bluuebunny/crossref_metadata_2025_split huggingface dataset:
Animal models for glutaryl‐CoA dehydrogenase deficiency
Authors: Koeller D. M. , Sauer S. , Wajner M. , de Mello C. F. , Goodman S. I. , Woontner M. , Mühlhausen C. , Okun J. G. , KÖlker S. 
Published: October 2004

AbstractSummary:In vitro studies suggest that excitotoxic cell damage is an underlying mechanism for the acute striatal damage in glutaryl‐CoA dehydrogenase (GCDH) deficiency. It is believed to result from an imbalance of glutamatergic and GABAergic neurotransmission induced by the accumulating organic acids 3‐hydroxyglutaric acid (3‐OH‐GA) and to a lesser extent glutaric acid (GA). Stereotaxic administration of 3‐OH‐GA and GA into the rat striatum have confirmed these results, but may not truly represent the effect of chronic exposure to these compounds. In an attempt to better understand the pathophysiology of GCDH deficiency in vivo, two animal models have been utilized. A mouse that lacks GCDH activity in all tissues was generated by gene targeting in embryonic stem cells. These animals develop the characteristic biochemical phenotype of the human disease. Pathologically, these mice have a diffuse spongiform myelinopathy similar to that in human patients; however, there is no evidence for acute striatal damage or sensitivity to acute encephalopathy induced by catabolism or inflammatory cytokines. A naturally occurring animal model, the fruit‐eating bat Rousettus aegypticus, lacks hepatic and renal GCDH activity, but retains cerebral enzyme activity. Like the mouse, these bats develop the characteristic biochemical phenotype of glutaryl‐CoA dehydrogenase deficiency, but lack overt neurological symptoms such as dystonia. It is not known whether they also develop the spongiform myelinopathy seen in the Gcdh‐deficient mice. Otherwise, these constellations would suggest that cerebral GCDH deficiency is responsible for the development of neuronal damage. The lack of striatal damage in these two rodent models may also be related to species differences. However, they also highlight our lack of a comprehensive understanding of additional factors that might modulate the susceptibiliy of neurons to accumulating 3‐OH‐GA and GA in GCDH deficiency. Unravelling these mechanisms may be the key to understanding the pathophysiology of this unique disease and to the development of neuroprotective strategies.
Glutaric aciduria type I and kynurenine pathway metabolites: A modified hypothesis
Authors: Varadkar S. , Surtees R. 
Published: October 2004

AbstractSummary: Glutaric aciduria type I is an inborn error of organic acid metabolism that demonstrates a particular temporal vulnerability (acute encephalopathic episodes in infancy) and a spatial vulnerability (acute striatal necrosis, focused on the putamen). Excitotoxic mechanisms involving 3‐hydroxyglutaric acid as the major neurotoxin have been suggested. This paper proposes a role for metabolites of the kynurenine pathway in the pathogenic process and modifies the hypothesis of Heyes. Deficiency of glutaryl‐CoA dehydrogenase blocking the glutarate pathway and activation of indoleamine 2,3‐dioxygenase in macrophages/monocytes by intercurrent inflammation may increase flux down the kynurenine pathway towards the production of quinolinic acid. Quinolinic acid is neurotoxic and is an endogenous agonist at N‐methyl‐D‐aspartate receptors. Synergistic excitation of these receptors by quinolinic acid and 3‐hydroxyglutaric acid, which alone does not have sufficient potency, may be involved in the pathogenesis of striatal necrosis.
Neonatal screening for glutaryl‐CoA dehydrogenase deficiency
Authors: Lindner M. , KÖlker S. , Schulze A. , Christensen E. , Greenberg C. R. , Hoffmann G. F. 
Published: October 2004

AbstractSummary: Acute encephalopathic crisis in glutaryl‐CoA dehydrogenase deficiency results in an unfavourable disease course and poor outcome, dominated by dystonia, feeding problems, seizures and secondary complications, and quite often leading to early death. The prerequisite for the prevention of irreversible brain damage in this disease is the detection of affected patients and initiation of treatment before the manifestation of such crisis. Apart from macrocephaly there are no signs or symptoms characteristic for this disease in presymptomatic children and, thus, they are usually missed. In some countries, implementation of extended neonatal screening programmes using electrospray ionization tandem mass spectrometry (ESI‐MS/MS) allows detection of affected newborns and start of therapy before onset of neurological complications. This article summarizes recent strategies, pitfalls and shortcomings of a mass screening for glutaryl‐CoA dehydrogenase deficiency using ESI‐MS/MS. Furthermore, an alternative strategy, namely DNA‐based neonatal screening for the Oji‐Cree variant of this disease, is demonstrated. An optimization of diagnostic as well as therapeutic procedures must be achieved before GCDH deficiency unequivocally fullfils the criteria of a reliable and successful newborn screening programme.
Neuroradiological findings in glutaric aciduria type I (glutaryl‐CoA dehydrogenase deficiency)
Authors: Neumaier‐Probst E. , Harting I. , Seitz A. , Ding C. , Kolker S. 
Published: October 2004

AbstractSummary: This article summarizes the magnetic resonance imaging features of glutaric aciduria type I (GA I) based on the cases presented at the 3rd International Workshop on Glutaryl‐CoA Dehydrogenase Deficiency together with a review of previously reported neuroimaging characteristics of GA I. Previous reports have focused on characteristic findings, such as basal ganglia injury and frontotemporal atrophy or hypoplasia, subdural effusions and white‐matter disease. Most of these findings have been demonstrated in symptomatic children, i.e. after manifestation of acute encephalopathic crises. In contrast, prospective investigations in presymptomatically diagnosed children are rare. Since more recent investigations have highlighted CNS changes in patients without encephalopathic crises, systematic prospective investigations of neuroradiological findings in this disease are indispensable for a better understanding of this disease. Based on these findings a suggestion for a MRI protocol is presented, supporting a standardized evaluation of patients with GA I.
Nuclear magnetic resonance spectroscopy in glutaryl‐CoA dehydrogenase deficiency
Authors: Bodamer O. A. , Gruber S. , StÖckler‐Ipsiroglu S. 
Published: October 2004

AbstractSummary: Nuclear magnetic resonance (NMR) spectroscopy is a safe, noninvasive method that is the preferred technique for in vivo analysis of specific chemical compounds in localized brain regions. Besides quantification of compounds, NMR spectroscopy allows the detailed analysis of neurotransmitter, glucose and lactate metabolism following peripheral infusions of stable isotopically labelled precursors. The latter has been successfully applied to patients with different neurological disease states not including glutaryl‐CoA dehydrogenase (GCDH) deficiency. In contrast, single patients with GCDH deficiency who were neurologically unremarkable have been studied with conflicting results. One patient was shown to have an increase in intracerebral creatine and phosphocreatine concentrations, while the second studied had unremarkable levels. In a 15‐year‐old patient, we were able to demonstrate elevated levels of intracerebral lactate and elevated choline/N‐acetylaspartate ratios, indicating potentially increased myelin turnover and reduced neuronal integrity in periventricular white matter. Interestingly, spectra in basal ganglia were within normal limits. Systematic studies to address well‐defined questions in GCDH deficiency are urgently needed. In particular, analysis of in vivo neurotransmitter metabolism following administration of isotopically labelled precursors in patients with GCDH deficiency, both when metabolically stable and when unstable, may help to advance our understanding of the pathophysiology of GCDH deficiency.
Emergency treatment in glutaryl‐CoA dehydrogenase deficiency
Authors: KÖlker S. , Greenberg C. R. , Lindner M. , Müller E. , Naughten E. R. , Hoffmann G. F. 
Published: October 2004

AbstractSummary: The history of glutaryl‐CoA dehydrogenase deficiency is determined by acute encephalopathic crises that are precipitated by common febrile diseases, vaccinations or surgical interventions during infancy and early childhood. Such crises result in an irreversible destruction of the basal ganglia (in particular of the putamina), and consequently dystonia, dyskinesia and choreoathetosis. Secondary complications include feeding and speech problems, failure to thrive, recurrent aspiration, immobilization, severe motor deficits and early death. It is generally accepted that maintenance treatment based on dietary lysine or protein restriction and supplementation with carnitine (and riboflavin) is insufficient to prevent acute crises during intercurrent illnesses or conditions that enhance catabolic state. Consequently, outpatient and inpatient emergency therapies have been implemented. The present review describes a recommended approach to emergency therapy for this disease.
Stability of malonylcarnitine and glutarylcarnitine in stored blood spots
Authors: Johnson D. W. , Trinh> M.‐U. 
Published: October 2004

AbstractSummary: Malonylcarnitine and glutarylcarnitine are important diagnostic metabolites in the screening of dried blood spots by tandem mass spectrometry. The stability of these compounds in spiked blood spots stored at room temperature was studied. Both showed biphasic curves. The malonylcarnitine concentration dropped to 61% in 38 days and averaged 51%±5% for the next 81 days. Glutarylcarnitine dropped to 60% in 42 days and averaged 56%±5% for the next 124 days.
S‐Acetylglutathione normalizes intracellular glutathione content in cultured fibroblasts from patients with glutathione synthetase deficiency
Authors: Okun J. G. , Sauer S. , Bähr S. , Lenhartz H. , Mayatepek E. 
Published: October 2004

AbstractSummary: Glutathione synthetase deficiency is an autosomal recessive inherited metabolic defect in the γ‐glutamyl cycle. Decreased intracellular glutathione levels are one of the characteristic biochemical features. In this study we show that addition of S‐acetylglutathione to the medium raised intracellular glutathione content in cultured fibroblasts from patients with glutathione synthetase deficiency. This has implications for the treatment of patients with this inborn error of metabolism.
Hyperhydroxyprolinaemia detected in newborn screening with tandem mass spectrometry
Authors: Baykal T. , Karaaslan I. , Gokcay G. , Demir F. , Laleli Y. , Demirkol M. 
Published: October 2004

AbstractSummary: Hydroxyproline has the same integer molecular weight as leucine and isoleucine and is quantified with these by tandem mass spectrometry. An infant was diagnosed with hyperhydroxyprolinaemia following further evaluation of an elevated “leucine” level in newborn screening by tandem mass spectrometry.
Two successful pregnancies in pyridoxine‐nonresponsive homocystinuria
Authors: Vilaseca M. A. , Cuartero M. L. , Martinez de Salinas M. , Lambruschini N. , Pintó X. , Urreizti R. , Balcells S. , Grinberg D. 
Published: October 2004

AbstractSummary: Two successful pregnancies are reported in a pyridoxine‐nonresponsive woman who was also homozygous for the MTHFR 677C>T polymorphism. Two healthy children were delivered, although there had also been an early miscarriage of an apparently normal fetus in another pregnancy. Management of the patient's homocystine and methionine levels was maintained throughout pregnancy and, in view of the increased thromoboembolic risk, anticoagulation therapy was also included in the management.
Mutational analysis of carbamoylphosphate synthetase I deficiency in three Japanese patients
Authors: Wakutani Y. , Nakayasu H. , Takeshima T. , Adachi M. , Kawataki M. , Kihira K. , Sawada H. , Bonno M. , Yamamoto H. , Nakashima K. 
Published: October 2004

AbstractSummary: We describe the results of mutational analysis of the carbamoylphosphate synthetase I (CPSI) gene in three nonconsanguineous patients with CPSI deficiency. Compound heterozygotes of 3422T/G (V1141G) plus 3784C/T (R1262X), 1528delG (510‐514 ARQLX) plus 2752T/C (S918P), and 2549G/A (R850H) plus 2797delT (L933X) were identified through genomic analysis; however, the 2797delT (L933X) mutation was not detected in cDNA analysis using biopsied liver, suggesting that mRNA expression from this mutant allele is absent or markedly low.
Purified recombinant human prosaposin forms oligomers that bind procathepsin D and affect its autoactivation
Authors: GOPALAKRISHNAN Madanan Madathiparambil , GROSCH Hans-Wilhelm , LOCATELLI-HOOPS Silvia , WERTH Norbert , SMOLENOVÁ Eva , NETTERSHEIM Michael , SANDHOFF Konrad , HASILIK Andrej 
Published: October 2004

Before delivery to endosomes, portions of proCD (procathepsin D) and proSAP (prosaposin) are assembled into complexes. We demonstrate that such complexes are also present in secretions of cultured cells. To study the formation and properties of the complexes, we purified proCD and proSAP from culture media of Spodoptera frugiperda cells that were infected with baculoviruses bearing the respective cDNAs. The biological activity of proCD was demonstrated by its pH-dependent autoactivation to pseudocathepsin D and that of proSAP was demonstrated by feeding to saposin-deficient cultured cells that corrected the storage of radioactive glycolipids. In gel filtration, proSAP behaved as an oligomer and proCD as a monomer. ProSAP altered the elution of proCD such that the latter was shifted into proSAP-containing fractions. ProSAP did not change the elution of mature cathepsin D. Using surface plasmon resonance and an immobilized biotinylated proCD, binding of proSAP was demonstrated under neutral and weakly acidic conditions. At pH 6.8, specific binding appeared to involve more than one binding site on a proSAP oligomer. The dissociation of the first site was characterized by a KD1 of 5.8±2.9×10−8 M−1 (calculated for the monomer). ProSAP stimulated the autoactivation of proCD and also the activity of pseudocathepsin D. Concomitant with the activation, proSAP behaved as a substrate yielding tri- and disaposins and smaller fragments. Our results demonstrate that proSAP forms oligomers that are capable of binding proCD spontaneously and independent of the mammalian type N-glycosylation but not capable of binding mature cathepsin D. In addition to binding proSAP, proCD behaves as an autoactivable and processing enzyme and its binding partner as an activator and substrate.
Structural organization of mitochondrial human complex I: role of the ND4 and ND5 mitochondria-encoded subunits and interaction with prohibitin
Authors: BOURGES Ingrid , RAMUS Claire , MOUSSON de CAMARET Bénédicte , BEUGNOT Réjane , REMACLE Claire , CARDOL Pierre , HOFHAUS Götz , ISSARTEL Jean-Paul 
Published: October 2004

Mitochondria-encoded ND (NADH dehydrogenase) subunits, as components of the hydrophobic part of complex I, are essential for NADH:ubiquinone oxidoreductase activity. Mutations or lack of expression of these subunits have significant pathogenic consequences in humans. However, the way these events affect complex I assembly is poorly documented. To understand the effects of particular mutations in ND subunits on complex I assembly, we studied four human cell lines: ND4 non-expressing cells, ND5 non-expressing cells, and rho° cells that do not express any ND subunits, in comparison with normal complex I control cells. In control cells, all the seven analysed nuclear-encoded complex I subunits were found to be attached to the mitochondrial inner membrane, except for the 24 kDa subunit, which was nearly equally partitioned between the membranes and the matrix. Absence of a single ND subunit, or even all the seven ND subunits, caused no major changes in the nuclear-encoded complex I subunit content of mitochondria. However, in cells lacking ND4 or ND5, very low amounts of 24 kDa subunit were found associated with the membranes, whereas most of the other nuclear-encoded subunits remained attached. In contrast, membrane association of most of the nuclear subunits was significantly reduced in the absence of all seven ND proteins. Immunopurification detected several subcomplexes. One of these, containing the 23, 30 and 49 kDa subunits, also contained prohibitin. This is the first description of prohibitin interaction with complex I subunits and suggests that this protein might play a role in the assembly or degradation of mitochondrial complex I.
Characterization of a novel low-molecular-mass dual-specificity phosphatase-3 (LDP-3) that enhances activation of JNK and p38
Authors: TAKAGAKI Kentaro , SATOH Takeshi , TANUMA Nobuhiro , MASUDA Kouhei , TAKEKAWA Mutsuhiro , SHIMA Hiroshi , KIKUCHI Kunimi 
Published: October 2004

We have isolated a mouse cDNA for a novel dual-specificity phosphatase designated LDP-3 (low-molecular-mass dual-specificity phosphatase 3). The 450 bp open reading frame encodes a protein of 150 amino acids with a predicted molecular mass of 16 kDa. Northern blot and reverse transcription–PCR analyses show that LDP-3 transcripts are expressed in almost all mouse tissues examined. In vitro analyses using several substrates and inhibitors indicate that LDP-3 possesses intrinsic dual-specificity phosphatase activity. When expressed in mammalian cells, LDP-3 protein is localized mainly to the apical submembrane area. Forced expression of LDP-3 does not alter activation of ERK (extracellular-signal-regulated kinase), but rather enhances activation of JNK (c-Jun N-terminal kinase) and p38 and their respective upstream kinases MKK4 (mitogen-activated protein kinase kinase 4) and MKK6 in cells treated with 0.4 M sorbitol. By screening with a variety of stimuli, we found that LDP-3 specifically enhances the osmotic stress-induced activation of JNK and p38.
Brassica juncea 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase 1: expression and characterization of recombinant wild-type and mutant enzymes
Authors: NAGEGOWDA Dinesh A. , BACH Thomas J. , CHYE Mee-Len 
Published: October 2004

3-Hydroxy-3-methylglutaryl (HMG)-CoA synthase (HMGS; EC 2.3.3.10) is the second enzyme in the cytoplasmic mevalonate pathway of isoprenoid biosynthesis, and catalyses the condensation of acetyl-CoA with acetoacetyl-CoA (AcAc-CoA) to yield S-HMG-CoA. In this study, we have first characterized in detail a plant HMGS, Brassica juncea HMGS1 (BjHMGS1), as a His6-tagged protein from Escherichia coli. Native gel electrophoresis analysis showed that the enzyme behaves as a homodimer with a calculated mass of 105.8 kDa. It is activated by 5 mM dithioerythreitol and is inhibited by F-244 which is specific for HMGS enzymes. It has a pH optimum of 8.5 and a temperature optimum of 35 °C, with an energy of activation of 62.5 J·mol−1. Unlike cytosolic HMGS from chicken and cockroach, cations like Mg2+, Mn2+, Zn2+ and Co2+ did not stimulate His6–BjHMGS1 activity in vitro; instead all except Mg2+ were inhibitory. His6–BjHMGS1 has an apparent Km-acetyl-CoA of 43 μM and a Vmax of 0.47 μmol·mg−1·min−1, and was inhibited by one of the substrates (AcAc-CoA) and by both products (HMG-CoA and HS-CoA). Site-directed mutagenesis of conserved amino acid residues in BjHMGS1 revealed that substitutions R157A, H188N and C212S resulted in a decreased Vmax, indicating some involvement of these residues in catalytic capacity. Unlike His6–BjHMGS1 and its soluble purified mutant derivatives, the H188N mutant did not display substrate inhibition by AcAc-CoA. Substitution S359A resulted in a 10-fold increased specific activity. Based on these kinetic analyses, we generated a novel double mutation H188N/S359A, which resulted in a 10-fold increased specific activity, but still lacking inhibition by AcAc-CoA, strongly suggesting that His-188 is involved in conferring substrate inhibition on His6–BjHMGS1. Substitution of an aminoacyl residue resulting in loss of substrate inhibition has never been previously reported for any HMGS.
The 161TT genotype in the exon 6 of the peroxisome-proliferator-activated receptor γ gene is associated with premature acute myocardial infarction and increased lipid peroxidation in habitual heavy smokers
Authors: CHAO Ting-Hsing , LI Yi-Heng , CHEN Jyh-Hong , WU Hua-Lin , SHI Guey-Yueh , LIU Ping-Yen , TSAI Wei-Chuan , GUO How-Ran 
Published: October 2004

PPAR (peroxisome-proliferator-activated receptor) is a nuclear receptor. Activation of PPARγ by its ligands could modulate gene transcription, thereby leading to multiple anti-atherogenic and fibrinolytic effects. However, the association between the 161T allele in exon 6 of the PPARγ gene and premature AMI (acute myocardial infarction) is not clear. We recruited 146 patients with premature AMI (onset age ≤50 years) and 146 controls. The C161T polymorphism was examined using PCR and restriction-fragment-length polymorphism. Plasma levels of Ab-ox-LDL (antibody against oxidized low-density lipoprotein) were measured in 27 male smokers, whose genotypes have been identified. The frequency of the PPARγ TT genotype among patients with AMI was significantly higher than that in controls [13% compared with 5.5%; OR (95% CI) 2.7, (1.1–6.5), where OR and CI are odds ratio and confidence interval respectively]. This association was not observed in CC or CT genotypes. Using multivariate logistic regression analyses, we found that the homozygous TT genotype [OR (95% CI), 3.1 (1.2–7.9)], smoking [OR (95% CI), 3.5, (2.1–6.0)], hypertension [OR (95% CI), 3.6, (1.9–6.9)] and diabetes mellitus [OR (95% CI), 3.5 (1.5–8.4)] were independent risk factors for premature AMI. Plasma levels of Ab-ox-LDL were significantly higher in healthy volunteers with the TT genotype compared with those with the CC genotype (49.3±18.1 compared with 24.2±15.2 units/l respectively; P=0.02). Therefore in our study we observed an association between the PPARγ 161 TT genotype and premature AMI. Lipid peroxidation was significantly influenced by the 161T allele.
Lack of association of a 9 bp insertion/deletion polymorphism within the bradykinin 2 receptor gene with myocardial infarction
Authors: FISCHER Marcus , LIEB Wolfgang , MAROLD Daniel , BERTHOLD Matthias , BAESSLER Andrea , LOWEL Hannelore , HENSE Hans-Werner , HENGSTENBERG Christian , HOLMER Stephan , SCHUNKERT Heribert , ERDMANN Jeanette 
Published: October 2004

The BK (bradykinin) B2 receptor is the major cellular mediator of the effects of BK. A 9 bp deletion in the promoter of the receptor gene represents an allelic variant that is associated with enhanced mRNA expression levels. We tested whether this polymorphism is associated with the prevalence of MI (myocardial infarction) or with echocardiographically determined left ventricular function in post-MI patients. Patients with documented MI (n=484), matched controls and controls without evidence of coronary heart disease (n=1363) constituted cases and controls. MI patients and controls were carefully matched for age, gender and cardiovascular risk factors. Genotype distributions of the 9 bp insertion/deletion polymorphism were similar across the groups: −9/−9, −9/+9 and +9/+9 were 22.1, 49.5 and 28.5% in MI patients, and 23.0, 44.6 and 32.5% in matched control subjects respectively. The lack of association was also observed in selected subgroups, stratified by age, gender and cardiovascular risk factors. Furthermore, there was no relation between this polymorphism and left ventricular systolic function in post-MI patients. These findings indicate that the 9 bp insertion/deletion polymorphism of the BK B2 receptor gene is neither related to the prevalence of MI nor to left ventricular function after MI.