Suzan J G Knottnerus1, Mia L Pras-Raves2, Maria van der Ham3, Sacha Ferdinandusse4, Riekelt H Houtkooper4, Peter C J I Schielen5, Gepke Visser6, Frits A Wijburg7, Monique G M de Sain-van der Velden8. 1. Section Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, 3584 EA, Utrecht, The Netherlands; Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 2. Section Metabolic Diagnostics, Department of Genetics, University Medical Center Utrecht, Utrecht University, Lundlaan 6, 3584 EA Utrecht, The Netherlands; Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 3. Section Metabolic Diagnostics, Department of Genetics, University Medical Center Utrecht, Utrecht University, Lundlaan 6, 3584 EA Utrecht, The Netherlands. 4. Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology and Metabolism, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 5. Reference Laboratory for Neonatal Screening, Center for Health Protection, National Institute for Public Health and Environment (RIVM), The Netherlands. 6. Section Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, 3584 EA, Utrecht, The Netherlands. 7. Section Metabolic Diseases, Emma's Children's Hospital, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. 8. Section Metabolic Diagnostics, Department of Genetics, University Medical Center Utrecht, Utrecht University, Lundlaan 6, 3584 EA Utrecht, The Netherlands. Electronic address: m.g.desain@umcutrecht.nl.
Abstract
PURPOSE: Newborns who test positive for very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) in newborn screening may have a severe phenotype with early onset of life-threatening symptoms but may also have an attenuated phenotype and never become symptomatic. The objective of this study is to investigate whether metabolomic profiles in dried bloodspots (DBS) of newborns allow early phenotypic prediction, permitting tailored treatment and follow-up. METHODS: A metabolic fingerprint was generated by direct infusion high resolution mass spectrometry in DBS of VLCADD patients (n = 15) and matched controls. Multivariate analysis of the metabolomic profiles was applied to differentiate subgroups. RESULTS: Concentration of six acylcarnitine species differed significantly between patients and controls. The concentration of C18:2- and C20:0-carnitine, 13,14-dihydroretinol and deoxycytidine monophosphate allowed separation between mild and severe patients. Two patients who could not be prognosticated on early clinical symptoms, were correctly fitted for severity in the score plot based on the untargeted metabolomics. CONCLUSION: Distinctive metabolomic profiles in DBS of newborns with VLCADD may allow phenotypic prognostication. The full potential of this approach as well as the underlying biochemical mechanisms need further investigation.
PURPOSE: Newborns who test positive for very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) in newborn screening may have a severe phenotype with early onset of life-threatening symptoms but may also have an attenuated phenotype and never become symptomatic. The objective of this study is to investigate whether metabolomic profiles in dried bloodspots (DBS) of newborns allow early phenotypic prediction, permitting tailored treatment and follow-up. METHODS: A metabolic fingerprint was generated by direct infusion high resolution mass spectrometry in DBS of VLCADDpatients (n = 15) and matched controls. Multivariate analysis of the metabolomic profiles was applied to differentiate subgroups. RESULTS: Concentration of six acylcarnitine species differed significantly between patients and controls. The concentration of C18:2- and C20:0-carnitine, 13,14-dihydroretinol and deoxycytidine monophosphate allowed separation between mild and severe patients. Two patients who could not be prognosticated on early clinical symptoms, were correctly fitted for severity in the score plot based on the untargeted metabolomics. CONCLUSION: Distinctive metabolomic profiles in DBS of newborns with VLCADD may allow phenotypic prognostication. The full potential of this approach as well as the underlying biochemical mechanisms need further investigation.
Authors: Alberto Burlina; Simon A Jones; Anupam Chakrapani; Heather J Church; Simon Heales; Teresa H Y Wu; Georgina Morton; Patricia Roberts; Erica F Sluys; David Cheillan Journal: Int J Neonatal Screen Date: 2022-03-25