Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently a new form of human mutation-expansion of trinucleotide repeats-has been found to cause the diseases of fragile X syndrome, spinal and bulbar muscular atrophy, myotonic dystrophy and, most recently, Huntington's disease. We review the emerging data on the genetics and neurobiology of these disorders. Three are characterized by unusual patterns of inheritance, in particular, genetic 'anticipation', in which the severity of the disorder increases and the age of onset decreases in successive generations of a pedigree. Several idiopathic neuropsychiatric disorders have features of inheritance consistent with anticipation. In bipolar affective disorder, there is evidence for both earlier age of onset and more severe illness in the second generation of a subset of unilineal pedigrees. There is also the suggestion of anticipation in some forms of schizophrenia, spinocerebellar atrophy and autism. Triplet repeats are present in additional known genes, both in coding regions and untranslated regions. Furthermore, many novel genes with triplet repeats are expressed in the human brain, and these are candidates to cause some forms of these neuropsychiatric disorders.
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PMID:Genes with triplet repeats: candidate mediators of neuropsychiatric disorders. 768 67

Recent studies have implicated central serotonergic systems in the modulation of prepulse inhibition (PPI), an operational measure of sensorimotor gating, which has been used to identify gating deficits in psychiatric disorders, such as schizophrenia, Huntington's disease, and obsessive compulsive disorder. Both serotonin (5-HT) releasers and agonists at 5-HT1A, 5-HT1B, and 5-HT2 receptors reduce PPI in the rat. The present experiments demonstrate that the disruption of PPI in rats induced by the systemic administration of the 5-HT1A agonist, 8-OH-DPAT (8-hydroxy-2(di-n-propylamino)tetralin; 0.2 mg/kg), can be attenuated by the novel, selective 5-HT1A antagonist (+)WAY 100,135, (20.0 mg/kg), N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenyl-propa namide. Further experiments addressing the central site of action of 8-OH-DPAT revealed that the microinjection of 8-OH-DPAT (5.0 micrograms/0.5 microliter) into either the median raphe nucleus (MR) or dorsal raphe nucleus (DR) disrupts PPI. The reduction in PPI produced by intra-raphe microinjections of 8-OH-DPAT was prevented by a systemic injection of (+)WAY 100,135. These results support the hypothesis that somatodendritic 5-HT1A autoreceptors within the midbrain raphe subserve the PPI-disruptive effects of systemically administered 8-OH-DPAT. The decrement in PPI after intra-raphe infusions of a high dose of 8-OH-DPAT, however, was substantially less than the decrement in PPI after systemic administration of the drug. Hence, sites in addition to the somatodendritic autoreceptors may also play an important role in 8-OH-DPAT-induced disruption of PPI.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:8-OH-DPAT disruption of prepulse inhibition in rats: reversal with (+)WAY 100,135 and localization of site of action. 772 1

Triplet-repeat mutations are a newly discovered class of mutations that have so far been described only in patients with neuropsychiatric disorders. The features of these so-called dynamic mutations are discussed with reference to the known examples (Huntington's chorea, fragile X syndrome, myotonic dystrophy, X-linked spinal and bulbar muscular atrophy, spinocerebellar ataxia type 1, and dentatorubral and pallidoluysian atrophy, DRPLA). These features not only explain a number of clinical-epidemiological facts that cannot be accounted for by Mendelian genetics, but also suggest that schizophrenia and major affective disorder may be the result of a similar mutation mechanism. The most important support for this suggestion can be derived from the observation that dynamic mutations cause anticipation-i.e., an increase in severity and/or an decrease in the age at onset of a disease in subsequent generations-which, in turn, has been discovered in schizophrenia and major affective disorder. From a systematic as well as from a historical perspective, we argue that in light of these findings, degeneration has been rediscovered in the disguise of a new name.
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PMID:[From degeneration to anticipation. Systematic and historical scientific aspects of the genetics of neuropsychiatric diseases]. 867 94

A retrospective study of 30 Huntington's disease families (110 patients: 75 alive and 35 dead) known to a regional genetic centre, using multiple sources of information, showed the minimum lifetime prevalence of depression to be 39% in the prodrome and the diagnosed disease phase of the illness. The frequency of symptomatic schizophrenia was found to be about 9% and significant personality changes were found in 72% of the sample, some of them leading to gross behavioural anomalies. The findings reinforce the point that depression and schizophrenia, unaccompanied or preceded by organic personality changes and/or very early neural symptoms, are unlikely to lead to the eventual manifestation of the disease.
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PMID:Psychopathology in Huntington's disease patients. 783 92

We utilized quantitative autoradiography to determine the distribution of receptors for thyrotropin-releasing hormone (TRH) throughout the human temporal lobe and to examine the distribution of these receptors in discrete subregions of the temporal lobe from patients diagnosed premortem with schizophrenia. When compared to non-neurologic controls, schizophrenic patients demonstrated an increase of 51% in the concentration of TRH receptors in the molecular layer of the dentate gyrus. Within nuclei of the schizophrenic amygdala, marked decreases were found in the central (44%), medial (38%), cortical (36%), accessory cortical (52%), lateral (54%), and medial basal (22%) nuclei. We also examined postmortem brain samples from patients with Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease for alterations in the distribution of TRH receptors. No significant differences from non-neuropsychiatric controls were noted within the hippocampus in any of these disease states; however, slight alterations were noted in the central and medial basal amygdala in Huntington's disease and in the cortical amygdala in Alzheimer's disease. These disease-specific findings suggest that TRH may play a role in the neurochemical dysfunction of schizophrenia.
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PMID:Alterations in TRH receptors in temporal lobe of schizophrenics: a quantitative autoradiographic study. 788 24

Dopamine receptors are the primary targets in the treatment of schizophrenia, Parkinson's disease, and Huntington's chorea, and are discussed in this review by Philip Seeman and Hubert Van Tol. Improved therapy may be obtained by drugs that selectively target a particular subtype of dopamine receptor. Most antipsychotic drugs block D2 receptors in direct correlation to clinical potency, except clozapine, which prefers D4 receptors. D1 and D2 receptors can enhance each other's actions, possibly through subunits of the G proteins. In schizophrenia, the D2 and D3 receptor density is elevated by 10%, while the D4 receptor density is elevated by 600%. Therefore, D4 receptors may be a target for future antipsychotic drugs. While antipsychotics originally helped to discover dopamine receptors, the five cloned dopamine receptors are now facilitating the discovery of selective antipsychotic and antiparkinson drugs.
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PMID:Dopamine receptor pharmacology. 794 Sep 91

The success of the neurosciences in opening pathways to the understanding of psychotic disorders has led to enormous optimism about solutions to the mysteries of these illnesses. Yet the Holy Grail for this field--the discovery linkage between a chromosomal locus that is linked to a diseased gene--has thus far eluded us, whereas it has been grasped in such disorders as cystic fibrosis, Huntington's disease, and neurofibromatosis. This paper argues that those biological studies that bypass the psychological domain, and have directly attempted to find biochemical measures associated with schizophrenia, probably will not succeed. Seeking direct links from such molar behaviors as psychotic symptoms to molecular events has not worked in the past, and is not likely to work in the future. The approach recommended here focuses on working one's way from the behavioral through the psychological and psychophysiological levels toward the neural, biochemical and molecular levels. Psychology has much strength to contribute in the search for traits that broaden the phenotype of schizophrenia. Examples are given in the study of eye movement abnormalities as aids in the genetic exploration of schizophrenia.
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PMID:The role of psychological probes in genetic studies of schizophrenia. 794 11

Programmed cell death, sometimes referred to as apoptosis, occurs through an active process requiring new gene transcription, in contrast to the passive cell death produced by metabolic toxins. Programmed cell death is an essential part of normal development, particularly in the nervous system. Spatial, temporal, or quantitative errors in the stimuli that initiate programmed cell death, or errors within the programmed cell death pathway itself, can result in an abnormal number of neurons and pathological neural development. Excesses and deficits in neuronal numbers have now been observed not only in typical neurodegenerative disorders such as Alzheimer's and Huntington's diseases, but also in several neurodevelopmental disorders, including schizophrenia and autism. Recent investigations into the mechanisms of cell death during C. elegans neurodevelopment thymocyte negative selection, and withdrawal of sympathetic ganglion cells trophic support provides intriguing clues to the etiology and pathophysiology of these neuropsychiatric disorders.
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PMID:Programmed cell death: implications for neuropsychiatric disorders. 808 Aug 94

We have investigated detection thresholds for a foveal blue test light using a Maxwellian view system in 61 normal subjects, 19 patients with Huntington's chorea, 14 patients with Tourette's syndrome, and 20 patients with schizophrenia. Ten measurements were made: The blue test light (1 degree diameter, 500 msec duration) was presented either superimposed on a yellow adaptation field (5 degree diameter) or 500 msec after switching off this field (transient tritanopia effect). In both cases five different background intensities were presented. The only abnormality found was in patients with Huntington's chorea. During adaptation these patients' thresholds are significantly higher than normal (p < 0.005). No change was found in the transient tritanopia effect. Huntington's disease causes degeneration of several different transmitter systems in the brain. Increment threshold testing allows for noninvasive investigation of patients and confirms the involvement of the retina in the degenerative process in Huntington's chorea.
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PMID:Impairment of retinal increment thresholds in Huntington's disease. 821 45

Trinucleotide microsatellites are widespread in the human and other mammalian genomes. Expansions of unstable trinucleotide repeats have been associated so far with a number of different genetic diseases including fragile X, myotonic dystrophy (DM) and Huntington disease. While ten possible trinucleotides can occur at the DNA level, only CTG and CCG repeats are involved in the disorders described so far. However, the repeat expansion detection (RED) technique has identified additional large repeats of ATG, CCT, CTT, and TGG of potentially pathological significance in the human genome. We now show that conclusive information about the chromosomal localization of long trinucleotide repeats can be achieved in a relatively short time using fluorescence in situ hybridization (FISH) with biotin-labelled trinucleotide polymers. Large CTG expansions (> 1 kb) in DM and an unstable (CTG)306 repeat in a patient with schizophrenia were detected by eye through the microscope without electronic enhancement. Digital imaging was used to analyse the chromosomal distribution of long CCA and AGG repeats. Our results suggest that long trinucleotide repeats occur in the normal human genome and that the size of individual repeat loci may be polymorphic.
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PMID:Chromosomal localization of long trinucleotide repeats in the human genome by fluorescence in situ hybridization. 856 57


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