24 results on '"Prinsen, Hubertus C M T"'
Search Results
2. Rapid quantification of underivatized amino acids in plasma by hydrophilic interaction liquid chromatography (HILIC) coupled with tandem mass-spectrometry
- Author
-
Prinsen, Hubertus C. M. T., Schiebergen-Bronkhorst, B. G. M., Roeleveld, M. W., Jans, J. J. M., de Sain-van der Velden, M. G. M., Visser, G., van Hasselt, P. M., and Verhoeven-Duif, N. M.
- Published
- 2016
- Full Text
- View/download PDF
3. Expanding the clinical phenotype of COG6 deficiency
- Author
-
Haijes, Hanneke, Prinsen, Hubertus C M T, Thiel, Christian, Koerner, Christian, Verhoeven-Duif, Nanda M, and van Hasselt, Peter M
- Published
- 2014
- Full Text
- View/download PDF
4. Monitoring phenylalanine concentrations in the follow‐up of phenylketonuria patients: An inventory of pre‐analytical and analytical variation.
- Author
-
Coene, Karlien L. M., Timmer, Corrie, Goorden, Susan M. I., Hoedt, Amber E., Kluijtmans, Leo A. J., Janssen, Mirian C. H., Rennings, Alexander J. M., Prinsen, Hubertus C. M. T., Wamelink, Mirjam M. C., Ruijter, George J. G., Körver‐Keularts, Irene M. L. W., Heiner‐Fokkema, M. Rebecca, Spronsen, Francjan J., Hollak, Carla E., Vaz, Frédéric M., Bosch, Annet M., and Huigen, Marleen C. D. G.
- Published
- 2021
- Full Text
- View/download PDF
5. Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy.
- Author
-
Rumping, Lynne, Büttner, Benjamin, Maier, Oliver, Rehmann, Holger, Lequin, Maarten, Schlump, Jan-Ulrich, Schmitt, Bernhard, Schiebergen-Bronkhorst, Birgit, Prinsen, Hubertus C. M. T., Losa, Michele, Fingerhut, Ralph, Lemke, Johannes R., Zwartkruis, Fried J. T., Houwen, Roderick H. J., Jans, Judith J. M., Verhoeven-Duif, Nanda M., van Hasselt, Peter M., and Jamra, Rami
- Published
- 2019
- Full Text
- View/download PDF
6. GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay.
- Author
-
Rumping, Lynne, Tessadori, Federico, Pouwels, Petra J W, Vringer, Esmee, Wijnen, Jannie P, Bhogal, Alex A, Savelberg, Sanne M C, Duran, Karen J, Bakkers, Mark J G, Ramos, Rúben J J, Schellekens, Peter A W, Kroes, Hester Y, Klomp, Dennis W J, Black, Graeme C M, Taylor, Rachel L, Bakkers, Jeroen P W, Prinsen, Hubertus C M T, Knaap, Marjo S van der, Dansen, Tobias B, and Rehmann, Holger
- Published
- 2019
- Full Text
- View/download PDF
7. Cross-Omics: Integrating Genomics with Metabolomics in Clinical Diagnostics.
- Author
-
Kerkhofs, Marten H. P. M., Haijes, Hanneke A., Willemsen, A. Marcel, van Gassen, Koen L. I., van der Ham, Maria, Gerrits, Johan, de Sain-van der Velden, Monique G. M., Prinsen, Hubertus C. M. T., van Deutekom, Hanneke W. M., van Hasselt, Peter M., Verhoeven-Duif, Nanda M., and Jans, Judith J. M.
- Subjects
METABOLOMICS ,INBORN errors of metabolism ,GENOMICS ,NUCLEOTIDE sequencing - Abstract
Next-generation sequencing and next-generation metabolic screening are, independently, increasingly applied in clinical diagnostics of inborn errors of metabolism (IEM). Integrated into a single bioinformatic method, these two –omics technologies can potentially further improve the diagnostic yield for IEM. Here, we present cross-omics: a method that uses untargeted metabolomics results of patient's dried blood spots (DBSs), indicated by Z-scores and mapped onto human metabolic pathways, to prioritize potentially affected genes. We demonstrate the optimization of three parameters: (1) maximum distance to the primary reaction of the affected protein, (2) an extension stringency threshold reflecting in how many reactions a metabolite can participate, to be able to extend the metabolite set associated with a certain gene, and (3) a biochemical stringency threshold reflecting paired Z-score thresholds for untargeted metabolomics results. Patients with known IEMs were included. We performed untargeted metabolomics on 168 DBSs of 97 patients with 46 different disease-causing genes, and we simulated their whole-exome sequencing results in silico. We showed that for accurate prioritization of disease-causing genes in IEM, it is essential to take into account not only the primary reaction of the affected protein but a larger network of potentially affected metabolites, multiple steps away from the primary reaction. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
8. Direct Infusion Based Metabolomics Identifies Metabolic Disease in Patients' Dried Blood Spots and Plasma.
- Author
-
Haijes, Hanneke A., Willemsen, Marcel, van der Ham, Maria, Gerrits, Johan, Pras-Raves, Mia L., Prinsen, Hubertus C. M. T., van Hasselt, Peter M., de Sain-van der Velden, Monique G. M., Verhoeven-Duif, Nanda M., and Jans, Judith J. M.
- Subjects
INFUSION therapy ,METABOLOMICS ,METABOLIC disorders ,BLOOD plasma ,MASS spectrometry - Abstract
In metabolic diagnostics, there is an emerging need for a comprehensive test to acquire a complete view of metabolite status. Here, we describe a non-quantitative direct-infusion high-resolution mass spectrometry (DI-HRMS) based metabolomics method and evaluate the method for both dried blood spots (DBS) and plasma. 110 DBS of 42 patients harboring 23 different inborn errors of metabolism (IEM) and 86 plasma samples of 38 patients harboring 21 different IEM were analyzed using DI-HRMS. A peak calling pipeline developed in R programming language provided Z-scores for ~1875 mass peaks corresponding to ~3835 metabolite annotations (including isomers) per sample. Based on metabolite Z-scores, patients were assigned a 'most probable diagnosis' by an investigator blinded for the known diagnoses of the patients. Based on DBS sample analysis, 37/42 of the patients, corresponding to 22/23 IEM, could be correctly assigned a 'most probable diagnosis'. Plasma sample analysis, resulted in a correct 'most probable diagnosis' in 32/38 of the patients, corresponding to 19/21 IEM. The added clinical value of the method was illustrated by a case wherein DI-HRMS metabolomics aided interpretation of a variant of unknown significance (VUS) identified by whole-exome sequencing. In summary, non-quantitative DI-HRMS metabolomics in DBS and plasma is a very consistent, high-throughput and nonselective method for investigating the metabolome in genetic disease. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
9. A one-year pilot study comparing direct-infusion high resolution mass spectrometry based untargeted metabolomics to targeted diagnostic screening for inherited metabolic diseases.
- Author
-
Willems AP, van der Ham M, Schiebergen-Bronkhorst BGM, van Aalderen M, de Barse MMJ, De Gruyter FE, van Hoek IN, Pras-Raves ML, de Sain-van der Velden MGM, Prinsen HCMT, Verhoeven-Duif NM, and Jans JJM
- Abstract
Background: Early diagnosis of inherited metabolic diseases (IMDs) is important because treatment may lead to reduced mortality and improved prognosis. Due to their diversity, it is a challenge to diagnose IMDs in time, effecting an emerging need for a comprehensive test to acquire an overview of metabolite status. Untargeted metabolomics has proven its clinical potential in diagnosing IMDs, but is not yet widely used in genetic metabolic laboratories. Methods: We assessed the potential role of plasma untargeted metabolomics in a clinical diagnostic setting by using direct infusion high resolution mass spectrometry (DI-HRMS) in parallel with traditional targeted metabolite assays. We compared quantitative data and qualitative performance of targeted versus untargeted metabolomics in patients suspected of an IMD ( n = 793 samples) referred to our laboratory for 1 year. To compare results of both approaches, the untargeted data was limited to polar metabolites that were analyzed in targeted plasma assays. These include amino acid, (acyl)carnitine and creatine metabolites and are suitable for diagnosing IMDs across many of the disease groups described in the international classification of inherited metabolic disorders (ICIMD). Results: For the majority of metabolites, the concentrations as measured in targeted assays correlated strongly with the semi quantitative Z-scores determined with DI-HRMS. For 64/793 patients, targeted assays showed an abnormal metabolite profile possibly indicative of an IMD. In 55 of these patients, similar aberrations were found with DI-HRMS. The remaining 9 patients showed only marginally increased or decreased metabolite concentrations that, in retrospect, were most likely to be clinically irrelevant. Illustrating its potential, DI-HRMS detected additional patients with aberrant metabolites that were indicative of an IMD not detected by targeted plasma analysis, such as purine and pyrimidine disorders and a carnitine synthesis disorder. Conclusion: This one-year pilot study showed that DI-HRMS untargeted metabolomics can be used as a first-tier approach replacing targeted assays of amino acid, acylcarnitine and creatine metabolites with ample opportunities to expand. Using DI-HRMS untargeted metabolomics as a first-tier will open up possibilities to look for new biomarkers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Willems, van der Ham, Schiebergen-Bronkhorst, van Aalderen, de Barse, De Gruyter, van Hoek, Pras-Raves, de Sain-van der Velden, Prinsen, Verhoeven-Duif and Jans.)
- Published
- 2023
- Full Text
- View/download PDF
10. A second case of glutaminase hyperactivity: Expanding the phenotype with epilepsy.
- Author
-
Rumping L, Pouwels PJW, Wolf NI, Rehmann H, Wamelink MMC, Waisfisz Q, Jans JJM, Prinsen HCMT, van de Kamp JM, and van Hasselt PM
- Abstract
Glutaminase (GLS) hyperactivity was first described in 2019 in a patient with profound developmental delay and infantile cataract. Here, we describe a 4-year-old boy with GLS hyperactivity due to a de novo heterozygous missense variant in GLS , detected by trio whole exome sequencing. This boy also exhibits developmental delay without dysmorphic features, but does not have cataract. Additionally, he suffers from epilepsy with tonic clonic seizures. In line with the findings in the previously described patient with GLS hyperactivity, in vivo 3 T magnetic resonance spectroscopy (MRS) of the brain revealed an increased glutamate/glutamine ratio. This increased ratio was also found in urine with UPLC-MS/MS, however, inconsistently. This case indicates that the phenotypic spectrum evoked by GLS hyperactivity may include epilepsy. Clarifying this phenotypic spectrum is of importance for the prognosis and identification of these patients. The combination of phenotyping, genetic testing, and metabolic diagnostics with brain MRS and in urine is essential to identify new patients with GLS hyperactivity and to further extend the phenotypic spectrum of this disease., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)
- Published
- 2023
- Full Text
- View/download PDF
11. Monitoring phenylalanine concentrations in the follow-up of phenylketonuria patients: An inventory of pre-analytical and analytical variation.
- Author
-
Coene KLM, Timmer C, Goorden SMI, Ten Hoedt AE, Kluijtmans LAJ, Janssen MCH, Rennings AJM, Prinsen HCMT, Wamelink MMC, Ruijter GJG, Körver-Keularts IMLW, Heiner-Fokkema MR, van Spronsen FJ, Hollak CE, Vaz FM, Bosch AM, and Huigen MCDG
- Abstract
Background: Reliable measurement of phenylalanine (Phe) is a prerequisite for adequate follow-up of phenylketonuria (PKU) patients. However, previous studies have raised concerns on the intercomparability of plasma and dried blood spot (DBS) Phe results. In this study, we made an inventory of differences in (pre-)analytical methodology used for Phe determination across Dutch laboratories, and compared DBS and plasma results., Methods: Through an online questionnaire, we assessed (pre-)analytical Phe measurement procedures of seven Dutch metabolic laboratories. To investigate the difference between plasma and DBS Phe, participating laboratories received simultaneously collected plasma-DBS sets from 23 PKU patients. In parallel, 40 sample sets of DBS spotted from either venous blood or capillary fingerprick were analyzed., Results: Our data show that there is no consistency on standard operating procedures for Phe measurement. The association of DBS to plasma Phe concentration exhibits substantial inter-laboratory variation, ranging from a mean difference of -15.5% to +30.6% between plasma and DBS Phe concentrations. In addition, we found a mean difference of +5.8% in Phe concentration between capillary DBS and DBS prepared from venous blood., Conclusions: The results of our study point to substantial (pre-)analytical variation in Phe measurements, implicating that bloodspot Phe results should be interpreted with caution, especially when no correction factor is applied. To minimize variation, we advocate pre-analytical standardization and analytical harmonization of Phe measurements, including consensus on application of a correction factor to adjust DBS Phe to plasma concentrations., Competing Interests: C. E. H. has been involved in premarketing studies with Sanofi‐Genzyme, Protalix, and Idorsia; A. M. B. has been a member of the advisory board of Biomarin and received speaker fee from Nutricia; F. J. van S. is/has been a member/chair of the following advisory boards: Biomarin, Agios, Applied Pharma Research, Arla Food Int. Eurocept, Lucane, Nestle‐Codexis Alliance, Nutricia, Orphan Europe, Origin, Rivium Medical BV, Sobi, Vivet, NKUV, NPKUA, and ESPKU, has received research grants from BioMarin, Codexis, ESPKU, NPKUA, NPKUV, Nutricia, Sobi, and Tyrosinemia Foundation, is/has been consultant to Applied Pharma Research, BioMarin, Nutricia, Orphan Europe, Pluvia Biotech, has given lectures for which his institute received financial compensation: BioMarin, MendeliKABS, and Nutricia. Apart from this, the University Medical Center of Groningen is involved in a research project—so far without financial compensation—to invent a home monitoring device. K. L. M. C., C. T., S. M. I. G., A. E. ten H., L. A. J. K., M. C. H. J., A. J. M. R., H. C. M. T. P., M. M. C. W., G. J. G. R., I. M. L. W. K.‐K., M. R. H.‐F., F. M. V. and M. C. D. G. H. declared no conflict of interests., (© 2020 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)
- Published
- 2020
- Full Text
- View/download PDF
12. Longitudinal Analysis of Ocular Disease in Children with Mucopolysaccharidosis I after Hematopoietic Cell Transplantation.
- Author
-
van den Broek BTA, van Egmond-Ebbeling MB, Achterberg JA, Boelens JJ, Vlessert IC, Prinsen HCMT, van Doorn J, and van Hasselt PM
- Subjects
- Child, Cornea, Humans, Intraocular Pressure, Phenotype, Hematopoietic Stem Cell Transplantation, Mucopolysaccharidosis I therapy
- Abstract
Corneal clouding, causing visual impairment, is seen in nearly all patients with mucopolysaccharidosis type 1 (MPS-1). Hematopoietic cell transplantation (HCT) is able to stabilize disease in many organs. Residual disease in several tissues is being increasingly recognized, however. Data on the effect of HCT on ocular disease in patients with MPS-1 are contradictory. With this study, we aim to clarify the long-term effects of HCT on ocular disease in these patients. Best corrected visual acuity (BCVA), refraction, intraocular pressure (IOP), and slit-lamp biomicroscopic and fundoscopic examinations, including corneal clouding, were collected prospectively from 24 patients with MPS-1 who underwent HCT successfully between 2003 and 2018 (92% with >95% chimerism and normal enzyme activity after HCT). The course of corneal clouding and BCVA after HCT were analyzed using a linear mixed model. Other parameters studied were clinical phenotype, age at time of transplantation, and hematologic enzyme activity after transplantation. Outcomes of additional ophthalmologic tests were described. In addition, IDUA and α-galactosidase A (AGAL) enzyme activity and glycosaminoglycan (GAG) concentration in tear fluid were determined. Corneal clouding stabilized in the first years after HCT but increased rapidly beyond 3 years (P < .0001). BCVA and IOP also worsened over time (P = .01 and P < .0001, respectively). IDUA activity in tear fluid remained very low (P < .0001). After initial stabilization in the cornea, ongoing ocular disease and low IDUA activity in tear fluid is seen in patients with MPS-1 despite treatment with HCT, unveiling a weak spot of current standard therapy. New therapies that overcome these shortcomings are needed to improve the late outcomes of patients., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
13. Untargeted Metabolomics for Metabolic Diagnostic Screening with Automated Data Interpretation Using a Knowledge-Based Algorithm.
- Author
-
Haijes HA, van der Ham M, Prinsen HCMT, Broeks MH, van Hasselt PM, de Sain-van der Velden MGM, Verhoeven-Duif NM, and Jans JJM
- Subjects
- Biomarkers metabolism, Case-Control Studies, Humans, Metabolism, Inborn Errors metabolism, Tandem Mass Spectrometry, Algorithms, Biomarkers blood, Data Interpretation, Statistical, Knowledge Bases, Mass Screening methods, Metabolism, Inborn Errors diagnosis, Metabolome
- Abstract
Untargeted metabolomics may become a standard approach to address diagnostic requests, but, at present, data interpretation is very labor-intensive. To facilitate its implementation in metabolic diagnostic screening, we developed a method for automated data interpretation that preselects the most likely inborn errors of metabolism (IEM). The input parameters of the knowledge-based algorithm were (1) weight scores assigned to 268 unique metabolites for 119 different IEM based on literature and expert opinion, and (2) metabolite Z-scores and ranks based on direct-infusion high resolution mass spectrometry. The output was a ranked list of differential diagnoses (DD) per sample. The algorithm was first optimized using a training set of 110 dried blood spots (DBS) comprising 23 different IEM and 86 plasma samples comprising 21 different IEM. Further optimization was performed using a set of 96 DBS consisting of 53 different IEM. The diagnostic value was validated in a set of 115 plasma samples, which included 58 different IEM and resulted in the correct diagnosis being included in the DD of 72% of the samples, comprising 44 different IEM. The median length of the DD was 10 IEM, and the correct diagnosis ranked first in 37% of the samples. Here, we demonstrate the accuracy of the diagnostic algorithm in preselecting the most likely IEM, based on the untargeted metabolomics of a single sample. We show, as a proof of principle, that automated data interpretation has the potential to facilitate the implementation of untargeted metabolomics for metabolic diagnostic screening, and we provide suggestions for further optimization of the algorithm to improve diagnostic accuracy.
- Published
- 2020
- Full Text
- View/download PDF
14. Accurate discrimination of Hartnup disorder from other aminoacidurias using a diagnostic ratio.
- Author
-
Haijes HA, Prinsen HCMT, de Sain-van der Velden MGM, Verhoeven-Duif NM, van Hasselt PM, and Jans JJM
- Abstract
Introduction: Hartnup disorder is caused by a deficiency of the sodium dependent B
0 AT1 neutral amino acid transporter in the proximal kidney tubules and jejunum. Biochemically, Hartnup disorder is diagnosed via amino acid excretion patterns. However, these patterns can closely resemble amino acid excretion patterns of generalized aminoaciduria, which may induce a risk for misdiagnosis and preclusion from treatment. Here we explore whether calculating a diagnostic ratio could facilitate correct discrimination of Hartnup disorder from other aminoacidurias., Methods: 27 amino acid excretion patterns from 11 patients with genetically confirmed Hartnup disorder were compared to 68 samples of 16 patients with other aminoacidurias. Amino acid fold changes were calculated by dividing the quantified excretion values over the upper limit of the age-adjusted reference value., Results: Increased excretion of amino acids is not restricted to amino acids classically related to Hartnup disorder ("Hartnup amino acids", HAA), but also includes many other amino acids, not classically related to Hartnup disorder ("other amino acids", OAA). The fold change ratio of HAA over OAA was 6.1 (range: 2.4-9.6) in the Hartnup cohort, versus 0.2 (range: 0.0-1.6) in the aminoaciduria cohort ( p < .0001), without any overlap observed between the cohorts., Discussion: Excretion values of amino acids not classically related to Hartnup disorder are frequently elevated in patients with Hartnup disorder, which may cause misdiagnosis as generalized aminoaciduria and preclusion from vitamin B3 treatment. Calculation of the HAA/OAA ratio improves diagnostic differentiation of Hartnup disorder from other aminoacidurias., Competing Interests: All authors state that they have no competing financial interests to declare. None of the authors accepted any reimbursements, fees or funds from any organization that may in any way gain or lose financially from the results of this review. The authors have not been employed by such an organization. The authors have not act as an expert witness on the subject of the review. The authors do not have any other competing financial interest., (© 2019 The Authors.)- Published
- 2019
- Full Text
- View/download PDF
15. Aspartylglycosamine is a biomarker for NGLY1-CDDG, a congenital disorder of deglycosylation.
- Author
-
Haijes HA, de Sain-van der Velden MGM, Prinsen HCMT, Willems AP, van der Ham M, Gerrits J, Couse MH, Friedman JM, van Karnebeek CDM, Selby KA, van Hasselt PM, Verhoeven-Duif NM, and Jans JJM
- Subjects
- Acetylglucosamine blood, Adolescent, Adult, Biomarkers blood, Case-Control Studies, Child, Child, Preschool, Congenital Disorders of Glycosylation blood, Dried Blood Spot Testing, Female, Humans, Infant, Male, Mass Spectrometry, Mutation, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase blood, Acetylglucosamine analogs & derivatives, Congenital Disorders of Glycosylation diagnosis, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase deficiency
- Abstract
Background: NGLY1-CDDG is a congenital disorder of deglycosylation caused by a defective peptide:N-glycanase (PNG). To date, all but one of the reported patients have been diagnosed through whole-exome or whole-genome sequencing, as no biochemical marker was available to identify this disease in patients. Recently, a potential urinary biomarker was reported, but the data presented suggest that this marker may be excreted intermittently., Methods: In this study, we performed untargeted direct-infusion high-resolution mass spectrometry metabolomics in seven dried blood spots (DBS) from four recently diagnosed NGLY1-CDDG patients, to test for small-molecule biomarkers, in order to identify a potential diagnostic marker. Results were compared to 125 DBS of healthy controls and to 238 DBS of patients with other diseases., Results: We identified aspartylglycosamine as the only significantly increased compound with a median Z-score of 4.8 (range: 3.8-8.5) in DBS of NGLY1-CDDG patients, compared to a median Z-score of -0.1 (range: -2.1-4.0) in DBS of healthy controls and patients with other diseases., Discussion: The increase of aspartylglycosamine can be explained by lack of function of PNG. PNG catalyzes the cleavage of the proximal N-acetylglucosamine residue of an N-glycan from the asparagine residue of a protein, a step in the degradation of misfolded glycoproteins. PNG deficiency results in a single N-acetylglucosamine residue left attached to the asparagine residue which results in free aspartylglycosamine when the glycoprotein is degraded. Thus, we here identified aspartylglycosamine as the first potential small-molecule biomarker in DBS for NGLY1-CDDG, making a biochemical diagnosis for NGLY1-CDDG potentially feasible., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
16. Direct-infusion based metabolomics unveils biochemical profiles of inborn errors of metabolism in cerebrospinal fluid.
- Author
-
Haijes HA, van der Ham M, Gerrits J, van Hasselt PM, Prinsen HCMT, de Sain-van der Velden MGM, Verhoeven-Duif NM, and Jans JJM
- Subjects
- Biomarkers cerebrospinal fluid, Humans, Mass Spectrometry, Metabolism, Inborn Errors cerebrospinal fluid, Metabolism, Inborn Errors diagnosis, Metabolomics methods
- Abstract
Background: For inborn errors of metabolism (IEM), metabolomics is performed for three main purposes: 1) development of next generation metabolic screening platforms, 2) identification of new biomarkers in predefined patient cohorts and 3) for identification of new IEM. To date, plasma, urine and dried blood spots are used. We anticipate that cerebrospinal fluid (CSF) holds additional - valuable - information, especially for IEM with neurological involvement. To expand metabolomics to CSF, we here tested whether direct-infusion high-resolution mass spectrometry (DI-HRMS) based non-quantitative metabolomics could correctly capture the biochemical profile of patients with an IEM in CSF., Methods: Eleven patient samples, harboring eight different IEM, and thirty control samples were analyzed using DI-HRMS. First we assessed whether the biochemical profile of the control samples represented the expected profile in CSF. Next, each patient sample was assigned a 'most probable diagnosis' by an investigator blinded for the known diagnoses of the patients., Results: the biochemical profile identified using DI-HRMS in CSF samples resembled the known profile, with - among others - the highest median intensities for mass peaks annotated with glucose, lactic acid, citric acid and glutamine. Subsequent analysis of patient CSF profiles resulted in correct 'most probable diagnoses' for all eleven patients, including non-ketotic hyperglycinaemia, propionic aciduria, purine nucleoside phosphorylase deficiency, argininosuccinic aciduria, tyrosinaemia type I, hyperphenylalaninemia and hypermethioninaemia., Conclusion: We here demonstrate that DI-HRMS based non-quantitative metabolomics accurately captures the biochemical profile of this set of patients in CSF, opening new ways for using metabolomics in CSF in the metabolic diagnostic laboratory., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
17. Beneficial Effect of BH 4 Treatment in a 15-Year-Old Boy with Biallelic Mutations in DNAJC12.
- Author
-
de Sain-van der Velden MGM, Kuper WFE, Kuijper MA, van Kats LAT, Prinsen HCMT, Balemans ACJ, Visser G, van Gassen KLI, and van Hasselt PM
- Abstract
Background: Biallelic mutations in DNAJC12 were recently identified as a BH
4 -responsive cause of hyperphenylalaninemia (HPA). Outcome was only favorable when treatment was initiated early in life. We report on a 15-year-old boy with HPA due to a homozygous deletion in DNAJC12 in whom - despite his advanced age - treatment was initiated., Case: A boy with developmental delay, an extrapyramidal movement disorder, and persistently elevated plasma phenylalanine levels was diagnosed with DNAJC12 deficiency at the age of 15 years. Diagnosis was made upon exome reanalysis revealing a homozygous 6.9 kb deletion in DNAJC12 which had not been detected by the standard exome analysis pipeline. Treatment with the BH4 analog sapropterin dihydrochloride (10 mg/kg/day) was initiated and evoked a 50% reduction of the plasma phenylalanine levels. More strikingly, a marked improvement in daily functioning and improved exercise tolerance was noted. Additionally, gait analysis before and after treatment initiation revealed a partial normalization of his movement disorder., Conclusion: Patients with hyperphenylalaninemia due to DNAJC12 deficiency may benefit from treatment with a BH4 analog - even when introduced at a later age.- Published
- 2018
- Full Text
- View/download PDF
18. Quantification of metabolites in dried blood spots by direct infusion high resolution mass spectrometry.
- Author
-
de Sain-van der Velden MGM, van der Ham M, Gerrits J, Prinsen HCMT, Willemsen M, Pras-Raves ML, Jans JJ, and Verhoeven-Duif NM
- Subjects
- Chromatography, Liquid, Humans, Methanol, Reference Standards, Tandem Mass Spectrometry, Dried Blood Spot Testing, Mass Spectrometry, Metabolomics
- Abstract
Diagnosis and treatment of inborn errors of metabolism (IEM) require the analysis of a variety of metabolites. These compounds are usually quantified by targeted platforms. High resolution mass spectrometry (HRMS) has the potential to detect hundreds to thousands of metabolites simultaneously. A chip-based nanoelectrospray source (chip-based nanoESI) enables the direct infusion of biological samples. Major advantages of this system include high sample throughput, no sample carryover, and low sample consumption. The combination, chip-based nanoESI-HRMS enables untargeted metabolomics of biological samples but its potential for quantification of metabolites has not been reported. We investigated whether chip-based nanoESI-HRMS is suitable for quantification of metabolites in dried blood spots (DBS). After addition of internal standards, metabolites were extracted with methanol. Aliquots of each extract were analysed by chip-based nanoESI-HRMS operating in both positive and negative mode with an m/z window of 70-600 and a resolution of 140,000. Total run time was 4.5 min per sample and a full report could be generated within 40 min. Concentrations of all 21 investigated diagnostic metabolites in DBS as quantified by chip-based nanoESI-HRMS correlated well with those obtained by targeted liquid chromatography-tandem mass spectrometry. We conclude that chip-based nanoESI-HRMS is suitable for quantification., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
19. Farnesoid X Receptor Activation Promotes Hepatic Amino Acid Catabolism and Ammonium Clearance in Mice.
- Author
-
Massafra V, Milona A, Vos HR, Ramos RJJ, Gerrits J, Willemsen ECL, Ramos Pittol JM, Ijssennagger N, Houweling M, Prinsen HCMT, Verhoeven-Duif NM, Burgering BMT, and van Mil SWC
- Subjects
- Animals, Bile Acids and Salts metabolism, Chenodeoxycholic Acid analogs & derivatives, Chenodeoxycholic Acid pharmacology, Dietary Proteins administration & dosage, Gene Expression, Hepatocytes, Liver enzymology, Male, Metabolome, Mice, Mice, Inbred C57BL, Mice, Knockout, Proteome, Rats, Rats, Wistar, Receptors, Cytoplasmic and Nuclear antagonists & inhibitors, Ammonia metabolism, Glutamine biosynthesis, Liver metabolism, Receptors, Cytoplasmic and Nuclear genetics, Receptors, Cytoplasmic and Nuclear metabolism, Urea metabolism
- Abstract
Background & Aims: The nuclear receptor subfamily 1 group H member 4 (NR1H4 or farnesoid X receptor [FXR]) regulates bile acid synthesis, transport, and catabolism. FXR also regulates postprandial lipid and glucose metabolism. We performed quantitative proteomic analyses of liver tissues from mice to evaluate these functions and investigate whether FXR regulates amino acid metabolism., Methods: To study the role of FXR in mouse liver, we used mice with a disruption of Nr1h4 (FXR-knockout mice) and compared them with floxed control mice. Mice were gavaged with the FXR agonist obeticholic acid or vehicle for 11 days. Proteome analyses, as well as targeted metabolomics and chromatin immunoprecipitation, were performed on the livers of these mice. Primary rat hepatocytes were used to validate the role of FXR in amino acid catabolism by gene expression and metabolomics studies. Finally, control mice and mice with liver-specific disruption of Nr1h4 (liver FXR-knockout mice) were re-fed with a high-protein diet after 6 hours fasting and gavaged a
15 NH4 Cl tracer. Gene expression and the metabolome were studied in the livers and plasma from these mice., Results: In livers of control mice and primary rat hepatocytes, activation of FXR with obeticholic acid increased expression of proteins that regulate amino acid degradation, ureagenesis, and glutamine synthesis. We found FXR to bind to regulatory sites of genes encoding these proteins in control livers. Liver tissues from FXR-knockout mice had reduced expression of urea cycle proteins, and accumulated precursors of ureagenesis, compared with control mice. In liver FXR-knockout mice on a high-protein diet, the plasma concentration of newly formed urea was significantly decreased compared with controls. In addition, liver FXR-knockout mice had reduced hepatic expression of enzymes that regulate ammonium detoxification compared with controls. In contrast, obeticholic acid increased expression of genes encoding enzymes involved in ureagenesis compared with vehicle in C57Bl/6 mice., Conclusions: In livers of mice, FXR regulates amino acid catabolism and detoxification of ammonium via ureagenesis and glutamine synthesis. Failure of the urea cycle and hyperammonemia are common in patients with acute and chronic liver diseases; compounds that activate FXR might promote ammonium clearance in these patients., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
20. A New Approach for Fast Metabolic Diagnostics in CMAMMA.
- Author
-
de Sain-van der Velden MG, van der Ham M, Jans JJ, Visser G, Prinsen HC, Verhoeven-Duif NM, van Gassen KL, and van Hasselt PM
- Abstract
Background: The presence of increased urinary concentrations of both methylmalonic acid (MMA) and malonic acid (MA) is assumed to differentiate combined malonic and methylmalonic aciduria (CMAMMA), due to mutations in the ACSF3 gene, from other causes of methylmalonic aciduria (classic MMAemia). Detection of MA in urine, however, is challenging since excretion of MA can be easily missed. The objective of the study was to develop a method for quantification of MA in plasma to allow differentiation between CMAMMA and classic MMAemia., Methods: Compound heterozygosity for mutations in the ACSF3 gene was detected in two female siblings using diagnostic exome sequencing. Urine (MMA and MA) was analyzed with GC/MS, while plasma was analyzed with UPLC-MS/MS. MA/MMA ratios were calculated., Results: Both patients had a severe psychiatric presentation (at the age of 6 years and 5.5 years, respectively) after a viral infection. MA excretion in the patients was only just above the highest control value in several samples. MA concentrations in plasma from the two patients were clearly above the highest value observed in control subjects. However, MA concentrations in plasma from patients with classic MMAemia were also elevated. Additional, calculation of MA/MMA ratio in plasma allowed to fully differentiate between CMAMMA and classic MMAemia., Conclusions: Calculating the MA/MMA ratio in plasma allows differentiation between CMAMMA and classic MMAemia. The full clinical spectrum of CMAMMA remains to be delineated.
- Published
- 2016
- Full Text
- View/download PDF
21. Key features and clinical variability of COG6-CDG.
- Author
-
Rymen D, Winter J, Van Hasselt PM, Jaeken J, Kasapkara C, Gokçay G, Haijes H, Goyens P, Tokatli A, Thiel C, Bartsch O, Hecht J, Krawitz P, Prinsen HC, Mildenberger E, Matthijs G, and Kornak U
- Subjects
- Adolescent, Child, Congenital Disorders of Glycosylation complications, Female, Genetic Association Studies, Glycosylation, Golgi Apparatus pathology, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Microcephaly etiology, Molecular Sequence Data, Mutation, Phenotype, Young Adult, Adaptor Proteins, Vesicular Transport genetics, Congenital Disorders of Glycosylation genetics, Congenital Disorders of Glycosylation physiopathology, Golgi Apparatus genetics
- Abstract
The conserved oligomeric Golgi (COG) complex consists of eight subunits and plays a crucial role in Golgi trafficking and positioning of glycosylation enzymes. Mutations in all COG subunits, except subunit 3, have been detected in patients with congenital disorders of glycosylation (CDG) of variable severity. So far, 3 families with a total of 10 individuals with biallelic COG6 mutations have been described, showing a broad clinical spectrum. Here we present 7 additional patients with 4 novel COG6 mutations. In spite of clinical variability, we delineate the core features of COG6-CDG i.e. liver involvement (9/10), microcephaly (8/10), developmental disability (8/10), recurrent infections (7/10), early lethality (6/10), and hypohidrosis predisposing for hyperthermia (6/10) and hyperkeratosis (4/10) as ectodermal signs. Regarding all COG6-related disorders a genotype-phenotype correlation can be discerned ranging from deep intronic mutations found in Shaheen syndrome as the mildest form to loss-of-function mutations leading to early lethal CDG phenotypes. A comparison with other COG deficiencies suggests ectodermal changes to be a hallmark of COG6-related disorders. Our findings aid clinical differentiation of this complex group of disorders and imply subtle functional differences between the COG complex subunits., (Copyright © 2015. Published by Elsevier Inc.)
- Published
- 2015
- Full Text
- View/download PDF
22. Suitability of methylmalonic acid and total homocysteine analysis in dried bloodspots.
- Author
-
de Sain-van der Velden MGM, van der Ham M, Jans JJ, Visser G, van Hasselt PM, Prinsen HCMT, and Verhoeven-Duif NM
- Subjects
- Blood Specimen Collection, Chromatography, High Pressure Liquid, Feasibility Studies, Homocysteine biosynthesis, Homocysteine metabolism, Humans, Limit of Detection, Methylmalonic Acid metabolism, Plasma chemistry, Plasma metabolism, Reproducibility of Results, Solvents chemistry, Tandem Mass Spectrometry, Dried Blood Spot Testing methods, Homocysteine blood, Methylmalonic Acid blood
- Abstract
Methylmalonic acid (MMA) and total homocysteine (tHCYS) concentrations are used to detect acquired and inborn errors of cobalamin (vitamin B12, Cbl) metabolism and to evaluate the effect of therapeutic interventions. Dried blood spot sampling offers a patient-friendly and easy alternative to plasma sampling. However, dried blood spot concentrations are not necessarily equal to plasma concentrations. Therefore, the objective of this work was to establish the relationship between MMA and tHYS dried blood spot and plasma concentrations to facilitate clinical implementation of dried blood spot sampling. MMA and tHCYS in both plasma and DBS were validated on ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). While position of the punch (in DBS) did affect tHCYS concentration, no influence of hematocrit (Ht) and blood volume on both MMA and tHCYS concentrations was observed. The plasma assay performed better than the DBS assay by most criteria. However, the DBS matrix was superior for tHCYS stability. Paired plasma and DBS samples were obtained from patients suspected for Cbl deficiency and from patients with a known inborn error of metabolism affecting MMA or tHCYS concentration. Based on the strong correlation of tHCYS in both matrices (y=0.46±1.12 (r(2)=0.91)), determination of tHCYS in plasma can be replaced by tHCYS in DBS. However, for MMA, a correlation in the higher (pathological) range of MMA exist, but no correlation was observed in the lower ranges. Therefore the added value of MMA concentrations in DBS is currently unknown and should be further investigated., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
23. Impaired cognitive functioning in patients with tyrosinemia type I receiving nitisinone.
- Author
-
Bendadi F, de Koning TJ, Visser G, Prinsen HC, de Sain MG, Verhoeven-Duif N, Sinnema G, van Spronsen FJ, and van Hasselt PM
- Subjects
- 4-Hydroxyphenylpyruvate Dioxygenase antagonists & inhibitors, Adolescent, Child, Child Development, Child, Preschool, Cognitive Dysfunction epidemiology, Cognitive Dysfunction physiopathology, Cross-Sectional Studies, Disease Progression, Enzyme Inhibitors therapeutic use, Female, Humans, Incidence, Male, Netherlands epidemiology, Prognosis, Risk Factors, Tyrosinemias drug therapy, Young Adult, Cognition physiology, Cognitive Dysfunction etiology, Cyclohexanones therapeutic use, Nitrobenzoates therapeutic use, Tyrosinemias complications
- Abstract
Objective: To examine cognitive functioning in patients with tyrosinemia type I treated with nitisinone and a protein-restricted diet., Study Design: We performed a cross-sectional study to establish cognitive functioning in children with tyrosinemia type I compared with their unaffected siblings. Intelligence was measured using age-appropriate Wechsler Scales. To assess cognitive development over time, we retrieved sequential IQ scores in a single-center subset of patients. We also evaluated whether plasma phenylalanine and tyrosine levels during treatment was correlated with cognitive development., Results: Average total IQ score in 10 patients with tyrosinemia type I receiving nitisinone was significantly lower compared with their unaffected siblings (71 ± 13 vs 91 ± 13; P = .008). Both verbal and performance IQ subscores differed (77 ± 14 vs 95 ± 11; P < .05 and 70 ± 11 vs 87 ± 15; P < .05, respectively). Repeated IQ measurements in a single-center subset of 5 patients revealed a decline in average IQ score over time, from 96 ± 15 to 69 ± 11 (P < .001). No significant association was found between IQ score and either plasma tyrosine or phenylalanine concentration., Conclusion: Patients with tyrosinemia type I treated with nitisinone are at risk for impaired cognitive function despite a protein-restricted diet., (Copyright © 2014 Mosby, Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
24. Reliable analysis of phenylalanine and tyrosine in a minimal volume of blood.
- Author
-
Prinsen HC, Holwerda-Loof NE, de Sain-van der Velden MG, Visser G, and Verhoeven-Duif NM
- Subjects
- Humans, Phenylalanine Hydroxylase genetics, Phenylketonurias blood, Phenylketonurias pathology, Tandem Mass Spectrometry, Dried Blood Spot Testing, Phenylalanine blood, Phenylketonurias diagnosis, Tyrosine blood
- Abstract
Objectives: Phenylketonuria (PKU) is an inborn error of phenylalanine metabolism due to a defect in phenylalanine hydroxylase (PAH). Treatment principle is to reduce phenylalanine concentration sufficiently to prevent neuropathological effects. Dietary management is performed and the effect of treatment is monitored by regular analysis of phenylalanine and tyrosine. The aim of the study was to develop a rapid method to routinely measure both metabolites in minimal bloodspot volume (1.5 mm Ø, corresponding with a volume of 1.3 μL blood)., Method: Whole blood was spiked with phenylalanine and tyrosine at 24 different concentrations. Dried blood spots (DBS) were prepared, after which punches of 1.5 mm Ø and 6 mm Ø (corresponding with a volume of 12.4 μL) were taken. Additionally, punches of both sizes were prepared from DBS of PKU-patients (n=77). All samples were analyzed by tandem mass-spectrometry and results between both punches were compared., Results: A good correlation between concentrations of phenylalanine and tyrosine in 1.5 and 6 mm punches was found (r(2)=0.9917 and r(2)=0.9892, respectively). Analysis of phenylalanine and tyrosine in punches of PKU-patients (n=77) showed similar results and fitted within the procentual range of the between run variation., Conclusion: We developed an accurate and rapid method to analyze phenylalanine and tyrosine concentrations in a 1.5 mm Ø bloodspot punch with an estimated whole blood volume of 1.3 μL. This technical improvement does not only result in a 10 fold reduction in required patients' material, but also in a 30-60 min time saving in sample preparation., (Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.