Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a patient with mitochondrial encephalomyopathy presenting parkinsonism, as well as her brother who had ataxia but not parkinsonism. Both patients had myopathy, deafness, and insulin-dependent diabetes mellitus. The proband was a 55-year-old woman, who has developed progressive difficulty in walking and slowness of movement since 53 years of age, becoming bed-ridden at 55. Neurological examination revealed mental impairment, a masked face, Myerson's sign, vertical supranuclear ophthalmoplegia, and severe sensorineural deafness, hypokinesia, rigidospasticity, and weakness of the extremities. But tremor and cerebellar ataxia were absent. Her 48-year-old brother gradually developed weakness of the lower extremities and drunken gait over a few years. On neurologic examination, vertical supranuclear ophthalmoplegia, moderate sensorineural deafness, and cerebellar ataxia were present, but parkinsonism was absent. Three other siblings were reported to have died in early childhood. Cranial MR imaging showed cerebral atrophy and mild atrophy of the cerebellar vermis as well as mild periventricular hyperintensities in T2-weighted images in both patients. However, no infarcts were seen. Laboratory investigations revealed slightly elevated lactate and pyruvate levels in the proband and elevation of pyruvate in her brother. A biopsy specimen obtained from the quadriceps muscle showed ragged-red fibers with modified Gomori trichrome staining, and a decrease of complex I+III and complex II+III activity in the proband. Mitochondrial DNA (mtDNA) analysis using the polymerase chain reaction and restriction enzyme Apa I showed a point mutation in the tRNA(Leu)(UUR)) gene (an A to G transition at nucleotide 3243) in both patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Mitochondrial encephalomyopathy associated with parkinsonism and a point mutation in the mitochondrial tRNA(Leu)(UUR)) gene]. 802 31

The concentrations of amino acids in the cerebrospinal fluid (CSF) (n = 20) and serum (n = 20) taken from patients with essential tremor were measured by HPLC and compared with those of controls (n = 10). Reduced concentrations of some amino acids (asparagine, glutamine, glycine, threonine, isoleucine, leucine) were observed in serum taken from patients with tremor. Significant increases were detected in the concentrations of glutamate (p < 0.001) and aspartate (p < 0.01). The general tendency of the changes in CSF and serum was similar; although the highest differences were observed in amino acid concentrations in the serum of patients with essential tremor. Opposite shifts of some amino acids were detected, in the concentrations of aspartate, serine, tyrosine, leucine, and isoleucine, which may indicate the independence of the changes in the serum from those in the CSF. This study raises the possibility that a genetically determined metabolic disorder is involved in the etiology of essential tremor that appears peripherally and, partly, centrally. The slight increase in the concentration of glutamate together with the reduced levels of GABA, glycine, and serine in CSF may form the neurochemical basis of the central oscillation observed in essential tremor.
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PMID:Change in the concentrations of amino acids in CSF and serum of patients with essential tremor. 881 1

Cucurbita maxima trypsin inhibitor I (CMTI-I), a member of the squash-type protease inhibitor family, is composed of 29 amino acids and shows strong inhibition of trypsin by its compact structure. To study the structure-function relationship of this inhibitor using protein engineering methods, we constructed an expression system for CMTI-I as a fused protein with porcine adenylate kinase (ADK). A Met residue was introduced into the junction of ADK and CMTI-I to cleave the fusion protein with CNBr, whereas a Met at position 8 of authentic CMTI-I was replaced by Leu. Escherichia coli JM109 transformed with the constructed plasmid expressed the fused protein as an inclusion body. After cleavage of the expressed protein with CNBr, fully reduced species of CMTI-I were purified by reversed-phase HPLC and then oxidized with air by shaking. For efficient refolding of CMTI-I, we used 50 mM NH4HCO3 (pH 7.8) containing 0.1% PEG 6000 at higher protein concentration. Strong inhibitory activity toward trypsin was detected only in the first of three HPLC peaks. The inhibitor constant of CMTI-I thus obtained, in which Met8 was replaced by Leu, was 1.4 x 10(-10) M. The effect of replacement of Met with Leu at position 8 was shown to be small by comparison of the inhibitor constant of authentic CMTI-III bearing Lys at position 9 (8.9 x 10(-11) M) with that of its mutant bearing Leu at position 8 and Lys at position 9 (1.8 x 10(-10) M). To investigate the role of the well conserved hydrophobic residues of CMTI-I in its interaction with trypsin, CMTI-I mutants in which one or all of the four hydrophobic residues were replaced by Ala were prepared. The inhibitor constants of these mutants indicated that those with single replacements were 5-40 times less effective as trypsin inhibitors and that the quadruple mutant was approximately 450 times less effective, suggesting that the hydrophobic residues in CMTI-I contribute to its tight binding with trypsin. However, each mutant was not converted to a temporary inhibitor.
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PMID:Synthesis of a squash-type protease inhibitor by gene engineering and effects of replacements of conserved hydrophobic amino acid residues on its inhibitory activity. 901 Sep 39

The primary objective of this study was to characterize an in-vitro model of the human placenta using morphological, biochemical and physiological parameters. Placental villi were obtained from normal first trimester and term pregnancies. The villi were incubated with Dulbecco's modified Eagle's medium: Ham's F12 nutrient mixture in a shaking water bath at 37 degrees C for up to 310 min. The viability was determined by the production of beta human chorionic gonadotrophin (HCG) and lactic dehydrogenase (LDH) and the incorporation of [3H]thymidine, [3H]L-leucine and L-[U14C]arginine, while ultrastructure was assessed by transmission electron microscopy. In the first and third trimester group, the release into the medium of the intracellular enzyme LDH remained unaltered throughout the experiment. By contrast, beta-HCG concentrations increased linearly and concentrations were higher in the first trimester than term villi (354.5 +/- 37.8 versus 107 +/- 8.1 IU/g villi protein; P < 0.001). Electron microscopy confirmed preservation of tissue viability for up to 4 h of incubation. The incorporation of thymidine (12.2 +/- 2.9 versus 5.2 +/- 0.5 nmol/g villi protein; P < 0.05), leucine (9.4 +/- 2.1 versus 1.9 +/- 0.4 nmol/g villi protein; P < 0.02) and arginine (17 +/- 4.4 versus 4.2 +/- 0.5 nmol/g villi protein; P < 0.05) were markedly higher in early than in term placenta. Furthermore, placental uptake of L-leucine by the first (9.4 +/- 2.1 versus 17 + 4.4 mol/g villi protein; P < 0.001) and third trimester placental villi (1.9 +/- 0.4 versus 4.2 + 0.5 mol/g villi protein; P < 0.001) was less than that of L-arginine. This study describes a simple technique using placental explants to determine relative rates of uptake of substrate amino acids throughout gestation.
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PMID:Characterization of human placental explants: morphological, biochemical and physiological studies using first and third trimester placenta. 1010 6

The metabolism of leucine by resting cells of Staphylococcus carnosus 833 was studied according to three physicochemical factors: preculture condition (defined medium; complex medium), nitrate concentration (0% and 0.03%) and stirring condition (static or shaking). A factorial design was set up to test the effects of these factors, each at two levels. The results showed that resting cells of S. carnosus 833 produced 3-methyl butanal, 3-methyl butanol and 3-methyl butanoic acid from leucine. Whatever the incubation conditions, there was greater quantity of 3-methyl butanoic acid than 3-methyl butanal and 3-methyl butanol. The preculture and incubation conditions influenced the level of production of the 3 metabolites. The highest overall production of the 3 metabolites was observed when cells were incubated without nitrate in the reaction mixture. 3-methylbutanoic acid production was enhanced when S. carnosus 833 was precultivated in complex medium. 3-methylbutanal was only detected when cells were precultivated in defined medium. Stirring condition had no effect on leucine catabolism of S. carnosus 833.
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PMID:Factors influencing leucine catabolism by a strain of Staphylococcus carnosus. 1049 Feb 28

We report three members of a family, who exhibited a phenotype similar to 'myoclonus epilepsy with ragged-red fibers' but had a genotype usually associated with 'mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes'. The patients, a 48-year-old female, and her two sons, aged 21 and 19 respectively, presented with photo-reactive syncopal episodes, disturbances of gait and writing, dysarthria and finger tremor since the 3rd and 2nd decade of life, respectively, that were accompanied also by numbness and weakness of the extremities. Subsequently, cerebellar ataxia and myoclonus were also noted. Electromyography revealed both myogenic and neurogenic muscular changes, and nerve conduction studies demonstrated a sensory-motor neuropathy. Biopsy showed ragged-red fibers with strongly stained SDH-positive vessels in skeletal muscles, and a marked loss of myelinated fibers of the sural nerves. Mitochondrial (mt) DNA analyses of peripheral blood, muscles and nerves revealed that all members had a heteroplasmic np3271 (T-C) point mutation in the mitochondrial tRNA-Leu gene (UUR). This family is unique, in that all patients presented with a myoclonus epilepsy with ragged-red fibers-like phenotype and had a distinctive peripheral neuropathy, while the detected mtDNA 327l (T-C) mutation has been reported to date only in rare cases of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes
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PMID:A mitochondrial encephalo-myo-neuropathy with a nucleotide position 3271 (T-C) point mutation in the mitochondrial DNA. 1140 19

The metabolites from leucine degradation are involved in dry fermented sausage aroma. The catabolism of leucine by a strain of Carnobacterium piscicola was studied directly in the growth medium with 3H-labelled leucine to investigate the effect of five parameters: phase of growth, pH, oxygen, glucose and alpha-ketoisocaproic acid. Resting cells (RC) were also incubated with 3H-labelled leucine. The radioactive metabolites from leucine catabolism were analysed by high performance liquid chromatography (HPLC). At pH 5.4 and 7.2, the main metabolites detected were 3-methyl butanal, 3-methyl butanol and alpha-ketoisocaproic acid. At pH 6.5, the leucine catabolism was maximum and was characterised by a high production of 3-methyl butanoic acid. Leucine catabolism was most important during the exponential phase of growth. The addition of alpha-ketoisocaproic acid at 1%, glucose at levels of 0.5% to 2% and shaking of the growth medium increased leucine catabolism.
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PMID:Effects of environmental factors on leucine catabolism by Carnobacterium piscicola. 1248 43

Interleukin-1 beta (IL-1 beta) is synthesized in the brain in response to LPS. Excessive IL-1 beta expression is observed in neurodegenerative diseases. The aim of this study was to evaluate the effects of methionine-enkephalin (ME) and leucine-enkephalin (LE) on the baseline and LPS-activated release of IL-1 beta in rat mixed glia cultures. ME and LE increased LPS-induced IL-1 beta release, which was not blocked by naloxone. Both ME and LE increased the baseline release of IL-1 beta, which was completely blocked by naloxone pretreatment. Mixed glia cultures deprived of microglia (by shaking and incubating with L-leucine methyl ester) did not release IL-1 beta, which indicates microglia as a source of the changes in IL-1 beta release. The results of the study suggest that neurons may regulate glial activity through releasing enkephalins.
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PMID:Methionine-enkephalin and leucine-enkephalin increase interleukin-1 beta release in mixed glia cultures. 1250 34

Human hereditary hyperekplexia ("startle disease") is a neurological disorder characterized by exaggerated, convulsive movements in response to unexpected stimuli. Molecular genetic studies have shown that this disease is often caused by amino acid substitutions at arginine 271 to glutamine or leucine of the alpha1 subunit of the inhibitory glycine receptor (GlyR). When exogenously expressed in Xenopus oocytes, agonist responses of mutant alpha1(R271Q) and alpha1(R271L) GlyRs show higher EC50 values and lower maximal inducible responses (relative efficacies) compared with oocytes expressing wild-type alpha1 GlyR subunits. Here, we report that the maximal glycine-induced currents (I(max)) of mutant alpha1(R271Q) and alpha1(R271L) GlyRs were dramatically potentiated in the presence of the anesthetic propofol (PRO), whereas the I(max) of wild-type alpha(1) receptors was not affected. Quantitative analysis of the agonist responses of the isofunctionally substituted alpha1(R271K) mutant GlyR revealed that saturating concentrations of PRO decreased the EC50 values of both glycine and the partial agonist beta-alanine by >10-fold, with relative efficacies increasing by 4- and 16-fold, respectively. Transgenic (tg) mice carrying the alpha1(R271Q) mutation (tg271Q-300) have both spontaneous and induced tremor episodes that closely resemble the movements of startled hyperekplexic patients. After treatment with subanesthetic doses of PRO, the tg271Q-300 mutant mice showed temporary reflexive and locomotor improvements that made them indistinguishable from wild-type mice. Together, these results demonstrate that the functional and behavioral effects of hyperekplexia mutations can be effectively reversed by drugs that potentiate GlyR responses.
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PMID:Propofol restores the function of "hyperekplexic" mutant glycine receptors in Xenopus oocytes and mice. 1499 83

Environmental toxins have been implicated in the etiology of Parkinson's disease. Recent findings of defects in the ubiquitin-proteasome system in hereditary and sporadic forms of the illness suggest that environmental proteasome inhibitors are candidate PD-inducing toxins. Here, we systemically injected six doses of naturally occurring (epoxomicin) or synthetic (Z-lle-Glu(OtBu)-Ala-Leu-al [PSI]) proteasome inhibitors into adult rats over a period of 2 weeks. After a latency of 1 to 2 weeks, animals developed progressive parkinsonism with bradykinesia, rigidity, tremor, and an abnormal posture, which improved with apomorphine treatment. Positron emission tomography demonstrated reduced carbon-11-labeled 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT) binding to dopaminergic nerve terminals in the striatum, indicative of degeneration of the nigrostriatal pathway. Postmortem analyses showed striatal dopamine depletion and dopaminergic cell death with apoptosis and inflammation in the substantia nigra pars compacta. In addition, neurodegeneration occurred in the locus coeruleus, dorsal motor nucleus of the vagus, and the nucleus basalis of Meynert. At neurodegenerative sites, intracytoplasmic, eosinophilic, alpha-synuclein/ubiquitin-containing, inclusions resembling Lewy bodies were present in some of the remaining neurons. This animal model induced by proteasome inhibitors closely recapitulates key features of PD and may be valuable in studying etiopathogenic mechanisms and putative neuroprotective therapies for the illness.
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PMID:Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease. 1686 91


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