Hannover, Germany
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Mayorandan S.,Hannover Medical School | Meyer U.,Hannover Medical School | Gokcay G.,Istanbul University | Segarra N.G.,Reference Center for Inherited Metabolic Diseases | And 29 more authors.
Orphanet Journal of Rare Diseases | Year: 2014

Background: Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data. Methods. Via questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications. Results: Early treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 μM) and NTBC-levels in the therapeutic range (20-40 μM). Side effects of NTBC are mild and often transient. Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood). Conclusion: Based on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations. © 2014 Mayorandan et al.; licensee BioMed Central Ltd.


Janzen N.,Screening Labor Hanover | Janzen N.,Hannover Medical School | Janzen N.,Ruhr University Bochum | Steuerwald U.,Screening Labor Hanover | And 5 more authors.
Clinica Chimica Acta | Year: 2013

Background: Metabolic screening including newborn screening requires further differentiation of C5-acylcarnitines in order to separate different metabolic disorders and to detect interferents like pivalic acid originating from antibiotics. Methods: For individual quantification of C5-acylcarnitine isoforms in dried blood spots we combined UPLC using a C18 column and gradient elution with tandem mass spectrometry in ESI+. mode. Results: Results were linear, coefficients of determination (R2)>0.9977, intra- and inter-assay coefficients of variations <5.2%, recovery 96.8-105.2%, limits of detection and quantitation <0.2μmol/L. Out of 29.309 blood samples of the isolated population of the Faroe Islands 56 exceeded the cut-off of 0.5μmol/L for C5-acylcarnitine; 45 of which could be retested using the method described. Pivaloylcarnitine was identified in 43 samples, isovalerylcarnitine was found in two samples. Conclusions: The method was developed to allow direct re-analysis of samples showing elevated concentrations of C5-acylcarnitines in a metabolic screening program based on quantification of acylcarnitines after butylation. The technique should be especially useful in newborn screening for exclusion of false positives and for differentiation between isovaleric acidemia and 2-methylbutyryl-CoA dehydrogenase deficiency. •Fast separation of C5-acylcarnitines•Separation and quantitation of acylcarnitines without derivatization•Identification of pivalic acid as causative drug in cases of carnitine depletion and of false positive screening results•Second tier testing for isoforms of C5-acylcarnitines in metabolic screening. © 2013 Elsevier B.V.


Janzen N.,Screening Labor Hanover | Janzen N.,Ruhr University Bochum | Janzen N.,Hannover Medical School | Terhardt M.,Screening Labor Hanover | And 7 more authors.
Clinica Chimica Acta | Year: 2014

Background: Orotic acid (OA) is the key parameter in the detection of ornithine transcarbamylase deficiency (OTC-D). Inclusion of OA into newborn screening compatibility with existing analytical procedures is necessary. Methods: OA was eluted from dried blood spots with methanol containing deuterated [1,3-15N2] OA as internal standard. Quantification by tandem mass spectrometry was accomplished without chromatographic separation. Samples were measured in MRM mode for the masses m/z 155.1→111 for OA and 157.1→113 for d2 OA. Results: OA was determined in a wide range of concentrations with high precision, LOD and LOQ being 0.21 and 0.65. μmol/L, respectively. Values correlated well with those obtained after chromatography. Pretreatment of samples with HCl-butanol regularly used for acylcarnitine measurement did not significantly affect quantitative results. Inclusion of the new method into the standard newborn screening procedure did not alter the results for acylcarnitines or amino acids; the total time per analysis, however, was increased from 1.15 to 1.85. min.OA levels of 707 unaffected newborns ranged from 0.28 to 3.73. μmol/L. Five newborns with OTC-D showed concentrations of 89.7-211.1. μmol/L. In newborns with severe citrullinaemia we found values in the range of 4.99-127.7. μmol/L. Conclusions: This new method can be used as a standalone measurement of OA but it can also easily be implemented into standard newborn screening techniques as a useful supplement. In this case the method allows detection of newborns with OTC deficiency without an extra analytical run. © 2013 Elsevier B.V.


Rasmussen J.,National Hospital | Nielsen O.W.,Copenhagen University | Janzen N.,Screening Labor Hanover | Janzen N.,Ruhr University Bochum | And 6 more authors.
Journal of Inherited Metabolic Disease | Year: 2014

Background: Primary carnitine deficiency (PCD) is an autosomal recessive disorder of fatty acid oxidation and has been associated to episodes of sudden death in the Faroe Islands. Data are presented from the nationwide population based Faroese screening program to find people with low carnitine levels indicating PCD. Methods: Whole blood samples from dried blood spots were analysed by tandem mass spectrometry with and without butylation. Genetic analyses were performed in all people with non-butylated free carnitine (fC0) below 7 μmol/L. Results: 55 % (n∈=∈26,462) of the entire population was screened and 89 PCD patients were identified, yielding an overall prevalence of 1:297 of PCD in the Faroe Islands. Carnitine levels were positively correlated to age in both males and females (p∈<∈0.003) although levels decreased in females when reaching fertile age. The gender difference in mean carnitine levels was significant during female fertile age (4.71 μmol/L fC0 in the age group 25-30 years, p∈<∈0.01). A lower cut-off of 5 μmol/L in fC0 identified all homozygous for the severe genotype c.95A∈>∈G (p.N32S) (n∈=∈20). Conclusion: Carnitine levels differ by gender and age. A lower cut-off of 5 μmol/L in fC0 was appropriate to identify c.95A∈>∈G homozygotes. The prevalence of PCD in the Faroe Islands is the highest reported in the world (1:297). © 2013 SSIEM and Springer Science+Business Media Dordrecht.


PubMed | Ruhr University Bochum, Screening Labor Hanover, Hannover Medical School and Istanbul University
Type: | Journal: Clinica chimica acta; international journal of clinical chemistry | Year: 2014

Orotic acid (OA) is the key parameter in the detection of ornithine transcarbamylase deficiency (OTC-D). Inclusion of OA into newborn screening compatibility with existing analytical procedures is necessary.OA was eluted from dried blood spots with methanol containing deuterated [1,3-(15)N2] OA as internal standard. Quantification by tandem mass spectrometry was accomplished without chromatographic separation. Samples were measured in MRM mode for the masses m/z 155.1 111 for OA and 157.1 113 for d2 OA.OA was determined in a wide range of concentrations with high precision, LOD and LOQ being 0.21 and 0.65 mol/L, respectively. Values correlated well with those obtained after chromatography. Pretreatment of samples with HCl-butanol regularly used for acylcarnitine measurement did not significantly affect quantitative results. Inclusion of the new method into the standard newborn screening procedure did not alter the results for acylcarnitines or amino acids; the total time per analysis, however, was increased from 1.15 to 1.85 min. OA levels of 707 unaffected newborns ranged from 0.28 to 3.73 mol/L. Five newborns with OTC-D showed concentrations of 89.7-211.1 mol/L. In newborns with severe citrullinaemia we found values in the range of 4.99-127.7 mol/L.This new method can be used as a standalone measurement of OA but it can also easily be implemented into standard newborn screening techniques as a useful supplement. In this case the method allows detection of newborns with OTC deficiency without an extra analytical run.


PubMed | Tierarztliche Klinik fur Pferde, Free University of Berlin and Screening Labor Hanover
Type: Journal Article | Journal: Equine veterinary journal | Year: 2016

Evidence suggest there is a link between equine atypical myopathy (EAM) and ingestion of sycamore maple tree seeds.To further evaluate the hypothesis that the ingestion of hypoglycin A (HGA) containing sycamore maple tree seeds causes acquired multiple acyl-CoA dehydrogenase deficiency and might be associated with the clinical and pathological signs of EAM.Case report.Necropsy and histopathology, using hematoxylin and eosin and Sudan III stains, were performed on a 2.5-year-old mare that died following the development of clinical signs of progressive muscle stiffness and recumbency. Prior to death, the animal ingested sycamore maple tree seeds (Acer pseudoplatanus). Detection of metabolites in blood and urine obtained post mortem was performed by rapid ultra-performance liquid chromatography-tandem mass spectrometry. Data from this case were compared with 3 geldings with no clinical history of myopathy.Macroscopic examination revealed fragments of maple tree seeds in the stomach and severe myopathy of several muscle groups including Mm.intercostales, deltoidei and trapezii. Histologically, the affected muscles showed severe, acute rhabdomyolysis with extensive accumulation of finely dispersed fat droplets in the cytoplasm of degenerated skeletal muscle cells not present in controls. Urine and serum concentrations of several acyl carnitines and acyl glycines were increased, and both contained metabolites of HGA, a toxic amino acid present in sycamore maple tree seeds.The study supports the hypothesis that ingestion of HGA-containing maple tree seeds may cause EAM due to acquired multiple acyl-CoA dehydrogenase deficiency.


Sander J.,Screening Labor Hanover | Terhardt M.,Screening Labor Hanover | Sander S.,Screening Labor Hanover | Janzen N.,Screening Labor Hanover | Janzen N.,Hannover Medical School
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2016

L-α-amino-methylenecyclopropyl propionic acid (Hypoglycin A, HGA) has been found to be the toxic compound in fruits of the Sapindaceae family causing acute intoxication when ingested as food or feed. Clinical symptoms are consistent with acquired multiple acyl-CoA dehydrogenase deficiency (MADD). Ultra performance liquid chromatography-tandem mass spectrometry was used to measure HGA after butylation. Sample volumes were 10 μL for serum and 20 μL for urine. Internal standard for HGA was d3-leucine, samples were plotted on a 7-point linear calibration curve. Coefficients of variation were <15% at 0.01 μmol HGA/L and ≤4.1% at 10 μmol/L. R2 values for linearity were ≥0.995. In order to quantify non-metabolized HGA together with some of its metabolites plus a spectrum of acyl glycines and acyl carnitines typical for acquired MADD in one single analysis HGA measurement was integrated into a method which we previously developed for metabolites of HGA and acyl conjugates. The new method is suitable for biochemical diagnosis of Ackee fruit poisoning or atypical myopathy in horses and for forensic purposes in cases of suspected HGA poisoning. © 2016 Elsevier B.V.


Neisse T.,Hannover Medical School | N. N.J.,Screening Labor Hanover | N. N.J.,Hannover Medical School | Das A.M.,Hannover Medical School
Journal of Pediatric Biochemistry | Year: 2015

Fetal infection is associated with considerable perinatal morbidity. Dysfunction of human umbilical venous endothelial cells (HUVEC) may compromise fetal blood supply from the placenta. HUVECs were incubated with one of the key inflammatory mediators, lipopolysaccharides (LPS), and activities of respiratory chain enzymes were measured. Based on gestational age, HUVEC were divided into a mature and two premature groups from otherwise uncomplicated pregnancies (four patients each) and incubated for 1, 6, or 12 hours with LPS (100 ng/mL), respectively, incubation without LPS served as a control. We analyzed the activities of respiratory chain enzymes and citrate synthase as a mitochondrial marker spectrophotometrically. No significant differences in respiratory chain activities between the LPS-incubated cells and internal controls could be observed. However, we were able to demonstrate significant differences depending on gestational age: respiratory chain complex IV (p < 0.01) showed higher activity and complex I + III (p = 0.01) lower activity at lower gestational age. No such differences were observed for complex II + III, complex V, and citrate synthase. No effect on the activities of mitochondrial respiratory chain enzymes induced by LPS could be shown. Activity of complex I + III was decreased and activity of complex IV was increased at lower gestational age in control and LPS-incubated cells. Copyright © 2015, Georg Thieme Verlag KG. All rights reserved.


PubMed | Screening Labor Hanover
Type: | Journal: Clinica chimica acta; international journal of clinical chemistry | Year: 2013

Metabolic screening including newborn screening requires further differentiation of C5-acylcarnitines in order to separate different metabolic disorders and to detect interferents like pivalic acid originating from antibiotics.For individual quantification of C5-acylcarnitine isoforms in dried blood spots we combined UPLC using a C18 column and gradient elution with tandem mass spectrometry in ESI+mode.Results were linear, coefficients of determination (R(2))>0.9977, intra- and inter-assay coefficients of variations <5.2%, recovery 96.8-105.2%, limits of detection and quantitation <0.2 mol/L. Out of 29.309 blood samples of the isolated population of the Faroe Islands 56 exceeded the cut-off of 0.5 mol/L for C5-acylcarnitine; 45 of which could be retested using the method described. Pivaloylcarnitine was identified in 43 samples, isovalerylcarnitine was found in two samples.The method was developed to allow direct re-analysis of samples showing elevated concentrations of C5-acylcarnitines in a metabolic screening program based on quantification of acylcarnitines after butylation. The technique should be especially useful in newborn screening for exclusion of false positives and for differentiation between isovaleric acidemia and 2-methylbutyryl-CoA dehydrogenase deficiency.

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