Megalobastic anemia, infantile leukemia, and immunodeficiency caused by a novel homozygous mutation in the DHFR gene

Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism that reduces folic acid to dihydrofolic and tetrahydrofolic acid and provides an important target for antineoplastic, antimicrobial, and anti-inflammatory drugs. Defective DHFR activity leads to megaloblastic anemia syndrome combined with severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germ line missense mutation in DHFR has been reported.1,2 Folate represents a large family of water-soluble vitamins that play an important role in DNA synthesis, repair, and transmethylation pathways.3 Folate is also a substrate for purine and thymidine synthesis and a methyl donor for homocysteine to methionine conversion, with low folate status being reflected by elevated plasma homocysteine concentrations.4 Cerebral tetrahydrobiopterin is required for the formation of dopamine, serotonin, and norepinephrine and the hydroxylation of aromatic amino acids as a link to neurodevelopmental symptoms.