Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital ornithine transcarbamylase (OTC) deficiency in humans is associated with seizures and mental retardation. As part of a series of studies to delineate the neurochemical features of OTC deficiency, activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), respectively, were measured in brain regions of the congenitally hyperammonemic sparse-fur (spf) mouse, a mutant with an X-linked inherited defect of OTC. ChAT activities were reduced by 63% (P < 0.01) in cerebral cortex of spf mice compared with CD-1/Y controls. Activities of the GABA nerve terminal marker enzyme, glutamic acid decarboxylase, on the other hand, were within normal limits. Using an immunohistochemical technique with a monoclonal antibody to ChAT, a significant loss of ChAT-positive neurons was observed throughout the cerebral cortex, septal area and diagonal band of spf mice. These results suggest that a loss of forebrain cholinergic neurons is a feature of congenital OTC deficiency in these mutants. Possible pathogenetic mechanisms responsible for the cholinergic neuronal loss in congenital OTC deficiency include neurotoxic effects of ammonia and accumulation of quinolinic acid.
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PMID:Evidence for cholinergic neuronal loss in brain in congenital ornithine transcarbamylase deficiency. 781 42

Peripheral vasodilatation with increased cardiac output, tachycardia and increased blood pressure are described after alcohol administration. An increased HDL-cholesterol is found in moderate drinkers (both HDL-2 and HDL-3 fractions), with diminishing risk of coronary heart diseases. Acute ethanol intake causes an increased the level of triglycerides without changes in HDL-cholesterol level. This may be put into correlation with higher incidence of cardiovascular diseases in so-called "week-end" drinkers. Alcohol abuse may result in central diabetes insipidus. An increased elimination of lactate diminishes tubular secretion of uric acid with subsequent secondary hyperuricemia. Ethanol reduced the number of lymphocytes, reduces phagocytosis by macrophages and diminishes the activity of NK-cells. Bone marrow cellulity diminishes with the subsequent reduction in erythropoiesis, trombopoiesis and leukopoiesis. Alcohol may cause sideropenic and megaloblastic anemia. There are two forms of alcohol muscle injury: the acute one, with myonecrosis and inflammatory reaction, and chronic one, with muscle weakness and atrophy. Alcohol is one of etiologic factors of osteoporosis. An acute intoxication result in transitory hypoparatthyreoidism, while chronic ethanol intake make grow the PTH level and decreases the level of D vitamin metabolises. Stimulation of cortisol secretion, decrease of testosterone level and a reversible decrease of T3 and T4 levels have been described following ethanol administration. Hypothalamic-pituitary-adrenal axis suffers alteration in alcoholics, and secondary amenorrhea is observed in female alcoholics. Ethanol behaves as an agonist on GABA receptor. Fetal alcohol syndrome together with Down's syndrome and spina bifida are the most frequent reasons of mental retardation in developed countries. Toxicity of ethanol affects the whole pregnancy period.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Ethanol metabolism and pathobiochemistry of organ damage--1992. IV. Ethanol in relation to the cardiovascular system. Hematologic, immunologic, endocrine disorders and muscle and bone damage caused by ethanol. Fetal alcohol syndrome]. 799 17

Careful clinical delineation and advances in analytical methods have opened new possibilities for the detection of inherited neurometabolic disorders, some of which require specific CSF analyses for diagnosis. Although patients suffering from these disorders have recognizable phenotypes, there are strong indications that remain many undiagnosed, leading to a continuation of futile diagnostic searches and, for most disorders, withholding of available rational therapy. As there is still widespread uncertainty about when to perform specialist CSF investigations, it is the aim of this paper to define the place for CSF investigations in the diagnostic work-up of a child with an encephalopathy of unknown origin. Most neurometabolic disorders can be identified through serum, plasma and urine analyses in conjunction with neuroradiological investigations. Whenever CSF investigations are performed, the analysis should include quantitative determination of lactate, pyruvate and amino acids, the latter by methods especially suited for CSF, in addition to cells, glucose, protein, immunoglobulin classes, specific immunoglobulins, and an evaluation of the blood-brain barrier. If the disease course is non-progressive or if extracerebral symptoms are present in addition to an encephalopathy, e.g. endocrinological, hepatic, muscular or renal symptoms, investigations of metabolites in CSF over and above lactate, pyruvate and amino acids are generally noncontributary. Specific CSF investigations, which are discussed in detail, test metabolic pathways of brain metabolism, especially of neurotransmission. For a successful diagnosis of these defects, analyses must be planned individually, before CSF samples are taken, based on family history, clinical findings and disease course. Different determinations require different logistics from taking of the sample to shipment. One indication for specialized CSF analyses including biogenic monoamines and GABA is severe neonatal/infantile epileptic encephalopathy. In addition to a therapeutic trial of B6, folinic acid should be tried empirically for two to three days as the emerging syndrome of folinic acid responsive seizures appears to be the underlying cause in a sizable proportion of patients. In later infancy and childhood, defects in the metabolism of the biogenic monoamines may be suspected in patients with (fluctuating) extrapyramidal disorders, in particular Parkinsonism dystonia or more general "athetoid cerebral palsy", and vegetative disturbances. A severe epileptic encephalopathy and progressive mental retardation may be present. Neuroimaging findings do not show specific lesions. Determinations of folates and organic acids in CSF appear at present only warrantable individually in special constellations, e.g. classical clinical findings and disease course suggestive of glutaryl-CoA dehydrogenase deficiency with repeated negative quantitative analyses of organic acids in urine. The diagnosis of disorders, which require specific analyses of CSF, can only be achieved by conscious diagnostic decisions based on a concept of the respective disease and repeated scrupolous expert clinical evaluation aided by an array of investigations in blood and urine as well as neuroimaging findings. No single one investigation in CSF can serve as a "selective screening" test. A growing awareness of these disorders is needed and should lead to increased and earlier diagnosis of patients through fewer rather than more lumbar punctures.
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PMID:Cerebrospinal fluid investigations for neurometabolic disorders. 963 60

Aggressive behavior has been associated with numerous neurologic conditions including traumatic brain injury, mental retardation, developmental disorders, Huntington disease, and several dementias. Preclinical and human studies suggest that dysfunction of neural systems involving the brainstem, hypothalamus, amygdala, or prefrontal cortex can give rise to aggression. Several neurochemicals are felt to be relevant to modulation of aggression, including serotonin, dopamine, norepinephrine, GABA, acetylcholine, and androgens. Pharmacologic intervention studies have targeted these systems but have been limited by inconsistent definitions of aggression and a relative paucity of controlled trials. This article briefly reviews studies of neural systems and medication trials relevant to aggression and propose a clinical approach to treatment of patients manifesting aggressive behavior.
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PMID:Pharmacologic approach to aggression in neuropsychiatric disorders. 1129 Oct 20

We report a female child with tetrasomy of the 15q11-q13 chromosomal region, and autistic disorder associated with mental retardation, developmental problems and behavioral disorders. Combining classical and molecular cytogenetic approaches by fluorescence in situ hybridization technique, the karyotype was demonstrated as 47,XX,+mar.ish der(15)(D15Z1++,D15S11++,GABRB3++,PML-). Duplication of the 15q proximal segment represents the most consistent chromosomal abnormality reported in association with autism. The contribution of the GABA receptor subunit genes, and other genes mapped to this region, to the clinical symptoms of the disease is discussed.
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PMID:Tetrasomy 15q11-q13 identified by fluorescence in situ hybridization in a patient with autistic disorder. 1206 63

Duchenne muscular dystrophy is characterized by a defect in dystrophin, which often causes mental retardation in addition to progressive muscular weakness. As dystrophin is localized in synaptic regions of the CNS, cognitive abnormalities associated with Duchenne muscular dystrophy are attributable to synaptic dysfunction. We report that dystrophin-deficient mdx mice were more resistant to kainic acid-induced seizures but not to GABA antagonist-induced seizures compared with the control mice. The kainic-acid receptor density in the brain was significantly lower in the mdx than in the control, although the density of muscarinic cholinergic receptors, another important neurotransmitter receptor for cognitive function, was normal. Moreover, mdx had significantly lower Timm staining intensity in the mossy fibers, which originate from the dentate granule cells and terminate on the pyramidal cells in the CA3 of the hippocampus. These results suggest that an instability of neurotransmitter receptors, such as kainate-type glutamate receptors, on synaptic membranes due to the disruption of dystrophin complex induces inefficient neurotransmission in Duchenne muscular dystrophy patients.
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PMID:Abnormal kainic acid receptor density and reduced seizure susceptibility in dystrophin-deficient mdx mice. 1261 79

To explore the hypothesis that L-phenylalanine (L-Phe) depresses glutamatergic synaptic transmission and thus contributes to brain dysfunction in phenylketonuria (PKU), the effects of L-Phe on spontaneous and miniature excitatory postsynaptic currents (s/mEPSCs) in rat and mouse hippocampal and cerebrocortical cultured neurons were studied using the patch-clamp technique. L-Phe depressed the amplitude and frequency of both N-methyl-D-aspartate (NMDA) and non-NMDA components of glutamate receptor (GluR) s/mEPSCs. The IC(50) of L-Phe to inhibit non-NMDAR mEPSC frequency was 0.98 +/- 0.13 mM, a brain concentration seen in classical PKU. In contrast, D-Phe had a significantly smaller effect, whereas L-leucine, an amino acid that competes with L-Phe for brain transporter, had no effect on mEPSCs. Unlike GluR s/mEPSCs, GABA receptor mIPSCs were not attenuated by L-Phe. A high extracellular concentration of glycine prevented the attenuation by L-Phe of NMDAR current, activated by exogenous agonist, and of NMDAR s/mEPSC amplitude, but not of NMDAR s/mEPSC frequency. On the other hand, L-Phe significantly depressed non-NMDAR current activated by low but not high concentrations of exogenous agonists. Glycine-independent attenuation of NMDAR s/mEPSC frequency suggests decreased presynaptic glutamate release caused by L-Phe, whereas decreased amplitudes of NMDAR and non-NMDAR s/mEPSCs are consistent with competition of L-Phe for the glycine- and glutamate-binding sites of NMDARs and non-NMDARs, respectively. The finding that GluR activity is significantly depressed at conditions characteristic of classical PKU indicates a potentially important contribution of impaired GluR function to PKU-related mental retardation and provides important insights into the potential physiological consequences of impaired GluR function.
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PMID:L-phenylalanine selectively depresses currents at glutamatergic excitatory synapses. 1264 85

Fragile X syndrome is an inherited cause of mental retardation. We used extra- and intracellular recordings in brain slices obtained from wild type and fragile X knockout mice to establish whether bath application of the cholinergic agent carbachol (5 microM) induces different responses in neurons of the subiculum, a limbic structure involved in learning and memory. We found that carbachol diminished excitatory post-synaptic responses induced by CA1 stratum radiatum stimulation in wild type mice, but caused an unexpected increase in knockout animals. Moreover, these responses augmented in knockout mice after carbachol washout, a phenomenon that resembled the muscarinic long-term potentiation seen in wild type mice during application of carbachol and GABA(A) receptor antagonists. We also used paired-pulse stimulation to determine whether the changes in synaptic excitability induced by carbachol were caused by pre- or post-synaptic mechanism. Under control conditions, this protocol induced facilitation in both wild type and knockout mice; in contrast, during carbachol application, this facilitatory effect was seen in wild type mice only. In conclusion, our data highlight for the first time differences in cholinergic and GABA-ergic mechanisms that may contribute to the phenotype of fragile X patients.
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PMID:Involvement of cholinergic and gabaergic systems in the fragile X knockout mice. 1276 63

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare disorder characterized by an inborn error of the catabolism of the inhibitory neurotransmitter GABA. Because of the deficiency of SSADH, the final enzyme of the GABA degradation pathway, the substrate, succinic semialdehyde, is shunted towards production of 4-hydroxybutyric acid (gamma-hydroxybutyric acid). Elevations of gamma-hydroxybutyric acid can be detected in the physiologic fluids of patients with SSADH deficiency, and forms the mainstay of diagnosis. The clinical features of SSADH deficiency include nonspecific neurologic manifestations such as mental retardation/developmental delay, absent speech, hypotonia, nonprogressive ataxia, features of autism or pervasive developmental delay, developmental language delay (dyspraxia, receptive, and expressive delays), and occasionally, seizures. Although the metabolic pathway has been established, it is not known whether insufficient GABA and/or excess gamma-hydroxybutyric acid contribute to the disease phenotype. Pharmacological therapy in patients with this disorder has been limited to vigabatrin, an anticonvulsant that blocks GABA transaminase. This review will discuss therapeutic options in SSADH deficiency, on the basis of patient experience, and preliminary work using a murine model. Finally, a discussion of adjunctive therapies will be included.
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PMID:Vigabatrin and newer interventions in succinic semialdehyde dehydrogenase deficiency. 1289 56

Canavan disease (CD) is an autosomal recessive leukodystrophy characterized by spongy degeneration of the brain. The clinical features of CD are hypotonia, megalencephaly, and mental retardation leading to early death. While aspartoacylase (ASPA) activity increases with age in the wild type mouse brain, there is no ASPA activity in the CD mouse brain. So far ASPA deficiency and elevated NAA have been ascribed with the CD. Other factors affecting the brain that result from ASPA deficiency may lead pathophysiology of CD. The NMR spectra and amino acid analysis showed lower levels of glutamate and gamma-aminobutyric acid in the CD mouse brain compared to the wild type. Microarray gene expression on CD mouse brain showed glutamate transporter-EAAT4 and gamma-aminobutyric acid-A receptor, subunit alpha6 (GABRA6) were lower 9.7- and 119.1-fold, respectively. Serine proteinase inhibitor 2 (Spi2) was 29.9-fold higher in the CD mouse brain compared to the wild type. The decrease of GABRA6 and high expression of Spi2 in CD mouse brain were also confirmed by real-time RT-PCR. This first report showing abnormal expression of EAAT4, GABRA6, Spi2 combined with lower levels of glutamate and GABA are likely to be associated with the pathophysiology of CD.
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PMID:Expression of glutamate transporter, GABRA6, serine proteinase inhibitor 2 and low levels of glutamate and GABA in the brain of knock-out mouse for Canavan disease. 1290 86


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