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)

This is a case of Ramsay Hunt syndrome with mental disorder. The patient had action myoclonus, grand mal seizure and severe cerebellar ataxia. Schizophrenia-like symptoms including delusion of persecution and self-reference, auditory hallucination and incoherence were characteristically observed before the neurological disturbance became manifest. Subsequently, euphoria, disinhibition, moria and mild dementia appeared with neurological symptoms. The possibility of Ramsay Hunt syndrome to accompany organic mental syndromes and the relationship between cerebellar dysfunction and psychiatric symptoms are discussed.
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PMID:Ramsay Hunt syndrome with mental disorder. 181 81

To investigate the possibility that anti-CNS antibodies may play a pathogenic role in a number of neurological and psychiatric disorders, a population study was undertaken. Serum samples were obtained from a total of 257 adults and were screened against sodium dodecyl sulphate polyacrylamide gel electrophoretic blots of various normal, necropsy-derived adult human brain regions. The incidence of IgG immunoreactive banding in the total sample was 30%. Within the diagnostic groups the incidence of banding was: controls 32%, schizophrenia 28%, mental retardation 27%, cerebellar ataxia 33%, Parkinson's disease 22%, myasthenia gravis 45% and epilepsy 31%. The differences are not statistically significant. There was no significant difference in the numbers and locations of bands between the various diagnostic groups and the controls. The overall incidence of immunoreactivity corresponding to the high molecular weight subunit of neurofilaments was only 6%, thus not confirming a previously reported incidence of 95%. The similarity between the diagnostic and the control sera suggests that caution should be exerted in interpreting the pathogenic significance of anti-CNS immunoreactive banding on Western blots.
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PMID:Anti-CNS antibodies in neurological and psychiatric disorders. 369 10

A sporadic case of neuronal ceroid lipofuscinosis (Kufs' disease) in a 29-year-old man is reported. At onset the disease resembled schizophrenia (thought disorder, flat affect, paranoia, hallucinations and inappropriate behaviour), but after the appearance of associated neurological symptoms such as myoclonic jerks, cerebellar ataxia, rigidity and involuntary movements a neurological disorder was suspected. Cortical biopsy established the diagnosis.
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PMID:Adult neuronal ceroid lipofuscinosis (Kufs' disease). A sporadic case. 730 34

Unstable (CAG)n trinucleotide repeat microsatellites are hypothesized to cause schizophrenia. The (CAG)n microsatellite of dominant spinal cerebellar ataxia type 1 (SCA1) is a candidate schizophrenia gene. Autism results from expansions of (CGG)n and (GAA)n trinucleotide repeat stretches at fragile X syndrome (FRAXA), and the recessive Friedreich's ataxia (FA). Dominant ataxia genes may cause schizophrenia and recessive ataxia genes may cause autism. Syndromes with autism show purine synthesis defects (PSDs) and/or pigmentation defects (PDs). Autism is caused by very lengthy expansions of (CAG)n, (CGG)n and (GAA)n repeats, while schizophrenia results from much smaller (CAG)n and (CGG)n repeat expansions.
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PMID:Expanded (CAG)n, (CGG)n and (GAA)n trinucleotide repeat microsatellites, and mutant purine synthesis and pigmentation genes cause schizophrenia and autism. 979

The P/Q type Ca2+ channel alpha 1-subunit (CACN1A4) gene on chromosome 19p13 is a promising candidate susceptibility locus for schizophrenia. Point mutations in CACN1A4 cause familial hemiplegic migraine and episodic ataxia. Expansion in a coding 3' CAG repeat causes spino-cerebellar ataxia type 6 (SCA6). The mouse mutant phenotype totterer has a form of petit-mal epilepsy. These are neurological conditions, all of which exhibit features in common with schizophrenia. The 19p13 area is also paralogous to other genomic regions of interest in schizophrenia genetics. For these reasons, we performed an association study with the CAG repeat and schizophrenia using 225 Scottish schizophrenia and 198 unrelated Scottish controls. The repeat was not associated with the disorder (P = 0.72) and neither did the schizophrenics have significantly longer alleles than the controls (P = 0.45). We conclude that the SCA6 CAG repeat is not associated with schizophrenia susceptibility. However, it remains possible that other variants in the region could be involved.
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PMID:Association study of the CACN1A4 (SCA6) triplet repeat and schizophrenia. 1041 93

A 33-year-old male patient began to develop schizophrenia-like symptoms and slowly progressive cerebellar ataxia. He was 170 cm tall and he had mild frontal baldness. Psychiatrically he was aconative, only willing to do nothing all day long after admission. He had neither hallucinations nor delusions, and his mental acuity was normal. Neurological examination revealed positive cerebellar signs including clumsiness in F-N-T and K-H-T and dysdiadochokinesis. He could neither stand up nor walk because of ataxia. The brain MRI showed severe cerebellar atrophy with normal basal ganglia. His EEG and the value of NCV were within normal range, whereas electroretinography showed a notable abnormality, pointing to the extremely small b-wave, resulting in a negative shape of the ERG. Although he was eating sufficiently, the level of serum iron and ferritin remained constantly low. The serum copper level was within normal range, whereas the serum ceruloplasmin level was mildly decreased. A hepatic biopsy indicated no accumulation of copper or iron. This case suggests the importance of the investigation of the serum iron and ceruloplasmin levels in patients who have cerebellar degeneration with psychosis.
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PMID:[A case of cerebellar degeneration with schizophrenia-like psychosis, severe iron deficiency, hypoceruloplasminemia and abnormal electroretinography: a new syndrome?]. 1188 36

Celiac disease (CD) long has been associated with neurologic and psychiatric disorders including cerebellar ataxia, peripheral neuropathy, epilepsy, dementia, and depression. Earlier reports mainly have documented the involvement of the nervous system as a complication of prediagnosed CD. However, more recent studies have emphasized that a wider spectrum of neurologic syndromes may be the presenting extraintestinal manifestation of gluten sensitivity with or without intestinal pathology. These include migraine, encephalopathy, chorea, brain stem dysfunction, myelopathy, mononeuritis multiplex, Guillain-Barre-like syndrome, and neuropathy with positive antiganglioside antibodies. The association between most neurologic syndromes described and gluten sensitivity remains to be confirmed by larger epidemiologic studies. It further has been suggested that gluten sensitivity (as evidenced by high antigliadin antibodies) is a common cause of neurologic syndromes (notably cerebellar ataxia) of otherwise unknown cause. Additional studies showed high prevalence of gluten sensitivity in genetic neurodegenerative disorders such as hereditary spinocerebellar ataxia and Huntington's disease. It remains unclear whether gluten sensitivity contributes to the pathogenesis of these disorders or whether it represents an epiphenomenon. Studies of gluten-free diet in patients with gluten sensitivity and neurologic syndromes have shown variable results. Diet trials also have been inconclusive in autism and schizophrenia, 2 diseases in which sensitivity to dietary gluten has been implicated. Further studies clearly are needed to assess the efficacy of gluten-free diet and to address the underlying mechanisms of nervous system pathology in gluten sensitivity.
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PMID:Neurologic presentation of celiac disease. 1582 33

Although classically considered to be involved only in motor coordination, the cerebellum has more recently been implicated also in cognitive control. Anatomical studies have shown the cerebellum to be linked to pre-frontal, occipito-parietal and temporal cortical associative areas, as well as to the limbic system, in a closed loop circuit. Functional studies revealed activation of the cerebellum during performance on cognitive tasks not related to movement. Pathological, morphological and functional imaging studies have shown the cerebellum to be one of the cerebral structures affected in some of the cognitive and behavioural developmental disorders, like Attention Deficit with Hyperactivity Disorder, Autism and Schizophrenia. Neuropsychological studies in patients with degenerative cerebellar ataxia also showed cognitive dysfunction, mainly of the executive type. Investigation performed with child and adult patients with focal lesions of the cerebellum has helped to better discriminate the cognitive role of specific areas on the cerebellum, revealing a characteristic constellation of cognitive deficits, affecting executive, visual-spatial, linguistic and behavioural functions. However, much remains to be explained on the precise nature of cerebellar contributions to cognition, in part because of the difficulty in finding adequate investigation models. Studies performed on primates have contributed to better delineate the connections between the cerebellum and cortical cognitive domains, but is always uncertain to transfer this kind of data to the human brain. Functional imaging studies although useful to investigate directly in the human model and in real time, are not yet able to completely isolate cerebellar cognitive and behavioural functions. Degenerative and developmental disorders are not the most adequate model for studying cerebellar influence on higher mental functions, as they affect other regions besides the cerebellum. Young patients with isolated cerebellar stroke provide a useful clinical model for investigating cerebellar cognitive functions, because they permit to isolate in space and time the specific contribution of the cerebellum to the cognitive deficits.
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PMID:[Role of the cerebellum in cognitive and behavioural control: scientific basis and investigation models]. 1723 89

AMPA receptors (AMPAR) mediate the majority of fast excitatory neurotransmission in the central nervous system (CNS). Transmembrane AMPAR regulatory proteins (TARPs) have been identified as a novel family of proteins which act as auxiliary subunits of AMPARs to modulate AMPAR trafficking and function. The trafficking of AMPARs to regulate the number of receptors at the synapse plays a key role in various forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Expression of the prototypical TARP, stargazin/TARPgamma2, is ablated in the stargazer mutant mouse, an animal model of absence epilepsy and cerebellar ataxia. Studies on the stargazer mutant mouse have revealed that failure to express TARPgamma2 has widespread effects on the balance of expression of both excitatory (AMPAR) and inhibitory receptors (GABA(A) receptors, GABAR). The understanding of TARP function has implications for the future development of AMPAR potentiators, which have been shown to have therapeutic potential in both psychological and neurological disorders such as schizophrenia, depression and Parkinson's disease.
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PMID:The role of transmembrane AMPA receptor regulatory proteins (TARPs) in neurotransmission and receptor trafficking (Review). 1844 21

Glutamate is the major excitatory neurotransmitter of the Central Nervous System (CNS), and it is crucially needed for numerous key neuronal functions. Yet, excess glutamate causes massive neuronal death and brain damage by excitotoxicity--detrimental over activation of glutamate receptors. Glutamate-mediated excitotoxicity is the main pathological process taking place in many types of acute and chronic CNS diseases and injuries. In recent years, it became clear that not only excess glutamate can cause massive brain damage, but that several types of anti-glutamate receptor antibodies, that are present in the serum and CSF of subpopulations of patients with a kaleidoscope of human neurological diseases, can undoubtedly do so too, by inducing several very potent pathological effects in the CNS. Collectively, the family of anti-glutamate receptor autoimmune antibodies seem to be the most widespread, potent, dangerous and interesting anti-brain autoimmune antibodies discovered up to now. This impression stems from taking together the presence of various types of anti-glutamate receptor antibodies in a kaleidoscope of human neurological and autoimmune diseases, their high levels in the CNS due to intrathecal production, their multiple pathological effects in the brain, and the unique and diverse mechanisms of action by which they can affect glutamate receptors, signaling and effects, and subsequently impair neuronal signaling and induce brain damage. The two main families of autoimmune anti-glutamate receptor antibodies that were already found in patients with neurological and/or autoimmune diseases, and that were already shown to be detrimental to the CNS, include the antibodies directed against ionotorpic glutamate receptors: the anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies and anti-NMDA-NR2 antibodies, and the antibodies directed against Metabotropic glutamate receptors: the anti-mGluR1 antibodies and the anti-mGluR5 antibodies. Each type of these anti-glutamate receptor antibodies is discussed separately in this very comprehensive review, with regards to: the human diseases in which these anti-glutamate receptor antibodies were found thus far, their presence and production in the nervous system, their association with various psychiatric/behavioral/cognitive/motor impairments, their possible association with certain infectious organisms, their detrimental effects in vitro as well as in vivo in animal models in mice, rats or rabbits, and their diverse and unique mechanisms of action. The review also covers the very encouraging positive responses to immunotherapy of some patients that have either of the above-mentioned anti-glutamate receptor antibodies, and that suffer from various neurological diseases/problems. All the above are also summarized in the review's five schematic and useful figures, for each type of anti-glutamate receptor antibodies separately. The review ends with a summary of all the main findings, and with recommended guidelines for diagnosis, therapy, drug design and future investigations. In the nut shell, the human studies, the in vitro studies, as well as the in vivo studies in animal models in mice, rats and rabbit revealed the following findings regarding the five different types of anti-glutamate receptor antibodies: (1) Anti-AMPA-GluR3B antibodies are present in ~25-30% of patients with different types of Epilepsy. When these anti-glutamate receptor antibodies (or other types of autoimmune antibodies) are found in Epilepsy patients, and when these autoimmune antibodies are suspected to induce or aggravate the seizures and/or the cognitive/psychiatric/behavioral impairments that sometimes accompany the seizures, the Epilepsy is called 'Autoimmune Epilepsy'. In some patients with 'Autoimmune Epilepsy' the anti-AMPA-GluR3B antibodies associate significantly with psychiatric/cognitive/behavior abnormalities. In vitro and/or in animal models, the anti-AMPA-GluR3B antibodies by themselves induce many pathological effects: they activate glutamate/AMPA receptors, kill neurons by 'Excitotoxicity', and/or by complement activation modulated by complement regulatory proteins, cause multiple brain damage, aggravate chemoconvulsant-induced seizures, and also induce behavioral/motor impairments. Some patients with 'Autoimmune Epilepsy' that have anti-AMPA-GluR3B antibodies respond well (although sometimes transiently) to immunotherapy, and thanks to that have reduced seizures and overall improved neurological functions. (2) Anti-NMDA-NR1 antibodies are present in patients with autoimmune 'Anti-NMDA-receptor Encephalitis'. In humans, in animal models and in vitro the anti-NMDA-NR1 antibodies can be very pathogenic since they can cause a pronounced decrease of surface NMDA receptors expressed in hippocampal neurons, and also decrease the cluster density and synaptic localization of the NMDA receptors. The anti-NMDA-NR1 antibodies induce these effects by crosslinking and internalization of the NMDA receptors. Such changes can impair glutamate signaling via the NMDA receptors and lead to various neuronal/behavior/cognitive/psychiatric abnormalities. Anti-NMDA-NR1 antibodies are frequently present in high levels in the CSF of the patients with 'Anti-NMDA-receptor encephalitis' due to their intrathecal production. Many patients with 'Anti-NMDA receptor Encephalitis' respond well to several modes of immunotherapy. (3) Anti-NMDA-NR2A/B antibodies are present in a substantial number of patients with Systemic Lupus Erythematosus (SLE) with or without neuropsychiatric problems. The exact percentage of SLE patients having anti-NMDA-NR2A/B antibodies varies in different studies from 14 to 35%, and in one study such antibodies were found in 81% of patients with diffuse 'Neuropshychiatric SLE', and in 44% of patients with focal 'Neuropshychiatric SLE'. Anti-NMDA-NR2A/B antibodies are also present in subpopulations of patients with Epilepsy of several types, Encephalitis of several types (e.g., chronic progressive limbic Encephalitis, Paraneoplastic Encephalitis or Herpes Simplex Virus Encephalitis), Schizophrenia, Mania, Stroke, or Sjorgen syndrome. In some patients, the anti-NMDA-NR2A/B antibodies are present in both the serum and the CSF. Some of the anti-NMDA-NR2A/B antibodies cross-react with dsDNA, while others do not. Some of the anti-NMDA-NR2A/B antibodies associate with neuropsychiatric/cognitive/behavior/mood impairments in SLE patients, while others do not. The anti-NMDA-NR2A/B antibodies can undoubtedly be very pathogenic, since they can kill neurons by activating NMDA receptors and inducing 'Excitotoxicity', damage the brain, cause dramatic decrease of membranal NMDA receptors expressed in hippocampal neurons, and also induce behavioral cognitive impairments in animal models. Yet, the concentration of the anti-NMDA-NR2A/B antibodies seems to determine if they have positive or negative effects on the activity of glutamate receptors and on the survival of neurons. Thus, at low concentration, the anti-NMDA-NR2A/B antibodies were found to be positive modulators of receptor function and increase the size of NMDA receptor-mediated excitatory postsynaptic potentials, whereas at high concentration they are pathogenic as they promote 'Excitotoxcity' through enhanced mitochondrial permeability transition. (4) Anti-mGluR1 antibodies were found thus far in very few patients with Paraneoplastic Cerebellar Ataxia, and in these patients they are produced intrathecally and therefore present in much higher levels in the CSF than in the serum. The anti-mGluR1 antibodies can be very pathogenic in the brain since they can reduce the basal neuronal activity, block the induction of long-term depression of Purkinje cells, and altogether cause cerebellar motor coordination deficits by a combination of rapid effects on both the acute and the plastic responses of Purkinje cells, and by chronic degenerative effects. Strikingly, within 30 min after injection of anti-mGluR1 antibodies into the brain of mice, the mice became ataxic. Anti-mGluR1 antibodies derived from patients with Ataxia also caused disturbance of eye movements in animal models. Immunotherapy can be very effective for some Cerebellar Ataxia patients that have anti-mGluR1 antibodies. (5) Anti-mGluR5 antibodies were found thus far in the serum and CSF of very few patients with Hodgkin lymphoma and Limbic Encephalopathy (Ophelia syndrome). The sera of these patients that contained anti-GluR5 antibodies reacted with the neuropil of the hippocampus and cell surface of live rat hippocampal neurons, and immunoprecipitation from cultured neurons and mass spectrometry demonstrated that the antigen was indeed mGluR5. Taken together, all these evidences show that anti-glutamate receptor antibodies are much more frequent among various neurological diseases than ever realized before, and that they are very detrimental to the nervous system. As such, they call for diagnosis, therapeutic removal or silencing and future studies. What we have learned by now about the broad family of anti-glutamate receptor antibodies is so exciting, novel, unique and important, that it makes all future efforts worthy and essential.
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PMID:Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy. 2508 Oct 16


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