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102. A non-enzymatic function of 17β-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival

Author

Rauschenberger, Katharina, Schöler, Katja, Sass, Jörn Oliver, Sauer, Sven, Djuric, Zdenka, Rumig, Cordula, Wolf, Nicole I., Okun, Jürgen G., Kölker, Stefan, Schwarz, Heinz, Fischer, Christine, Grziwa, Beate, Runz, Heiko, Nümann, Astrid, Shafqat, Naeem, Kavanagh, Kathryn L., Hämmerling, Günter, Wanders, Ronald J. A., Shield, Julian P. H., Wendel, Udo, Stern, David, Nawroth, Peter, Hoffmann, Georg F., Bartram, Claus R., Arnold, Bernd, Bierhaus, Angelika, Oppermann, Udo, Steinbeisser, Herbert, and Zschocke, Johannes

Published
2010
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105. 1H-NMR-based metabolic profiling identifies non-invasive diagnostic and predictive urinary fingerprints in 5q spinal muscular atrophy.

Author

Saffari, Afshin, Cannet, Claire, Blaschek, Astrid, Hahn, Andreas, Hoffmann, Georg F., Johannsen, Jessika, Kirsten, Romy, Kockaya, Musa, Kölker, Stefan, Müller-Felber, Wolfgang, Roos, Andreas, Schäfer, Hartmut, Schara, Ulrike, Spraul, Manfred, Trefz, Friedrich K., Vill, Katharina, Wick, Wolfgang, Weiler, Markus, Okun, Jürgen G., and Ziegler, Andreas

Subjects
SPINAL muscular atrophy, DUCHENNE muscular dystrophy, NEUROMUSCULAR diseases, NEWBORN screening, GENETIC testing, URINE
Abstract

Background: 5q spinal muscular atrophy (SMA) is a disabling and life-limiting neuromuscular disease. In recent years, novel therapies have shown to improve clinical outcomes. Yet, the absence of reliable biomarkers renders clinical assessment and prognosis of possibly already affected newborns with a positive newborn screening result for SMA imprecise and difficult. Therapeutic decisions and stratification of individualized therapies remain challenging, especially in symptomatic children. The aim of this proof-of-concept and feasibility study was to explore the value of 1H-nuclear magnetic resonance (NMR)-based metabolic profiling in identifying non-invasive diagnostic and prognostic urinary fingerprints in children and adolescents with SMA.Results: Urine samples were collected from 29 treatment-naïve SMA patients (5 pre-symptomatic, 9 SMA 1, 8 SMA 2, 7 SMA 3), 18 patients with Duchenne muscular dystrophy (DMD) and 444 healthy controls. Using machine-learning algorithms, we propose a set of prediction models built on urinary fingerprints that showed potential diagnostic value in discriminating SMA patients from controls and DMD, as well as predictive properties in separating between SMA types, allowing predictions about phenotypic severity. Interestingly, preliminary results of the prediction models suggest additional value in determining biochemical onset of disease in pre-symptomatic infants with SMA identified by genetic newborn screening and furthermore as potential therapeutic monitoring tool.Conclusions: This study provides preliminary evidence for the use of 1H-NMR-based urinary metabolic profiling as diagnostic and prognostic biomarker in spinal muscular atrophy. [ABSTRACT FROM AUTHOR]

Published
2021
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107. Health Outcomes of Infants with Vitamin B12 Deficiency Identified by Newborn Screening and Early Treated.

Author

Mütze, Ulrike, Walter, Magdalena, Keller, Mareike, Gramer, Gwendolyn, Garbade, Sven F., Gleich, Florian, Haas, Dorothea, Posset, Roland, Grünert, Sarah C., Hennermann, Julia B., Thimm, Eva, Fang-Hoffmann, Junmin, Syrbe, Steffen, Okun, Jürgen G., Hoffmann, Georg F., and Kölker, Stefan

Abstract

Objective: To evaluate the clinical outcomes at age 1.5 ± 0.5 years of infants with vitamin B12 deficiency identified by newborn screening (NBS).Study Design: Prospective multicenter observational study on health outcomes of 31 infants with vitamin B12 deficiency identified by NBS. Neurodevelopment was assessed by the Denver Developmental Screening Test.Results: In 285 862 newborns screened between 2016 and 2019, the estimated birth prevalence of vitamin B12 deficiency was 26 in 100 000 newborns, with high seasonal variations (lowest in summer: 8 in 100 000). Infants participating in the outcome study (N = 31) were supplemented with vitamin B12 for a median (range) of 5.9 (1.1-16.2) months. All achieved age-appropriate test results in Denver Developmental Screening Test at age 15 (11-23) months and did not present with symptoms characteristic for vitamin B12 deficiency. Most (81%, n = 25) mothers of affected newborns had a hitherto undiagnosed (functional) vitamin B12 deficiency, and, subsequently, received specific therapy.Conclusions: Neonatal vitamin B12 deficiency can be screened by NBS, preventing the manifestation of irreversible neurologic symptoms and the recurrence of vitamin B12 deficiency in future pregnancies through adequate treatment of affected newborns and their mothers. The high frequency of mothers with migrant background having a newborn with vitamin B12 deficiency highlights the need for improved prenatal care. [ABSTRACT FROM AUTHOR]

Published
2021
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108. Pharmacologic rescue of hyperammonemia-induced toxicity in zebrafish by inhibition of ornithine aminotransferase

Author

Zielonka, Matthias, Breuer, Maximilian, Okun, Jürgen Günther, Carl, Matthias, Hoffmann, Georg Friedrich, and Kölker, Stefan

Subjects
Ornithine, Genetics and Molecular Biology (all), Life Cycles, Embryology, Glutamine, lcsh:Medicine, Aminotransferases, Acetates, Biochemistry, Larvae, Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), Urea, Hyperammonemia, Amino Acids, lcsh:Science, Zebrafish, Ornithine-Oxo-Acid Transaminase, Organic Compounds, Acidic Amino Acids, Eukaryota, Neurochemistry, Animal Models, Neurotransmitters, Ketones, Enzymes, Chemistry, Experimental Organism Systems, Osteichthyes, Vertebrates, Physical Sciences, Glutamate, Research Article, Signal Transduction, Pyruvate, Research and Analysis Methods, Receptors, N-Methyl-D-Aspartate, Model Organisms, Transferases, Animals, lcsh:R, Organic Chemistry, Embryos, Organisms, Chemical Compounds, Biology and Life Sciences, Proteins, Fish, Enzymology, lcsh:Q, Acids, Developmental Biology, Neuroscience
Abstract

Hyperammonemia is the common biochemical hallmark of urea cycle disorders, activating neurotoxic pathways. If untreated, affected individuals have a high risk of irreversible brain damage and mortality. Here we show that acute hyperammonemia strongly enhances transamination-dependent formation of osmolytic glutamine and excitatory glutamate, thereby inducing neurotoxicity and death in ammoniotelic zebrafish larvae via synergistically acting overactivation of NMDA receptors and bioenergetic impairment induced by depletion of 2-oxoglutarate. Intriguingly, specific and irreversible inhibition of ornithine aminotransferase (OAT) by 5-fluoromethylornithine rescues zebrafish from lethal concentrations of ammonium acetate and corrects hyperammonemia-induced biochemical alterations. Thus, OAT inhibition is a promising and effective therapeutic approach for preventing neurotoxicity and mortality in acute hyperammonemia.

Published
2018

118. Simultaneous determination of 3-hydroxypropionic acid, methylmalonic acid and methylcitric acid in dried blood spots: Second-tier LC-MS/MS assay for newborn screening of propionic acidemia, methylmalonic acidemias and combined remethylation disorders

Author

Monostori, Péter, Klinke, Glynis, Richter, Sylvia, Baráth, Ákos, Fingerhut, Ralph, Baumgartner, Matthias R, Kölker, Stefan, Hoffmann, Georg F, Gramer, Gwendolyn, Okun, Jürgen G, University of Zurich, and Monostori, Péter

Subjects
Male, Propionic Acidemia, Physiology, Systems Engineering, lcsh:Medicine, 610 Medicine & health, 1100 General Agricultural and Biological Sciences, Research and Analysis Methods, Biochemistry, Mass Spectrometry, 1300 General Biochemistry, Genetics and Molecular Biology, Specimen Storage, Medicine and Health Sciences, Humans, Mass Screening, Citrates, Lactic Acid, lcsh:Science, Amino Acid Metabolism, Inborn Errors, 1000 Multidisciplinary, lcsh:R, Chromatographic Techniques, Infant, Newborn, Chemical Compounds, Biology and Life Sciences, Anemia, Megaloblastic anemia, Hematology, Body Fluids, Chemistry, Blood, Vitamin B12 deficiency, 10036 Medical Clinic, Specimen Preparation and Treatment, Storage and Handling, Physical Sciences, Engineering and Technology, lcsh:Q, Female, Dried Blood Spot Testing, Anatomy, Quality Assurance, Acids, Biomarkers, Chromatography, Liquid, Methylmalonic Acid, Research Article
Abstract

Background and aims Increased propionylcarnitine levels in newborn screening are indicative for a group of potentially severe disorders including propionic acidemia (PA), methylmalonic acidemias and combined remethylation disorders (MMACBL). This alteration is relatively non-specific, resulting in the necessity of confirmation and differential diagnosis in subsequent tests. Thus, we aimed to develop a multiplex approach for concurrent determination of 3-hydroxypropionic acid, methylmalonic acid and methylcitric acid from the same dried blood spot (DBS) as in primary screening (second-tier test). We also set out to validate the method using newborn and follow-up samples of patients with confirmed PA or MMACBL. Methods The assay was developed using liquid chromatography–tandem mass spectrometry and clinically validated with retrospective analysis of DBS samples from PA or MMACBL patients. Results Reliable determination of all three analytes in DBSs was achieved following simple and fast (

Published
2017

119. Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children.

Author

Holle, Johannes, Kirchner, Marietta, Okun, Jürgen, Bayazit, Aysun K., Obrycki, Lukasz, Canpolat, Nur, Bulut, Ipek Kaplan, Azukaitis, Karolis, Duzova, Ali, Ranchin, Bruno, Shroff, Rukshana, Candan, Cengiz, Oh, Jun, Klaus, Günter, Lugani, Francesca, Gimpel, Charlotte, Büscher, Rainer, Yilmaz, Alev, Baskin, Esra, and Erdogan, Hakan

Subjects
PEDIATRIC nephrology, CHRONIC kidney failure, PROPORTIONAL hazards models, SULFATES
Abstract

The uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) accumulate in patients with chronic kidney disease (CKD) as a consequence of altered gut microbiota metabolism and a decline in renal excretion. Despite of solid experimental evidence for nephrotoxic effects, the impact of uremic toxins on the progression of CKD has not been investigated in representative patient cohorts. In this analysis, IS and pCS serum concentrations were measured in 604 pediatric participants (mean eGFR of 27 ± 11 ml/min/1.73m2) at enrolment into the prospective Cardiovascular Comorbidity in Children with CKD study. Associations with progression of CKD were analyzed by Kaplan-Meier analyses and Cox proportional hazard models. During a median follow up time of 2.2 years (IQR 4.3–0.8 years), the composite renal survival endpoint, defined as 50% loss of eGFR, or eGFR <10ml/min/1.73m2 or start of renal replacement therapy, was reached by 360 patients (60%). Median survival time was shorter in patients with IS and pCS levels in the highest versus lowest quartile for both IS (1.5 years, 95%CI [1.1,2.0] versus 6.0 years, 95%CI [5.0,8.4]) and pCS (1.8 years, 95%CI [1.5,2.8] versus 4.4 years, 95%CI [3.4,6.0]). Multivariable Cox regression disclosed a significant association of IS, but not pCS, with renal survival, which was independent of other risk factors including baseline eGFR, proteinuria and blood pressure. In this exploratory analysis we provide the first data showing a significant association of IS, but not pCS serum concentrations with the progression of CKD in children, independent of other known risk factors. In the absence of comorbidities, which interfere with serum levels of uremic toxins, such as diabetes, obesity and metabolic syndrome, these results highlight the important role of uremic toxins and accentuate the unmet need of effective elimination strategies to lower the uremic toxin burden and abate progression of CKD. [ABSTRACT FROM AUTHOR]

Published
2020
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123. Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy

Author

Iuso, Arcangela, primary, Wiersma, Marit, additional, Schüller, Hans-Joachim, additional, Pode-Shakked, Ben, additional, Marek-Yagel, Dina, additional, Grigat, Mathias, additional, Schwarzmayr, Thomas, additional, Berutti, Riccardo, additional, Alhaddad, Bader, additional, Kanon, Bart, additional, Grzeschik, Nicola A., additional, Okun, Jürgen G., additional, Perles, Zeev, additional, Salem, Yishay, additional, Barel, Ortal, additional, Vardi, Amir, additional, Rubinshtein, Marina, additional, Tirosh, Tal, additional, Dubnov-Raz, Gal, additional, Messias, Ana C., additional, Terrile, Caterina, additional, Barshack, Iris, additional, Volkov, Alex, additional, Avivi, Camilla, additional, Eyal, Eran, additional, Mastantuono, Elisa, additional, Kumbar, Muhamad, additional, Abudi, Shachar, additional, Braunisch, Matthias, additional, Strom, Tim M., additional, Meitinger, Thomas, additional, Hoffmann, Georg F., additional, Prokisch, Holger, additional, Haack, Tobias B., additional, Brundel, Bianca J.J.M., additional, Haas, Dorothea, additional, Sibon, Ody C.M., additional, and Anikster, Yair, additional

Published
2018
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124. Cutis laxa, exocrine pancreatic insufficiency and altered cellular metabolomics as additional symptoms in a new patient with ATP6AP1-CDG

Author

Dimitrov, Bianca, primary, Himmelreich, Nastassja, additional, Hipgrave Ederveen, Agnes L., additional, Lüchtenborg, Christian, additional, Okun, Jürgen G., additional, Breuer, Maximilian, additional, Hutter, Anna-Marlen, additional, Carl, Matthias, additional, Guglielmi, Luca, additional, Hellwig, Andrea, additional, Thiemann, Kai Christian, additional, Jost, Markus, additional, Peters, Verena, additional, Staufner, Christian, additional, Hoffmann, Georg F., additional, Hackenberg, Annette, additional, Paramasivam, Nagarajan, additional, Wiemann, Stefan, additional, Eils, Roland, additional, Schlesner, Matthias, additional, Strahl, Sabine, additional, Brügger, Britta, additional, Wuhrer, Manfred, additional, Christoph Korenke, G., additional, and Thiel, Christian, additional

Published
2018
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126. Angiocrine Wnt signaling controls liver growth and metabolic maturation in mice

Author

Leibing, Thomas, primary, Géraud, Cyrill, additional, Augustin, Iris, additional, Boutros, Michael, additional, Augustin, Hellmut G., additional, Okun, Jürgen G., additional, Langhans, Claus-Dieter, additional, Zierow, Johanna, additional, Wohlfeil, Sebastian A., additional, Olsavszky, Victor, additional, Schledzewski, Kai, additional, Goerdt, Sergij, additional, and Koch, Philipp-Sebastian, additional

Published
2018
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127. Simultaneous determination of 3-hydroxypropionic acid, methylmalonic acid and methylcitric acid in dried blood spots: Second-tier LC-MS/MS assay for newborn screening of propionic acidemia, methylmalonic acidemias and combined remethylation disorders

Author

Monostori, Péter; https://orcid.org/0000-0003-3591-6054, Klinke, Glynis, Richter, Sylvia, Baráth, Ákos, Fingerhut, Ralph, Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826, Kölker, Stefan, Hoffmann, Georg F, Gramer, Gwendolyn, Okun, Jürgen G, Monostori, Péter; https://orcid.org/0000-0003-3591-6054, Klinke, Glynis, Richter, Sylvia, Baráth, Ákos, Fingerhut, Ralph, Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826, Kölker, Stefan, Hoffmann, Georg F, Gramer, Gwendolyn, and Okun, Jürgen G

Abstract

BACKGROUND AND AIMS: Increased propionylcarnitine levels in newborn screening are indicative for a group of potentially severe disorders including propionic acidemia (PA), methylmalonic acidemias and combined remethylation disorders (MMACBL). This alteration is relatively non-specific, resulting in the necessity of confirmation and differential diagnosis in subsequent tests. Thus, we aimed to develop a multiplex approach for concurrent determination of 3-hydroxypropionic acid, methylmalonic acid and methylcitric acid from the same dried blood spot (DBS) as in primary screening (second-tier test). We also set out to validate the method using newborn and follow-up samples of patients with confirmed PA or MMACBL. METHODS: The assay was developed using liquid chromatography-tandem mass spectrometry and clinically validated with retrospective analysis of DBS samples from PA or MMACBL patients. RESULTS: Reliable determination of all three analytes in DBSs was achieved following simple and fast (<20 min) sample preparation without laborious derivatization or any additional pipetting steps. The method clearly distinguished the pathological and normal samples and differentiated between PA and MMACBL in all stored newborn specimens. Methylcitric acid was elevated in all PA samples; 3-hydroxypropionic acid was also high in most cases. Methylmalonic acid was increased in all MMACBL specimens; mostly together with methylcitric acid. CONCLUSIONS: A liquid chromatography-tandem mass spectrometry assay allowing simultaneous determination of the biomarkers 3-hydroxypropionic acid, methylmalonic acid and methylcitric acid in DBSs has been developed. The assay can use the same specimen as in primary screening (second-tier test) which may reduce the need for repeated blood sampling. The presented preliminary findings suggest that this method can reliably differentiate patients with PA and MMACBL in newborn screening. The validated assay is being evaluated prospectively in a pilot proje

Published
2017

129. Human heterologous liver cells transiently improve hyperammonemia and ureagenesis in individuals with severe urea cycle disorders

Author

Meyburg, Jochen, primary, Opladen, Thomas, additional, Spiekerkötter, Ute, additional, Schlune, Andrea, additional, Schenk, Jens-Peter, additional, Schmidt, Jan, additional, Weitz, Jürgen, additional, Okun, Jürgen, additional, Bürger, Friederike, additional, Omran, Tawfeg Ben, additional, Abdoh, Ghassan, additional, Al Rifai, Hilal, additional, Monavari, Ahmad, additional, Konstantopoulou, Vassiliki, additional, Kölker, Stefan, additional, Yudkoff, Marc, additional, and Hoffmann, Georg F., additional

Published
2017
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133. Significant prevalence of sickle cell disease in Southwest Germany: results from a birth cohort study indicate the necessity for newborn screening.

Author

Lindner, Martin, Kunz, Joachim, Awad, Saida, Happich, Margit, Muckenthaler, Lena, Muckenthaler, Martina, Kulozik, Andreas, Gramer, Gwendolyn, Okun, Jürgen, Hoffmann, Georg, Bruckner, Thomas, Kunz, Joachim B, Okun, Jürgen G, Hoffmann, Georg F, Muckenthaler, Martina U, and Kulozik, Andreas E

Subjects
SICKLE cell anemia, NEWBORN screening, EPIDEMIOLOGY, POLYMERASE chain reaction, BETA globin, JUVENILE diseases, SICKLE cell anemia diagnosis, BLOOD testing, LONGITUDINAL method, DISEASE prevalence, SICKLE cell trait, DIAGNOSIS
Abstract

Children with sickle cell disease (SCD) benefit from newborn screening, because life-threatening complications can be prevented by pre-symptomatic diagnosis. In Germany, the immigration of people from endemic countries is steadily growing. Comprehensive data about the epidemiology and prevalence of SCD in Germany are however lacking, and SCD is not included in the national newborn screening program. We provide data on the prevalence of SCD in a population from both urban and rural areas in Southwest Germany. Anonymized dried blood spots from 37,838 unselected newborns were analyzed by allele-specific PCR for the HbS mutation. Samples tested positive were subjected to Sanger sequencing of the entire β-globin coding sequence firstly to validate the screening and secondly to identify compound heterozygous SCD patients with other mutations of the β-globin gene. We identified 83 carriers of the sickle cell trait, three compound heterozygous SCD patients (two with sickle cell-β-thalassemia, one with sickle cell-Hb Tianshui) but no homozygous SCD patients. The novel molecular method and strategy for newborn screening for SCD presented here compares favorably in terms of sensitivity (1.0 for homozygous HbS, 0.996 for heterozygous HbS), specificity (0.996), practicability, and costs with conventional biochemical screening. Our results demonstrate a significant prevalence of SCD of approximately 1:12,000 in an unselected urban and rural population in Southwest Germany. Together with previously published even higher results from exclusively urban populations in Berlin and Hamburg, our data provide the basis for the decision on a newborn screening program for SCD in Germany. [ABSTRACT FROM AUTHOR]

Published
2016
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135. Fasting‐induced liver GADD 45β restrains hepatic fatty acid uptake and improves metabolic health

Author

Fuhrmeister, Jessica, primary, Zota, Annika, additional, Sijmonsma, Tjeerd P, additional, Seibert, Oksana, additional, Cıngır, Şahika, additional, Schmidt, Kathrin, additional, Vallon, Nicola, additional, Guia, Roldan M, additional, Niopek, Katharina, additional, Berriel Diaz, Mauricio, additional, Maida, Adriano, additional, Blüher, Matthias, additional, Okun, Jürgen G, additional, Herzig, Stephan, additional, and Rose, Adam J, additional

Published
2016
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137. Significant prevalence of sickle cell disease in Southwest Germany: results from a birth cohort study indicate the necessity for newborn screening

Author

Kunz, Joachim B., primary, Awad, Saida, additional, Happich, Margit, additional, Muckenthaler, Lena, additional, Lindner, Martin, additional, Gramer, Gwendolyn, additional, Okun, Jürgen G., additional, Hoffmann, Georg F., additional, Bruckner, Thomas, additional, Muckenthaler, Martina U., additional, and Kulozik, Andreas E., additional

Published
2015
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138. High incidence of maternal vitamin B12 deficiency detected by newborn screening: first results from a study for the evaluation of 26 additional target disorders for the German newborn screening panel.

Author

Gramer, Gwendolyn, Fang-Hoffmann, Junmin, Feyh, Patrik, Klinke, Glynis, Monostori, Peter, Okun, Jürgen G., and Hoffmann, Georg F.

Abstract

Background: Newborn screening (NBS) in Germany currently includes 15 target disorders. Recent diagnostic improvements suggest an extension of the screening panel.Methods: Since August 2016, a prospective study evaluating 26 additional target disorders (25 metabolic disorders and vitamin B12-deficiency) in addition to the German screening panel is performed at the Newborn Screening Center Heidelberg. First-tier results from tandem-MS screening are complemented by second-tier strategies for 15 of the additional target disorders. NBS results of seven patients diagnosed symptomatically with one of the additional target disorders by selective screening since August 2016 are retrospectively evaluated.Results: Over a 13-month period, 68,418 children participated in the study. Second-tier analyses were performed in 5.4% of samples. Only 59 (0.1%) of study participants had abnormal screening results for one of the additional target disorders. Target disorders from the study panel were confirmed in 12 children: 1 3-hydroxy-3-methylglutaryl coenzyme A (CoA)-lyase deficiency, 1 citrullinemia type I, 1 multiple acyl-CoA dehydrogenase-deficiency, 1 methylenetetrahydrofolate reductase-deficiency, and 8 children with maternal vitamin B12-deficiency. In addition, six of seven patients diagnosed symptomatically outside the study with one of the target disorders would have been identified by the study strategy in their NBS sample.Conclusions: Within 13 months, the study “Newborn Screening 2020” identified additional 12 children with treatable conditions while only marginally increasing the recall rate by 0.1%. Maternal vitamin B12-deficiency was the most frequent finding. Even more children could benefit from screening for the additional target disorders by extending the NBS panel for Germany and/or other countries. [ABSTRACT FROM AUTHOR]

Published
2018
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139. Glutaric aciduria type I: A translational approach to an enigmatic disease

Author

BOY, Sp, OPP, Silvana, HERINGER, Jana, OKUN, Jürgen, SAUER, Sven, and KÖLKER, Stefan

Subjects
organic aciduria,newborn screening,striatum,dystonia,guideline
Abstract

Glutaric aciduria type I (GA-I) is an autosomal recessively inherited disorder of L-lysine, L-tryptophan and L-hydroxylysine metabolism which is biochemically characterized by the accumulation of putatively toxic glutaric and 3-hydroxyglutaric acids, and non-toxic glutarylcarnitine due to deficient activity of glutaryl-CoA dehydrogenase. The prognostic relevant event of this disease is the manifestation of a complex movement disorder with predominant dystonia superimposed on axial hypotonia. This movement disorder most often manifests during infancy or early childhood after the precipitation of acute encephalopathic crises by catabolic state but it may also develop insidiously without clinically apparent crises. Advances have been made in the description of the natural disease course and neuroradiological abnormalities demonstrating overlapping episodes of cerebral alterations including (reversible) maturational delay of the brain in utero, (irreversible) acute striatal injury during a vulnerable period of brain development and chronic progressive changes that may continue lifelong and involving extrastriatal brain regions. Neonatal identification of asymptomatic patients by tandem mass spectrometry allowing to start combined metabolic treatment in asymptomatic patients has significantly improved the neurological outcome in countries with such newborn screening programmes. In contrast, therapeutic concepts for symptomatic patients are much less effective. Post mortem studies and investigations in Gcdh-deficient mice, a transgenic mouse model for GA-I, have helped to unravel the pathomechanism. Evidence is increasing that some of the accumulating metabolites in GA-I patients are neurotoxic due to their interference with glutamatergic neurotransmission, inhibition of the 2-oxoglutarate dehydrogenase complex and impairment of the dicarboxylic acid shuttle between astrocytes and neurons. Strikingly, glutaric and 3-hydroxylgutaric acids massively accumulate in the brain of patients due to the low permeability of the blood brain barrier for dicarboxylic acids which may explain the selective neurological phenotype of GA-I. Current therapeutic concepts aim to reduce the cerebral concentrations of neurotoxic metabolites by modulating lysine influx to the brain and stimulating the formation of non-toxic glutarylcarnitine. Despite the outlined progress, the mechanism of current neuroprotective concepts is still quite hypothetical and lack a proof of principle. Our understanding has been hampered by the fact that in affected patients the biochemical effect of metabolic treatment could be determined only by using invasive methods (which would be unethical), whereas the concentrations of these biomarkers in body fluids are unlikely to correlate with the brain tissue. Therefore, a translational approach to this disease is indispensable to further unravel the mechanisms of neurologic disease and to elucidate the major principles of neuroprotective strategies.

Published
2011

141. Significance of the Extent of Intestinal Resection on the Outcome of a Short-bowel Syndrome in a Porcine Model

Author

Frongia, Giovanni, primary, Nickkholgh, Arash, additional, Hafezi M, Mohammad Reza, additional, Arvin, Jalal, additional, Saffari, Arash, additional, Golriz, Mohammad, additional, Aydin, Esvad, additional, Weih, Sandra, additional, Kessler, Markus, additional, Emami, Golnaz, additional, Garoussi, Camelia, additional, Okun, Jürgen G., additional, Schmidt, Kathrin, additional, Thiel, Christian, additional, Brune, Maik, additional, Günther, Patrick, additional, Holland-Cunz, Stefan, additional, and Mehrabi, Arianeb, additional

Published
2015
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145. Dietary tryptophan is required for CNS infiltration of encephalitogenic T cells

Author

Keil, Melanie, primary, Paulsen, Maren, additional, Sonner, Jana, additional, Wanke, Florian, additional, Oezen, Iris, additional, Schumacher, Theresa, additional, Okun, Jürgen G., additional, Kurschuss, Florian, additional, Reinhardt, Christoph, additional, Rosenstiel, Philip, additional, Wick, Wolfgang, additional, and Platten, Michael, additional

Published
2014
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147. The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

Author

Rahman, Mahbubur, primary, Muhammad, Sajjad, additional, Khan, Mahtab A., additional, Chen, Hui, additional, Ridder, Dirk A., additional, Müller-Fielitz, Helge, additional, Pokorná, Barbora, additional, Vollbrandt, Tillman, additional, Stölting, Ines, additional, Nadrowitz, Roger, additional, Okun, Jürgen G, additional, Offermanns, Stefan, additional, and Schwaninger, Markus, additional

Published
2014
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148. Diagnosis and therapeutic monitoring of inborn errors of creatine metabolism and transport using liquid chromatography–tandem mass spectrometry in urine, plasma and CSF

Author

Haas, Dorothea, primary, Gan-Schreier, Hongying, additional, Langhans, Claus-Dieter, additional, Anninos, Alexandros, additional, Haege, Gisela, additional, Burgard, Peter, additional, Schulze, Andreas, additional, Hoffmann, Georg F., additional, and Okun, Jürgen G., additional

Published
2014
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149. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate

Author

Bunse, Lukas, Pusch, Stefan, Bunse, Theresa, Sahm, Felix, Sanghvi, Khwab, Friedrich, Mirco, Alansary, Dalia, Sonner, Jana K., Green, Edward, Deumelandt, Katrin, Kilian, Michael, Neftel, Cyril, Uhlig, Stefanie, Kessler, Tobias, von Landenberg, Anna, Berghoff, Anna S., Marsh, Kelly, Steadman, Mya, Zhu, Dongwei, Nicolay, Brandon, Wiestler, Benedikt, Breckwoldt, Michael O., Al-Ali, Ruslan, Karcher-Bausch, Simone, Bozza, Matthias, Oezen, Iris, Kramer, Magdalena, Meyer, Jochen, Habel, Antje, Eisel, Jessica, Poschet, Gernot, Weller, Michael, Preusser, Matthias, Nadji-Ohl, Minou, Thon, Niklas, Burger, Michael C., Harter, Patrick N., Ratliff, Miriam, Harbottle, Richard, Benner, Axel, Schrimpf, Daniel, Okun, Jürgen, Herold-Mende, Christel, Turcan, Sevin, Kaulfuss, Stefan, Hess‐Stumpp, Holger, Bieback, Karen, Cahill, Daniel P., Plate, Karl H., Hänggi, Daniel, Dorsch, Marion, Suvà, Mario L., Niemeyer, Barbara A., von Deimling, Andreas, Wick, Wolfgang, and Platten, Michael

Abstract

The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell–derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment.

Published
2018
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150. Inborn oxidative phosphorylation defect as risk factor for propofol infusion syndrome

Author

Vanlander, Arnaud Vincent, Jorens, Philippe P.G., Smet, Joel, De Paepe, Boel, Verbrugghe, Walter, Van den Eynden, Gert, Meire, Françoise, Pauwels, Patrick, Van Der Aa, Nathalie, Seneca, Sara, Lissens, Willy, Okun, Jürgen, Van Coster, Rudy, Vanlander, Arnaud Vincent, Jorens, Philippe P.G., Smet, Joel, De Paepe, Boel, Verbrugghe, Walter, Van den Eynden, Gert, Meire, Françoise, Pauwels, Patrick, Van Der Aa, Nathalie, Seneca, Sara, Lissens, Willy, Okun, Jürgen, and Van Coster, Rudy

Abstract

Propofol is an anesthetic agent widely used for induction and maintenance of anesthesia, and sedation in children. Although generally considered as reliable and safe, administration of propofol can occasionally induce a potentially fatal complication known as propofol infusion syndrome (PRIS). Mitochondrial dysfunction has been implicated in the pathogenesis of PRIS. We report on an adult patient with Leber hereditary optic neuropathy (LHON) who developed PRIS. He was a carrier of the m.3460G>A mutation, one of the major three pathogenic point mutations associated with LHON. The propositus was blind and underwent propofol sedation after severe head injury. Five days after start of propofol infusion, the patient died. The activity of complex I of the oxidative phosphorylation (OXPHOS) system was severely deficient in skeletal muscle. Our observation indicates that fulminate PRIS can occur in an adult patient with an inborn OXPHOS defect and corroborates the hypothesis that PRIS is caused by inhibition of the OXPHOS system. © 2012 The Acta Anaesthesiologica Scandinavica Foundation., SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published

Published
2012

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