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Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency.

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

American journal of human genetics. 2011;88(2):216-25.

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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.

Bibliographic metadata

Type of resource:
Content type:
Publication type:
Published date:
Abbreviated journal title:
ISSN:
Place of publication:
United States
Volume:
88
Issue:
2
Pagination:
216-25
Digital Object Identifier:
10.1016/j.ajhg.2011.01.004
Pubmed Identifier:
21310276
Pii Identifier:
S0002-9297(11)00005-X
Access state:
Active

Institutional metadata

University researcher(s):

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:135455
Created by:
Urquhart, Jill
Created:
4th November, 2011, 14:59:49
Last modified by:
Urquhart, Jill
Last modified:
4th November, 2011, 14:59:49