Identification and Characterization of an Inborn Error of Metabolism Caused by Dihydrofolate Reductase Deficiency

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• 作者：Siddharth Banka¹ ; Henk J. Blom² ; John Walter¹ ; Majid Aziz³ ; Jill Urquhart¹ ; Christopher M. Clouthier⁴ ; Gillian I. Rice¹ ; Arjan P.M. de Brouwer⁵ ; Emma Hilton¹ ; Grace Vassallo³ ; Andrew Will⁶ ; Desiré ; e E.C. Smith² ; Yvo M. Smulders⁷ ; Ron A. Wevers⁸ ; Robert Steinfeld⁹ ; Simon Heales¹⁰ ; Yanick J. Crow¹ ; Joelle N. Pelletier⁴ ; Simon Jones¹ ; ^{simon.jones@cmft.nhs.uk} ; William G. Newman¹ ; ^{william.newman@manchester.ac.uk}
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：11 February 2011
• 年：2011
• 卷：88
• 期：2
• 页码：216-225
• 全文大小：968 K

文摘

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.