Johannes - Sander

Hepatorenal tyrosinaemia (HT1) is an autosomal recessive disorder of tyrosine degradation resulting in hepatic and renal dysfunction, neurological sequelae may occur in some patients. The use of nitisinone (NTBC) has revolutionised treatment and outcome of this disorder. NTBC has to be combined with a low protein diet. While NTBC modulates the dise...

Zusammenfassung Seit mehr als 5 Jahrzehnten wird allen Neugeborenen in Deutschland eine Vorsorgeuntersuchung zur Früherkennung angeborener behandelbarer Krankheiten angeboten. Seit Beginn sind so etwa 35 Mio. Kinder untersucht worden. Anfangs ging es nur um die Früherkennung der Phenylketonurie, die ohne frühzeitige Behandlung zu nicht mehr korrigi...

Equine atypical myopathy is caused by hypoglycin A (HGA) and methylenecyclopropylglycine (MCPrG), the known protoxins of sycamore maple (Acer pseudoplatanus). Various tissues from five atypical myopathy cases were analyzed but only HGA was found. Whether deamination of MCPrG has already occurred in the intestine as the first stage of metabolization...

In horses, congenital defects of energy production from long-chain fatty acids have not been described so far. In contrast, inhibition of fatty acid degradation caused by the toxins hypoglycin A and methylenecyclopropylglycine from various maple species are observed frequently. These non-proteinogenic aminoacids are passed on placentally to fetuses...

Atypical myopathy (AM) is an acute seasonal rhabdomyolysis seen primarily in equids, caused by the ingestion of sycamore maple samaras containing hypoglycin A (HGA) and methylenecyclopropyl-glycine (MCPG). Toxic metabolites inhibit acyl-CoA dehydrogenases and enoyl-CoA hydratases, causing selective hyaline degeneration of type I muscle fibers. Two...

Background Plants from the Sapindaceae family that are consumed by horses (maple) and humans (ackee and litchi) are known to contain the toxins hypoglycin A and methylenecyclopropylglycine which cause seasonally occurring myopathy in horses and entero‐encephalopathic sickness in humans. Vertical transmission of these toxins from a mare to her foal...

Background Hypoglycin A (HGA) and methylenecyclopropylglycine (MCPrG) from seeds/seedlings of Sycamore maple (SM, Acer pseudoplatanus) causes atypical myopathy (AM) in horses. AM was not known to occur in wild ruminants until several fatalities in milus (Elaphurus davidianus) following the ingestion of HGA in SM seeds. However, a role for MCPrG has...

Ackee fruits (Blighia sapida), an important food source in some tropical countries, can be the cause of serious poisoning. Ackees contain hypoglycin A and methylenecyclopropylglycine. Experiments were undertaken by a volunteer to elucidate the metabolic details of poisoning. Rapid intestinal absorption of the toxins was followed by their slow degra...

Background: Up to now quantification of hypoglycin A in serum and urine in the range of nmols to μmols per liter plus the measurement of accumulated acyl conjugates have been used for the diagnosis of poisoning by fruits or seeds ofSapindaceae in humans and animals. A second poison, methylenecyclopropylglycine, however, is known to occur in this m...

Atypical myopathy (AM) in horses is caused by ingestion of seeds of the Acer species (Sapindaceae family). Methylenecyclopropylacetyl-CoA (MCPA-CoA), derived from hypoglycin A (HGA), is currently the only active toxin in Acer pseudoplatanus or Acer negundo seeds related to AM outbreaks. However, seeds or arils of various Sapindaceae (e.g., ackee, l...

Background Atypical myopathy in horses is caused by ingestion of seeds or seedlings of some maple trees (Acer species, family Sapindaceae). Elevated concentrations of acyl conjugates, a sign of inhibited ß-oxidation of fatty acids, are diagnostic for atypical myopathy. Quantification of acyl conjugates is currently not part of the standard test sch...

Hypoglycin A (HGA) and its metabolites have been associated with equine atypical myopathy (AM). AM is often fatal and can be treated solely symptomatically. Intestinal absorption of HGA was already investigated. After absorption and metabolism of HGA, biochemical modification is triggered similarly to congenital multiple acyl CoA dehydrogenase defi...

Background: Intestinal absorption of hypoglycin A (HGA) and its metabolism are considered major prerequisites for atypical myopathy (AM). The increasing incidence and the high mortality rate of AM urgently necessitate new therapeutic and/or preventative approaches. Objectives: To identify a substance for oral administration capable of binding HG...

The consumption of ackee (Blighia sapida) and lychee (Litchi chinensis) fruit has led to severe poisoning. Considering their expanded agricultural production, toxicological evaluation has become important. Therefore, the biochemical effects of eating 1 g/kg canned ackee containing 99.2 µmol/kg hypoglycin A and 5 g/kg canned lychee containing 1.3 µm...

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...

Hypoglycin A (HGA) was detected in blood and urine of a horse suffering from atypical myopathy (AM; Day 2, serum, 8290 μg/l; urine: Day 1, 574, Day 2, 742 μg/l) and in its cograzing partners with a high variability (46-1570 μg/l serum). Over the period of disease, the level of the toxic metabolites (methylencyclopropylacetic acid [MCPA]-conjugates)...

Tyrosinemia type I is an autosomal recessively inherited metabolic disease of tyrosine metabolism due to the deficiency of fumarylacetoacetate hydrolase. Clinical manifestations include hepatic failure, cirrhosis, hepatocellular carcinoma, renal fanconi syndrome, and neurologic crisis. With the introduction of 2-(2-nitro-4-trifluoro-methylbenzyol)-...

Hypoglycin A (2-amino-3-(2-methylidenecyclopropyl)propanoic acid) is the plant toxin shown to cause atypical myopathy in horses. It is converted in vivo to methylenecyclopropyl acetic acid, which is transformed to a coenzyme A ester that subsequently blocks beta oxidation of fatty acids. Methylenecyclopropyl acetic acid is also conjugated with carn...

Hypoglycin A (HGA) in seeds of Acer spp. is suspected to cause seasonal pasture myopathy in North America and equine atypical myopathy (AM) in Europe, fatal diseases in horses on pasture. In previous studies, this suspicion was substantiated by the correlation of seed HGA content with the concentrations of toxic metabolites in urine and serum (MCPA...

Evidence suggests 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 (MADD) and might be associated with the clinical and patholog...

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...

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 u...

21-Hydroxylase deficiency (21-OHD) is the target disease of newborn screening for congenital adrenal hyperplasia (CAH). We describe the additional detection of patients suffering from 11β-hydroxylase deficiency (11-OHD) by second-tier testing. Over a period of 5 years, screening for CAH was done in a total of 986,098 newborns by time-resolved immun...

Galactokinase (GALK) deficiency is an autosomal recessive disorder causing cataract formation that can be prevented or mitigated by early diagnosis and galactose-restricted diet. The aim of this retrospective study was to explore whether GALK-deficiency meets the criteria for neonatal mass screening programs. From 2000 until 2010, the Screening Lab...

Newborn screening for congenital adrenal hyperplasia (CAH) is usually done by quantifying 17α-hydroxyprogesterone using immunoassay. However, this test produces high rates of false positive results caused by cross reacting steroids. Therefore we have developed a selective and specific method with a short run time (1.25 min) for quantification of 17...

Although cyclosporine A (CSA) is considered to be an efficient immunosuppressive compound in transplantation, vascular side effects like arterial hypertension, neurologic complications and other adverse reactions occur. Interference of CSA with mitochondrial function may be responsible for these side effects. We evaluated the effect of CSA on mitoc...

Wie die Praxis zeigt, lassen sich beim Neugeborenen-Screening falsch-positive und falsch-negative Ergebnisse nicht vollständig verhindern. Diese Arbeit soll helfen, falsch-negative Ergebnisse zu vermeiden und mögliche Ursachen aufzuzeigen, die zu einem auffälligen Neugeborenen-Screening führen.

Background and aims: Hypoglycemia is a typical, potentially life-threatening symptom in classical galactosemia with blood galactose considerably elevated (up to ∼100 mg/dl). Therefore we tested the interference of galactose on POCT glucose meters. Methods: Galactose was added to heparin whole blood (glucose concentration 48-63 mg/dl in series I, 0...

The aim of the study was to develop a method for fast and reliable diagnosis of peroxisomal diseases and to facilitate differential diagnosis of cholestatic hepatopathy. For the quantification of bile acids and their conjugates as well as C(27) precursors di- and trihydroxycholestanoic acid (DHCA, THCA), in small pediatric blood samples we combined...

Blood samples for neonatal screening for inborn errors of metabolism are collected and shipped on standardized filter paper cards. Occasionally these samples are contaminated with EDTA, which is often used for anticoagulation. EDTA may interfere with newborn screening tests based on lanthanide fluorescence and thus lead to false-negative or false-p...

Guidelines for neonatal screening for inborn errors of metabolism published by the Federal Joint Committee of physicians and health insurances in Germany include preanalytical specifications, e. g. blood collection at 36 to 72 hours of life and rapid sample transportation which is necessary with respect to those target diseases of the German progra...

Hintergrund und Fragestellung: Für das Management des Neugeborenenscreenings auf angeborene Stoffwechselstörungen und Endokrinopathien sind bindende Forderungen bezüglich des Termins der Blutentnahme, des Probenversandes und der Fertigstellung der Laborbefunde in der einschlägigen Richtlinie des Gemeinsamen Bundesausschusses der Ärzte und Krankenka...

21-Hydroxylase deficiency congenital adrenal hyperplasia (CAH) is one of the target diseases in many newborn screening programs. 11beta-Hydroxylase defiency is less frequent and does not cause salt-losing crisis. Thus, it is not a target disease for newborn screening. However, affected newborns might show slightly elevated levels of 17-OH-progester...

Hintergrund: Viele Fruhgeborene entwickeln eine cholestatische Hepatopathie, die unbehandelt zu einer Gedeihstorung, Minderresorption fettloslicher Vitamine mit z.B. Gefahr einer Hirnblutung und sekundaren Leberschadigung fuhren kann, ferner bei etwa 10% der kleinen Fruhgeborenen zu Gallensteinen. Fragestellung: Welchen Verlauf haben die Serumgalle...

We present a fast and reproducible method for steroid analysis (corticosterone, deoxycorticosterone, progesterone, 17alpha-hydroxyprogesterone, 11-deoxycortisol, 21-deoxycortisol, androstenedione, testosterone, dihydrotestosterone and cortisol) in small volumes of serum and in dried blood spot samples by LC-MS/MS. No derivatisation was needed. LC s...

Neonatal screening programs for congenital adrenal hyperplasia (21-CAH) using an immunoassay for 17alpha-hydroxyprogesterone (17-OHP) generate a high rate of positive results attributable to physiological reasons and to cross-reactions with steroids other than 17alpha-OHP, especially in preterm neonates and in critically ill newborns. To increase t...

Tumor necrosis factor (TNF) is a central mediator of sepsis. The NcoI polymorphism within the TNF locus has been described as a prognostic marker for mortality in adult patients with sepsis. The aim of our study was to investigate the genotype and allele distribution of 2 TNF gene polymorphisms in preterm infants <32 weeks of gestational age, who d...

We investigated 80 patients affected by medium chain AcylCoA dehydrogenase deficiency (MCADD) in a German population, and found the following frequencies of mutation: 985A>G (81.9%); 157C>T (3.1%), 799G>A (3.1%), 244–245 insT (3.1%), 362C>T (1.3%) as well as five rare mutations at frequencies below 0.6%. About 4.4% of the mutations in our patients...

False-positive and false-negative results occur in current newborn-screening programs for hepatorenal tyrosinemia, which measure tyrosine concentrations in blood spots, sometimes in combination with other metabolites, including succinylacetone. We present our experience with a newly described method for succinylacetone quantification in routine new...

17-OHP immunoassays for neonatal screening often produce false positive results due to neonatal stress, low birth weight, low gestational age as well as cross-reacting antibodies. We have developed a refined method for steroid analysis in dried blood spots using high performance liquid chromatography and tandem mass spectrometry (LC-MS/MS). Steroid...

There are no molecular markers predicting susceptibility to cerebral morbidity in premature infants and therapeutic strategies are still limited. Genetic polymorphisms in the tumour necrosis factor (TNF) gene modify TNF expression. A systemic perinatal inflammatory response is known to be a risk factor for severe intraventricular haemorrhage (IVH)...

Zusammenfassung Defizienzen der langkettigen 3-Hydroxy-Acyl-CoA-Dehydrogenase (LCHAD) sind selten. Es treten akut hypoketotische Hypoglykämie mit Hepatopathie und Enzephalopathie, chronisch Myopathie, Kardiomyopathie, Neuropathie und Retinopathie auf. Über 80% der in einer Stoffwechseldekompensation stationär Aufgenommenen sterben vor Vollendung de...

Long-chain l-3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency has been included in the routine neonatal screening program by the German screening commission. As tandem mass spectrometry (TMS) does not discriminate between the different defects of the mitochondrial trifunctional protein (MTP) screening for isolated LCHAD deficiency includes the de...

Background: A systemic perinatal inflammatory response is known to be a risk factor of severe intraventricular hemorrhage (IVH) in preterm infants. Molecular markers predicting susceptibility to cerebral morbidity in premature infants are missing. Genetic polymorphisms in the tumor necrosis factor (TNF) -gene are known to modify TNF expression.

In Germany, neuroblastoma is the most frequent extracranial solid childhood tumour. Its properties made it seem an ideal candidate for screening. A German trial assessed the effect of screening at one year of age from 1995-2001 in a nationwide project. We present here the methods developed for the estimation of lead-time and overdiagnosis in this p...

In 1979, a test to detect syphilis specific antibodies was added to the neonatal screening programme for metabolic diseases in Lower Saxony.1 We report test results for the period 1993 to the end of 2001 (684 156 samples). Analysis of data included calculation of annual incidence rates, dependency of maternal age, and birth weight of infants on the...

Neuroblastoma is the second most frequent malignancy in childhood. We investigated whether screening for neuroblastoma at 1 year of age reduces the incidence of metastatic disease or mortality. Screening was offered in 6 of the 16 German states from 1995 to 2000 with the remaining states serving as controls. We studied 2,581,188 children in the scr...

Unlabelled: In a period of 40 months (1st March 1999 to 30th June 2002) 610,000 blood samples were analysed in one screening centre for citrulline as a pilot study for neonatal screening using tandem mass spectrometry. Persistent hypercitrullinaemia (Cit >1.5 mg/dl or 85.5 micro mol/l, not corrected for recovery) was identified in 15 newborns. Fou...

We report a patient with BH(4)-sensitive phenylketonuria. In neonatal screening, phenylalanine levels above 10 mg/dl were detected. In the tetrahydrobiopterin- (BH(4)) loading test, phenylalanine concentrations in serum fell significantly. Dihydropteridine reductase activity in blood, pterines, and neurotransmitters in cerebrospinal fluid, as well...

We report a patient with BH4-sensitive phenylketonuria. In neonatal screening, phenylalanine levels above 10 mg/dl were detected. In the tetrahydrobiopterin- (BH4) loading test, phenylalanine concentrations in serum fell significantly. Dihydropteridine reductase activity in blood, pterines, and neurotransmitters in cerebrospinal fluid, as well as p...

Die Frage, ob eine Neuroblastomscreening im Alter von 1 Jahr die Inzidenz der metastasierten Neuroblastome bzw. die krankheitsbedingte Sterblichkeit senken kann, war bisher unbeantwortet. Ein einfacher Windeltest auf Neuroblastom wurde 2.581.188 Kindern im Alter von 1 Jahr in 6 von 16 Bundesländern von 1995–2000 angeboten (Screeningregion). Im glei...

The question whether neuroblastoma screening at one year of age reduces either incidence of stage 4 disease and/or mortality was open. We offered 2,581,188 children at one year of age a urine test in six of 16 German states from 1995 to 2000, the 2,117,600 children in the remaining states acted as contemporary controls. We compared the incidence of...

Neuroblastoma is the second most common type of childhood tumor. It is not known whether screening for neuroblastoma at one year of age reduces the incidence of metastatic disease or mortality due to neuroblastoma. We offered urine screening for neuroblastoma at approximately one year of age to 2,581,188 children in 6 of 16 German states from 1995...

Background The German Neuroblastoma Screening Project is the first controlled and population-based screening study to evaluate the presumed benefit of neuroblastoma mass screening at 1 year of age (10–18 months).ProcedureScreening takes place in 6 of the 16 German states; children from the remainder serve as controls. The German Childhood Cancer Re...

Background. As part of our neonatal screening program we applied tandem mass spectrometry on 128.225 dried blood samples for detection of inborn errors of metabolism. Results. Eleven patients with phenylketonuria and three patients with hyperphenylalaninemia were detected. Tyrosinemia and citrullinemia were found in one and four newborns, respectiv...

Background: With resprect to very early screening it has become necessary to apply laboratory techniques more sensitive and more precise than the formerly used Guthrie-test to guarantee correct detection of hyperphenylalaninemias. Three quantitative methods were compared. Methods and results: Phenylalanine was measured using tandem mass spectrometr...

Neuroblastoma screening during the first half-year of life is associated with a two- to three-fold overdiagnosis. Because regression processes seem to be confined to infancy, we investigated whether screening at 1 year would be associated with fewer overdiagnoses, and we investigated the characteristics of thus-detected and not-detected patients. T...

Background The question of whether screening for neuroblastoma (NB) results in a substantial improvement of the prognosis of the disease is still open. All data, including those of the European pilot studies, indicate the possibility of overdiagnosis in the case of possibly spontaneously regressing NBs if the screening is performed before 6 months...

Background The question of whether screening for neuroblastoma (NB) results in a substantial improvement of the prognosis of the disease is still open. All data, including those of the European pilot studies, indicate the possibility of overdiagnosis in the case of possibly spontaneously regressing NBs if the screening is performed before 6 months...

ZusammenfassungHintergrund: Das Neuroblastom ist der häufigste extrakranielle Tumor des Kindesal-ters. Die Prognose ist im wesentlichen von der Ausbreitung des Tumors und dem Patientenalter bei Diagnosestellung abhängig. Auf der einen Seite haben Patienten mit disseminierten Neuroblastomen eine sehr niedrige Überlebenswahrscheinlich-keit, auf der a...

We describe an assay for adenine phosphoribosyltransferase (APRT) activity, using dried blood spots on filter paper. The method is suitable for small amounts of blood but does not need radioactive reagents. This enzyme assay is tested for its practicability within routine neonatal screening. Activities are measured by spectrophotometric detection o...

A fluorometric assay in microtitre plates for the screening of phenylketonuria was evaluated and adapted to a neonatal screening programme. Using this assay, it is possible to determine quantitatively the phenylalanine concentration in dried blood spots on filter paper. The test exhibited a linear calibration curve with a good slope as well as suff...

Volatile anesthetics are suspected to cause various health risks even in subnarcotic concentrations (hepatotoxicity, mutagenicity, teratogenicity). Yet only for halothane a limit (MAK-value = 5 ppm) has been established for the entire FRG. In addition, in 1991 Hamburg and Schleswig-Holstein defined preliminary limits for isoflurane, enflurane and n...

69 children with congenital hypothyroidism, who were detected by neonatal screening in Lower Saxony, were reevaluated 1-12 years after diagnosis. They had been treated either by regional children's hospitals, local pediatricians or general practitioners. Substitution of thyroid hormone had started for the majority between day 7 and 14, for 17%, how...

This short communication compares a novel fluorimetric microplate enzyme immunoassay (FEIA) with a commercial time-resolved fluoroimmunoassay for the determination of thyrotropin in dried blood spots. The evaluation was performed using a retrospective study design with newborn blood samples from three screening centres. Non-parametric Spearman rank...

A new enzymatic, fluorometric method for screening newborns for phenylketonuria is described. The method makes a quantitative measurement of phenylalanine in dried blood possible using a NAD(H) dependent L-phenylalanine dehydrogenase in microtiter plates. The test is quick, precise and sensitive. It is not influenced by antibiotics and other amino...

Der Beweis für den regelhaften Übergang lokalisierter Neuroblastome in metastasierte Erkrankungen steht noch aus. Ein epidemiologischer Lösungsansatz erfordert, daß durch ein Screening die Zahl der Fälle mit metastasierter Erkrankung pro Bevölkerungseinheit reduziert wird und daraus folgend die Neuroblastom-Mortalität zurückgeht. Von 1983 bis 1990...

A colorimetric microassay for the simultaneous quantitative determination of galactose (Gal) and galactose-1-phosphate (Gal-1-P) in dried blood spots is described. An enzymatic reaction involving alkaline phosphatase (EC 3.1.3.1) and galactose dehydrogenase (EC 1.1.1.48) produces NADH, which is coupled with diaphorase (EC 1.8.1.4) and iodonitrotetr...

The proof for the general evolution of metastatic neuroblastoma from localized disease by a low-speed process is lacking. The epidemiological approach would require the decrease of neuroblastoma related mortality by reduction of the number of metastatic cases per population unit as a result of a screening program. During 1983 through 1990 the neuro...

During a five-year-period (1985-1989) 420,000 newborns in Lower Saxony, FRG, were screened for biotinidase deficiency using biotinyl-para-amino-benzoic-acid as substrate. Three newborns with profound biotinidase deficiency (activity 1.1%, 2.1%, 2.3% of mean normal activity level) were detected. Nine newborns had partial biotinidase deficiency (acti...

We adapted the recently described colorimetric method for the specific determination of phenylalanine to a microplate assay using a NAD(H)-dependent L-phenylalanine dehydrogenase. With respect to sensitivity, analytical recovery and interrun imprecision this method for measuring phenylalanine in eluates of paper-dried blood spots is suitable for ro...

The investigation of 8544 water samples from central water supply plants and of about 20,000 from own water supply plants of Southwest Lower Saxony with respect to nitrate pollution showed that 97.5% of the samples from the central water supply plants and of 63.6% from the own water supply plants contained nitrate concentrations lower than 50 mg/l....

Biotinidase activity was determined in a pilot study of 78,000 dried blood samples on filter paper. In the assay the liberation of p-aminobenzoic-acid from biotinyl-p-aminobenzoic-acid by biotinidase is tested. One boy was identified to be with biotinidase deficiency. Transient reduction of biotinidase activity to virtually negative test results wa...

A commercial immunoradiometric assay (IRMA) for thyroid stimulating hormone (TSH) was modified to be used with dried blood on filter paper of our neonatal screening programme. Sensitivity and precision were as good as with the conventional radioimmunoassay (RIA), but the IRMA was faster. In addition the IRMA was extremely cheap, because all kit rea...

IgG and IgM rubella antibodies were measured in dried blood samples from the neonatal metabolic screening program. Of 6613 samples from four central screening laboratories, 2