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

Am J Hum Genet. 2011 Feb 11;88(2):216-25. doi: 10.1016/j.ajhg.2011.01.004.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Metabolism, Inborn Errors / drug therapy
  • Amino Acid Metabolism, Inborn Errors / genetics*
  • Amino Acid Metabolism, Inborn Errors / pathology
  • Amino Acid Sequence
  • Anemia, Megaloblastic / drug therapy
  • Anemia, Megaloblastic / genetics*
  • Anemia, Megaloblastic / pathology
  • Base Sequence
  • Biopterins / analogs & derivatives
  • Biopterins / metabolism
  • Brain / enzymology
  • Brain / pathology
  • Female
  • Folic Acid / cerebrospinal fluid
  • Folic Acid Deficiency / cerebrospinal fluid
  • Humans
  • Infant
  • Leucovorin / therapeutic use
  • Magnetic Resonance Imaging
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Pancytopenia / drug therapy
  • Pancytopenia / genetics*
  • Pancytopenia / pathology
  • Pedigree
  • Protein Conformation
  • Sequence Homology, Amino Acid
  • Tetrahydrofolate Dehydrogenase / chemistry
  • Tetrahydrofolate Dehydrogenase / deficiency*
  • Tetrahydrofolate Dehydrogenase / genetics*

Substances

  • Biopterins
  • Folic Acid
  • Tetrahydrofolate Dehydrogenase
  • sapropterin
  • Leucovorin