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PubMed | Shinshu University, University Hospital Freiburg, National Hospital for Neurology and Neurosurgery, National Taiwan University Hospital and 31 more.
Type: | Journal: Orphanet journal of rare diseases | Year: 2015

This paper summarizes the results of a group effort to bring together the worldwide available data on patients who are either homozygotes or compound heterozygotes for mutations in MAT1A. MAT1A encodes the subunit that forms two methionine adenosyltransferase isoenzymes, tetrameric MAT I and dimeric MAT III, that catalyze the conversion of methionine and ATP to S-adenosylmethionine (AdoMet). Subnormal MAT I/III activity leads to hypermethioninemia. Individuals, with hypermethioninemia due to one of the MAT1A mutations that in heterozygotes cause relatively mild and clinically benign hypermethioninemia are currently often being flagged in screening programs measuring methionine elevation to identify newborns with defective cystathionine -synthase activity. Homozygotes or compound heterozygotes for MAT1A mutations are less frequent. Some but not all, such individuals have manifested demyelination or other CNS abnormalities.The goals of the present effort have been to determine the frequency of such abnormalities, to find how best to predict whether they will occur, and to evaluate the outcomes of the variety of treatment regimens that have been used. Data have been gathered for 64 patients, of whom 32 have some evidence of CNS abnormalities (based mainly on MRI findings), and 32 do not have such evidence.The results show that mean plasma methionine concentrations provide the best indication of the group into which a given patient will fall: those with means of 800M or higher usually have evidence of CNS abnormalities, whereas those with lower means usually do not. Data are reported for individual patients for MAT1A genotypes, plasma methionine, total homocysteine (tHcy), and AdoMet concentrations, liver function studies, results of 15 pregnancies, and the outcomes of dietary methionine restriction and/or AdoMet supplementation. Possible pathophysiological mechanisms that might contribute to CNS damage are discussed, and tentative suggestions are put forth as to optimal management.


Marquard J.,University Childrens Hospital Duesseldorf | Stahl A.,Leibniz Institute for Diabetes Research | Lerch C.,Heinrich Heine University Düsseldorf | Wolters M.,University Childrens Hospital Duesseldorf | And 3 more authors.
Journal of Pediatric Endocrinology and Metabolism | Year: 2011

Background: Low-glycemic index (GI) diet vs. high-GI diet improves glycemic control, but it is not clear whether a low-GI diet is superior to an optimized mixed diet (OMD). Methods: This was a 12-week parallel-group pilot-trial including 17 children with type 1 diabetes. A separate dietary education into the allocated diet (OMD vs. low-GI) was performed. Nutrition was recorded by means of a three-day dietary record. Objectives: The primary objective was to determine the macro- and micronutrient composition of the different diets, the secondary objective was to determine the short-term effect on HbA1c levels. Results: In the low-GI group carbohydrate intake decreased, fat intake increased by trend. In the OMD group fat and energy intake decreased. No changes of HbA1c levels between the groups were observed. Conclusion: OMD could have positive effects in overweight and obese diabetic children, since a reduction in fat and energy intake can be achieved. The findings of this pilot-trial suggest that OMD could be superior to a low-GI diet. © 2011 by Walter de Gruyter Berlin Boston.


Kummer S.,University Childrens Hospital Duesseldorf | Jeruschke S.,University Childrens Hospital Duesseldorf | Jeruschke S.,University of Duisburg - Essen | van Wegerich L.,University Childrens Hospital Duesseldorf | And 12 more authors.
PLoS ONE | Year: 2011

Context/Objective: Epidemiological studies have demonstrated that women have a significantly better prognosis in chronic renal diseases compared to men. This suggests critical influences of gender hormones on glomerular structure and function. We examined potential direct protective effects of estradiol on podocytes. Methods: Expression of estrogen receptor alpha (ERα) was examined in podocytes in vitro and in vivo. Receptor localization was shown using Western blot of separated nuclear and cytoplasmatic protein fractions. Podocytes were treated with Puromycin aminonucleoside (PAN, apoptosis induction), estradiol, or both in combination. Apoptotic cells were detected with Hoechst nuclear staining and Annexin-FITC flow cytometry. To visualize mitochondrial membrane potential depolarization as an indicator for apoptosis, cells were stained with tetramethyl rhodamine methylester (TMRM). Estradiol-induced phosphorylation of ERK1/2 and p38 MAPK was examined by Western blot. Glomeruli of ERα knock-out mice and wild-type controls were analysed by histomorphometry and immunohistochemistry. Results: ERα was consistently expressed in human and murine podocytes. Estradiol stimulated ERα protein expression, reduced PAN-induced apoptosis in vitro by 26.5±24.6% or 56.6±5.9% (flow cytometry or Hoechst-staining, respectively; both p&0.05), and restored PAN-induced mitochondrial membrane potential depolarization. Estradiol enhanced ERK1/2 phosphorylation. In ERα knockout mice, podocyte number was reduced compared to controls (female/male: 80/86 vs. 132/135 podocytes per glomerulus, p&0.05). Podocyte volume was enhanced in ERα knockout mice (female/male: 429/371 μm 3 vs. 264/223 μm 3 in controls, p&0.05). Tgfβ1 and collagen type IV expression were increased in knockout mice, indicating glomerular damage. Conclusions: Podocytes express ERα, whose activation leads to a significant protection against experimentally induced apoptosis. Possible underlying mechanisms include stabilization of mitochondrial membrane potential and activation of MAPK signalling. Characteristic morphological changes indicating glomerulopathy in ERα knock-out mice support the in vivo relevance of the ERα for podocyte viability and function. Thus, our findings provide a novel model for the protective influence of female gender on chronic glomerular diseases. © 2011 Kummer et al.


Stienen A.,University Childrens Hospital Duesseldorf | Stienen A.,RWTH Aachen | Feyen O.,University Childrens Hospital Duesseldorf | Niehues T.,University Childrens Hospital Duesseldorf | Niehues T.,Helios Hospital Krefeld
European Cytokine Network | Year: 2011

Interleukin (IL)-7 is thought to be a non-redundant cytokine for lymphopoiesis as there is a reduction of T and B cells in peripheral blood (PB) and a loss of TCRγδ+ cells in PB and bone marrow (BM) in IL-7-/- mice. To investigate whether the absence of IL-7 influences the organ-dependent distribution of the lymphocytes, we analyzed single cell suspensions of several organs (BM, lung, liver, small intestine, and spleen) at different ages (three and 12 months) of IL-7+/+ and IL-7-/- mice using flow cytometry; immunohistochemical staining was performed on frozen sections of various organs.We observed lymphocytopenia in almost all organs of IL-7-/- mice, but normal counts in the liver and the lung of three-month-old IL-7-/- mice. CD4+ and CD8+ cell numbers were decreased in the spleen and the BM. With aging, we found a greater increase in CD4+ and CD8+ cells in the BM of IL-7-/- than in IL-7+/+ mice, particularly of memory cells. The spleen of IL-7-/- mice was characterized by lymphocytopenia.We challenge the view that IL-7 is a non-redundant cytokine for lymphocyte development. Some of the changes observed, e.g. partial absence of TCRγδ+ T cells in the PB,BMand small intestine and complete loss in liver, lung and spleen, may be due to the altered organ distribution instead of a defect in γδ+ T cell lymphopoiesis. In this model, aging leads to a significantly altered composition of lymphocyte subsets, and the lack of IL-7 seems to accelerate this process.


Tucci S.,University Hospital Freiburg | Tucci S.,University Childrens Hospital Duesseldorf | Flogel U.,Heinrich Heine University Düsseldorf | Hermann S.,University of Munster | And 3 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2014

Hypertrophic cardiomyopathy is a typical manifestation of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), the most common long-chain β-oxidation defects in humans; however in some patients cardiac function is fully compensated. Cardiomyopathy may also be reversed by supplementation of medium-chain triglycerides (MCT). We here characterize cardiac function of VLCAD-deficient (VLCAD-/-) mice over one year. Furthermore, we investigate the long-term effect of a continuous MCT diet on the cardiac phenotype. We assessed cardiac morphology and function in VLCAD-/- mice by in vivo MRI. Cardiac energetics were measured by 31P-MRS and myocardial glucose uptake was quantified by positron-emission-tomography (PET). Metabolic adaptations were identified by the expression of genes regulating glucose and lipid metabolism using real-time-PCR. VLCAD-/- mice showed a progressive decrease in heart function over 12months accompanied by a reduced phosphocreatine-to-ATP-ratio indicative of chronic energy deficiency. Long-term MCT supplementation aggravated the cardiac phenotype into dilated cardiomyopathy with features similar to diabetic heart disease. Cardiac energy production and function in mice with a β-oxidation defect cannot be maintained with age. Compensatory mechanisms are insufficient to preserve the cardiac energy state over time. However, energy deficiency by impaired β-oxidation and long-term MCT induce cardiomyopathy by different mechanisms. Cardiac MRI and MRS may be excellent tools to assess minor changes in cardiac function and energetics in patients with β-oxidation defects for preventive therapy. © 2014 Elsevier B.V.


Vogel M.,University Childrens Hospital Duesseldorf | Grund S.,Heinrich Heine University Düsseldorf | Pandey S.,University Childrens Hospital Duesseldorf | Mayatepek E.,University Childrens Hospital Duesseldorf | And 3 more authors.
Japanese Journal of Infectious Diseases | Year: 2016

The influenza pandemic in 2009/2010 shifted public awareness to respiratory tract infections caused by the influenza virus. A prospective study was conducted during the influenza pandemic from November 2009 through April 2010 to determine the causative pathogens and clinical symptoms present in all children and adolescents admitted to the University Children’s Hospital, Duesseldorf, Germany, with signs and symptoms of respiratory tract infection. A total of 272 children and adolescents were admitted with symptomes of acute respiratory tract infection (ARI) or influenza-like illness. Viral pathogens were detected in 80z(218/272). However, influenza A pH1N1 infection was only detected in 11z (30/272) of children. Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) were the predominant identified pathogens that led to the admission of young tachypneic children with pneumonia in the post pandemic phase and the requirement for more intense treatment. During the pandemic and early post-pandemic phase the clinical impact of other respiratory viruses, such as HMPV and RSV, led to a higher clinical disease burden than pH1N1. Consequently, HMPV testing should be performed as routinely as RSV testing in patients hospitalized for ARI. Even while preparing for pandemics, the awareness of other respiratory viruses must be maintained. © 2016, National Institute of Health. All rights reserved.


Hadzik B.,University Childrens Hospital Duesseldorf | Grass H.,Heinrich Heine University Düsseldorf | Mayatepek E.,Heinrich Heine University Düsseldorf | Daldrup T.,Heinrich Heine University Düsseldorf | Hoehn T.,Heinrich Heine University Düsseldorf
Klinische Padiatrie | Year: 2014

The aim of our report is to increase awareness that the antioxidant alpha-lipoic acid, which is marketed primarily as weight loss and energy supplement, has potentially lethal effects. A 14-year-old girl ingested in suicidal intention a large amount of alpha-lipoic acid, which led to multiorgan failure and subsequent death within 24 h. Multiorgan failure consisted of decreased myocardial contractility, seizures, anuria, thrombocytopenia, and coagulopathy. Therapy consisted of ventilation, anticonvulsive treatment and circulatory support with high-dose catecholamines. Conclusion: According to alpha-lipoic acid serum levels following ingestion the girl must have ingested a minimum of 10 alpha-lipoic acid tablets of 600 mg each. This is the first report on a fatal case of alpha-lipoic acid ingestion, which is intended to inform physicians, pharmacists and patients about critical side effects of this allegedly innocuous drug. © Georg Thieme Verlag KG Stuttgart New York ISSN 0300-8630.


PubMed | University Childrens Hospital Duesseldorf, University of Munster, Heinrich Heine University Düsseldorf and University Hospital Freiburg
Type: Journal Article | Journal: Biochimica et biophysica acta | Year: 2014

Hypertrophic cardiomyopathy is a typical manifestation of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), the most common long-chain -oxidation defects in humans; however in some patients cardiac function is fully compensated. Cardiomyopathy may also be reversed by supplementation of medium-chain triglycerides (MCT). We here characterize cardiac function of VLCAD-deficient (VLCAD(-/-)) mice over one year. Furthermore, we investigate the long-term effect of a continuous MCT diet on the cardiac phenotype. We assessed cardiac morphology and function in VLCAD(-/-) mice by in vivo MRI. Cardiac energetics were measured by (31)P-MRS and myocardial glucose uptake was quantified by positron-emission-tomography (PET). Metabolic adaptations were identified by the expression of genes regulating glucose and lipid metabolism using real-time-PCR. VLCAD(-/-) mice showed a progressive decrease in heart function over 12 months accompanied by a reduced phosphocreatine-to-ATP-ratio indicative of chronic energy deficiency. Long-term MCT supplementation aggravated the cardiac phenotype into dilated cardiomyopathy with features similar to diabetic heart disease. Cardiac energy production and function in mice with a -oxidation defect cannot be maintained with age. Compensatory mechanisms are insufficient to preserve the cardiac energy state over time. However, energy deficiency by impaired -oxidation and long-term MCT induce cardiomyopathy by different mechanisms. Cardiac MRI and MRS may be excellent tools to assess minor changes in cardiac function and energetics in patients with -oxidation defects for preventive therapy.


PubMed | University Childrens Hospital Duesseldorf
Type: Comparative Study | Journal: Journal of pediatric endocrinology & metabolism : JPEM | Year: 2011

Low-glycemic index (GI) diet vs. high-GI diet improves glycemic control, but it is not clear whether a low-GI diet is superior to an optimized mixed diet (OMD).This was a 12-week parallel-group pilot-trial including 17 children with type 1 diabetes. A separate dietary education into the allocated diet (OMD vs. low-GI) was performed. Nutrition was recorded by means of a three-day dietary record.The primary objective was to determine the macro- and micronutrient composition of the different diets, the secondary objective was to determine the short-term effect on HbA(1c) levels.In the low-GI group carbohydrate intake decreased, fat intake increased by trend. In the OMD group fat and energy intake decreased. No changes of HbA(1c) levels between the groups were observed.OMD could have positive effects in overweight and obese diabetic children, since a reduction in fat and energy intake can be achieved. The findings of this pilot-trial suggest that OMD could be superior to a low-GI diet.


PubMed | University Childrens Hospital Duesseldorf
Type: Journal Article | Journal: Klinische Padiatrie | Year: 2012

Diagnosis of pseudotumor cerebri (PTC) requires proper documentation of raised CSF opening-pressure. In childhood results may not be reliable due to insufficient sedation/analgesia or drug effects. We aimed to evaluate the current practice regarding pain and stress management in children undergoing lumbar puncture (LP) for pressure measurement.A one-year survey was conducted involving 368 German paediatric departments. All children with newly diagnosed PTC should be reported. Details analyzed here included: age, sex, CSF opening pressure and type of procedural sedation and analgesia (PSA) during LP.61 patients were analyzed, aged 6 months to 17 years. 29 patients (47%) did not receive any kind of PSA. In children receiving PSA the following regimens were used: Ketamine; Midazolam; Ketamine + Midazolam; Midazolam + Piritramide; Propofol; Profofol + Midazolam; general anaesthesia.Pain and stress management in children undergoing LP for CSF opening pressure measurement is often insufficient. Pain, stress and the variability of PSA regimen may be confounders of pressure measurement. In order to prevent false diagnoses of PTC and to obtain comparable results at different centers, a general consensus on PSA in children undergoing LP for CSF opening pressure measurements is required.

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