D. S. M. Schor
VU University Medical Center
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Featured researches published by D. S. M. Schor.
Pediatric Research | 1993
K. M. Gibson; H. J. Ten Brink; D. S. M. Schor; R. M. Kok; A H Bootsma; Georg F. Hoffmann; C. Jakobs
ABSTRACT: A stable-isotope dilution assay has been developed for quantitation of D- and L-2-hydroxyglutaric acids in physiologic fluids. D- and L-2-hydroxyglutaric acids are separated as the O-acetyl-di-(o)-2-butyl esters. The method uses D,L-[3,3,4,4-2H4]-2-hydroxyglutaric acid as internal standard with ammonia chemical ionization, selected ion monitoring gas chromatography-mass spectrometry. For 13 patients with L-2-hydroxyglutaric aciduria, the concentrations of L-2-hydroxyglutaric acid were urine, 1283 ± 676 mmol/mol creatinine (range, 332–2742; n = 12 patients); plasma, 47 ± 13 μmol/L (range, 27–62; n = 8); cerebrospinal fluid, 62 ± 30 μmol/L (range, 34–100; n = 6). In a child with D-2-hydroxyglutaric aciduria, the levels of D-2-hydroxyglutaric acid were urine, 1565 ± 847 mmol/mol creatinine (range, 729–2668; n = 4); plasma, 61 ± 14 μmol/L (range, 46–73; n = 3); cerebrospinal fluid, 15 and 25 μmol/L (n = 2). Control concentrations of D-and L-2-hydroxyglutaric acids were (D:L): urine (n = 18), 6.0 ± 3.6 mmol/mol creatinine (range, 2.8–17): 6.0 ± 5.4 (range, 1.3–19); plasma (n = 10), 0.7 ± 0.2 μmol/L (range, 0.3− −0.9): 0.6 ± 0.2 (range, 0.5–1.0); cerebrospinal fluid (n = 10), 0.1 ± 0.1 μmol/L (range, 0.07–0.3): 0.7 ± 0.6 (range, 0.3–2.3). Investigation of control amniotic fluid (n = 10) revealed the following values (D:L): 1.2 ± 0.4 μmol/L (range, 0.6–1.8): 4.0 ± 0.7 (range, 3.1–5.2), suggesting the feasibility of prenatal diagnosis in families at risk.
Biochimica et Biophysica Acta | 1994
Carlo W.T. van Roermund; D. S. M. Schor; Herman J. ten Brink; Cornelis Jakobs
Phytanic acid is a saturated, branched-chain fatty acid which as a consequence of the presence of a methyl group at the 3-position cannot be degraded by beta-oxidation. Instead, phytanic acid first undergoes alpha-oxidation to yield pristanic acid which can be degraded by beta-oxidation. The structure of the alpha-oxidation pathway and its subcellular localization has remained an enigma although there is convincing evidence that 2-hydroxyphytanic acid is an obligatory intermediate. We have now studied the degradation of 2-hydroxyphytanic acid in both rat and human liver. The results show that 2-hydroxyphytanic acid is converted to 2-ketophytanic acid in homogenates of rat as well as human liver. Detailed studies in rat liver showed that the enzyme involved is localized in peroxisomes accepting molecular oxygen as second substrate and producing H2O2. 2-Ketophytanic acid formation from 2-hydroxyphytanic acid was found to be strongly deficient in liver samples from Zellweger patients which lack morphologically distinguishable peroxisomes. The latter results not only provide an explanation for the elevated levels of 2-hydroxyphytanic acid in Zellweger patients but also suggest that the subcellular localization of 2-hydroxyphytanic acid dehydrogenation is identical in rat and man, i.e., in peroxisomes.
Molecular Genetics and Metabolism | 2002
Denise L.M Goh; Ankita Patel; George H. Thomas; Gajja S. Salomons; D. S. M. Schor; Cornelis Jakobs; Michael T. Geraghty
In mammals, the conversion of alpha-aminoadipate to alpha-ketoadipate by alpha-aminoadipate aminotransferase (AADAT) is an intermediate step in lysine degradation. A gene encoding for alpha-aminoadipate aminotransferase and kynurenine aminotransferase activities had been previously identified in the rat (KAT/AadAT). We identified the human gene (AADAT) encoding for AADAT. It has a 2329 bp cDNA, a 1278 bp open-reading frame, and is predicted to encode 425 amino acids with a mitochondrial cleavage signal and a pyridoxal-phosphate binding site. AADAT is 73% and 72% identical to the mouse and rat orthologs, respectively. The genomic structure spans 30 kb and consists of 13 exons. FISH studies localized the gene to 4q32.2. Two transcripts (approximately 2.9 and approximately 4.7 kb) were identified, with expression highest in liver. Bacterial expression studies confirm that the gene encodes for AADAT activity. The availability of the DNA sequence and enzyme assay will allow further evaluation of individuals suspected to have defects in this enzyme.
Journal of Chromatography B | 2002
D. S. M. Schor; Nanda M. Verhoeven; Eduard A. Struys; H.J. ten Brink; C. Jakobs
This paper describes a stable isotope dilution method for quantification of 3-hydroxyglutaric acid (3-HGA) in body fluids. The method comprises a solid-phase extraction procedure, followed by gas chromatographic separation and negative chemical ionization mass spectrometric detection. This method is selective and sensitive, and enables measurement of 3-HGA concentrations in urine-, plasma-, and CSF- samples of controls. The control ranges for 3-HGA were: urine 0.88-4.5 mmol/mol creatinine (n=12); plasma 0.018-0.10 micro mol/l (n=10), CSF 0.022-0.067 micro mol/l (n=10). We applied this method to measure 3-HGA in body fluids of three patients with glutaric aciduria type I. We also quantified 3-HGA in amniotic fluid of controls (range 0.056-0.11 micro mol/l; n=12) and in two samples from fetuses affected with glutaric aciduria type I.
Pediatric Research | 1992
H. J. Ten Brink; D. S. M. Schor; R. M. Kok; F. Stellaard; J. Kneer; B. T. Poll-The; J.-M. Saudubray; C. Jakobs
A series of in vivo experiments is described in which [1-13C]phytanic acid was given as an oral substrate to a healthy subject and two patients showing an impairment in phytanic acid degradation, one with Refsums disease and one with Chondrodysplasia punctata. After intake of the substrate by the control in a dose of 20 mg/kg body weight, the production of 13CO2 was measured in exhaled breath air and the concomitant formation of labeled 2-hydroxyphytanic acid and of pristanic acid was demonstrated by plasma analysis. After application of a substrate dose of 1 mg/kg body weight to the control, no substantial amounts of 13CO2 were measured, whereas time-dependent analysis of labeled 2-hydroxyphytanic acid in plasma yielded a concentration curve superimposed upon the baseline value (0.2 mol/L) of the unlabeled substance. Phytanic acid accumulated in plasma from the Refsums disease patient [649 mol/L, controls > 1 y (n = 100): <10 mol/L], whereas the pristanic acid concentration was within the control range [1.4 mol/L, controls > 1 y (n = 100): <3 mol/L]. Low amounts of 2-hydroxyphytanic acid were found normally present [0.04 mol/L, controls > 1 y (n = 11): <0.2 mol/L], and formation of labeled 2− hydroxyphytanic acid could not be demonstrated after ingestion of [1-13C]phytanic acid in a dose of 1 mg/kg body weight. In addition to phytanic acid accumulation (232 mol/L), the Chondrodysplasia punctata patient showed an elevated 2-hydroxyphytanic acid plasma concentration (0.4 mol/L), whereas the plasma pristanic acid level was in the control range (0.7 mol/L). Oral administration of [1-13C]phytanic acid (1 mg/kg body weight) to this patient resulted in a plasma concentration/time profile of labeled 2-hydroxyphytanic acid similar to that of the control. These findings demonstrate that α-hydroxylation of phytanic acid is a physiologic process and indicate that Refsums disease and Chondrodysplasia punctata patients have a different ability to convert phytanic acid into 2-hydroxyphytanic acid.
Journal of Inherited Metabolic Disease | 1997
Nanda M. Verhoeven; D. S. M. Schor; Gerbert A. Jansen; R. M. Kok; H. J. ten Brink; R. J. A. Wanders; C. Jakobs
Studies concerning peroxisomal β-oxidation have mainly been performed using radiolabelled fatty acids, after which the end products, 14 CO 2 and water-soluble radiolabelled products were measured (Wanders et al 1995). These studies only enable the investigation of a complete β-oxidation cycle and do not distinguish between the individual steps of βoxidation. We have developed a method for investigation of the first two steps of peroxisomal β-oxidation of pristanic acid in human liver. After incubation of human liver homogenates with pristanic acid or pristanoyl-CoA, the intermediates formed were hydrolysed to give their free acids, derivatized, and quantified by stable-isotop e dilution gas chromatography ‐mass fragmentography with negative chemical ionization. The applicability of the method described in this paper is demonstrated by showing the deficient oxidation of 2,3-pristanic acid to pristenic acid and 3-hydroxypristanic acid in liver from a Zellweger (McKusick 214100) patient.
Biochemical and Biophysical Research Communications | 1997
Nanda M. Verhoeven; D. S. M. Schor; H. J. ten Brink; R. J. A. Wanders; C. Jakobs
Journal of Lipid Research | 1992
H. J. Ten Brink; F. Stellaard; C. M. M. van den Heuvel; R. M. Kok; D. S. M. Schor; R. J. A. Wanders; C. Jakobs
Journal of Lipid Research | 1992
H. J. Ten Brink; D. S. M. Schor; R. M. Kok; B. T. Poll-The; R. J. A. Wanders; C. Jakobs
Journal of Lipid Research | 1997
Nanda M. Verhoeven; R. J. A. Wanders; D. S. M. Schor; Gerbert A. Jansen; C. Jakobs