title: Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency.
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.
authors.affiliation: Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester, Manchester, UK.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Banka
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Blom
authors.forename: John
authors.initials: J
authors.lastname: Walter
authors.forename: Majid
authors.initials: M
authors.lastname: Aziz
authors.forename: Jill
authors.initials: J
authors.lastname: Urquhart
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Clouthier
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.forename: Emma
authors.initials: E
authors.lastname: Hilton
authors.forename: Grace
authors.initials: G
authors.lastname: Vassallo
authors.forename: Andrew
authors.initials: A
authors.lastname: Will
authors.forename: Desirée E C
authors.initials: DE
authors.lastname: Smith
authors.forename: Yvo M
authors.initials: YM
authors.lastname: Smulders
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.forename: Robert
authors.initials: R
authors.lastname: Steinfeld
authors.forename: Simon
authors.initials: S
authors.lastname: Heales
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
authors.forename: Joelle N
authors.initials: JN
authors.lastname: Pelletier
authors.forename: Simon
authors.initials: S
authors.lastname: Jones
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D000749:Anemia, Megaloblastic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D001921:Brain / Q000201:enzymology / Q000473:pathology; D005260:Female; D005492:Folic Acid / Q000134:cerebrospinal fluid; D005494:Folic Acid Deficiency / Q000134:cerebrospinal fluid; D006801:Humans; D007223:Infant; D002955:Leucovorin / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010198:Pancytopenia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*
chemical_list: D001708:Biopterins; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; C003402:sapropterin; D002955:Leucovorin