A A Roscher's research while affiliated with Ludwig-Maximilians-University of Munich and other places

Publications (76)

Article
Hintergrund Im Rahmen eines Pilotprojekts wurde der Umfang des deutschen Neugeborenenscreenings (NGS) um 14 Erkrankungen erweitert. Die bisher untersuchten Probenzahlen erlauben eine Zwischenbilanz für (a) Hypertyrosinämie Typ I (TYR I) und (b) Propionacidämie, Methylmalonacidurie sowie Vitamin-B12-abhängige Störungen (PA/MMA/B12). Material und Met...
Article
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) represents a potentially fatal fatty acid beta-oxidation disorder. Newborn screening (NBS) by tandem mass spectrometry (MS/MS) has been implemented worldwide, but is associated with unresolved questions regarding population heterogeneity, burden on healthy carriers, cut-off policies, false-posi...
Article
Full-text available
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) represents a potentially fatal fatty acid β-oxidation disorder. Newborn screening (NBS) by tandem mass spectrometry (MS/MS) has been implemented worldwide, but is associated with unresolved questions regarding population heterogeneity, burden on healthy carriers, cut-off policies, false-positiv...
Article
Motivation: During the Bavarian newborn screening programme all newborns have been tested for about 20 inherited metabolic disorders. Owing to the amount and complexity of the generated experimental data, machine learning techniques provide a promising approach to investigate novel patterns in high-dimensional metabolic data which form the source...
Article
Full-text available
In a random sample of children (aged 9-11 years; n = 5629), who were studied according to the ISAAC phase II protocol, heterozygosity of the alpha1 antitrypsin (alpha1-AT) Pi genotypes MS or MZ, or low alpha1-AT plasma levels, were not associated with an increased risk of developing asthma. Asthmatics with low levels of alpha1-AT were particularly...
Article
Full-text available
In a random sample of children (aged 9–11 years; n = 5629), who were studied according to the ISAAC phase II protocol, heterozygosity of the α1 antitrypsin (α1-AT) Pi genotypes MS or MZ, or low α1-AT plasma levels, were not associated with an increased risk of developing asthma. Asthmatics with low levels of α1-AT were particularly prone to develop...
Chapter
Angeborene Stoffwechseldefekte können sich in jedem Alter (bevorzugt im Neugeborenen-/Säuglingsalter) manifestieren. Die klinische Symptomatik kann sehr unspezifisch sein und beispielsweise einer Sepsis, einer zentralnervösen Blutung/Infektion oder einer kardialen Dekompensation ähneln. Eine rasche Diagnosestellung ist entscheidend. Die Primärdiagn...
Article
Lung disease is the direct cause of death in more than 90% of cystic fibrosis (CF) patients. Proteinase-antiproteinase imbalances are common in CF and alpha-1-antitrypsin (AAT) deficiency. We investigated the hypothesis that the AAT deficiency alleles PiS and PiZ contribute to pulmonary prognosis in CF. Two hundred and sixty-nine CF patients from S...
Article
Full-text available
Exposure to environmental tobacco smoke (ETS) and other air pollutants has been associated with small decrements in lung function. The susceptibility to pollution exposure may, however, vary substantially between individuals. Children with an impaired protease-antiprotease balance may be particularly vulnerable. Therefore this study aimed to invest...
Article
Newborn sceening programs are facing the challenge of an ethical responsible dealing with new screening technologies. Tandem mass spectrometry has the potential for simultaneous multi-disease screening using a single analytical technique. Therefore, classic requirements for the introduction of screening for the single disease are put in a modified...
Article
Die Tandemmassenspektrometrie ist eine neue, vielversprechende Screeningtechnologie. Neben der Phenylketonurie können im gleichen Analysengang ohne Mehraufwand eine Vielzahl weiterer behandelbarer Aminoazidopathien, Erkrankungen der Fettsäureoxidation und Organoazidurien erfasst werden. Dem potenziellen Nutzen stehen Risiken einer unkontrollierten,...
Article
Visual evoked potentials (VEP) were measured in 36 patients with early-treated phenylketonuria (PKU; aged 1 to 11 years) and good metabolic control before and after supplementation with omega-3 long-chain polyunsaturated fatty acids (LC-PUFA) from fish oil. Patients with PKU had significantly longer P100 latencies than 22 age-matched control subjec...
Article
There is a growing number of inborn errors of metabolism (IEM) with late onset but nevertheless life threatening course. Patients: Patients with late onset variants of urea cycle defects, fatty acid oxidation defects and organic acidurias are demonstrated. Methods: Biochemical, enzymatic, molecular methods and especially tandem mass spectrometry (T...
Article
3-Methylcrotonyl-CoA: carboxylase (EC 6.4.1.4; MCC) deficiency is an inborn error of the leucine degradation pathway (MIM *210200) characterized by increased urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. The clinical phenotypes are highly variable ranging from asymptomatic to profound metabolic acidosis and death in inf...
Article
Microdialysis is an in vivo technique to monitor tissue concentrations of low molecular weight substances by means of a continuously perfused artificial capillary with a semipermeable membrane placed into the region of interest. The suitability of microdialysis to determine tissue concentrations of amino acids was evaluated in vitro by placing the...
Article
Full-text available
Neugeborenenscreeningprogramme stehen vor der Herausforderung eines ethisch verantwortlichen Umgangs mit neuen Screeningtechnologien. Die Tandemmassenspektrometrie ermöglicht es, mit einem einzigen Analyseverfahren sehr viele Erkrankungen unterschiedlicher Inzidenz und Therapierbarkeit gleichzeitig zu erfassen. Klassische Voraussetzungen für die Ei...
Article
Many clinically relevant human diseases with genetic contribution are the result of partial, but not complete defects in specific gene functions. Chemical mutagenesis followed by phenotype screening is enabling the selection of mouse models suitable to study such consequences at the biochemical level by applying novel screening technologies for lar...
Chapter
Die bisherigen Ergebnisse des Modellprojekts zeigen, daß durch die Implementierung von TMS-Screening und dafür geeigneter Organisationsstrukturen die Gesamtzahl der durch das Screening erfaßten Neugeborenen mit behandelbaren Defekten von 1: 2600 (ehemaliges Programm) auf 1: 1350 nahezu verdoppelt werden konnte. Durch die frühzeitige Diagnose und Mö...
Article
Two distinct disorders with elevated urinary excretion of 2-hydroxyglutaric acid are known: L-2-hydroxyglutaric aciduria and D-2-hydroxyglutaric aciduria. This paper presents clinical and biochemical studies in three patients and unsuccessful prenatal diagnosis in one case with combined D-2- and L-2-hydroxyglutaric aciduria. We suggest that these p...
Article
The newborn screening programme in Bavaria was confronted with several problems. Number of disorders and process quality no longer complied with screening guidelines. Mixed financing, distributed between the state (PKU, galactosaemia) and health insurances (hypothyroidism) had promoted an increasing dissipation of the system. Notified participation...
Article
Das bayerische Neugeborenen-Screening-Programm war mit einer Reihe von Problemen konfrontiert. Untersuchungsumfang und Prozessqualität entsprachen nicht mehr den Screening-Richtlinien. Begünstigt durch eine Mischfinanzierung verteilt auf Staat (PKU, Galaktosämie) und Krankenkassen (Hypothyreose) war es zu einer zunehmenden Zersplitterung des System...
Article
Four ATP-binding cassette (ABC) half-transporters have been identified in mammalian peroxisomes: adrenoleukodystrophy protein (ALDP), adrenoleukodystrophy-related protein (ALDRP), 70-kDa peroxisomal membrane protein (PMP70) and PMP70-related protein (P70R). Inherited defects in ALDP cause the neurodegenerative disorder X-linked adrenoleukodystrophy...
Article
Full-text available
Ceramide (CER) is an important signaling molecule involved in a variety of cellular processes, including differentiation, cell growth, and apoptosis. Currently, different techniques are applied for CER quantitation, some of which are relatively insensitive and/or time consuming. Tandem mass spectrometry with its high selectivity and sensitivity is...
Article
Amniocentesis was performed at 17 weeks' gestation on a 39-year-old woman at risk of being a carrier for X-linked adrenoleukodystrophy (X-ALD). Her first son had been affected with childhood cerebral X-ALD and had died at the age of nine years. DNA analysis had not been performed nor was any material available. The amniotic fluid cells (AFC) karyot...
Article
Full-text available
The feasibility of rectal administration of didanosine (DDI) was studied in six human immunodeficiency virus-infected patients. After oral intake of a DDI solution (100 mg/m2 of body surface area) combined with an antacid (Maalox), pharmacokinetic parametric values were in accordance with previously published data; the mean +/- standard deviation f...
Article
Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disease with a wide range of clinical manifestation. In 90-95% of the cases it is caused by 21-hydroxylase deficiency (OMIM #201910) due to mutations of the CYP21 gene (GDB Accession #M12792). In most cases the CYP21-inactivating point mutations are transferred by apparent gene co...
Article
Newborn screening for inborn errors of metabolism is one of the most important achievements of preventive medicine to avoid disabilities and childrens death. In Bavaria, like in the rest of germany, the guthrie test for phenylketonuria was established in the late sixties. In the early eighties the introduction of screening for galactosemia and hypo...
Article
X-linked adrenoleukodystrophy (ALD), a leukodystrophy characterized by abnormal accumulation of saturated very long chain fatty acids in brain white matter and adrenal cortex, is the most common inherited peroxisomal disorder. The biochemical defect is localized to the level of lignoceroyl-CoA synthesis, a step in the peroxisomal beta-oxidation of...
Article
The stimulating effect of bradykinin on phosphorylation of proteins at tyrosine residues was visualized on human keratinocytes in primary culture. Keratinocytes were subjected either to short-time (30 s) or to long-time stimulation (4 h) with 200 nM bradykinin. Especially keratinocytes of the G1 phase showed bright immunofluorescence with monoclona...
Article
1. In this study, the abilities of PC12 cells to synthesize and degrade kinins were investigated. Kinin formation was assessed as kinin and kininogen content of cells and supernatants in serum-free incubations by use of a bradykinin-specific radioimmunoassay. Expression of kininogen mRNA was demonstrated by reverse-transcriptase PCR. Kinin degradat...
Article
Full-text available
We evaluated the pharmacokinetics of rectally administered zidovudine (ZDV) in 10 human immunodeficiency virus-infected adults. After rectal administration of an aqueous ZDV solution (250 mg of ZDV), mean peak ZDV levels were 1.3 +/- 0.7 micromol/liter (mean +/- standard deviation) versus 5.0 +/- 2.2 micromol/liter (P < 0.0001) after oral intake of...
Article
We describe a simple DNA-based method to assign the two common alpha 1-proteinase inhibitor (alpha 1-antitrypsin) deficiency alleles in the Pi-system (Pi*Z and Pi*S). Two sets of mutated primers are used in the polymerase chain reaction (PCR), followed by a restriction enzyme digest of the products. The mutated forward primers create a Taq I site o...
Article
The distribution of a nucleotide polymorphism in the core promoter of the human B2-bradykinin receptor gene was examined in the population of southern Germany. The allelic frequencies were 0.595 for C allele and 0.405 for the T allele. The allele frequencies were in Hardy-Weinberg equilibrium. This new marker provides a valuable tool to assess the...
Article
Full-text available
Receptors for bradykinin (BK) were characterized in primary cultures of beating neonatal rat cardiomyocytes using [3H]BK was radioligand. Degradation studies demonstrated that [3H]BK was stable for at least 2 h when incubated with cardiomyocytes at 2 and 37 degrees C in the presence of bacitracin in combination with captopril or ramiprilat. Without...
Article
Inflammatory demyelination in the central nervous system in the childhood cerebral phenotype of X-linked adrenoleukodystrophy (X-ALD) bears resemblance to that of multiple sclerosis. With a view to an association of HLA class II genes, specifically HLA-DRB1 subtype DRB1*15 to multiple sclerosis we investigated the HLA class II DR haplotype in 29 un...
Article
The characterization of the genomic organization of the B2 bradykinin receptor gene enabled us to systematically search for polymorphic markers in this gene in a South German cohort (N = 179). We identified at least three polymorphic sites in each of the three exons existing: (i) in exon 1 next to the promoter region, a tandem repeat polymorphism c...
Article
Hybridization of Northern blots with a probe corresponding to the coding region of the bradykinin B2 receptor revealed a single transcript of approximately 4.0 kb. Using the same probe, we detected a 2.6 kb human cDNA clone that overlapped 103 bp with the 3' end of the known coding region and contained a classical polyadenylation site and a polyA t...
Article
Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expression of X-ALD an...
Article
The distribution of a nucleotide polymorphism in intron 2 of the ß-globin gene (IVS-2 nt 666 C > T was examined in populations in southern Germany and Cameroon. The allelic frequencies were 0.86 for T and 0.14 for C in southern Germany and 0.87 for T and 0.13 for C in Cameroon, respectively.
Article
The pharmacokinetics of oral zidovudine in HIV-infected children and adults are reported. Fourty-six patients were investigated. For data analysis three groups of similar size were formed: young children 4 months-4 years, n = 15 (group 1), older children up to 13 years, n = 16 (group 2) and young adults, n = 15 (group 3). After a single oral dose r...
Article
Bradykinin exerts a broad spectrum of cellular effects on different tissues. It is believed that these effects are predominantly mediated by the recently cloned B2 receptor. The mechanism of post-receptor signal transduction is not known in detail. Involvement of protein kinase C (PKC) was suggested and activation of the classical PKC isoforms alph...
Article
Zidovudine (ZDV) is widely used in patients with HIV infection. Although major pharmacokinetic parameters have been evaluated with comparable results, the available data so far on the protein binding of ZDV in serum are contradictory. A method for the determination of the unbound drug in sera was used to investigate different experimental condition...
Article
Clinical, biochemical, neuropathological and neurochemical findings in a case of Hartnup syndrome are reported. After initially normal development, the affected girl suffered progressive neuropsychiatric decline with statomotor and mental retardation and intractable seizures and died at the age of 2 years. Postmortem neuropathological and neurochem...
Article
Three sets of monoclonal antibodies against bradykinin (MBK1, MBK2, MBK3) were generated by somatic cell fusion, characterized by their peptide specificity and compared to the known ligand specificity of the kinin receptor subtypes. By these criteria the paratope of MBK3 resembled the B2 receptor binding site whereas MBK1 shared principal binding c...
Article
Three sets of monoclonal antibodies against bradykinin (MBK1, MBK2, and MBK3) were generated by somatic cell fusion, characterized by their peptide specificity, and compared with the known ligand specificity of the kinin receptor subtypes. By these criteria, the paratope of MBK3 resembled the B2 receptor binding site, whereas MBK1 shared principal...
Article
mAb against bradykinin, the prototypic member of the kinin family of vasodilator peptides, were generated by somatic cell fusion. The antibodies were isotyped as IgG1, kappa-type, and their target epitopes mapped with bradykinin, lysyl-bradykinin (kallidin), kinin receptor antagonists, and fragments thereof, revealing three distinct sets of mAb, i....
Article
Full-text available
Active B2 bradykinin (BK) receptors were solubilized in high yields from intact monolayers or particulate fractions of cultured human foreskin fibroblasts using 4 mM of the non-denaturing zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS). Other detergents showed only minor (digitonin) or no (Triton X-100,...
Article
Full-text available
In order to study hormone-dependent transport properties of VIP-sensitive colonic crypt cells were prepared using chelators and mechanical forces. Thymidine kinase activities in crypt cells and absorptive cells were 77±8 and 9±2 nmol/min/mg protein respectively. Hormone sensitivity was shown by a dose-dependent increase of cAMP levels up to 18-fold...
Article
The influence of plasmalogen deficiency on membrane lipid mobility was determined by measuring fluorescence anisotropy of trimethylammoniumdiphenylhexatriene (TMA-DPH) and diphenylhexatrienylpropanoylhydrazylstachyose (glyco-DPH) inserted in the plasma membranes of human skin fibroblasts deficient in plasmalogens. The cells used were from patients...
Article
Plasmalogens (1-0-alkenyl-2-acyl-glycerophospholipids) are important constituents of most animal cell membranes. In artificial membranes, they differ from the “common” diacyl glycerophospholipids with regard to physical properties and interaction with sterols and proteins. Nothing is known, however, about the impact of plasmalogens on the propertie...
Article
Wir berichten über ein reifes, männliches Neugeborenes, das klinisch erstmals am 2. Lebenstag durch Trinkschwäche und Kußmaul'sche Atmung auffällig wurde. Laborbefunde wie ausgeprägte metabolische Azidose, Hyperammoniämie, Hyperglycinämie, Ketonurie und eine erhöhte Ausscheidung von Lactat und Propionat im Harn ließen an das Vorliegen einer Organoa...
Article
An impairment in the regulation of N-acetylneuraminic acid (NANA) biosynthesis might potentially contribute to accumulation of free NANA in fibroblasts of patients with sialic acid storage disease (ISSD). By the use of a glucosamine loading test an increase in uridine-diphosphate-N-acetyl-hexosamines (UDP-HexNAc) but not in free NANA was found. NAN...
Article
We describe a male infant of Austrian ancestry, the main clinical features including attacks of dyspnea due to laryngomalacia, severe mental and motor retardation, pronounced splenohepa-tomegaly and vacuolisation of peripheral lymphocytes. The clinical condition deteriorated progressively and the child died at the age of 21 months. Phase and electr...
Article
We report on a mature male newborn who presented clinically on the 2nd day of live with poor feeding and acidotic breathing. Laboratory findings like severe metabolic acidosis, hyperammonemia, hyperglycinemia, ketonuria and elevated urinary excretion of lactate and propionate suggested the presence of organoacidopathia. Propionic acidemia, however...
Article
There is a growing number of inborn errors of metabolism (IEM) with late onset but nevertheless life threatening course. Patients with late onset variants of urea cycle defects, fatty acid oxidation defects and organic acidurias are demonstrated. Biochemical, enzymatic, molecular methods and especially tandem mass spectrometry (TMS) are used for di...

Citations

... As for the kinin receptors, the Müller-Esterl laboratory has experimented with polyclonal antibodies that exhibited affinity to the native BK B 2 R, though not with monoclonal antibody ligands. Firstly, polyclonal an- tibodies raised against an anti-BK monoclonal behaved as an agonist anti-idiotype antibody, suggesting that a successive molding process may have retained some conformational features of BK in the final antibodies [80]. An ambitious project consisted of raising polyclonal antibodies to each extracellular domain of the rat B 2 R, and to some intracellular domains as well [81]. ...
... A feature that distinguishes MAT I/III deficiency from above disorders is that SAM is not elevated, while methionine is persistently high. Elevation of plasma total homocysteine level in severe cases can confuse the diagnostic process, misleading to homocystinuria due to CBS deficiency [10,17,24]. Mitochondrial disorders can also be genetic causes of hypermethioninemia [25]. ...
... As defined recently, any condition in which the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease is considered an IMD. 1 The cumulative incidence of IMDs varies between one in 1400 and one in 3000. 2,3 The measured prevalence in a particular country depends on the population selected and the method employed for screening. The prevalence of IMDs is unknown in Pakistan but is expected to be high due to the cultural preference of consanguineous marriages. ...
... The prevalence of vitamin B 12 deficiency detected by NBS varies between countries, also depending on the NBS strategies applied. The NBS for vitamin B 12 deficiency has been shown to be feasible under the application of second-tier strategies with a prevalence between 1 in 30,000 [20] and 1 in 5300 detected newborns in Germany [21,22]. An Italian study found a prevalence of 1 per 5000 in a cohort of 35,000 newborns [12]. ...
... In a study by Braun et al. on African and Mediterranean populations, the frequency of polymorphism in the SspI position was reported to be 14%. 14 In another study by Akhavan Niaki et al. in Mazandaran, 211 thalassemia carriers were examined. Of the 422 chromosomes examined, 20.6% were negative for SspI. ...
... In the period 1999-2001, a model trial was carried out in the German state of Bavaria, financed by the statutory health insurance carriers, in which the Guthrie test cards of more than 300 000 neonates were studied by TMS in order to demonstrate the benefit of TMS for population-wide neonatal screening. Through the introduction of AGS (adrenogenital syndrome), biotinidase, and TMS screening, the model trial was able to identify considerably more neonates with congenital metabolic diseases and endocrinopathies than had previously been possible (8,9). At the same time, the percentage of false positive findings was markedly reduced. ...