Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency |
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| Authors: | Banka Siddharth Blom Henk J Walter John Aziz Majid Urquhart Jill Clouthier Christopher M Rice Gillian I de Brouwer Arjan P M Hilton Emma Vassallo Grace Will Andrew Smith Desirée E C Smulders Yvo M Wevers Ron A Steinfeld Robert Heales Simon Crow Yanick J Pelletier Joelle N Jones Simon Newman William G |
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| Affiliation: | 1Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester, Manchester M13 9WL, UK;2Metabolic Unit, Department of Clinical Chemistry, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands;3Paediatric Neurology, MAHSC, St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK;4Département de Biochimie and Département de Chimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada;5Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands;6Paediatric Haematology, MAHSC, St. Mary's Hospital, Central Manchester Foundation NHS Trust, Manchester M13 9WL, UK;7Department of Internal Medicine, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands;8Laboratory of Genetic Endocrine and Metabolic Diseases, Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands;9Department of Pediatrics, University of Goettingen, Robert-Koch-Str. 40, D-37075 Goettingen, Germany;10Neurometabolic Unit, National Hospital, Queen Square, Clinical and Molecular Genetics Unit, UCL Institute of Child Health & Enzyme and Metabolic Unit, Great Ormond Street Hospital, London WC1N 3JH, UK |
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| Abstract: | Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism and an important target of antineoplastic, antimicrobial, and antiinflammatory drugs. We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germline missense mutation in DHFR, resulting in profound enzyme deficiency. We show that cerebral folate levels, anemia, and pancytopenia of DHFR deficiency can be corrected by treatment with folinic acid. The characterization of this disorder provides evidence for the link between DHFR and metabolism of cerebral tetrahydrobiopterin, which is required for the formation of dopamine, serotonin, and norepinephrine and for the hydroxylation of aromatic amino acids. Moreover, this relationship provides insight into the role of folates in neurological conditions, including depression, Alzheimer disease, and Parkinson disease. |
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