Author(s):
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Banka, S.;
Blom, H.J.
; Walter, J.; Aziz, M.; Urquhart, J.; Clouthier, C.M.; Rice, G.I.;
Brouwer, A.P.M. de
; Hilton, E.; Vassallo, G.; Will, A.; Smith, D.E.; Smulders, Y.M.;
Wevers, R.A.
; Steinfeld, R.; Heales, S.; Crow, Y.J.; Pelletier, J.N.; Jones, S.; Newman, W.G.
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Subject:
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DCN 1: Perception and Action IGMD 4: Glycostation disorders DCN 3: Neuroinformatics IGMD 3: Genomic disorders and inherited multi-system disorders NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disorders Tijdelijke code tbv inlezen publicaties Radboudumc - Alleen voor gebruik door Radboudumc |
Organization:
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Human Genetics Laboratory of Genetic, Endocrine and Metabolic Diseases Paediatrics - OUD tm 2017 Neurology |
Journal title:
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American Journal of Human Genetics
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Abstract:
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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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