report two brothers with methylenetetrahydrofolate reductase deficiency: the first was undiagnosed and died at 8 months of age from neurologic deterioration and apnea, while his brother, who was treated with betaine from the age of 4 months, is now 3 years old and has developmental delay.
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PMID:Methylenetetrahydrofolate reductase deficiency: importance of early diagnosis. 1096 93


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