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)

Fetal ischemia or hypoxia can lead to cerebral palsy, mental retardation and epilepsy. We propose that the production of nitric oxide and oxygen radicals by neurons when ischemic or hypoxic brain is reperfused may contribute to cerebral injury. Ischemia will depolarize neuronal membranes causing the synaptic discharge of the excitatory neurotransmitter glutamate, which in turn opens the voltage-dependent, N-methyl-D-aspartic acid-specific glutamate receptor/ionophore, allowing calcium to accumulate in the neuron. Calcium in turn activates an oxygen-dependent neuronal nitric oxide synthetase, which oxidizes arginine to produce nitric oxide (.NO) when oxygen is readmitted to brain by reperfusion. Nitric oxide reacts with the oxygen radical superoxide (O2-), also produced by reperfusion, to form peroxynitrite (ONOO-). Peroxynitrite can diffuse for several micrometers before decomposing to form the powerful and cytotoxic oxidants hydroxyl radical and nitrogen dioxide. The hypothesis is consistent with available evidence on the protective action of glutamate antagonists and of oxygen radical scavengers for limiting cerebral infarction following focal ischemia.
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PMID:The double-edged role of nitric oxide in brain function and superoxide-mediated injury. 167 55

We report a 13-year-old boy with peripheral dysostosis, nasal hypoplasia, brachydactyly and a tracheal stenosis of unknown origin. Acrodysostosis is usually caused by an autosomal gene, but in this case it was probably due to a new mutation. The frequently described mental retardation is not essential feature. Ectopic calcification has not been previously reported.
HNO 1989 Apr
PMID:[Acrodysostosis: an autosomal inherited form of peripheral dysostosis]. 272 79

The tetrahydrobiopterin (BH4) cofactor is essential for the aromatic amino acid hydroxylases that are involved in phenylalanine degradation and catecholamine and serotonin biosynthesis. Furthermore, BH4 is an essential and limiting cofactor for all types of nitric oxide synthases. BH4 deficiency results in hyperphenylalaninemia and monoamine neurotransmitter depletion associated with progressive mental retardation and is most commonly due to autosomal recessive mutations in 6-pyruvoyltetrahydropterin synthase (PTPS), the second enzyme for cofactor biosynthesis. Due to the relatively poor blood-brain barrier penetration of the cofactor, conventional therapy requires, besides oral doses of synthetic BH4, administration of neurotransmitter precursors and an aromatic amino acid decarboxylase inhibitor. The outcome of this therapy is not always beneficial. In this study we transduced into primary patient fibroblasts the human cDNAs for the BH4 biosynthetic enzymes GTP cyclohydrolase I and PTPS, expressed from different retroviral vectors. This allowed BH4 biosynthesis in originally PTPS-deficient cells. Moreover, the double-transduced fibroblasts released between 200 and 800 pmol of BH4/10(6) cells/day. Such engineered fibroblasts may be grafted into the central nervous system and used as depository cells for constitutive delivery of BH4.
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PMID:Retrovirus-mediated double transduction of the GTPCH and PTPS genes allows 6-pyruvoyltetrahydropterin synthase-deficient human fibroblasts to synthesize and release tetrahydrobiopterin. 964 48

Lysinuric protein intolerance (LPI) results in low serum L-arginine, hyperammonemia, mental retardation, thrombocytopenia, and an increased frequency of bowel movements. Our objective was to evaluate the effects of low serum L-arginine, the essential substrate for reactions catalyzed by nitric oxide synthetase (NOS), on the serum nitric oxide (NO) level and coagulation activity in a patient with LPI. A 37-year-old Japanese man who presented with abdominal pain and subnormal fasting levels of serum L-arginine and L-lysine was found to have LPI. The result of oral administration of diamino acids was an increased in urine and a decrease in serum, thus confirming the diagnosis. A decrease in the platelet count and an increase in the plasma levels of thrombin-antithrombin III complex (TAT) and fibrin degradation products (FDPs) indicated the presence of subclinical intravascular coagulation. Serum levels of NO derivatives and L-arginine were determined after intravenous administration of L-arginine. The effects of intravenous L-arginine or transdermal nitroglycerin on the plasma level of TAT were also investigated. Serum levels of NO derivatives were significantly reduced in the LPI patient versus the healthy control group (n = 5). Intravenous administration of L-arginine increased the serum level of NO derivatives and the platelet count and reduced plasma TAT and FDP levels. The plasma level of TAT was also reduced by transdermal nitroglycerin. A decrease in the serum level of L-arginine in patients with LPI appears to result in a decrease in NO production. The improvement in plasma TAT levels produced by administration of intravenous L-arginine or transdermal nitroglycerin suggests that intravascular coagulation is exacerbated by the decrease of NO production in patients with LPI.
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PMID:Reduced nitric oxide production by L-arginine deficiency in lysinuric protein intolerance exacerbates intravascular coagulation. 1048 53

Family and adoption studies indicate that genetic factors play a role in the development of many psychiatric disorders. A variable number of possible interacting genes predisposing to the diseases is likely. The genetic dissection has been hampered by genetic complexity as well as by difficulties in defining the phenotypes. Genetic mapping efforts using sib pairs, twins and individual large families has revealed preliminary or tentative evidence for susceptibility loci for a number of psychiatric disorders. Illnesses include the prion disease familial fatal insomnia (FFI), alcoholism, anorexia nervosa, autism, bipolar affective disorder, dyslexia, enuresis nocturnal, epilepsia, obsessive-compulsive disorders (OCD), schizophrenia, as well as the dementias, Alzheimer's disease and frontal lobe dementia, and mental retardation. The genes and proteins related to the newly discovered transmitter in the central nervous system, nitric oxide (NO), and its genes and proteins are also reviewed. The number of mapped human genes now exceeds 30,000 of the estimated total number of 60,000 to 100,000 genes. This rapid development will facilitate gene mapping, as well as efforts to isolate and identify the genes responsible for symptom susceptibility in many of the etiologically unclear psychiatric diseases with complex genetic origin.
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PMID:[Mental disease a heritage. New genetic knowledge can reveal "public diseases" such as autism, dyslexia, alcoholism, anorexia, schizophrenia]. 1070 80

Cerebral hypoxia in the fetus and newborn results in neonatal morbidity and mortality as well as long-term sequelae such as mental retardation, seizure disorders, and cerebral palsy. In the developing brain, determinants of susceptibility to hypoxia should include the lipid composition of the brain cell membrane, the rate of lipid peroxidation, the presence of antioxidant defenses, and the development and modulation of excitatory amino acid neurotransmitter receptors such as the N-methyl-D-aspartate (NMDA) receptor, the intracellular Ca2+, and the intranuclear Ca(2+)-dependent mechanisms. In addition to the developmental status of these cellular components, the response of these potential mechanisms to hypoxia determines the fate of the hypoxic brain cell in the developing brain. Using electron spin resonance spectroscopy of alpha-phenyl-N-tert-butyl-nitrone spin adducts, studies from our laboratory demonstrated that tissue hypoxia results in increased free radical generation in the cortex of fetal guinea pigs and newborn piglets. Pretreatment with MgSO4 significantly decreased the hypoxia-induced increase in free radical generation in the term fetal brain. We also showed that brain tissue hypoxia modifies the NMDA receptor ion-channel recognition and modulatory sites. Furthermore, a higher increase in NMDA receptor agonist-dependent Ca2+ in synaptosomes was demonstrated. The increase in intracellular Ca2+ may activate several enzymatic pathways such as phospholipase A2 and metabolism of archidonic acid by cyclooxygenase and lipoxygenase, conversion of xanthine dehydrogenase to xanthine oxidase by proteases, and activation of nitric oxide synthase. Using inhibitors of each of these enzymes such as cyclooxygenase (indomethacin), lipoxygenase (nordihydroguaiaretic acid), xanthine oxidase (allopurinol), and nitric oxide synthase (N-nitro-L-arginine), studies have shown that these enzyme reactions result in oxygen free radical generation, membrane peroxidation, and cell membrane dysfunction in the hypoxic brain. Specifically, generation of nitric oxide free radicals during hypoxia may lead to nitration and nitrosylation of specific membrane proteins and receptors, resulting in dysfunction of receptors and enzymes. We conclude that hypoxia-induced modification of the NMDA receptor leading to increased intracellular Ca2+ results in free radical generation and cell injury. We suggest that during hypoxia the increased intracellular Ca2+ may lead to increased intranuclear Ca2+ concentration and alter nuclear events including transcription of specific apoptotic genes and activation of endonucleases, resulting in programmed cell death.
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PMID:Mechanisms of perinatal cerebral injury in fetus and newborn. 1081 2

The Niikawa-Kuroki syndrome is a rare syndrome characterized by multiple congenital anomalies, mental retardation, postnatal growth deficiency, dermatoglyphic abnormalities and a characteristic facial appearance. More than 100 cases of the syndrome have been described in Europe. Here we report a 10 year old girl with this syndrome. Recurrent infections of the middle ear as well as delayed motor and speech development were present. The physiognomy since early infancy showed a flat profil, long palpebral fissures, long eyelashes, high arched eyebrows, missing lateral incisors and persistent fetal pads on the fingers. The patient was referred to us because of hearing impairment. Her parents also described a delayed motor development, mental retardation and a language impairment. Audiometry demonstrated a pantonal hearing loss. Since children affected by this syndrome may also have a severe hearing impairment early testing is mandatory.
HNO 2004 May
PMID:[Niikawa-Kuroki (Kabuki) syndrome and hearing impairment]. 1513 52

Guanidinoacetate methyltransferase deficiency (GAMT-deficiency) is an inherited neurometabolic disorder clinically characterized by epilepsy and mental retardation and biochemically by accumulation of guanidinoacetate (GAA) and depletion of creatine. Although the neurological symptoms are predominant, the pathogenesis of the brain dysfunction in this disorder is not yet established. In the present study we investigated the in vitro effect of GAA on Na+, K+-ATPase and Mg2+-ATPase activities in synaptic plasma membrane from hippocampus of young rats. Results showed that GAA significantly inhibited Na+, K+-ATPase activity without affecting Mg2+-ATPase activity. We also evaluated the effect of glutathione (GSH), trolox, Nomega-nitro-L-arginine methyl ester (L-NAME) and taurine (Tau) on the inhibition elicited by GAA on Na+, K+-ATPase activity. GSH, trolox, L-NAME and Tau per se did not alter Na+, K+-ATPase activity. However, L-NAME and taurine prevented the inhibitory effect of GAA on this enzyme activity. Our findings suggest that the inhibition of Na+, K+-ATPase activity caused by GAA is possibly mediated by nitric oxide (NO) formation and/or synaptic membrane alteration. The present data may contribute to the understanding of the neurological dysfunction characteristic of GAMT-deficient patients.
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PMID:Evaluation of the mechanism underlying the inhibitory effect of guanidinoacetate on brain Na+, K+-ATPase activity. 1524 54

Nitric oxide (NO) is a short-life key bioregulatory active molecule in the cardiovascular, immune and nervous systems. NO is synthesized by converting L-arginine to L-citrulline by enzymes called NO synthase (NOS). The growing body of evidence strongly supports the theory that this molecule appears to be one of the key targets for the disruption of normal brain homeostasis, which causes the development of brain lesions and pathology such as in Alzheimer's disease (AD) or other related dementia. The vascular content of NO activity appears especially to be a main contributor to this pathology before the over-expression of other NOS isoforms activity in a different brain cellular compartment. We speculate that pharmacological intervention using NO donors and/or NO suppressors will be able to delay or minimize the development of brain pathology and further progression of mental retardation.
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PMID:Is nitric oxide a key target in the pathogenesis of brain lesions during the development of Alzheimer's disease? 1526 72

Recent studies suggest that apart from nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) is another inorganic gaseous mediator in the cardiovascular system. H2S is synthesized from L-cysteine by either cystathionine beta-synthase (CBS) or cystathionin gamma--lyase (CSE), both using pyridoxal 5'-phosphate (vitamin B6) as a cofactor. CBS is the main H2S-producing enzyme in the brain and CSE is involved in H2S formation in the cardiovascular system. H2S induces hypotension in vivo and vasodilation vitro by opening KATP channels in vascular smooth muscle cells. Chronic administration of CSE inhibitor induces arterial hypertension in the rat. In addition, decreased H2S generation has been demonstrated in the vasculature of spontaneously hypertensive rat, in experimental hypertension induced by NO synthase blockade, and in hypoxia-induced pulmonary hypertension, and administration of exogenous H2S donor has significant therapeutic effects in these models. Deficiency of H2S may contribute to atherogenesis in some patients with hyperhomocysteinemia, in whom the metabolism of homocysteine to cysteine and H2S is compromised by vitamin B6 deficiency. Reduced H2S production in the brain was observed in patients with Alzheimer's disease. On the other hand, excess of H2S may lead to mental retardation in patients with Down's syndrome and may be involved in the pathogenesis of hypotension associated with septic shock.
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PMID:[Hydrogen sulfide as a biologically active mediator in the cardiovascular system]. 1528 Jul 98


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