Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pre-weaning rat pups emit ultrasonic vocalizations when removed from the litter. These 'separation-induced vocalizations' (SIV) are suppressed by classical benzodiazepine anxiolytics and by non-benzodiazepine anxiolytics which lack muscle relaxant and sedative properties. The present study used the SIV model to assess potential anxiolytic properties of compounds which target different sites associated with the NMDA receptor complex. Comparison was made to drugs which affect benzodiazepine or serotonin (5-HT) receptors. Muscle relaxant potential was assessed using 'TIP' (time on an inclined plane), the amount of time a pup was able to retain its position on a steeply inclined surface. Mephenesin, a centrally acting muscle relaxant, significantly suppressed TIP but not SIV. The benzodiazepine agonist diazepam suppressed both SIV and TIP, whereas the 5-HT1A partial agonists, buspirone and MDL 73,005EF, suppressed SIV without affecting TIP. The 5-HT2 antagonist MDL 11,939 suppressed TIP but not SIV, whereas neither measure was affected by the 5-HT3 antagonist MDL 73,147EF. SIV was suppressed by NMDA antagonists including those acting at the glutamate recognition site (D,L-amino-phosphonovaleric acid (AP5) and MDL 100,453) or at the ion channel (MK-801), or by the strychnine-insensitive glycine antagonist 5,7-dichlorokynurenic acid (5,7-DCKA). TIP was suppressed even more potently by AP5, MDL 100,453 and MK-801, whereas 5,7-DCKA was inactive on this measure. Thus, antagonists acting at different sites present on the glutamate recognition site exhibit potential anxiolytic activity, but the glycine antagonist was unusual in its lack of prominent muscle relaxant side effects.
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PMID:NMDA receptor complex antagonists have potential anxiolytic effects as measured with separation-induced ultrasonic vocalizations. 167 93

We observed a deficiency of both the mitochondrial and cytosolic forms of fumarase in a male infant with mitochondrial encephalomyopathy who presented at one month of age with failure to thrive, developmental delay, hypotonia, cerebral atrophy, lactic and pyruvic acidemia, and fumaric aciduria. The patient died at eight months of age. Isolated skeletal-muscle mitochondria showed selective defects in the oxidation of glutamate (31 ng atoms of oxygen consumed per minute per milligram of mitochondrial protein, as compared with 94 +/- 19 [mean +/- SD] in five controls) and of succinate (18 vs. 145 +/- 18 ng atoms of oxygen per minute per milligram of protein), whereas isolated liver mitochondria oxidized these and other substrates normally. Fumarase activity was virtually absent in both liver mitochondria (53 vs. 2878 +/- 248 nmol per minute per milligram of protein [5 controls]) and skeletal-muscle mitochondria (23 vs. 1997 +/- 717 nmol per minute per milligram [12 controls]). Seventeen other mitochondrial enzymes had normal activity in both liver and muscle mitochondrial extracts. Fumarase activity was also significantly reduced in homogenates of liver tissue (less than 1 vs. 90 +/- 25 mumol per minute per gram of wet weight [five controls]) and skeletal muscle (less than 1 vs. 21 +/- 4 mumol per minute per gram [five controls]), indicating a deficiency of both mitochondrial and cytosolic fumarases. Organ differences in intramitochondrial accumulation of fumarate may have accounted for the selective oxidative defects observed in the skeletal-muscle mitochondria but not liver mitochondria. All these findings are consistent with a profound combined fumarase deficiency.
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PMID:Fumarase deficiency: a new cause of mitochondrial encephalomyopathy. 373 29

Two new familial cases of 2-ketoglutarate dehydrogenase (2-KGD) deficiency are reported: a girl who died at 10 years and a boy, still alive at 4 years, born to consanguineous parents. The cases developed progressively severe encephalopathy with axial hypotonia, psychotic behaviour, pyramidal symptoms and failure to thrive. Both children exhibited permanent lactic acidosis with acute episodes during emotional stress and various infections, associated with elevated lactate/pyruvate (L/P) ratio and slightly decreased ketone body ratio in plasma. In fibroblasts, the L/P ratio was greatly increased in the boy. No respiratory chain complex deficiency could be demonstrated in cultured fibroblasts or in mitochondria isolated from a muscle biopsy performed on the boy. In muscle isolated mitochondria, a progressive decrease of the rate of glutamate oxidation was observed after ADP addition; the rate of 2-ketoglutarate oxidation was low in the absence of ADP and did not increase after ADP addition. 2-KGD deficiency was demonstrated in fibroblasts from both children and in the boy's muscle and myoblasts. The 2-KGD complex is composed of three separate enzymes: E1, E2 and E3. We could demonstrate in our patient that the E1 and E3 subunits were normal, suggesting that the E2 component could be responsible for the defect.
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PMID:2-Ketoglutarate dehydrogenase deficiency, a rare cause of primary hyperlactataemia: report of a new case. 829 96

Three patients with propionic acidemia were studied. The first patient was diagnosed at the age of 9 mo, 3 mo after he developed hypotonia and choreoathetoid movements after an upper respiratory tract infection. The second patient was diagnosed at the age of 1.5 mo when she became comatose after nasogastric tube feeding because of failure to thrive. The third patient was diagnosed at the age of 5 d when she presented with feeding difficulties, hypotonia, and respiratory insufficiency. Magnetic resonance imaging (MRI) of the brain in all patients revealed delayed myelination and some cerebral atrophy. In the patient with choreoathetosis, MRI showed bilateral abnormalities in the signal intensity of the putamen and caudate nuclei. MRI of the other two patients showed normal basal ganglia. Proton magnetic resonance spectroscopy (1H MRS) from a voxel located in the basal ganglia revealed a decrease in N-acetylaspartate and myo-inositol peaks and an elevation of glutamine/ glutamate. The presence of spectroscopic abnormalities in a stable metabolic condition, in particular the rise in glutamine/ glutamate, indicates that the metabolic balance on cerebral parenchymal level is less optimal than estimated from biochemical analysis of urine, plasma, or cerebrospinal fluid.
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PMID:Magnetic resonance imaging and spectroscopy of the brain in propionic acidemia: clinical and biochemical considerations. 886 76

Hypoxia-ischemia damages selected regions of the immature at different ages. Prior to 32 weeks gestation the periventricular white matter is selectively vulnerable but in the last trimester the basal ganglia become especially vulnerable to injury. Hypoxia-ischemia causes injury by activating a series of biochemical events that unfolds over a period of hours to days following the initial insult and we are investigating the ways in which age modifies these events. The cascade includes release of glutamate, overstimulation of excitatory amino acid receptors and raised intracellular levels of calcium. Clinically this series is manifested by hypoxic-ischemic encephalopathy (HIE), a syndrome that includes coma, seizures, a burst suppression EEG, respiratory depression and severe hypotonia. Clinical studies have established a relationship between the severity of neonatal encephalopathy and later manifestations of brain damage or cerebral palsy. Potential neuroprotective therapies need to be effective when given after the insult but the 'therapeutic time window' for most N-methyl-D-aspartate (NMDA) glutamate antagonists is limited after injury. Using a model of hypoxic-ischemic injury and neonatal rats and hypothermic-circulatory arrest in dogs, we found that immunohistochemical staining for neuronal nitric oxide synthase (nNOS) is markedly increased from 6 to 24 h after the insult in the basal ganglia and cortex. The induction of nNOS preceded the time of maximal neuronal necrosis and during the time when many apoptotic nuclei were appearing. We have also found that a brief period of 2 h of mild hypothermia (32 degrees C) following hypoxia-ischemia in neonatal rats delayed neuronal necrosis by more than a week. We are determining whether this delay is related to a change in nNOS activation. Induction of nNOS in the post-insult period may contribute to expression of injury and signs of encephalopathy following a hypoxic-ischemic insult.
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PMID:Hypoxic and ischemic disorders of infants and children. Lecture for 38th meeting of Japanese Society of Child Neurology, Tokyo, Japan, July 1996. 918 71

Serotonergic neurons decrease their activity during sleep, especially rapid eye movement sleep, thereby reducing their facilitatory effect on upper airway motoneurons. The magnitude of teh sleep-related loss of tone varies among upper airway muscles (e.g., pharyngeal dilator motoneurons are more suppressed than laryngeal motoneurons). We hypothesized that these differences may be related to the sensitivity of different groups of upper airway motoneurons to serotonin. Experiments were done on decerebrate, vagotomized, paralysed and artificially-ventilated cats. Hypoglossal and laryngeal motoneurons were recorded extracellularly using five-barrel pipettes filled with: serotonin, glutamate and methysergide (serotonergic antagonist) for iontophoresis, and NaCl for recording and current balancing. All but two of the 65 hypoglossal motoneurons (45 inspiratory, 10 expiratory, 10 tonic) and 27 out of 32 laryngeal motoneurons (14 inspiratory, 18 expiratory) were excited by serotonin, and the excitation was abolished by methysergide. To compare the magnitude of the excitatory effect among distinct motoneuronal groups, we applied small ejection currents in a standardized manner (+15 nA for 3 min; 10 mM serotonin in 150 NaCl) onto spontaneously active motoneurons (13 inspiratory hypoglossal, 11 inspiratory laryngeal and 11 expiratory laryngeal). Serotonin increased the number of spikes per respiratory burst of inspiratory hypoglossal motoneurons from 19 +/- 4.0 (S.E.M.) to 35 +/- 4.8, of inspiratory laryngeal motoneurons from 44 +/- 8.3 to 55 +/- 8.8, and of expiratory laryngeal motoneurons from 23 +/- 4.8 to 33 +/- 6.2. The relative increases in activity (to 220% +/- 24, 147% +/- 23 and 148% +/- 9 of control, respectively) were significantly higher in hypoglossal than in laryngeal motoneurons. In addition, the excitatory effect developed significantly faster in hypoglossal than in laryngeal motoneurons. Methysergide reduced the spontaneous activity of about half the hypoglossal and laryngeal motoneurons to 66% +/- 5 of control. Thus, the sensitivity to the excitatory effects of serotonin varies among different pools of upper airway motoneurons. These differences correlate with the pattern of airway muscle hypotonia seen during sleep.
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PMID:Differential sensitivity of laryngeal and pharyngeal motoneurons to iontophoretic application of serotonin. 931 35

Ornithine Transcarbamylase (OTC) is a key urea cycle enzyme. Congenital OTC deficiencies in humans result in hyperammonemia and a spectrum of neurological symptoms including hypotonia, seizures and mental retardation. Neuropathologic evaluation reveals cerebral atrophy, ventricular enlargement and Alzheimer type II astrocytosis. Using an animal model of congenital OTC deficiency, the sparse fur (spf) mouse, recent studies have revealed significant alterations of cholinergic, serotoninergic and glutamatergic neurotransmitter systems. Possible pathophysiologic mechanisms responsible for neuronal cell loss in OTC deficiency include a deficit in cerebral energy metabolism, and glutamate excitotoxicity. Therapy continues to rely on alternative substrate administration including sodium benzoate and sodium phenylacetate. Experimental evidence suggests that acetyl-L-carnitine and glutamate (NMDA) receptor antagonists could be potentially useful therapeutic agents. Liver transplantation is effective in many patients and recent experimental studies using adenoviral vectors suggest that gene therapy may ultimately be useful in the treatment of congenital OTC deficiency.
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PMID:Ornithine transcarbamylase deficiency: pathogenesis of the cerebral disorder and new prospects for therapy. 934 66

The RSH/Smith--Lemli--Opitz syndrome (RSH/SLOS) is a human autosomal recessive syndrome characterized by multiple malformations, a distinct behavioral phenotype with autistic features and mental retardation. RSH/SLOS is due to an inborn error of cholesterol biosynthesis caused by mutation of the 3 beta-hydroxysterol Delta(7)-reductase gene. To further our understanding of the developmental and neurological processes that underlie the pathophysiology of this disorder, we have developed a mouse model of RSH/SLOS by disruption of the 3 beta-hydroxysterol Delta(7)-reductase gene. Here we provide the biochemical, phenotypic and neurophysiological characterization of this genetic mouse model. As in human patients, the RSH/SLOS mouse has a marked reduction of serum and tissue cholesterol levels and a marked increase of serum and tissue 7-dehydrocholesterol levels. Phenotypic similarities between this mouse model and the human syndrome include intra-uterine growth retardation, variable craniofacial anomalies including cleft palate, poor feeding with an uncoordinated suck, hypotonia and decreased movement. Neurophysiological studies showed that although the response of frontal cortex neurons to the neurotransmitter gamma-amino-n-butyric acid was normal, the response of these same neurons to glutamate was significantly impaired. This finding provides insight into potential mechanisms underlying the neurological dysfunction seen in this human mental retardation syndrome and suggests that this mouse model will allow the testing of potential therapeutic interventions.
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PMID:Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith--Lemli--Opitz syndrome. 1123 Jan 74

The inherited neurometabolic disease d-2-hydroxyglutaric aciduria is complicated by progressive neurodegeneration of vulnerable brain regions during infancy and early childhood, frequently presenting with hypotonia, epilepsy and psychomotor retardation. Here, we report that the pathogenetic role of the endogenously accumulating metabolite d-2-hydroxyglutarate (D-2), which is structurally similar to the excitatory amino acid glutamate, is mediated by at least three mechanisms. (i) D-2-induced excitotoxic cell damage in primary neuronal cultures from chick and rat involved N-methyl-d-aspartate (NMDA) receptor activation. Indeed, D-2 activated recombinant NMDA receptors (NR1/NR2A, NR1/NR2B) but not recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptors in HEK293 cells. (ii) Fluorescence microscopy using fura-2 as a calcium indicator and the oxidant-sensitive dye dihydrorhodamine-123 revealed that D-2 disturbed intracellular calcium homeostasis and elicited the generation of reactive oxygen species. (iii) D-2 reduced complex V (ATP synthase) activity of the mitochondrial respiratory chain, reflecting an impaired energy metabolism due to inhibition of ATP synthesis but without affecting the electron-transferring complexes I-IV. Thus, D-2 stimulates neurodegeneration by mechanisms well-known for glutamate, NMDA or mitochondrial toxins. In conclusion, excitotoxicity contributes to the neuropathology of d-2-hydroxyglutaric aciduria, highlighting new neuroprotective strategies.
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PMID:NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria. 1215 28

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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