Opladen T.,University of Heidelberg |
Lindner M.,University of Heidelberg |
Lindner M.,University Childrens Hospital Frankfurt |
Das A.M.,Hannover Medical School |
And 16 more authors.
Molecular Genetics and Metabolism | Year: 2016
Background: The hepatic urea cycle is the main metabolic pathway for detoxification of ammonia. Inborn errors of urea cycle function present with severe hyperammonemia and a high case fatality rate. Long-term prognosis depends on the residual activity of the defective enzyme. A reliable method to estimate urea cycle activity in-vivo does not exist yet. The aim of this study was to evaluate a practical method to quantify 13C-urea production as a marker for urea cycle function in healthy subjects, patients with confirmed urea cycle defect (UCD) and asymptomatic carriers of UCD mutations. Methods: 13C-labeled sodium acetate was applied orally in a single dose to 47 subjects (10 healthy subjects, 28 symptomatic patients, 9 asymptomatic carriers). Results: The oral 13C-ureagenesis assay is a safe method. While healthy subjects and asymptomatic carriers did not differ with regards to kinetic variables for urea cycle flux, symptomatic patients had lower 13C-plasma urea levels. Although the 13C-ureagenesis assay revealed no significant differences between individual urea cycle enzyme defects, it reflected the heterogeneity between different clinical subgroups, including male neonatal onset ornithine carbamoyltransferase deficiency. Applying the 13C-urea area under the curve can differentiate between severe from more mildly affected neonates. Late onset patients differ significantly from neonates, carriers and healthy subjects. Conclusion: This study evaluated the oral 13C-ureagenesis assay as a sensitive in-vivo measure for ureagenesis capacity. The assay has the potential to become a reliable tool to differentiate UCD patient subgroups, follow changes in ureagenesis capacity and could be helpful in monitoring novel therapies of UCD. © 2015 Elsevier Inc.
Posset R.,University of Heidelberg |
Garcia-Cazorla A.,Hospital San Joan Of Deu |
Valayannopoulos V.,Assistance Publique Hopitaux de Paris |
Teles E.L.,Hospital Of S Joao |
And 34 more authors.
Journal of Inherited Metabolic Disease | Year: 2016
Background: Patients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation. Aims: Determining the effect of diagnostic and therapeutic interventions on the neurological outcome. Methods: Evaluation of baseline, regular follow-up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E-IMD patient registry. Results: About two-thirds of UCD patients remained asymptomatic until age 12 days [i.e. the median age at diagnosis of patients identified by newborn screening (NBS)] suggesting a potential benefit of NBS. In fact, NBS lowered the age at diagnosis in patients with late onset of symptoms (>28 days), and a trend towards improved long-term neurological outcome was found for patients with argininosuccinate synthetase and lyase deficiency as well as argininemia identified by NBS. Three to 17 different drug combinations were used for maintenance therapy, but superiority of any single drug or specific drug combination above other combinations was not demonstrated. Importantly, non-interventional variables of disease severity, such as age at disease onset and peak ammonium level of the initial hyperammonemic crisis (cut-off level: 500 μmol/L) best predicted the neurological outcome. Conclusions: Promising results of NBS for late onset UCD patients are reported and should be re-evaluated in a larger and more advanced age group. However, non-interventional variables affect the neurological outcome of UCD patients. Available evidence-based guideline recommendations are currently heterogeneously implemented into practice, leading to a high variability of drug combinations that hamper our understanding of optimised long-term and emergency treatment. © 2016 SSIEM
Zils K.,Klinikum Stuttgart Olgahospital |
Klingebiel T.,University Childrens Hospital Frankfurt |
Behnisch W.,University of Heidelberg |
Mueller H.L.,Hematology and Oncology |
And 6 more authors.
Pediatric Hematology and Oncology | Year: 2015
Background: Rothmund-Thomson syndrome (RTS) is associated with an increased risk of osteosarcoma, but information about affected patients is limited. Procedure: Seven patients with osteosarcoma, treated in the Cooperative Osteosarcoma Study Group-trials, had a diagnosis of RTS. Their patient-, tumor- and treatment-related variables and outcome were reviewed retrospectively. Results: Median age at diagnosis of osteosarcoma was 13 years (range 7-16), five were female, two male. Tumor involved proximal tibia (n = 4), distal tibia (n = 1), distal fibula (n = 1) and proximal ulna (n = 1). Three patients hadmetastatic disease at diagnosis. All patients received surgery and chemotherapy. Four of seven patients required dose modifications and three of them terminated treatment prematurely. Complete resection of the primary tumor was achieved in all individuals. Two of three affected patients failed to achieve surgical clearance of their primarymetastases and died. The third patient relapsed with multiple metastases and died. Two of four patients with localized diseasewere alive in first complete remission, a third patient in second complete remission after recurrence and a fourth patient died of acute leukemia, while still in first complete remission of osteosarcoma. Conclusions: Patients with RTS and osteosarcoma may be cured of their cancer with appropriate multimodal therapy. They should be treated like other osteosarcoma patients but preexisting disorders, needs for special support and development of toxicities have to be considered. Copyright © Informa Healthcare USA, Inc.
Staufner C.,University of Heidelberg |
Lindner M.,University of Heidelberg |
Lindner M.,University Childrens Hospital Frankfurt |
Dionisi-Vici C.,Bambino Gesu Childrens Hospital Irccs |
And 13 more authors.
Journal of Inherited Metabolic Disease | Year: 2016
Background: Adenosine kinase deficiency is a recently described defect affecting methionine metabolism with a severe clinical phenotype comprising mainly neurological and hepatic impairment and dysmorphism. Methods: Clinical data of 11 additional patients from eight families with adenosine kinase deficiency were gathered through a retrospective questionnaire. Two liver biopsies of one patient were systematically evaluated. Results: The main clinical symptoms are mild to severe liver dysfunction with neonatal onset, muscular hypotonia, global developmental retardation and dysmorphism (especially frontal bossing). Hepatic involvement is not a constant finding. Most patients have epilepsy and recurrent hypoglycemia due to hyperinsulinism. Major biochemical findings are intermittent hypermethioninemia, increased S-adenosylmethionine and S-adenosylhomocysteine in plasma and increased adenosine in urine. S-adenosylmethionine and S-adenosylhomocysteine are the most reliable biochemical markers. The major histological finding was pronounced microvesicular hepatic steatosis. Therapeutic trials with a methionine restricted diet indicate a potential beneficial effect on biochemical and clinical parameters in four patients and hyperinsulinism was responsive to diazoxide in two patients. Conclusion: Adenosine kinase deficiency is a severe inborn error at the cross-road of methionine and adenosine metabolism that mainly causes dysmorphism, brain and liver symptoms, but also recurrent hypoglycemia. The clinical phenotype varies from an exclusively neurological to a multi-organ manifestation. Methionine-restricted diet should be considered as a therapeutic option. © 2015, SSIEM.
Chien Y.-H.,National Taiwan University Hospital |
Abdenur J.E.,CHOC Childrens |
Baronio F.,University of Bologna |
Bannick A.A.,Childrens Hospital of Michigan Metabolic Clinic |
And 36 more authors.
Orphanet Journal of Rare Diseases | Year: 2015
Background: 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 β-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. Purpose of the study: 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. Results and Discussion: 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 800 μM 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. © 2015 Chien et al.
Feucht J.,University of Tübingen |
Opherk K.,University of Tübingen |
Lang P.,University of Tübingen |
Kayser S.,University of Tübingen |
And 16 more authors.
Blood | Year: 2015
Hematopoietic stem cell transplantation (HSCT) has improved over the last few decades. However, viral infections are often refractory to pharmacologic treatment and require alternative treatment strategies such as immunotherapy. Adenovirus (AdV) is th predominant disease-causing pathogen in pediatric HSCT. In a clinical trial, we analyzed safety and efficacy of ex vivo adoptive T-cell transfer (ACT) with hexon-specific T cells, predominantly of the T-helper cell 1 (Th1) phenotype, in 30 patients with AdV disease or viremia.ACTwasfeasible with noacute toxicities or significant onset of graft-versus-host disease. ACT led to in vivo antiviral immunity for up to 6 months with viral control, resulting in complete clearance of viremia in 86% of patients with antigen-specific T-cell responses. After ACT and a follow-up of 6 months, overall survival was markedly increased in responders (mean, 122 days; 15 survivors) compared with nonresponderswho all died shortly afterACT(mean, 24 days;no survivors). AdV-related mortalitywas100%in nonresponders compared with 9.5% in responders (≥1 log reduction of DNA copies per milliliter after ACT). Insummary, ex vivoACTofAdV-specific Th1 cellswaswell tolerated and led to successful and sustained restoration of T-cell immunity correlated with virologic response and protection from virus-related mortality. This cellular immunotherapy is a short-term available and broadly applicable treatment. The study is registered at European Union Clinical Trials Register as 2005-001092-35. © 2015 by The American Society of Hematology.
Grunert S.C.,University of Zürich |
Grunert S.C.,University Hospital Freiburg |
Stucki M.,University of Zürich |
Morscher R.J.,University of Zürich |
And 17 more authors.
Orphanet Journal of Rare Diseases | Year: 2012
Background: Isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine metabolism caused by mutations in MCCC1 or MCCC2 encoding the α and β subunit of MCC, respectively. The phenotype is highly variable ranging from acute neonatal onset with fatal outcome to asymptomatic adults. Methods. We report clinical, biochemical, enzymatic and mutation data of 88 MCC deficient individuals, 53 identified by newborn screening, 26 diagnosed due to clinical symptoms or positive family history and 9 mothers, identified following the positive newborn screening result of their baby. Results: Fifty-seven percent of patients were asymptomatic while 43% showed clinical symptoms, many of which were probably not related to MCC deficiency but due to ascertainment bias. However, 12 patients (5 of 53 identified by newborn screening) presented with acute metabolic decompensations. We identified 15 novel MCCC1 and 16 novel MCCC2 mutant alleles. Additionally, we report expression studies on 3 MCCC1 and 8 MCCC2 mutations and show an overview of all 132 MCCC1 and MCCC2 variants known to date. Conclusions: Our data confirm that MCC deficiency, despite low penetrance, may lead to a severe clinical phenotype resembling classical organic acidurias. However, neither the genotype nor the biochemical phenotype is helpful in predicting the clinical course. © 2012 Grünert et al.; licensee BioMed Central Ltd.
Heusch P.,University of Duisburg - Essen |
Aker S.,University of Duisburg - Essen |
Boengler K.,University of Duisburg - Essen |
Deindl E.,Ludwig Maximilians University of Munich |
And 10 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2010
Our objective was to address the balance of inducible nitric oxide (NO) synthase (iNOS) and arginase and their contribution to contractile dysfunction in heart failure (HF). Excessive NO formation is thought to contribute to contractile dysfunction; in macrophages, increased iNOS expression is associated with increased arginase expression, which competes with iNOS for arginine. With substrate limitation, iNOS may become uncoupled and produce reactive oxygen species (ROS). In rabbits, HF was induced by left ventricular (LV) pacing (400 beats/min) for 3 wk. iNOS mRNA [quantitative real-time PCR (qRT-PCR)] and protein expression (confocal microscopy) were detected, and arginase II expression was quantified with Western blot; serum arginine and myocardial nitrite and nitrate concentrations were determined by chemiluminescence, and protein S-nitrosylation with Western blot. Superoxide anions were quantified with dihydroethidine staining. HF rabbits had increased LV end-diastolic diameter [20.0 ± 0.5 (SE) vs. 17.2 ± 0.3 mm in sham] and decreased systolic fractional shortening (11.1 ± 1.4 vs. 30.6 ± 0.7% in sham; both P < 0.05). Myocardial iNOS mRNA and protein expression were increased, however, not associated with increased myocardial nitrite or nitrate concentrations or protein S-nitrosylation. The serum arginine concentration was decreased (124.3 ± 5.6 vs. 155.4 ± 12.0 μmol/l in sham; P < 0.05) at a time when cardiac arginase II expression was increased (0.06 ± 0.01 vs. 0.02 ± 0.01 arbitrary units in sham; P < 0.05). Inhibition of iNOS with 1400W attenuated superoxide anion formation and contractile dysfunction in failing hearts. Concomitant increases in iNOS and arginase expression result in unchanged NO species and protein S-nitrosylation; with substrate limitation, uncoupled iNOS produces superoxide anions and contributes to contractile dysfunction. Copyright © 2010 the American Physiological Society.
Doring M.,University of Tübingen |
Rohrer K.M.,University of Tübingen |
Erbacher A.,University of Tübingen |
Gieseke F.,Research Institute Childrens Cancer Center Hamburg |
And 5 more authors.
Annals of Hematology | Year: 2015
The human leukocyte antigen DR surface expression on CD14+ monocytes reflects the degree to which these cells have been activated. Given the central role monocytes and macrophages play in the immune system, a decreased human leukocyte antigen DR expression on CD14+ monocytes results in a hallmark of altered immune status during systemic inflammatory response syndrome. We hypothesize that human leukocyte antigen DR expression might be similarly altered after hematopoietic stem cell transplantation and during post-transplant complications. Using flow cytometry, this study investigates the human leukocyte antigen DR surface expression of CD14+ monocytes in 30 pediatric and young adult patients up to 1 year after hematopoietic stem cell transplantation. Normal values were derived from a control group of healthy children, adolescents, and young adults. Human leukocyte antigen DR expression decreased significantly prior and during bacterial infection or sepsis. By contrast, human leukocyte antigen DR expression levels were elevated before and at the time of viremia. Human leukocyte antigen DR expression was also elevated during acute graft-versus-host disease. In contrast, the expression was reduced when patients had hepatic veno-occlusive disease. A significant decrease of human leukocyte antigen DR expression was associated with a relapse of the underlying disease and before death. Human leukocyte antigen DR expression on CD14+ monocytes appears to be a promising parameter that might allow identification of patients at risk after hematopoietic stem cell transplantation. © 2014, Springer-Verlag Berlin Heidelberg.